US20150224118A1 - Natural combination hormone replacement formulations and therapies - Google Patents
Natural combination hormone replacement formulations and therapies Download PDFInfo
- Publication number
- US20150224118A1 US20150224118A1 US14/690,955 US201514690955A US2015224118A1 US 20150224118 A1 US20150224118 A1 US 20150224118A1 US 201514690955 A US201514690955 A US 201514690955A US 2015224118 A1 US2015224118 A1 US 2015224118A1
- Authority
- US
- United States
- Prior art keywords
- estradiol
- progesterone
- solubilized
- oil
- capmul
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- This disclosure relates to natural estrogen and progesterone replacement therapies, with formulations provided for each estradiol and progesterone alone and in combination for the treatment of pre, peri-menopausal, menopausal and post-menopausal females in relation to the treatment of Estrogen- and Progesterone-deficient States, each as herein below defined.
- HRT Hormone replacement therapy
- a group of medications designed to increase hormone levels in women who lack adequate hormone production.
- HRT can mitigate and prevent symptoms caused by diminished circulating estrogen and progesterone hormones regardless as to whether the subject is pre-menopausal, peri-menopausal, menopausal or post-menopausal.
- specific disease states can exist during each stage of menopausal progression.
- HRT is presently available in various forms.
- One therapy involves administration of low dosages of one or more estrogens.
- Another involves administration of progesterone or a chemical analogue, called a progestin.
- Progesterone administration acts, among treating other disease states, to mitigate certain undesirable side effects from estrogen administration including, for example, endometrial hyperplasia (thickening), reducing the incidence of endometrial cancer.
- Timing for dosage administration is often varied cyclically, with estrogens taken daily and progesterone taken for approximately two weeks of every month; a method often referred to as “Cyclic-Sequential” or “Sequentially-Combined HRT.” This method is intended to mimic the natural menstrual cycle and typically causes menstruation similar to a period after the progesterone is stopped. This regimen is most typically used in peri-menopausal or newly menopausal women as the alternative continuous method often results in irregular bleeding in such women.
- An alternate method, a constant dosage with both estrogen and progesterone taken daily, is called “continuous-combined HRT.” This method usually results in no menstruation and is used most often after a woman has been menopausal for some time.
- Estrogen in its various forms, and progesterone, in its various forms, are used in HRT via a variety of administered dosage forms including, for example, via tablets, capsules and patches.
- Bio-identical hormones which are identical in chemical structure to the hormones naturally produced by human bodies can be used and are often referred to as natural hormone replacement therapy, or NHRT.
- estradiol the 3 primary estrogens
- progesterone the 3 primary estrogens
- bio-identical estradiol is available in both branded and generic FDA approved versions.
- FDA-approved bio-identical progesterone for HRT is available as the branded stand-alone drug commercially identified as PROMETRIUM (Progesterone, USP) (Abbott Laboratories, Abbott Park, Ill.), with a generic authorized by the innovator, and generic products provided by Teva (Israel) and Sofgen Americas, Inc (New York).
- Prometrium was approved for sale in the United States on May 14, 1998 under NDA #N019781.
- Prometrium prescribing information Prometrium comprises synthetic progesterone that is chemically identical to progesterone of human ovarian origin.
- Capsules comprise 100 mg or 200 mg of micronized progesterone.
- the inactive ingredients include peanut oil, gelatin, glycerin, lecithin, titanium dioxide, and yellow and red dyes.
- Prempro® and Premphase® provide both continuous-combined and cyclic-sequential products containing Premarin (estrogen derived from mare's urine) and synthetic medroxyprogesterone acetate. Other products are available. However, no FDA approved product exists on the market today with combination bio-identical estradiol and bio-identical progesterone.
- natural hormone replacement therapies comprising cyclic/sequential and continuous-combined delivery via pharmaceutical formulations of solubilized estradiol and micronized and/or partially or completely solubilized progesterone.
- Estradiol and micronized and/or partially or completely solubilized progesterone delivered together daily can be combined in either a single unit dose or in separate unit doses, typically in a soft capsule.
- a 28-day or monthly regimen of tablets or capsules can be packaged in a single blister pack having delivery days identified to improve compliance.
- formulations of natural hormones, and the use of these formulations for hormone replacement therapies, each in accordance with the invention are set forth below.
- FIG. 1 illustrates an exemplary manufacturing process of a fill material in accordance with various embodiments
- FIG. 2 illustrates an exemplary manufacturing process of a softgel material in accordance with various embodiments
- FIG. 3 illustrates an exemplary manufacturing process in accordance with various embodiments.
- FIG. 4 illustrates a graph of the particle distribution obtained in Example 10.
- FIG. 5 illustrates a dissolution study of a formulation in accordance with various embodiments of the invention.
- a better-absorbed dosage form of a medicament such as, for example, progesterone, or dosage forms that provide greater consistency of absorption of progesterone among subjects, alone or in combination with estradiol, may be able to be administered at dosage strengths lower than presently recommended, potentially resulting in a reduced or minimized side effect profile, among other potential benefits.
- micronized progesterone includes micronized progesterone having an X50 particle size value below about 15 microns and/or having an X90 particle size value below about 25 microns.
- X50 means that one-half of the particles in a sample are smaller in diameter than a given number.
- micronized progesterone having an X50 of 5 microns means that, for a given sample of micronized progesterone, one-half of the particles have a diameter of less than 5 microns.
- X90 means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.
- medium chain means any medium chain carbon-containing substance, including C4-C18, and including C6-C12 substances, fatty acid esters of glycerol, fatty acids, and mono-, di-, and tri-glycerides of such substances.
- uniform distribution means at least one of uniform dispersion, solubility, or lack of agglomeration of progesterone in a dissolution test compared to Prometrium at a similar dosage strength and the same USP dissolution apparatus.
- bioavailability means the concentration of an active ingredient (e.g., progesterone or estradiol or estrone) in the blood (serum or plasma).
- the relative bioavailability may be measured as the concentration in the blood (serum or plasma) versus time.
- Other pharmacokinetic (pK) indicators may be used to measure and assess bioavailability, determined by suitable metrics including AUC, Cmax, and optionally, Tmax.
- AUC refers to the area under the curve that represents changes in blood concentration of progesterone, estradiol or estrone over time.
- Cmax refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of progesterone, estradiol or estrone over time.
- Tmax refers to the time that it takes for progesterone, estradiol or estrone blood concentration to reach the maximum value.
- AUC, Cmax and, optionally, Tmax are the principle pharmacokinetic parameters that can characterize the pharmacokinetic responses of a particular drug product such as progesterone in an animal especially a mammal, including human, subject.
- solvent any substance or mixture of substances that may be used to enhance the solubility of estradiol, including, for example and without limitation, appropriate pharmaceutically acceptable excipients, such as solvents, co-solvents, surfactants, emulsifiers, oils and carriers.
- excipients refer to nonactive pharmaceutical ingredients (“API”) substances such as carriers, solvents, oils, lubricants and others used in formulating pharmaceutical products. They are generally safe for administering to animals, especially mammals, including humans, according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
- API nonactive pharmaceutical ingredients
- oils may be any pharmaceutically acceptable substance, such as an organic oil, other than peanut oil, that would suspend and/or solubilize any suitable progesterone, starting material, or precursor, including micronized progesterone as described herein. More specifically, oils may include, for example and without limitation, medium chain fatty acids, generally of the group known as medium chain fatty acids consisting of at least one mono-, di-, and triglyceride, or derivatives thereof, or combinations thereof.
- “Fully solubilized progesterone,” as used herein, means progesterone which is about 100% in solution, i.e., at least 98% in solution.
- Partially solubilized progesterone means progesterone which is in any state of solubilization up to but not including about 100%, i.e., up to but not including 98% in solution.
- estradiol includes estradiol in anhydrous and hemihydrate forms.
- solubilized estradiol without progesterone solubilized estradiol without progesterone
- micronized progesterone without estradiol solubilized progesterone without estradiol
- micronized progesterone with partially solubilized progesterone solubilized estradiol with micronized progesterone
- solubilized estradiol with solubilized progesterone solubilized estradiol without progesterone.
- the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules.
- Micronized progesterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.
- Another aspect of the present disclosure includes a pharmaceutical formulation of micronized progesterone, micronized progesterone with partially solubilized progesterone and fully solubilized progesterone, wherein said formulation may provide increased progesterone bioavailability in a treated subject compared to the bioavailability provided by Prometrium® when administered at equal dosage strengths.
- the solubility proportion i.e., the proportion of a solute that enters solution
- the weight ratio of estradiol to the weight of the entire solution is also notable due to the intended dose amounts, discussed herein.
- a target dosage of estradiol in an amount of solution that may be readily administered via a capsule.
- a target dosage of estradiol in an amount of solution that may be readily administered via a capsule.
- a total solution weight to be between about 250 mg to about 400 mg, preferably about 300 mg to about 350 mg, and more preferably about 325 mg.
- the following weight ratios of estradiol to total solution is from about 0.125/50 mg to about 0.125/1000 mg, from about 1 mg:500 mg to about 1 mg:50 mg; from about 1 mg:250 mg to about 1 mg:60 mg; from about 1 mg:100 mg to about 1 mg:66 mg; from about 2 mg/50 mg to about 2 mg/1000 mg.
- the target for single dose product is 325 mg
- a target fill weight for a combination product e.g., two or more sterol APIs
- total progesterone i.e., dissolved and micronized
- estradiol is 0.1 to 0.8 wt %, e.g., 0.15 to 0.35 wt %.
- aspects of the present disclosure further provide: more uniform dissolution of progesterone, and reduced intra- and inter-patient blood level variability in formulations of progesterone of the present disclosure, typically in combinations with solubilized estradiol, when compared to equal dosages of Prometrium. Blood level variability is also compared at equal sampling times following administration. Not to be limited by theory, these aspects are believed to be influenced by the percentage of solubilized progesterone in a respective formulation wherein such more uniform dissolution of progesterone, and lower intra- and inter-patient blood level variability, are influenced by a greater proportion of solubilized progesterone relative to total progesterone. A reduced food effect with the present formulations comprising progesterone may also be implicated.
- More uniform dissolution of progesterone in a formulation of the present disclosure compared to the dissolution of Prometrium at equal dosage strengths and using the same USP apparatus can be determined using standard techniques established for API dissolution testing, including that which is described in the examples below.
- progesterone is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans: for endometrial hyperplasia; for secondary amenorrhea; as a method of treatment for preterm birth, when said animal has a shortened cervix, and other disease states or conditions treated with supplemental progesterone (collectively, “Progesterone-deficient States”); and the use of formulations as described herein wherein estradiol is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans, having menopause-related symptoms including, for example, vasomotor symptoms; in relation to treatment of hypoestrogenism related symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes and vulvo-vaginal atrophy; and osteoporosis and other non-menopausal disease states or conditions treated with supplemental estrogen.
- Estrogen-deficient States each in a subject in need of treatment, and each with a non-toxic effective amount of said formulations.
- treatment contemplates partial or complete inhibition of the stated disease state when a formulation as described herein is administered prophylactically or following the onset of the disease state for which such formulation is administered.
- prophylaxis refers to administration of the active ingredient(s) to an animal especially a mammal, to protect the animal from any of the disorders set forth herein, as well as others.
- “natural,” as used herein with reference to hormones discussed herein, means bio-identical hormones formulated to match the chemical structure and effect of those that occur naturally in the human body (endogenous).
- An exemplary natural estrogen is estradiol (also described as 17 ⁇ -estradiol and E2) and a natural progestin is progesterone.
- An exemplary cyclic/sequential regimen comprises delivery of from about 0.125 mg to about 2.0 mg of estradiol daily for 14-18 days, followed by delivery of from about 0.125 mg to about 2 mg of estradiol and about 25 mg to about 200 mg of progesterone daily for 10-14 days. Cyclic/sequential regimens may be especially useful for menopausal females.
- exemplary dosage strengths for estradiol for use in the formulations described herein include, without limitation, 0.125, 0.25, 0.375, 0.50, 0.625, 0.75, 1.00, 1.125, 1.25, 1.375, 1.50, 1.625, 1.75 and 2.00 mg.
- Other exemplary dosage strengths for progesterone for use in the formulations described herein include, without limitation, 25, 50, 75, 100, 125, 150, 175, 200 mg, 250 mg, 300 mg, 350 mg and 400 mg. These dosage strengths for each of estradiol and progesterone can be administered in formulations described herein either alone or in combination.
- Progesterone active pharmaceutical ingredient may be micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan.
- micronized progesterone has an X50 particle size value of less than about 15 microns, less than about 10 microns, less than about 5 microns and/or less than about 3 microns.
- micronized progesterone has an X90 particle size value of less than about 25 microns, less than about 20 microns, and/or less than about 15 microns.
- Particle size may be determined in any suitable manner.
- a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the “Beckman Device”) may be used to determine particle size.
- particle size may be represented by various metrics, for example, through an X50 particle size, and/or X90 particle size, or similar descriptions of particle size.
- the Beckman Device may be used with various modules for introducing a sample for analysis.
- the Beckman Device may be used with the LS 13 320 Universal Liquid Module (“ULM”).
- the ULM is capable of suspending samples in the size range of 0.017 ⁇ m to 2000 ⁇ m.
- the ULM is a liquid based module that allows for delivery of the sample to the sensing zone.
- the ULM recirculates the sample through the Beckman Device.
- the ULM comprises two hoses, one for fluid delivery and another for waste.
- the total volume used may be 125 mL or less.
- a sample mass of from about 1 mg to about 10 g may be used.
- the ULM may interact with the Beckman Device via pins that fit into slots on the ULM.
- the ULM may use a variety of suspension fluids, for example, water, butonol, ethanol, chloroform, heptanes, toluene, propanol, COULTER Type 1B Dispersant (“Coulter 1B”), and a variety of other suspension fluids. Surfactants may also be used, though pump speed should be adjusted to prevent excessive bubbling. Coulter 1B may comprise one or more of acetaldehyde, ethylene oxide, and/or 1,4-dioxane.
- the Beckman Device may be configured to use a variety of optical theories, including the Fraunhofer optical model and the Mie Theory.
- the Beckman Device may comprise software to control the Beckman Device while the ULM is in use.
- the software may control, for example, pump speed, use of de-bubble routine, rinse routine, sonicate routine, and fill routine, among others. Parameters regarding the sample run may also be configured. For example, run length may be set. Though any suitable run length may be used, in various embodiments, a time period of 30 seconds to 120 seconds, and preferably between 30 seconds and 90 seconds may be used.
- the Beckman Device may be used with the LS 13 320 Micro Liquid Module (“MLM”).
- MLM is capable of suspending samples in the size range of 0.4 ⁇ m to 2000 ⁇ m.
- the MLM is a liquid based module that allows for delivery of the sample to the sensing zone.
- the MLM includes a stirrer.
- the total volume used may be 12 mL or less.
- the MLM may use a variety of suspension fluids, both aqueous and non-aqueous.
- estradiol and progesterone as described herein can be formulated alone pursuant to the teachings below. These formulations can be prepared for oral administration or can be combined, based on compatibility, for co-administration of estradiol and progesterone in a single oral unit dosage form.
- Progesterone formulations of the present disclosure are prepared via blending with a pharmaceutically acceptable oil; generally, the oil comprises at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof.
- a pharmaceutically acceptable oil generally, the oil comprises at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof.
- other excipients including, for example and without limitation, anti-oxidants, lubricants and the like.
- Sufficient oil is used to form a suspension of micronized progesterone or, in the alternative, solubilize progesterone.
- Pharmaceutically acceptable oils include, without limitation, the use of at least one of caproic fatty acid; caprylic fatty acid; capric fatty acid; tauric acid; myristic acid; linoleic acid; succinic acid; glycerin; mono-, di-, or triglycerides and combinations and derivatives thereof; a polyethylene glycol; a polyethylene glycol glyceride (Gelucire®; GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a caprylic/capric triglyceride (Miglyol®; SASOL Germany GMBH, Hamburg; Miglyol includes Miglyol 810, 812, 816 and 829); a caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a caprylic/capric/succinic triglyceride; propylene glyco
- progesterone is fully solubilized using, for example and without limitation, sufficient amounts of: Transcutol and Miglyol; Transcutol, Miglyol and Capmul PG 8 and/or PG 10; Capmul MCM; Capmul MCM and a non-ionic surfactant; and Capmul MCM and Gelucire.
- Capmul MCM and a non-ionic surfactant can be used at ratios of about 99:1 to 2:1, including, for example and without limitation: 60:40, 65:35, 70:30, 75:25, 80:10, 80:15, 85:20, 90:10, and 98:1.
- the ratios of oil (e.g., medium chain fatty acid esters of monoglycerides and diglycerides) to non-ionic surfactant can be significantly higher.
- Capmul MCM and Gelucire were used in ratios of up to about 65:1, e.g., 8:1, 22:1, 49:1, 65:1 and 66:1. See, e.g., Tables 13-17, below.
- useful ratios can be 8:1 or greater, e.g., 60 to 70:1.
- these oils and/or solubilizers, as defined herein, and combinations thereof, can be used to form combination estradiol and progesterone formulations of the present disclosure.
- Combinations of these oils can produce partially solubilized progesterone, depending upon the desired unit dosage amount of progesterone.
- the upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form.
- oils used to solubilize estradiol and to suspend, partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, polyethylene glycol, or propylene glycol) and mixtures thereof.
- the medium chain fatty acids are C6 to C14 or C6 to C12 fatty acids.
- estradiol or progesterone (or both) is soluble in the oils at room temperature, although it may be desirable to warm the oils up until they are in a liquid state.
- the oil or oil/surfactant is liquid at between room temperature and about 50° C., e.g., at or below 50° C., at or below 40° C., or at or below 50° C.
- Gelucire 44/14 is heated to about 65° C. and Capmul MCM is heated to about 40° C. to facilitate mixing of the oil and non-surfactant, although such heating is not necessary to dissolve the estradiol or progesterone.
- the solubility of estradiol in the oil (or oil/surfactant) is at least about 0.5 wt %, e.g., 0.8 wt % or higher, or 1.0 wt % or higher.
- Illustrative examples of mono- and diglycerides of medium chain fatty acids include, among others, Capmul MCM, Capmul MCM C10, Capmul MCM C8, and Capmul MCM C8 EP. These oils are C8 and C10 fatty acid mono- and diglycerides.
- oils that are triglycerides of medium chain fatty acids include, among others, Miglyol 810 and Miglyol 812.
- oils that are medium chain fatty acid esters of propylene glycol include, among others, Capmul PG-8, Capmul PG-2L EP/NF, Capmul PG-8 NF, Capmul PG-12 EP/NF and Capryol.
- Other illustrative examples include Miglyol 840.
- oils that are medium chain fatty acid esters of polyethylene glycol include, among others, Gelucire 44/14 (PEG-32 glyceryl laurate EP), which is polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. Without intending to be bound to any particular mechanism, it appears that at least in formulations comprising small amounts of Gelucire, e.g., 10 wt % or less, the primary function of this oil is as a non-ionic surfactant.
- Gelucire 44/14 PEG-32 glyceryl laurate EP
- fatty acids comprise predominantly medium chain length, saturated, fatty acids, specifically predominantly C8 to C12 saturated fatty acids.
- a product information sheet for Myglyol by SASOL provides as the composition of fatty acids as follows:
- Tests 810 812 818 829 840 Caproic acid max. 2.0 max. 2.0 max. 2 max. 2 max. 2 (C6:0) Caprylic acid 65.0-80.0 50.0-65.0 45-65 45-55 65-80 (C8:0) Capric acid 20.0-35.0 30.0-45.0 30-45 30-40 20-35 (C10:0) Lauric acid max. 2 max. 2 max. 3 max. 3 max. 2 (C12:0) Myristic acid max. 1.0 max. 1.0 max. 1 max. 1 max. 1 (C14:0) Linoleic acid — — 2-5 — — (C18:2) Succinic acid — — — 15-20 —
- oils are often mixtures. So, for example, when an oil is described herein as a saturated C8 fatty acid mono- or diester of glycerol, it will be understood that the predominant component of the oil, i.e., >50 wt % (e.g., >75 wt %, >85 wt % or >90 wt %) are caprylic monoglycerides and caprylic diglycerides.
- medium chain fatty acid glycerides e.g., C6-C12, C8-C12, or C8-C10 fatty acid mono- and diglycerides or mono-, di-, and triglycerides are very well suited for dissolving estradiol; good results have been obtained with an oil that is predominantly a mixture of C8-C10 saturated fatty acid mono- and diglycerides. Longer chain glycerides appear to be not as well suited for dissolution of estradiol. On the other hand, high solubility of progesterone has been obtained in mixtures that are predominantly medium chain fatty acid triglycerides.
- estradiol has been obtained in 2-(2-Ethoxyethoxyl)ethanol, e.g., Transcutol and in Propylene glycol monocaprylate, e.g., CapryolTM 90 (Gattefosse).
- the selected oil does not require excessive heating in order to solubilize progesterone or estradiol.
- the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., Capmul MCM) and polyethylene glycol glycerides (e.g., Gelucire) as a surfactant
- the oil and/or the surfactant can be warmed up, e.g., to about 65° C. in the case of the surfactant and less in the case of the oil, to facilitate mixing of the oil and surfactant.
- the estradiol can be added at this temperature or at lower temperatures as the mixture cools or even after it has cooled as temperatures above room temperature, e.g., about 20° C., are not required to solubilize the estradiol in preferred oils.
- the progesterone can also be added as the mixture cools, e.g., to below about 40° C. or to below about 30° C., even down to room temperature.
- estradiol is solubilized.
- Solubilized estradiol may include estradiol that is approximately: 90% soluble in a solvent; 93% soluble in a solvent; 95% soluble in a solvent; 97% soluble in a solvent; 99% soluble in a solvent; and 100% soluble in a solvent.
- Solubility may be expressed as a mass fraction (% w/w, also referred to as wt %).
- the solubilizing agent is selected from at least one of a solvent or co-solvent.
- Suitable solvents and co-solvents include any mono-, di- or triglyceride and glycols, and combinations thereof.
- solubilizers include, for example and without limitation, glyceryl mono- and di-caprylates, propylene glycol and 1,2,3-propanetriol (glycerol, glycerin, glycerine).
- Anionic and/or non-ionic surfactants can be used in other embodiments of the presently disclosed formulations containing estradiol, progesterone or a combination thereof.
- a non-ionic surfactant is used.
- Exemplary non-ionic surfactants may include, for example and without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid esters or alcohols.
- the non-ionic surfactant may comprise polyethylene sorbitol esters, including polysorbate 80, which is commercially available under the trademark TWEEN 80® (Sigma Aldrich, St. Louis, Mo.).
- Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids. Polysorbate 80 may be used in amounts ranging from about 5 to 50%, and in certain embodiments, about 30% of the formulation total mass.
- the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of fatty acids, for example, lauroyl macrogol-32 glycerides and/or lauroyl polyoxyl-32 glycerides, commercially available as Gelucire, including, for example, Gelucire 44/11 and Gelucire 44/14. These surfactants may be used at concentrations greater than about 0.01%, and typically in various amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%. In certain examples, below, Gelucire 44/14 is used as a surfactant in amounts of 1 to 10 wt %. See, e.g., Tables 13-17, below.
- Other non-ionic surfactants include, e.g., Labrasol® PEG-8 Caprylic/Capric Glycerides (Gattefosse) and Labarafil® corn/apricot oil PEG-6 esters (Gattefosse).
- a lubricant is used. Any suitable lubricant may be used, such as for example lecithin. Lecithin may comprise a mixture of phospholipids.
- an antioxidant is used. Any suitable anti-oxidant may be used such as, for example and without limitation, butylated hydroxytoluene.
- a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
- excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste-masking agents. Colorants, for example, may comprise about 0.1% to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.
- solubilizers As is with all oils, solubilizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.
- the formulations of the present disclosure are generally orally administered, typically via, for example, capsules such as soft capsules.
- the present formulations can also be used to form transdermal patches using standard technology known in the art.
- Solubilized formulations of the present invention can also be formulated for intraperitoneal administration using techniques well known in the art.
- formulations do not include peanut oil.
- the lack of peanut oil obviates the risk posed to those having peanut-based allergies.
- an illustrative embodiment of a pharmaceutical composition of the invention comprises solubilized estradiol, progesterone at least 75% of the progesterone being solubilized (the balance being micronized as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and diesters of glycerol, with or without surfactant.
- a specification for progesterone is set at >80% solubilized, ⁇ 20% micronized or >85% solubilized, ⁇ 15% micronized.
- Specific examples of such illustrative embodiments, with Gelucire as surfactant, in which at least about 85% of the progesterone can be solubilized include, e.g., the following four formulations:
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 50.00 Estradiol Hemihydrate 0.17 0.26 Capmul MCM, NF 65.49 98.24 Gelucire 44/14, NF 1.00 1.50 Total 100.00 150.00
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 50.00 Estradiol Hemihydrate 0.35 0.52 Capmul MCM, NF 65.32 97.98 Gelucire 44/14, NF 1.00 1.50 Total 100.00 150.00
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 100.00 Estradiol Hemihydrate 0.17 0.52 Capmul MCM, NF 65.49 196.48 Gelucire 44/14, NF 1.00 3.00 Total 100.00 300.00
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 100.00 Estradiol Hemihydrate 0.34 1.03 Capmul MCM, NF 65.32 195.97 Gelucire 44/14, NF 1.00 3.00 Total 100.00 300.00
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 200.00 Estradiol Hemihydrate 0.34 2.06 Capmul MCM, NF 65.32 391.94 Gelucire 44/14, NF 1.00 6.00 Total 100.00 600.00
- the above formulations comprise 30 to 35 wt % progesterone, 0.1 to 0.4 wt % estradiol (or estradiol hemihydrate), 55 to 75 wt % of an oil that is predominantly medium chain fatty acid mono- and diglycerides, such as Capmul MCM, and 0.5 to 10 wt % non-ionic surfactant, such as Gelucire 44/14.
- the above formulations may be modified to comprise excipients, e.g., gelatin such as Gelatin 200 Bloom, glycerin, coloring agents such as Opatint red and white, and, optionally, Miglyol 812.
- Estradiol solubilization helps ensure high content uniformity and enhanced stability.
- Fully solubilized progesterone formulations or partially solubilized progesterone formulations in which at least about 50% of the progesterone, e.g., 75%, 80%, 85%, 90%, or >95%, is solubilized appear to provide improved PK-related properties.
- a 28-day or monthly regimen of capsules can be packaged in a single kit (e.g., a blister pack) having administration days identified to improve compliance and reduce associated symptoms, among others.
- a single kit e.g., a blister pack
- One or more of the capsules may contain no estradiol, for example, and/or no progesterone.
- Capsules that comprise no estrogen or progesterone API may be referred to as placebos.
- a blister pack can have a plurality of scores or perforations separating blister pack into 28 days. Each day may further comprise a single blister or a plurality of blisters.
- each unit dose may contain micronized and/or partially solubilized, or fully solubilized progesterone and/or solubilized estradiol in amounts as set forth herein above, although other dose ranges may be contemplated.
- kits having other configurations are also contemplated herein.
- kits having such blister packs may contain any number of capsules.
- Orally administered formulations of the present disclosure containing micronized and/or partially solubilized, or fully solubilized, progesterone are also used for the treatment of endometrial hyperplasia, secondary amenorrhea and other disease states treated with supplemental progesterone.
- progesterone-containing formulations described herein are used to treat the effects of the administration of supplemental estrogen whether administered alone or in combination with solubilized estradiol of the present disclosure or other estrogen-containing formulations.
- a capsule containing formulations of the present disclosure for example a softgel capsule, may be applied in or around the vagina.
- Formulations of the present disclosure containing solubilized estradiol are used to treat Estrogen-deficient States, including vasomotor symptoms, for example, in relation to treatment of hypoestrogenism related symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvo-vaginal atrophy, and osteoporosis and other non-menopausal disease states treated with supplemental estrogen.
- vasomotor symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvo-vaginal atrophy, and osteoporosis and other non-menopausal disease states treated with supplemental estrogen.
- Formulations of the present disclosure containing solubilized estradiol may be used to treat or prevent atrophic vaginitis or vulvo-vaginal atrophy.
- a capsule for example a softgel capsule, may be applied in or around the vagina.
- Additional objects of the present disclosure includes: providing increased patient compliance secondary to ease of use; providing increased physician adoption secondary to ease of use/instruction with less worry of side effects from inappropriate usage; providing decreased side-effects from erroneous use (decreased irregular bleeding); providing better efficacy/control of symptoms secondary to appropriate use; reducing the metabolic and vascular side effects of the commonly used synthetic progestins when administered alone or in combination with an estrogen (norethindrone acetate, medroxyprogesterone acetate, etc.) including, for example, stroke, heart attacks, blood clots and breast cancer.
- an estrogen nodethindrone acetate, medroxyprogesterone acetate, etc.
- suitable solvents were determined for providing sufficient solubility to make 2 mg of estradiol in a 100 mg fill mass, with a desired goal of achieving ⁇ 20 mg/g solubility for estradiol.
- Initial solubility experiments were done by mixing estradiol with various solvents, saturate the solution with the estradiol, equilibrate for at least 3 days and filter the un-dissolved particles and analyzing the clear supernatant for the amount of estradiol dissolved by HPLC.
- estradiol solubility experiments were performed. From this list at least one item (e.g. propylene glycol) is known to be unsuitable for encapsulation.
- estradiol was soluble at at least 6 mg/gm Miglyol Transcutol in ratios of 81:19 to 95:5, in Miglyol; ethanol at 91:11, and in Miglyol:Capmul PG8 at 88:11, but not in Miglyol:Transcutol at 96:4, Miglyol:Labrasol at 70:30 to 80:20, or Miglyol:Capmul PG8 at 86:14.
- estradiol solutions at a concentration of 6 mg/g in Polyethylene Glycol 400 and Capmul MCM are able to absorb a minimum of 7% water without recrystallization, whereas the same concentration in Miglyol 812:Capmul PG8 (75:25) precipitates.
- Estradiol solutions at a concentration of 12 mg/g in Polyethylene Glycol 400 and Capmul MCM are able to absorb a minimum of 7% water without recrystallization. All Capmul PG8 containing formulations turned hazy on the addition of water. However, it should be noted that estradiol recrystallization was not observed, and the addition of water to Capmul PG 8 alone (without any estradiol) also turns hazy on the addition of water.
- a capsule containing a fill material comprising:
- a capsule containing a fill material comprising:
- a capsule containing a fill material comprising:
- estradiol is added to Capmul MCM and mixed until dissolved.
- both estradiol and progesterone may be dissolved in a solvent.
- the solubility of both estradiol and progesterone will be such that a therapeutically effective dose may be obtained in a reasonably sized mass, generally considered to be between 1 mg and 1200 mg, preferably suitable for encapsulation in a size 3 to 22 oval or oblong capsule.
- 50 mg to 100 mg of progesterone may be dissolved in a volume of solvent; i.e., the solubility would be 50 mg to 100 mg per capsule.
- Miglyol was attempted, and while it can be considered a good carrier for progesterone, it alone did not provide a desirable level of solubilization of estradiol (e.g., solubility of 12 mg/g may be desirable in various embodiments). Thus, Miglyol may be used in embodiments comprising a suspension of progesterone, though Miglyol, standing alone, is not desirable for use in embodiments having fully solubilized progesterone and/or estradiol.
- the solubility of progesterone in Capmul MCM is ⁇ 73 mg/g. Therefore, by suspending 200 mg progesterone in 400 mg of solvent, part of the dose ( ⁇ 14%) is already dissolved and the remaining is still a suspension. In some aspects and embodiments, it is desired to minimize the partial solubility of progesterone in the formulation in order to minimize the possibility of recrystalization.
- the capsule size required to make a capsule of 50 mg solubilized progesterone would be 685 mg. Therefore, it was shown that it would be feasible to make a 50 mg progesterone and 2 mg estradiol solubilized formulation.
- Myglyol had the lowest solubility, but that solvent is unable to dissolve the estradiol, therefore under further experiments, it was decided to proceed with the second lowest or Capmul MCM. It has also been found that 2 mg of estradiol may also be dissolved in 685 mg of Capmul MCM.
- progesterone and/or estradiol may be dissolved in a Capmul MCM and Gelucire 44/14 system, wherein the ratio of Capmul MCM to Gelucire 44/14 is 9:1.
- a capsule containing a fill material having fully solubilized progesterone and estradiol comprising:
- a capsule such as that shown in TABLE 11 may be manufactured in any suitable manner.
- mixing may be facilitated by an impellor, agitator, or other suitable means.
- heating and/or mixing may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 .
- Mixing and/or heating for the purposes of this Example may be performed in any suitable vessel, such as a stainless steel vessel.
- Campul MCM may be heated to between 30° C. to 50° C., more preferably from 35° C. to 45° C., and more preferably to 40° C. ⁇ 2° C.
- Gelucire 44/14 may be added to the Campul MCM and mixed until dissolved. The addition may occur all at once or may occur gradually over a period of time. Heat may continue to be applied during the mixing of the Gelucire 44/14 and the Campul MCM.
- Heat may be removed from the Gelucire 44/14 and Campul MCM mixture.
- Estradiol Hemihydrate may be added to the mixture. The addition may occur all at once or may occur gradually over a period of time.
- Micronized progesterone may then be added to the Gelucire 44/14, Campul MCM and Estradiol Hemihydrate mixture until dissolved. The addition may occur all at once or may occur gradually over a period of time.
- a capsule containing a fill material having suspended progesterone comprising:
- the above formulation is prepared as follows: MIGLYOL is heated to about 45° C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- a capsule containing a fill material having partially solubilized progesterone comprising:
- GELUCIRE 44/14 may be added at 1% to 2% w/w to increase viscosity.
- the above formulation is prepared as follows: Capmul MCM is heated to about 65° C. GELUCIRE 44/14 is added and mixed until dissolved. Heat is removed. Progesterone is added and the mixture is passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- a capsule containing a fill material having suspended progesterone comprising:
- amounts of MIGLYOL may be present in a range from about 35-95% by weight; GELUCIRE 44/14 from about 0.5-30% by weight; and BHT from about 0.01-0.1% by weight.
- a particle size analysis is conducted by using the Beckman Device.
- a sample API comprising micronized progesterone in accordance with various embodiments is provided for analysis.
- Approximately 0.01 g of a sample API in accordance with various embodiments was combined with Coulter 1B and 10 mL of deionized water. Sonication was performed for 15 seconds.
- the Beckman Device equipped with a ULM, performed analysis for 90 seconds.
- the Beckman Device was configured to use the Fraunhofer optical model.
- the Beckman Device yielded that the sample has an X50 of 4.279 ⁇ m, an X75 of 7.442 ⁇ m, and an X25 of 1.590 ⁇ m.
- the Beckman Device also yielded that the mean particle size is 4.975 ⁇ m, the median particle size is 4.279 ⁇ m, the mode particle size is 6.453 ⁇ m, and the standard deviation is 3.956 ⁇ m.
- a graph of the particle distribution obtained is shown in FIG. 4 .
- a formulation sample having approximately 200 mg of micronized progesterone and 2 mg of estradiol was dispersed with oil.
- the Beckman Device equipped with a MLM, performed analysis for 60 seconds.
- the Beckman Device was configured to use the Fraunhofer optical model.
- the Beckman Device yielded that the sample has an X50 of 11.0 ⁇ m, an X75 of 17.3 ⁇ m, and an X25 of 5.3 ⁇ m.
- the Beckman Device also yielded that the mean particle size is 11.8 ⁇ m, the median particle size is 11.04 ⁇ m, the mode particle size is 13.6 ⁇ m, and the standard deviation is 7.8 ⁇ m.
- Gelucire 44/14 was added at about 10% w/w.
- Table 15 An example of the final formulation is provided in Table 15. The manufacturing process is as follows. Capmul MCM is heated to 40° C. Gelucire 44/14 is heated to 65° C. and added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and mixed until dissolved.
- a capsule containing a fill material having fully solubilized estradiol and partially solubilized progesterone comprising:
- the manufacturing process is as follows. Capmul MCM is heated to 65° C. Gelucire 44/14 is added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- a capsule containing a fill material having fully solubilized estradiol and partially solubilized progesterone comprising:
- the manufacturing process is as follows. Capmul MCM is heated to 65° C. Gelucire 44/14 is added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- Gelucire 44/14 is heated to 65° C. and Capmul MCM is heated to 40° C. ⁇ 5° C. to achieve mixing of the oil and the surfactant before heat is removed; estradiol is added while the mixture is cooling; progesterone is added when the mixture has dropped below about 40° C.; the mixture is then passed through a colloid mill, e.g., three times.
- Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 7.14 50.00 Estradiol Hemihydrate, USP Micronized 0.30 2.07 Capmul MCM, NF, USP 83.27 582.93 Gelucire 44/14, NF 9.29 650 Total 100.00 700
- the Study Design An open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, two-way crossover study.
- the subjects were housed in the clinical facility from at least 11.00 hours pre-dose to at least 48.00 hours post-dose in each period, with a washout period of at least 14 days between the successive dosing days.
- Subjects were fasted for at least about 10.00 hours before being served a high-fat, high-calorie breakfast, followed by dosing, then followed by a 04.00 hour, post-dose additional period of fasting.
- Standard meals were provided at about 04.00, 09.00, 13.00, 25.00, 29.00, 34.00 and 38.00 hours post-dose, respectively.
- Subjects were instructed to abstain from consuming caffeine and/or xanthine containing products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least about 24.00 hours prior to dosing and throughout the study, grapefruit and ⁇ or its juice and poppy containing foods for at least about 48.00 hours prior to dosing and throughout the study.
- caffeine and/or xanthine containing products i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.
- Subjects remained seated upright for about the first 04.00 hours post-dose, and only necessary movements were allowed during this period. Thereafter, subjects were allowed to ambulate freely during the remaining part of the study. Subjects were not allowed to lie down (except as directed by the physician secondary to adverse events) during restriction period.
- Subjects were instructed not to take any prescription medications within 14 days prior to study check in and throughout the study. Subjects were instructed not to take any over the counter medicinal products, herbal medications, etc., within 7 days prior to study check-in and throughout the study.
- test product of Progesterone 200 mg & Estradiol 2 mg tablets or the reference product (R) PROMETRIUM® (Progesterone) soft gel Capsule 200 mg and ESTRACE® (Estradiol) Tablets 2 mg (according to the randomization schedule) were administered with about 240 mL of water under fed condition, at ambient temperature in each period in sitting posture. A thorough mouth check was done to assess the compliance to dosing.
- the pre-dose (10 mL) blood samples at ⁇ 01.00, ⁇ 00.50, 00.00 hours and the post-dose blood samples (08 mL each) were collected at 00.25, 00.50, 00.67, 00.83, 01.00, 01.33, 01.67, 02.00, 02.50, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 10.00, 12.00, 18.00, 24.00 and 48.00 hours in labeled K2EDTA—vacutainers via an indwelling cannula placed in one of the forearm veins of the subjects.
- Each intravenous indwelling cannula was kept in situ as long as possible by injecting about 0.5 mL of 10 IU/mL of heparin in normal saline solution to maintain the cannula for collection of the post-dose samples. In such cases blood samples were collected after discarding the first 0.5 mL of heparin containing blood. Each cannula was removed after the 24.00 hour sample was drawn or earlier or if blocked.
- the samples were transferred to the bio-analytical facility in a box containing sufficient dry ice to maintain the integrity of the samples. These samples were stored at a temperature of ⁇ 70° C. ⁇ 20° C. in the bio-analytical facility until analysis.
- Progesterone (Corrected and Uncorrected) and Estradiol (unconjugated) and estrone (total) in plasma samples is assayed using a validated LC-MS/MS method.
- the pharmacokinetic parameters Cmax, AUC0-t & AUC0- ⁇ were calculated on data obtained from 24 subjects for the test product and reference product. In general, bioavailability of progesterone and estradiol were similar but bioequivalence was not established.
- the pharmacokinetic parameters Cmax, AUC0-t & AUC0- ⁇ were calculated on data obtained from 23 subjects under fasting conditions for the test product and reference product. In general, bioavailability of progesterone and estradiol were similar, but bioequivalence was not established.
- the data indicate good (i.e., low) inter-patient and intra-patient variability relative to Prometrium.
- Step 102 comprises heating an oily vehicle carrier to 40° C. ⁇ 5° C. Heating may be accomplished through any suitable means. The heating may be performed in any suitable vessel, such as a stainless steel vessel.
- the oily vehicle may be any oily vehicle described herein, for example, Capmul MCM.
- Step 104 comprises mixing Gelucire 44/14 with the oily vehicle. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 102 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Mixing may be performed in any suitable vessel, such as a stainless steel vessel.
- Step 106 comprises mixing estradiol into the mixture of the oily vehicle and Gelucire 44/14. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 106 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 .
- Step 108 comprises cooling to room temperature. Cooling may be allowed to occur without intervention or cooling may be aided by application of a cooling system.
- Step 110 comprises mixing micronized progesterone into the mixture of oily vehicle, estradiol and Gelucire 44/14. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 110 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Step 112 comprises degasing. The resulting mixture from step 112 may comprise a fill material suitable for production into a softgel capsule.
- Step 202 comprises mixing glyercin with water.
- the water used in step 202 may be purified by any suitable means, such as reverse osmosis, ozonation, filtration (e.g., through a carbon column), or the like. Mixing may be facilitated by an impellor, agitator, or other suitable means.
- Step 202 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . Heating may be performed until the temperature reaches 80° C. ⁇ 5° C.
- Step 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 . A vacuum may be drawn in step 204 to de-aerate.
- N 2 nitrogen gas
- Step 206 comprises addition of a coloring agent such as a dye.
- a coloring agent may comprise products sold under the trademark OPATINT or other suitable agent.
- Step 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N 2 .
- Step 208 comprises degasing.
- the resulting mixture from step 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule.
- Step 302 comprises heating the fill material.
- the fill material may be heated to any suitable temperature.
- the fill material is heated to 30° C. ⁇ 3° C.
- Fill material maybe heated in a fill hopper.
- a fill hopper may comprise a device configured to hold a volume of the fill material and/or to dispense the fill material in controlled volumes.
- Step 304 comprises filling a gel mass.
- a gel mass may be taken from the gel capsule material produced in step 208 of FIG. 2 .
- Filling may be performed by injecting, placing, or otherwise disposing the fill material within a volume defined by the gel capsule material. The filling may occur in an encapsulator.
- the spreader boxes may be a temperature of 55° C. ⁇ 10° C.
- the wedge temperature may be 38° C. ⁇ 3° C.
- the drum cooling temperature may be 4° C. ⁇ 2° C.
- the encapsulator may be lubricated using MIGLYOL 812 or other suitable lubricant.
- Step 304 thus produces one or more softgel capsules.
- Filling may comprise producing a ribbon of thickness 0.85 mm ⁇ 0.05 mm using spreader box knobs.
- the fill material may be injected into the gel to produce a fill weight having target weight ⁇ 5% (i.e., 650 ⁇ 33 mg and 325 ⁇ 16.3 mg).
- Step 306 comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours.
- Step 308 may comprise inspection and/or polishing. Polishing may be performed with isopropyl alcohol.
- Step 310 may comprise packaging. Packaging may be accomplished through any suitable means. Packaging may comprise packing softgel capsules into a blister pack, bottle, box, pouch, or other acceptable packaging.
- Estradiol suspension in each oil was prepared by adding 30 mg Estradiol to solvent and QS to 10 g. Samples were mixed on vortex for 2 hours, heated @ 50° C. for 30 minutes and then mixed for 1 hour more. All samples were still in suspension form.
- Each sample was diluted to 0.24% (by adding 2.5 g more oil) and mixed for 2 hours and heated @ 50° C. for 30 min and mixed again for one hour. All the samples were still cloudy. Samples were kept at room temperature overnight to see if they precipitate or if undissolved API settles out. After 20 hours at room temperature, it was observed that all samples still had undissolved API.
- Estradiol Solubility Ingredient (mg/g) (% w/w) Peanut Oil ⁇ 2 ⁇ 0.2 Safflower Oil ⁇ 2 ⁇ 0.2 Soy Bean Oil ⁇ 2 ⁇ 0.2
- estradiol in all three oils was less than 2 mg/g (0.2% w/w). This level of solubility is significantly below the solubility that the present inventors have discovered can be achieved in other oils, e.g., medium chain fatty acid esters, such as the mono/diglycerides, propylene glycol esters, and polyethylene glycol esters discussed above.
- medium chain fatty acid esters such as the mono/diglycerides, propylene glycol esters, and polyethylene glycol esters discussed above.
- estradiol in safflower oil, it will not go into solution. Given that the estradiol did not dissolve at 50° C., oils such as safflower oil will not be useful in the methods of the invention using medium chain fatty acid esters as described hereinabove.
- Dissolution studies were performed using a formulation of this invention comparing the dissolution of progesterone to the dissolution of Prometrium and comparing the dissolution of estradiol to the dissolution of Estrace.
- a formulation of the invention in capsules comprising 200 mg of progesterone and 2 mg estradiol was used.
- a formulation of the invention in capsules comprising 50 mg of progesterone and 2 mg estradiol was used.
- the two formulations comprised:
- USP Apparatus 3 The dissolution study was performed using a USP dissolution apparatus (reciprocating cylinder) (“USP Apparatus 3”). The apparatus was set to 30 dips per minute. 250 mL of a solution of 0.1 NHCl with 3% sodium lauryl sulfate was used at 37° C.
- Both capsules of the invention were stable on storage in white HDPE bottles. Positive stability data were obtained with the 200 mg progesterone formulation over 6 months (>6 months data unavailable) and with the 50 mg progesterone formulation over 3 months (>3 months data unavailable).
Abstract
Description
- This application is a divisional of U.S. patent application Ser. No. 14/099,582, filed Dec. 6, 2013, which is a continuation of U.S. patent application Ser. No. 13/843,428, filed Mar. 15, 2013, which is a CIP of U.S. patent application Ser. No. 13/684,002, filed Nov. 21, 2012, now U.S. Pat. No. 8,633,178, issued Jan. 21, 2014, which claims the benefit of U.S. Provisional Patent Application No. 61/662,265, filed Jun. 20, 2012 and U.S. Provisional Patent Application No. 61/661,302 filed Jun. 18, 2012, which are incorporated herein by reference in their entirety for all purposes.
- 1. Field
- This disclosure relates to natural estrogen and progesterone replacement therapies, with formulations provided for each estradiol and progesterone alone and in combination for the treatment of pre, peri-menopausal, menopausal and post-menopausal females in relation to the treatment of Estrogen- and Progesterone-deficient States, each as herein below defined.
- 2. Discussion of the Related Art
- Hormone replacement therapy (HRT) is a medical treatment that involves the use of one or more of a group of medications designed to increase hormone levels in women who lack adequate hormone production. HRT can mitigate and prevent symptoms caused by diminished circulating estrogen and progesterone hormones regardless as to whether the subject is pre-menopausal, peri-menopausal, menopausal or post-menopausal. However, specific disease states can exist during each stage of menopausal progression.
- HRT is presently available in various forms. One therapy involves administration of low dosages of one or more estrogens. Another involves administration of progesterone or a chemical analogue, called a progestin. Progesterone administration acts, among treating other disease states, to mitigate certain undesirable side effects from estrogen administration including, for example, endometrial hyperplasia (thickening), reducing the incidence of endometrial cancer.
- Timing for dosage administration is often varied cyclically, with estrogens taken daily and progesterone taken for approximately two weeks of every month; a method often referred to as “Cyclic-Sequential” or “Sequentially-Combined HRT.” This method is intended to mimic the natural menstrual cycle and typically causes menstruation similar to a period after the progesterone is stopped. This regimen is most typically used in peri-menopausal or newly menopausal women as the alternative continuous method often results in irregular bleeding in such women. An alternate method, a constant dosage with both estrogen and progesterone taken daily, is called “continuous-combined HRT.” This method usually results in no menstruation and is used most often after a woman has been menopausal for some time.
- Estrogen, in its various forms, and progesterone, in its various forms, are used in HRT via a variety of administered dosage forms including, for example, via tablets, capsules and patches.
- “Bio-identical” hormones, which are identical in chemical structure to the hormones naturally produced by human bodies can be used and are often referred to as natural hormone replacement therapy, or NHRT.
- These natural or bio-identical hormones are formulated from various ingredients to match the chemical structure and effect of estradiol, estrone, or estriol (the 3 primary estrogens) as well as progesterone that occur naturally in the human body (endogenous).
- Currently, bio-identical estradiol is available in both branded and generic FDA approved versions. FDA-approved bio-identical progesterone for HRT is available as the branded stand-alone drug commercially identified as PROMETRIUM (Progesterone, USP) (Abbott Laboratories, Abbott Park, Ill.), with a generic authorized by the innovator, and generic products provided by Teva (Israel) and Sofgen Americas, Inc (New York). Prometrium was approved for sale in the United States on May 14, 1998 under NDA #N019781. According to the prescribing information approved for this product (Rev June 2009) (“Prometrium prescribing information”), Prometrium comprises synthetic progesterone that is chemically identical to progesterone of human ovarian origin. Capsules comprise 100 mg or 200 mg of micronized progesterone. The inactive ingredients include peanut oil, gelatin, glycerin, lecithin, titanium dioxide, and yellow and red dyes.
- Other products such as Prempro® and Premphase® (Wyeth Laboratories, a division Pfizer, Inc., New York) provide both continuous-combined and cyclic-sequential products containing Premarin (estrogen derived from mare's urine) and synthetic medroxyprogesterone acetate. Other products are available. However, no FDA approved product exists on the market today with combination bio-identical estradiol and bio-identical progesterone.
- According to various embodiments of the disclosure, natural hormone replacement therapies are provided comprising cyclic/sequential and continuous-combined delivery via pharmaceutical formulations of solubilized estradiol and micronized and/or partially or completely solubilized progesterone. Estradiol and micronized and/or partially or completely solubilized progesterone delivered together daily can be combined in either a single unit dose or in separate unit doses, typically in a soft capsule. A 28-day or monthly regimen of tablets or capsules can be packaged in a single blister pack having delivery days identified to improve compliance. Various examples formulations of natural hormones, and the use of these formulations for hormone replacement therapies, each in accordance with the invention are set forth below.
- The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the present disclosure and, together with the description, further serve to explain the principles of the disclosure and to enable a person skilled in the pertinent art to make and use the disclosed embodiments.
-
FIG. 1 illustrates an exemplary manufacturing process of a fill material in accordance with various embodiments; -
FIG. 2 illustrates an exemplary manufacturing process of a softgel material in accordance with various embodiments; -
FIG. 3 illustrates an exemplary manufacturing process in accordance with various embodiments; and -
FIG. 4 illustrates a graph of the particle distribution obtained in Example 10. -
FIG. 5 illustrates a dissolution study of a formulation in accordance with various embodiments of the invention. - Frequently, higher recommended oral dosages of pharmaceuticals are necessary to treat a given disease state because many active ingredients are not completely absorbed by a patient in need of treatment. In other words, a better-absorbed dosage form of a medicament such as, for example, progesterone, or dosage forms that provide greater consistency of absorption of progesterone among subjects, alone or in combination with estradiol, may be able to be administered at dosage strengths lower than presently recommended, potentially resulting in a reduced or minimized side effect profile, among other potential benefits.
- The term “micronized progesterone,” as used herein, includes micronized progesterone having an X50 particle size value below about 15 microns and/or having an X90 particle size value below about 25 microns.
- The term “X50,” as used herein, means that one-half of the particles in a sample are smaller in diameter than a given number. For example, micronized progesterone having an X50 of 5 microns means that, for a given sample of micronized progesterone, one-half of the particles have a diameter of less than 5 microns. Similarly, the term “X90” means that ninety percent (90%) of the particles in a sample are smaller in diameter than a given number.
- The term “medium chain,” as used herein, means any medium chain carbon-containing substance, including C4-C18, and including C6-C12 substances, fatty acid esters of glycerol, fatty acids, and mono-, di-, and tri-glycerides of such substances.
- The term “uniform distribution” means at least one of uniform dispersion, solubility, or lack of agglomeration of progesterone in a dissolution test compared to Prometrium at a similar dosage strength and the same USP dissolution apparatus.
- The term “bioavailability,” as used herein, means the concentration of an active ingredient (e.g., progesterone or estradiol or estrone) in the blood (serum or plasma). The relative bioavailability may be measured as the concentration in the blood (serum or plasma) versus time. Other pharmacokinetic (pK) indicators may be used to measure and assess bioavailability, determined by suitable metrics including AUC, Cmax, and optionally, Tmax.
- The term “AUC,” as used herein, refers to the area under the curve that represents changes in blood concentration of progesterone, estradiol or estrone over time.
- The term, “Cmax,” as used herein, refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of progesterone, estradiol or estrone over time.
- The term “Tmax,” as used herein, refers to the time that it takes for progesterone, estradiol or estrone blood concentration to reach the maximum value.
- Collectively, AUC, Cmax and, optionally, Tmax, are the principle pharmacokinetic parameters that can characterize the pharmacokinetic responses of a particular drug product such as progesterone in an animal especially a mammal, including human, subject.
- The term “solubilizer,” as used herein, means any substance or mixture of substances that may be used to enhance the solubility of estradiol, including, for example and without limitation, appropriate pharmaceutically acceptable excipients, such as solvents, co-solvents, surfactants, emulsifiers, oils and carriers.
- The term “excipients,” as used herein, refer to nonactive pharmaceutical ingredients (“API”) substances such as carriers, solvents, oils, lubricants and others used in formulating pharmaceutical products. They are generally safe for administering to animals, especially mammals, including humans, according to established governmental standards, including those promulgated by the United States Food and Drug Administration.
- The term “oil,” as used herein, may be any pharmaceutically acceptable substance, such as an organic oil, other than peanut oil, that would suspend and/or solubilize any suitable progesterone, starting material, or precursor, including micronized progesterone as described herein. More specifically, oils may include, for example and without limitation, medium chain fatty acids, generally of the group known as medium chain fatty acids consisting of at least one mono-, di-, and triglyceride, or derivatives thereof, or combinations thereof.
- “Fully solubilized progesterone,” as used herein, means progesterone which is about 100% in solution, i.e., at least 98% in solution.
- “Partially solubilized progesterone,” as used herein, means progesterone which is in any state of solubilization up to but not including about 100%, i.e., up to but not including 98% in solution.
- As used herein, unless specified, estradiol includes estradiol in anhydrous and hemihydrate forms.
- Provided herein are the following formulations: solubilized estradiol without progesterone; micronized progesterone without estradiol; micronized progesterone with partially solubilized progesterone; solubilized estradiol with micronized progesterone; solubilized estradiol with micronized progesterone in combination with partially solubilized progesterone; and solubilized estradiol with solubilized progesterone. The underlying formulation concepts provided herein may be used with other natural or synthetic forms of estradiol and progesterone. Micronization specifications, aspects and embodiments are further defined herein.
- Generally, the pharmaceutical formulations described herein are prepared and administered as filled capsules, typically soft capsules of one or more materials well known in the art including, for example and without limitation, soft gelatin capsules. Micronized progesterone, as described herein, may also be prepared for administration in tablets or other well-known orally administered dosage forms using standard techniques.
- Another aspect of the present disclosure includes a pharmaceutical formulation of micronized progesterone, micronized progesterone with partially solubilized progesterone and fully solubilized progesterone, wherein said formulation may provide increased progesterone bioavailability in a treated subject compared to the bioavailability provided by Prometrium® when administered at equal dosage strengths.
- In accordance with various aspects and embodiments, the solubility proportion (i.e., the proportion of a solute that enters solution) is notable. The weight ratio of estradiol to the weight of the entire solution is also notable due to the intended dose amounts, discussed herein. In particular, it is desirable to obtain a target dosage of estradiol in an amount of solution that may be readily administered via a capsule. For example, if it is desired to have a dose of estradiol in a capsule of between about 0.125 mg to about 2 mg, it would also be desirable to have a total solution weight to be between about 250 mg to about 400 mg, preferably about 300 mg to about 350 mg, and more preferably about 325 mg. In various embodiments, the following weight ratios of estradiol to total solution is from about 0.125/50 mg to about 0.125/1000 mg, from about 1 mg:500 mg to about 1 mg:50 mg; from about 1 mg:250 mg to about 1 mg:60 mg; from about 1 mg:100 mg to about 1 mg:66 mg; from about 2 mg/50 mg to about 2 mg/1000 mg. In various embodiments, the target for single dose product is 325 mg, and a target fill weight for a combination product (e.g., two or more sterol APIs) is 650 mg.
- In illustrative embodiments, total progesterone, i.e., dissolved and micronized, is 20 to 50 wt %, e.g., 30 to 35 wt %; estradiol is 0.1 to 0.8 wt %, e.g., 0.15 to 0.35 wt %.
- Other aspects of the present disclosure further provide: more uniform dissolution of progesterone, and reduced intra- and inter-patient blood level variability in formulations of progesterone of the present disclosure, typically in combinations with solubilized estradiol, when compared to equal dosages of Prometrium. Blood level variability is also compared at equal sampling times following administration. Not to be limited by theory, these aspects are believed to be influenced by the percentage of solubilized progesterone in a respective formulation wherein such more uniform dissolution of progesterone, and lower intra- and inter-patient blood level variability, are influenced by a greater proportion of solubilized progesterone relative to total progesterone. A reduced food effect with the present formulations comprising progesterone may also be implicated.
- According to the Prometrium prescribing information, clinical trials have shown significant patient variability. For example, a clinical trial involving postmenopausal women who were administered Prometrium once a day for five days resulted in the mean PK parameters listed in the following table:
-
Prometrium Capsules Daily Dose Parameter 100 mg 200 mg 300 mg Cmax 17.3 ± 21.9 38.1 ± 37.8 60.6 ± 72.5 (ng/ml) Tmax 1.5 ± 0.8 2.3 ± 1.4 1.7 ± 0.6 (hr) AUC0-10 43.4 ± 30.8 101.2 ± 66.0 175.7 ± 170.3 (ng × hr/ml) - In a particular illustrative aspects and embodiments of this invention, it is possible, though not necessary, to reduce the standard deviations in one or more of these PK parameters.
- More uniform dissolution of progesterone in a formulation of the present disclosure compared to the dissolution of Prometrium at equal dosage strengths and using the same USP apparatus can be determined using standard techniques established for API dissolution testing, including that which is described in the examples below.
- Reduced intra- and inter-patient variability of progesterone formulated pursuant to the present disclosure compared to Prometrium can be demonstrated via a fed bio-study such as that described below.
- Other aspects of the present disclosure includes the use of formulations as described herein wherein progesterone is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans: for endometrial hyperplasia; for secondary amenorrhea; as a method of treatment for preterm birth, when said animal has a shortened cervix, and other disease states or conditions treated with supplemental progesterone (collectively, “Progesterone-deficient States”); and the use of formulations as described herein wherein estradiol is at least one API in said formulation for the treatment of an animal, especially a mammal, including humans, having menopause-related symptoms including, for example, vasomotor symptoms; in relation to treatment of hypoestrogenism related symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes and vulvo-vaginal atrophy; and osteoporosis and other non-menopausal disease states or conditions treated with supplemental estrogen. (collectively, “Estrogen-deficient States”), each in a subject in need of treatment, and each with a non-toxic effective amount of said formulations. As used herein, the term “treatment,” or a derivative thereof, contemplates partial or complete inhibition of the stated disease state when a formulation as described herein is administered prophylactically or following the onset of the disease state for which such formulation is administered. For the purposes of the present disclosure, “prophylaxis” refers to administration of the active ingredient(s) to an animal especially a mammal, to protect the animal from any of the disorders set forth herein, as well as others.
- Unless otherwise specified, “natural,” as used herein with reference to hormones discussed herein, means bio-identical hormones formulated to match the chemical structure and effect of those that occur naturally in the human body (endogenous). An exemplary natural estrogen is estradiol (also described as 17β-estradiol and E2) and a natural progestin is progesterone. An exemplary cyclic/sequential regimen comprises delivery of from about 0.125 mg to about 2.0 mg of estradiol daily for 14-18 days, followed by delivery of from about 0.125 mg to about 2 mg of estradiol and about 25 mg to about 200 mg of progesterone daily for 10-14 days. Cyclic/sequential regimens may be especially useful for menopausal females. Other exemplary dosage strengths for estradiol for use in the formulations described herein include, without limitation, 0.125, 0.25, 0.375, 0.50, 0.625, 0.75, 1.00, 1.125, 1.25, 1.375, 1.50, 1.625, 1.75 and 2.00 mg. Other exemplary dosage strengths for progesterone for use in the formulations described herein include, without limitation, 25, 50, 75, 100, 125, 150, 175, 200 mg, 250 mg, 300 mg, 350 mg and 400 mg. These dosage strengths for each of estradiol and progesterone can be administered in formulations described herein either alone or in combination.
- Progesterone active pharmaceutical ingredient may be micronized via any one of the multiple methods typically utilized by the ordinarily skilled artisan. In various embodiments, micronized progesterone has an X50 particle size value of less than about 15 microns, less than about 10 microns, less than about 5 microns and/or less than about 3 microns. In various embodiments, micronized progesterone has an X90 particle size value of less than about 25 microns, less than about 20 microns, and/or less than about 15 microns.
- Particle size may be determined in any suitable manner. For example, a Beckman Coulter LS 13 320 Laser Diffraction Particle Size Analyzer (the “Beckman Device”) may be used to determine particle size. As described above, particle size may be represented by various metrics, for example, through an X50 particle size, and/or X90 particle size, or similar descriptions of particle size.
- The Beckman Device may be used with various modules for introducing a sample for analysis. The Beckman Device may be used with the LS 13 320 Universal Liquid Module (“ULM”). The ULM is capable of suspending samples in the size range of 0.017 μm to 2000 μm. The ULM is a liquid based module that allows for delivery of the sample to the sensing zone. The ULM recirculates the sample through the Beckman Device. The ULM comprises two hoses, one for fluid delivery and another for waste. The total volume used may be 125 mL or less. A sample mass of from about 1 mg to about 10 g may be used. The ULM may interact with the Beckman Device via pins that fit into slots on the ULM. The ULM may use a variety of suspension fluids, for example, water, butonol, ethanol, chloroform, heptanes, toluene, propanol, COULTER Type 1B Dispersant (“Coulter 1B”), and a variety of other suspension fluids. Surfactants may also be used, though pump speed should be adjusted to prevent excessive bubbling. Coulter 1B may comprise one or more of acetaldehyde, ethylene oxide, and/or 1,4-dioxane. The Beckman Device may be configured to use a variety of optical theories, including the Fraunhofer optical model and the Mie Theory.
- The Beckman Device may comprise software to control the Beckman Device while the ULM is in use. The software may control, for example, pump speed, use of de-bubble routine, rinse routine, sonicate routine, and fill routine, among others. Parameters regarding the sample run may also be configured. For example, run length may be set. Though any suitable run length may be used, in various embodiments, a time period of 30 seconds to 120 seconds, and preferably between 30 seconds and 90 seconds may be used.
- The Beckman Device may be used with the LS 13 320 Micro Liquid Module (“MLM”). The MLM is capable of suspending samples in the size range of 0.4 μm to 2000 μm. The MLM is a liquid based module that allows for delivery of the sample to the sensing zone. The MLM includes a stirrer. The total volume used may be 12 mL or less. The MLM may use a variety of suspension fluids, both aqueous and non-aqueous.
- Each of estradiol and progesterone as described herein can be formulated alone pursuant to the teachings below. These formulations can be prepared for oral administration or can be combined, based on compatibility, for co-administration of estradiol and progesterone in a single oral unit dosage form.
- Progesterone formulations of the present disclosure are prepared via blending with a pharmaceutically acceptable oil; generally, the oil comprises at least one medium chain fatty acid such as medium chain fatty acids consisting of at least one mono-, di-, or triglyceride, or derivatives thereof, or combinations thereof. Optionally added are other excipients including, for example and without limitation, anti-oxidants, lubricants and the like. Sufficient oil is used to form a suspension of micronized progesterone or, in the alternative, solubilize progesterone.
- Pharmaceutically acceptable oils include, without limitation, the use of at least one of caproic fatty acid; caprylic fatty acid; capric fatty acid; tauric acid; myristic acid; linoleic acid; succinic acid; glycerin; mono-, di-, or triglycerides and combinations and derivatives thereof; a polyethylene glycol; a polyethylene glycol glyceride (Gelucire®; GATTEFOSSE SAS, Saint-Priest, France); a propylene glycol; a caprylic/capric triglyceride (Miglyol®; SASOL Germany GMBH, Hamburg; Miglyol includes Miglyol 810, 812, 816 and 829); a caproic/caprylic/capric/lauric triglyceride; a caprylic/capric/linoleic triglyceride; a caprylic/capric/succinic triglyceride; propylene glycol monocaprylate; propylene glycol monocaprate; (Capmul® PG-8 and 10; the Capmul brands are owned by ABITEC, Columbus Ohio); propylene glycol dicaprylate; propylene glycol dicaprylate; medium chain mono- and di-glycerides (Capmul MCM); a diethylene glycol mono ester (including 2-(2-Ethoxyethoxyl)ethanol: Transcutol); diethylene glycol monoethyl ether; esters of saturated coconut and palm kernel oil and derivatives thereof; triglycerides of fractionated vegetable fatty acids, and combinations and derivatives thereof.
- In other aspects and embodiments, progesterone is fully solubilized using, for example and without limitation, sufficient amounts of: Transcutol and Miglyol; Transcutol, Miglyol and Capmul PG 8 and/or
PG 10; Capmul MCM; Capmul MCM and a non-ionic surfactant; and Capmul MCM and Gelucire. - Various ratios of these oils can be used for full solubilization of progesterone. Capmul MCM and a non-ionic surfactant, e.g., Gelucire 44/14, can be used at ratios of about 99:1 to 2:1, including, for example and without limitation: 60:40, 65:35, 70:30, 75:25, 80:10, 80:15, 85:20, 90:10, and 98:1. The ratios of oil (e.g., medium chain fatty acid esters of monoglycerides and diglycerides) to non-ionic surfactant can be significantly higher. For example, in certain examples, below, Capmul MCM and Gelucire were used in ratios of up to about 65:1, e.g., 8:1, 22:1, 49:1, 65:1 and 66:1. See, e.g., Tables 13-17, below. Thus, useful ratios can be 8:1 or greater, e.g., 60 to 70:1. Among other combinations, these oils and/or solubilizers, as defined herein, and combinations thereof, can be used to form combination estradiol and progesterone formulations of the present disclosure.
- Combinations of these oils can produce partially solubilized progesterone, depending upon the desired unit dosage amount of progesterone. The greater the amount of progesterone per unit dosage form, the less progesterone may be solubilized. The upward limit of dosage strength per unit dose it generally limited only by the practical size of the final dosage form.
- In illustrative embodiments of the invention, oils used to solubilize estradiol and to suspend, partially solubilize, or fully solubilize progesterone include medium chain fatty acid esters, (e.g., esters of glycerol, polyethylene glycol, or propylene glycol) and mixtures thereof. In illustrative embodiments, the medium chain fatty acids are C6 to C14 or C6 to C12 fatty acids. In illustrative embodiments, the medium chain fatty acids ore saturated, or predominantly saturated, e.g., greater than about 60% or greater than about 75% saturated. In illustrative embodiments, estradiol or progesterone (or both) is soluble in the oils at room temperature, although it may be desirable to warm the oils up until they are in a liquid state. In illustrative embodiments, the oil or oil/surfactant is liquid at between room temperature and about 50° C., e.g., at or below 50° C., at or below 40° C., or at or below 50° C. In illustrative embodiments, Gelucire 44/14 is heated to about 65° C. and Capmul MCM is heated to about 40° C. to facilitate mixing of the oil and non-surfactant, although such heating is not necessary to dissolve the estradiol or progesterone. In illustrative embodiments, the solubility of estradiol in the oil (or oil/surfactant) is at least about 0.5 wt %, e.g., 0.8 wt % or higher, or 1.0 wt % or higher.
- Illustrative examples of mono- and diglycerides of medium chain fatty acids include, among others, Capmul MCM, Capmul MCM C10, Capmul MCM C8, and Capmul MCM C8 EP. These oils are C8 and C10 fatty acid mono- and diglycerides.
- Illustrative examples of oils that are triglycerides of medium chain fatty acids include, among others, Miglyol 810 and Miglyol 812.
- Illustrative examples of oils that are medium chain fatty acid esters of propylene glycol include, among others, Capmul PG-8, Capmul PG-2L EP/NF, Capmul PG-8 NF, Capmul PG-12 EP/NF and Capryol. Other illustrative examples include Miglyol 840.
- Illustrative examples of oils that are medium chain fatty acid esters of polyethylene glycol include, among others, Gelucire 44/14 (PEG-32 glyceryl laurate EP), which is polyethylene glycol glycerides composed of mono-, di- and triglycerides and mono- and diesters of polyethylene glycol. Without intending to be bound to any particular mechanism, it appears that at least in formulations comprising small amounts of Gelucire, e.g., 10 wt % or less, the primary function of this oil is as a non-ionic surfactant.
- These illustrative examples comprise predominantly medium chain length, saturated, fatty acids, specifically predominantly C8 to C12 saturated fatty acids. Specifically, a product information sheet for Myglyol by SASOL provides as the composition of fatty acids as follows:
-
Tests 810 812 818 829 840 Caproic acid max. 2.0 max. 2.0 max. 2 max. 2 max. 2 (C6:0) Caprylic acid 65.0-80.0 50.0-65.0 45-65 45-55 65-80 (C8:0) Capric acid 20.0-35.0 30.0-45.0 30-45 30-40 20-35 (C10:0) Lauric acid max. 2 max. 2 max. 3 max. 3 max. 2 (C12:0) Myristic acid max. 1.0 max. 1.0 max. 1 max. 1 max. 1 (C14:0) Linoleic acid — — 2-5 — — (C18:2) Succinic acid — — — 15-20 — - It will be understood that oils are often mixtures. So, for example, when an oil is described herein as a saturated C8 fatty acid mono- or diester of glycerol, it will be understood that the predominant component of the oil, i.e., >50 wt % (e.g., >75 wt %, >85 wt % or >90 wt %) are caprylic monoglycerides and caprylic diglycerides. For example, the Technical Data Sheet by ABITEC for Capmul MCM C8 describes Capmul MCM C8 as being composed of mono and diglycerides of medium chain fatty acids (mainly caprylic) and describes the alkyl content as <=1% C6, >=95% C8, <=5% C10, and <=1.5% C12 and higher.
- Mixtures of medium chain fatty acid glycerides, e.g., C6-C12, C8-C12, or C8-C10 fatty acid mono- and diglycerides or mono-, di-, and triglycerides are very well suited for dissolving estradiol; good results have been obtained with an oil that is predominantly a mixture of C8-C10 saturated fatty acid mono- and diglycerides. Longer chain glycerides appear to be not as well suited for dissolution of estradiol. On the other hand, high solubility of progesterone has been obtained in mixtures that are predominantly medium chain fatty acid triglycerides.
- High solubility of estradiol has been obtained in 2-(2-Ethoxyethoxyl)ethanol, e.g., Transcutol and in Propylene glycol monocaprylate, e.g., Capryol™ 90 (Gattefosse).
- In illustrative embodiments of the invention, the selected oil does not require excessive heating in order to solubilize progesterone or estradiol. For example, when the formulation comprises medium chain fatty acid mono- and diglycerides (e.g., Capmul MCM) and polyethylene glycol glycerides (e.g., Gelucire) as a surfactant, the oil and/or the surfactant can be warmed up, e.g., to about 65° C. in the case of the surfactant and less in the case of the oil, to facilitate mixing of the oil and surfactant. The estradiol can be added at this temperature or at lower temperatures as the mixture cools or even after it has cooled as temperatures above room temperature, e.g., about 20° C., are not required to solubilize the estradiol in preferred oils. The progesterone can also be added as the mixture cools, e.g., to below about 40° C. or to below about 30° C., even down to room temperature.
- In various embodiments, estradiol is solubilized. Solubilized estradiol may include estradiol that is approximately: 90% soluble in a solvent; 93% soluble in a solvent; 95% soluble in a solvent; 97% soluble in a solvent; 99% soluble in a solvent; and 100% soluble in a solvent. Solubility may be expressed as a mass fraction (% w/w, also referred to as wt %).
- In various embodiments, the solubilizing agent is selected from at least one of a solvent or co-solvent. Suitable solvents and co-solvents include any mono-, di- or triglyceride and glycols, and combinations thereof.
- In addition to the oils referenced above for progesterone, which can also be used as solubilizers for estradiol, other solubilizers include, for example and without limitation, glyceryl mono- and di-caprylates, propylene glycol and 1,2,3-propanetriol (glycerol, glycerin, glycerine).
- Anionic and/or non-ionic surfactants can be used in other embodiments of the presently disclosed formulations containing estradiol, progesterone or a combination thereof. In certain embodiments, a non-ionic surfactant is used. Exemplary non-ionic surfactants may include, for example and without limitation, one or more of oleic acid, linoleic acid, palmitic acid, and stearic acid esters or alcohols. In further embodiments, the non-ionic surfactant may comprise polyethylene sorbitol esters, including
polysorbate 80, which is commercially available under thetrademark TWEEN 80® (Sigma Aldrich, St. Louis, Mo.).Polysorbate 80 comprises approximately 60%-70% oleic acid with the remainder comprising primarily linoleic acids, palmitic acids, and stearic acids.Polysorbate 80 may be used in amounts ranging from about 5 to 50%, and in certain embodiments, about 30% of the formulation total mass. - In various other embodiments, the non-ionic surfactant is selected from one or more of glycerol and polyethylene glycol esters of fatty acids, for example, lauroyl macrogol-32 glycerides and/or lauroyl polyoxyl-32 glycerides, commercially available as Gelucire, including, for example, Gelucire 44/11 and Gelucire 44/14. These surfactants may be used at concentrations greater than about 0.01%, and typically in various amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%. In certain examples, below, Gelucire 44/14 is used as a surfactant in amounts of 1 to 10 wt %. See, e.g., Tables 13-17, below. Other non-ionic surfactants include, e.g., Labrasol® PEG-8 Caprylic/Capric Glycerides (Gattefosse) and Labarafil® corn/apricot oil PEG-6 esters (Gattefosse).
- In other embodiments, a lubricant is used. Any suitable lubricant may be used, such as for example lecithin. Lecithin may comprise a mixture of phospholipids.
- In additional embodiments, an antioxidant is used. Any suitable anti-oxidant may be used such as, for example and without limitation, butylated hydroxytoluene.
- For example, in various embodiments, a pharmaceutical formulation comprises about 20% to about 80% carrier by weight, about 0.1% to about 5% lubricant by weight, and about 0.01% to about 0.1% antioxidant by weight.
- The choice of excipient will, to a large extent, depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Excipients used in various embodiments may include colorants, flavoring agents, preservatives and taste-masking agents. Colorants, for example, may comprise about 0.1% to about 2% by weight. Preservatives may comprise methyl and propyl paraben, for example, in a ratio of about 10:1, and at a proportion of about 0.005% and 0.05% by weight.
- As is with all oils, solubilizers, excipients and any other additives used in the formulations described herein, each is to be non-toxic and pharmaceutically acceptable.
- As referenced above, the formulations of the present disclosure are generally orally administered, typically via, for example, capsules such as soft capsules. The present formulations can also be used to form transdermal patches using standard technology known in the art. Solubilized formulations of the present invention can also be formulated for intraperitoneal administration using techniques well known in the art.
- In accordance with various embodiments, formulations do not include peanut oil. The lack of peanut oil obviates the risk posed to those having peanut-based allergies.
- Thus, an illustrative embodiment of a pharmaceutical composition of the invention comprises solubilized estradiol, progesterone at least 75% of the progesterone being solubilized (the balance being micronized as discussed elsewhere herein), and an oil, wherein the oil is medium chain fatty acid mono- and diesters of glycerol, with or without surfactant. In certain embodiments, a specification for progesterone is set at >80% solubilized, <20% micronized or >85% solubilized, <15% micronized. Specific examples of such illustrative embodiments, with Gelucire as surfactant, in which at least about 85% of the progesterone can be solubilized, include, e.g., the following four formulations:
-
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 50.00 Estradiol Hemihydrate 0.17 0.26 Capmul MCM, NF 65.49 98.24 Gelucire 44/14, NF 1.00 1.50 Total 100.00 150.00 -
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 50.00 Estradiol Hemihydrate 0.35 0.52 Capmul MCM, NF 65.32 97.98 Gelucire 44/14, NF 1.00 1.50 Total 100.00 150.00 -
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 100.00 Estradiol Hemihydrate 0.17 0.52 Capmul MCM, NF 65.49 196.48 Gelucire 44/14, NF 1.00 3.00 Total 100.00 300.00 -
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 100.00 Estradiol Hemihydrate 0.34 1.03 Capmul MCM, NF 65.32 195.97 Gelucire 44/14, NF 1.00 3.00 Total 100.00 300.00 -
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 33.33 200.00 Estradiol Hemihydrate 0.34 2.06 Capmul MCM, NF 65.32 391.94 Gelucire 44/14, NF 1.00 6.00 Total 100.00 600.00 - *Note: 1.00 mg Estradiol equivalent to 1.03 mg Estradiol Hemihydrate.
- In general terms, the above formulations comprise 30 to 35 wt % progesterone, 0.1 to 0.4 wt % estradiol (or estradiol hemihydrate), 55 to 75 wt % of an oil that is predominantly medium chain fatty acid mono- and diglycerides, such as Capmul MCM, and 0.5 to 10 wt % non-ionic surfactant, such as Gelucire 44/14. The above formulations may be modified to comprise excipients, e.g., gelatin such as
Gelatin 200 Bloom, glycerin, coloring agents such as Opatint red and white, and, optionally, Miglyol 812. - Estradiol solubilization helps ensure high content uniformity and enhanced stability. Fully solubilized progesterone formulations or partially solubilized progesterone formulations in which at least about 50% of the progesterone, e.g., 75%, 80%, 85%, 90%, or >95%, is solubilized appear to provide improved PK-related properties.
- According to various embodiments described herein, a 28-day or monthly regimen of capsules can be packaged in a single kit (e.g., a blister pack) having administration days identified to improve compliance and reduce associated symptoms, among others. One or more of the capsules may contain no estradiol, for example, and/or no progesterone. Capsules that comprise no estrogen or progesterone API may be referred to as placebos. A blister pack can have a plurality of scores or perforations separating blister pack into 28 days. Each day may further comprise a single blister or a plurality of blisters. In various embodiments, each unit dose may contain micronized and/or partially solubilized, or fully solubilized progesterone and/or solubilized estradiol in amounts as set forth herein above, although other dose ranges may be contemplated. In addition, kits having other configurations are also contemplated herein. For example, without limitation, kits having such blister packs may contain any number of capsules.
- Orally administered formulations of the present disclosure containing micronized and/or partially solubilized, or fully solubilized, progesterone are also used for the treatment of endometrial hyperplasia, secondary amenorrhea and other disease states treated with supplemental progesterone. Generally, progesterone-containing formulations described herein are used to treat the effects of the administration of supplemental estrogen whether administered alone or in combination with solubilized estradiol of the present disclosure or other estrogen-containing formulations. In various other embodiments, a capsule containing formulations of the present disclosure, for example a softgel capsule, may be applied in or around the vagina.
- Formulations of the present disclosure containing solubilized estradiol are used to treat Estrogen-deficient States, including vasomotor symptoms, for example, in relation to treatment of hypoestrogenism related symptoms including, for example and without limitation, hot flashes and night sweats (vasomotor symptoms), sleep disturbances, mood changes, vulvo-vaginal atrophy, and osteoporosis and other non-menopausal disease states treated with supplemental estrogen.
- Formulations of the present disclosure containing solubilized estradiol may be used to treat or prevent atrophic vaginitis or vulvo-vaginal atrophy. In various embodiments, a capsule, for example a softgel capsule, may be applied in or around the vagina.
- Additional objects of the present disclosure includes: providing increased patient compliance secondary to ease of use; providing increased physician adoption secondary to ease of use/instruction with less worry of side effects from inappropriate usage; providing decreased side-effects from erroneous use (decreased irregular bleeding); providing better efficacy/control of symptoms secondary to appropriate use; reducing the metabolic and vascular side effects of the commonly used synthetic progestins when administered alone or in combination with an estrogen (norethindrone acetate, medroxyprogesterone acetate, etc.) including, for example, stroke, heart attacks, blood clots and breast cancer.
- In various experiments, suitable solvents were determined for providing sufficient solubility to make 2 mg of estradiol in a 100 mg fill mass, with a desired goal of achieving ˜20 mg/g solubility for estradiol. Initial solubility experiments were done by mixing estradiol with various solvents, saturate the solution with the estradiol, equilibrate for at least 3 days and filter the un-dissolved particles and analyzing the clear supernatant for the amount of estradiol dissolved by HPLC.
- Estradiol solubility experiments were performed. From this list at least one item (e.g. propylene glycol) is known to be unsuitable for encapsulation.
-
TABLE 1 Ingredient Solubility (mg/g) PEG 400105* Propylene Glycol 75* Polysorbate 8036* Transcutol HP 141 Capmul PG8 31.2 *Literature reference -Salole, E. G. (1987) The Physicochemical Properties of Oestradiol, J Pharm and Biomed Analysis, 5, 635-640. - In further solubility studies, estradiol was soluble at at least 6 mg/gm Miglyol Transcutol in ratios of 81:19 to 95:5, in Miglyol; ethanol at 91:11, and in Miglyol:Capmul PG8 at 88:11, but not in Miglyol:Transcutol at 96:4, Miglyol:Labrasol at 70:30 to 80:20, or Miglyol:Capmul PG8 at 86:14.
- It was desired to achieve 50 mg of progesterone suspended in a medium that can also solubilize 2 mg estradiol in a total capsule fill mass of 200 mg. In order to achieve this formulation, the required solubility of estradiol needs to be ˜10 mg/g. A total fill weight of 200 mg was considered suitable for a
size 5 oval soft gelatin capsule. - Additional solubility studies were performed to find solvent mixtures that might possibly be more suitable for soft gelatin encapsulation. Solubility studies were conducted with Capmul PG8 and Capmul MCM by mixing estradiol with various solvent systems and as before by analyzing for the amount of estradiol dissolved by HPLC after filtration. Results of these experiments are presented in Table 2. It can be seen from these results that mixtures containing Miglyol:Capmul PG8 at 50%; and also Capmul MCM alone or in combination with 20
% Polysorbate 80 can achieve sufficient solubility to meet the target of 10 mg/g. Capmul PG8 mixed with Miglyol at the 15 and 30% level did not provide sufficient solubility. -
TABLE 2 Ingredient Solubility (mg/g) Miglyol:Capmul PG8 (85:15) 4.40 Miglyol:Capmul PG8 (70:30) 8.60 Transcutol:Miglyol 812:Capmul PG8 >12 (5:65:28) Transcutol:Miglyol 812:Capmul PG8 >12 (5:47:47) Miglyol:Capmul PG8 (50:50) 14.0 Capmul MCM 19.8 Polysorbate 80:Capmul MCM (20:80) 15.0 - Additional studies were performed to assess the stability of estradiol (4-6 mg) in solvent mixtures, as reported in Table 3. Miglyol 812 with 4% Transcutol precipitated on Hot/Cold cycling after 96 hours, while estradiol solubilized in Miglyol:Capmul blends at 30 and 50% or in Capmul MCM alone, did not precipitate under the same conditions for a minimum of 14 days.
-
TABLE 3 Estradiol Results Hot/Cold Formulation mg/g Cycling Transcutol:Miglyol 812 (4:96) 4 Crystallizes after 96 hours Miglyol 812:Capmul PG8 (70:30) 6 Clear, after 14 days Miglyol 812:Capmul PG8 (50:50) 6 Clear, after 14 days Transcutol:Miglyol 812: Capmul PG8 6 Clear, after 14 days (5:80:15) Capmul MCM 6 Clear after 14 days - 12 mg estradiol solubilized in Miglyol:Capmul PG8 50:50, Capmul MCM, and in mixtures of Transcutol:Miglyol:Capmul PG8 are stable and do not precipitate for at least 12 days.
-
TABLE 4 Estradiol Results Hot/Cold Formulation mg/g Cycling Miglyol 812:Capmul PG8 (50:50) 12 Clear, after 12 days Transcutol:Miglyol 812:Capmul PG8 12 Clear, after 12 days (5:65:28) Transcutol:Miglyol 812:Capmul PG8 12 Clear, after 12 days (5:47:47) Capmul MCM 12 Clear after 12 days - In addition to determining physical stability of the estradiol solutions over time, it is necessary to determine if the fill material will be stable during the encapsulation process. One way to test these preparations is with the addition of water to the fill mass. As can be seen in Table 5, estradiol solutions at a concentration of 6 mg/g in
Polyethylene Glycol 400 and Capmul MCM are able to absorb a minimum of 7% water without recrystallization, whereas the same concentration in Miglyol 812:Capmul PG8 (75:25) precipitates. - Estradiol solutions at a concentration of 12 mg/g in
Polyethylene Glycol 400 and Capmul MCM are able to absorb a minimum of 7% water without recrystallization. All Capmul PG8 containing formulations turned hazy on the addition of water. However, it should be noted that estradiol recrystallization was not observed, and the addition of water to Capmul PG 8 alone (without any estradiol) also turns hazy on the addition of water. -
TABLE 5 Estradiol Results after addition Formulation mg/g of 7% water Miglyol 812:Capmul PG8 (75:25) 6 Precipitated Miglyol 812:Capmul PG8 (50:50) 12 Hazy Transcutol:Miglyol 812:Capmul PG8 12 Hazy (5:65:28) Capmul MCM 12 Clear Transcutol:Miglyol 812:Capmul PG8 12 Hazy (5:47:47) Polyethylene Glycol 40012 clear - In an exemplary embodiment, a capsule is provided containing a fill material comprising:
-
TABLE 6 Mg/ Ingredient Capsule Estradiol Hemihydrate 2.00 Mono-, di- or triglyceride (Miglyol 812) qs Diethylene Glycol Monoethylether (Transcutol HP) 65.00 Liquid lecithin 1.63 Butylated Hydroxytoluene 0.13 Total Fill Weight 325 - In an exemplary embodiment, a capsule is provided containing a fill material comprising:
-
TABLE 7 Mg/ Ingredient Capsule Estradiol Hemihydrate 2.00 Monoglycerides/diglycerides/triglycerides of qs caprylic/capric acid (Capmul MCM) Liquid lecithin 1.63 Polysorbate 80 97.5 Total Fill Weight 325 - In an exemplary embodiment, a capsule is provided containing a fill material comprising:
-
TABLE 8 Mg/ Amount/ Ingredient Capsule % w/w Batch Estradiol Hemihydrate 2.03 0.62 20.2 g Monoglycerides/diglycerides/triglycerides 322.97 99.38 3.23 kg of caprylic/capric acid (Capmul MCM) Total 100 3.25 kg - The above formulation is prepared as follows: estradiol is added to Capmul MCM and mixed until dissolved.
- In various embodiments, both estradiol and progesterone may be dissolved in a solvent. In various embodiments, the solubility of both estradiol and progesterone will be such that a therapeutically effective dose may be obtained in a reasonably sized mass, generally considered to be between 1 mg and 1200 mg, preferably suitable for encapsulation in a
size 3 to 22 oval or oblong capsule. For example, in various embodiments, 50 mg to 100 mg of progesterone may be dissolved in a volume of solvent; i.e., the solubility would be 50 mg to 100 mg per capsule. Miglyol was attempted, and while it can be considered a good carrier for progesterone, it alone did not provide a desirable level of solubilization of estradiol (e.g., solubility of 12 mg/g may be desirable in various embodiments). Thus, Miglyol may be used in embodiments comprising a suspension of progesterone, though Miglyol, standing alone, is not desirable for use in embodiments having fully solubilized progesterone and/or estradiol. - As can be seen in Table 9, the solubility of progesterone in Capmul MCM is ˜73 mg/g. Therefore, by suspending 200 mg progesterone in 400 mg of solvent, part of the dose (˜14%) is already dissolved and the remaining is still a suspension. In some aspects and embodiments, it is desired to minimize the partial solubility of progesterone in the formulation in order to minimize the possibility of recrystalization.
- Based on 73 mg/g solubility, the capsule size required to make a capsule of 50 mg solubilized progesterone would be 685 mg. Therefore, it was shown that it would be feasible to make a 50 mg progesterone and 2 mg estradiol solubilized formulation. Myglyol had the lowest solubility, but that solvent is unable to dissolve the estradiol, therefore under further experiments, it was decided to proceed with the second lowest or Capmul MCM. It has also been found that 2 mg of estradiol may also be dissolved in 685 mg of Capmul MCM.
-
TABLE 9 Progesterone Solubility Ingredient (mg/g) Capmul MCM 73.4 Capmul PG8 95 Miglyol 812 27.8 CapmulMCM:Gelucire 44/14 (9:1) 86.4 CapmulMCM:Gelucire 44/14 (7:3) 70.5 CapmulMCM:Gelucire 44/14 (6:3) 57.4 - In addition, it has been found that the solubility of progesterone in a solvent of Capmul MCM in combination with Gelucire 44/14 in a 9:1 ratio increases the solubility to approximately 86 mg/g. Therefore, in various embodiments, progesterone and/or estradiol may be dissolved in a Capmul MCM and Gelucire 44/14 system, wherein the ratio of Capmul MCM to Gelucire 44/14 is 9:1.
-
TABLE 10 Progesterone Solubility Ingredient (mg/g) Capmul MCM:Gelucire 44/14 (9:1) 86.4 Capmul MCM:Gelucire 44/14 (7:3) 70.5 Capmul MCM:Gelucire 44/14 (6:4) 57.4 - In an exemplary embodiment, a capsule is provided containing a fill material having fully solubilized progesterone and estradiol comprising:
-
TABLE 11 Qty/Capsule Ingredient Mass (mg) % w/w (mg) Progesterone, USP, micronized 50.00 7.14 50.00 Estradiol Hemihydrate, USP 2.03 0.29 2.03 Capmul MCM, NF 82.57 577.97 Gelucire 44/14, NF 10.0 70.00 TOTAL 100.00 700.00 - A capsule such as that shown in TABLE 11 may be manufactured in any suitable manner. For the purposes of this Example, mixing may be facilitated by an impellor, agitator, or other suitable means. Also for the purposes of this Example, heating and/or mixing may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Mixing and/or heating for the purposes of this Example may be performed in any suitable vessel, such as a stainless steel vessel.
- For example, Campul MCM may be heated to between 30° C. to 50° C., more preferably from 35° C. to 45° C., and more preferably to 40° C.±2° C. Gelucire 44/14 may be added to the Campul MCM and mixed until dissolved. The addition may occur all at once or may occur gradually over a period of time. Heat may continue to be applied during the mixing of the Gelucire 44/14 and the Campul MCM.
- Heat may be removed from the Gelucire 44/14 and Campul MCM mixture. Estradiol Hemihydrate may be added to the mixture. The addition may occur all at once or may occur gradually over a period of time. Micronized progesterone may then be added to the Gelucire 44/14, Campul MCM and Estradiol Hemihydrate mixture until dissolved. The addition may occur all at once or may occur gradually over a period of time.
- In an exemplary embodiment, a capsule is provided containing a fill material having suspended progesterone comprising:
-
TABLE 12 mg/ Ingredient Capsule % Function Micronized Progesterone 200.00 30.77 Active Medium Chain Triglyceride qs qs Carrier (MIGLYOL 812 or equivalent) Lecithin Liquid 1.63 0.25 Lubricant/Emulsifier Butylated Hydroxytoluene 0.13 0.02 Antioxidant (also referred to as “BHT”) - The above formulation is prepared as follows: MIGLYOL is heated to about 45° C. GELUCIRE 44/14 is added and mixed until dissolved. BHT is added and mixed until dissolved. Progesterone is suspended and passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- In an exemplary embodiment, a capsule is provided containing a fill material having partially solubilized progesterone comprising:
-
TABLE 13 Qty/ Qty/ Amount/ Capsule Capsule Batch Ingredient (mg) % w/w (mg) (kg) Micronized Progesterone, 200.00 33.33 Active 2.0 USP Monoglycerides/diglyc- 394.0 65.67 Carrier 3.94 erides/triglycerides of caprylic/capric acid (Capmul MCM) Lauroyl polyoxyl-32- 6.0 1 Lubricant/ 0.06 glycerides (Gelucire 44/14 Emulsifier or equivalent) Total 600.00 mg 100 6.0 kg - For suspensions of progesterone and partially solubilized progesterone, GELUCIRE 44/14 may be added at 1% to 2% w/w to increase viscosity. The above formulation is prepared as follows: Capmul MCM is heated to about 65° C. GELUCIRE 44/14 is added and mixed until dissolved. Heat is removed. Progesterone is added and the mixture is passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- In an exemplary embodiment, a capsule is provided containing a fill material having suspended progesterone comprising:
-
TABLE 14 mg/ Ingredient % Capsule Function Micronized Progesterone 30.77 200.00 Active Medium Chain Triglyceride 65.93 428.55 Carrier (MIGLYOL 812 or equivalent) Lauroyl polyoxyl-32-glycerides 3.00 19.50 Suspending Agent (Gelucire 44/14 or equivalent) Butylated Hydroxytoluene 0.03 1.95 Antioxidant Total 100 650 - In various embodiments, amounts of MIGLYOL may be present in a range from about 35-95% by weight; GELUCIRE 44/14 from about 0.5-30% by weight; and BHT from about 0.01-0.1% by weight.
- For the purposes of this Example, a particle size analysis is conducted by using the Beckman Device. A sample API comprising micronized progesterone in accordance with various embodiments is provided for analysis.
- Approximately 0.01 g of a sample API in accordance with various embodiments was combined with
Coulter 1B and 10 mL of deionized water. Sonication was performed for 15 seconds. The Beckman Device, equipped with a ULM, performed analysis for 90 seconds. The Beckman Device was configured to use the Fraunhofer optical model. The Beckman Device yielded that the sample has an X50 of 4.279 μm, an X75 of 7.442 μm, and an X25 of 1.590 μm. The Beckman Device also yielded that the mean particle size is 4.975 μm, the median particle size is 4.279 μm, the mode particle size is 6.453 μm, and the standard deviation is 3.956 μm. A graph of the particle distribution obtained is shown inFIG. 4 . - A formulation sample having approximately 200 mg of micronized progesterone and 2 mg of estradiol was dispersed with oil. The Beckman Device, equipped with a MLM, performed analysis for 60 seconds. The Beckman Device was configured to use the Fraunhofer optical model. The Beckman Device yielded that the sample has an X50 of 11.0 μm, an X75 of 17.3 μm, and an X25 of 5.3 μm. The Beckman Device also yielded that the mean particle size is 11.8 μm, the median particle size is 11.04 μm, the mode particle size is 13.6 μm, and the standard deviation is 7.8 μm.
- In order to increase the solubility of progesterone in the final solution, Gelucire 44/14 was added at about 10% w/w.
-
TABLE 15 Quantitative Formula: Batch Size 10,000 capsules Label Qty/ Amount/ Item Claim Capsule Batch No. Ingredient(s) (mg) % w/w (mg) (kg) 1. Progesterone, USP, 50.00 7.14 50.00 0.50 micronized 2. Estradiol Hemihydrate, 2.03 0.29 2.03 0.02 USP 3. Capmul MCM, NF 82.57 577.97 5.78 4. Gelucire 44/14, NF 10.0 70.00 0.70 Total: 100.00 700.00 7.00 - An example of the final formulation is provided in Table 15. The manufacturing process is as follows. Capmul MCM is heated to 40° C. Gelucire 44/14 is heated to 65° C. and added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and mixed until dissolved.
- In an exemplary embodiment, a capsule is provided containing a fill material having fully solubilized estradiol and partially solubilized progesterone comprising:
-
TABLE 16 Label Qty/ Amount/ Item Claim Capsule Batch No. Ingredient(s) (mg) % w/w (mg) (g) 1. Progesterone, USP, 50.00 25.000 50.00 500.00 micronized 2. Estradiol Hemihydrate 0.25 0.129 0.26 2.58 3. Capmul MCM, NF 73.371 146.74 1467.42 4. Gelucire 44/14, NF 1.500 3.00 30.00 Total: 100.000 200.00 mg 2000.00 - The manufacturing process is as follows. Capmul MCM is heated to 65° C. Gelucire 44/14 is added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resultant fill mass can be used for encapsulation.
- In an exemplary embodiment, a capsule is provided containing a fill material having fully solubilized estradiol and partially solubilized progesterone comprising:
-
TABLE 17 Label Qty/ Amount/ Item Claim Capsule Batch No. Ingredient(s) (mg) % w/w (mg) (g) 1. Progesterone, USP, 200.00 33.33 200.0 2000.0 micronized 2. Estradiol Hemihydrate 2.00 0.35 2.07 20.7 3. Capmul MCM, NF 65.32 391.93 3919.3 4. Gelucire 44/14, NF 1.00 6.0 60.0 Total: 100.00 600.0 mg 6000.0 - The manufacturing process is as follows. Capmul MCM is heated to 65° C. Gelucire 44/14 is added and mixed until dissolved. Heat is removed. Estradiol is added and mixed until dissolved. Micronized progesterone is then added and dispersed. The mixture is then passed through a colloid mill. The resultant fill mass can be used for encapsulation. Alternatively, Gelucire 44/14 is heated to 65° C. and Capmul MCM is heated to 40° C.±5° C. to achieve mixing of the oil and the surfactant before heat is removed; estradiol is added while the mixture is cooling; progesterone is added when the mixture has dropped below about 40° C.; the mixture is then passed through a colloid mill, e.g., three times.
- Study 352—Progesterone and Estradiol Combination Study under Fed Conditions.
- This following study protocol was used to establish bio-availability and bio-equivalence parameters for a combination product of the present disclosure comprising progesterone (200 mg) and estradiol (2.0 mg) as prepared via the process described in Example 14 and compared to 200 mg of PROMETRIUM® (Catalent Pharmaceuticals, St. Petersburg, Fla. (and 2.0 mg of ESTRACE® (Bristol-Myers Squibb Co. Princeton, N.J.), administered to twenty-four (24) normal healthy, adult human post-menopausal female subjects under fed conditions.
- The pharmaceutical formulation of the invention used in these PK studies had substantially the following formula:
-
Amount Qty/Capsule Ingredient(s) (% w/w) (mg) Progesterone, USP, micronized 7.14 50.00 Estradiol Hemihydrate, USP Micronized 0.30 2.07 Capmul MCM, NF, USP 83.27 582.93 Gelucire 44/14, NF 9.29 650 Total 100.00 700 - The Study Design: An open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, two-way crossover study.
- The subjects were housed in the clinical facility from at least 11.00 hours pre-dose to at least 48.00 hours post-dose in each period, with a washout period of at least 14 days between the successive dosing days.
- Subjects were fasted for at least about 10.00 hours before being served a high-fat, high-calorie breakfast, followed by dosing, then followed by a 04.00 hour, post-dose additional period of fasting.
- Standard meals were provided at about 04.00, 09.00, 13.00, 25.00, 29.00, 34.00 and 38.00 hours post-dose, respectively.
- Water was restricted at least about 01 hour prior to dosing until about 01 hour post-dose (except for water given during dosing). At other times, drinking water was provided ad libitum.
- Subjects were instructed to abstain from consuming caffeine and/or xanthine containing products (i.e. coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least about 24.00 hours prior to dosing and throughout the study, grapefruit and\or its juice and poppy containing foods for at least about 48.00 hours prior to dosing and throughout the study.
- Subjects remained seated upright for about the first 04.00 hours post-dose, and only necessary movements were allowed during this period. Thereafter, subjects were allowed to ambulate freely during the remaining part of the study. Subjects were not allowed to lie down (except as directed by the physician secondary to adverse events) during restriction period.
- Subjects were instructed not to take any prescription medications within 14 days prior to study check in and throughout the study. Subjects were instructed not to take any over the counter medicinal products, herbal medications, etc., within 7 days prior to study check-in and throughout the study.
- After overnight fasting of at least about 10.00 hours, a high-fat high-calorie breakfast was served about 30 minutes prior to administration of investigational product(s). All subjects were required to consume their entire breakfast within about 30 minutes of it being served, a single dose of either test product (T) of
Progesterone 200 mg &Estradiol 2 mg tablets or the reference product (R) PROMETRIUM® (Progesterone)soft gel Capsule 200 mg and ESTRACE® (Estradiol)Tablets 2 mg (according to the randomization schedule) were administered with about 240 mL of water under fed condition, at ambient temperature in each period in sitting posture. A thorough mouth check was done to assess the compliance to dosing. - All dosed study subjects were assessed for laboratory tests at the end of the study or as applicable.
- In each period, twenty-three (23) blood samples were collected. The pre-dose (10 mL) blood samples at −01.00, −00.50, 00.00 hours and the post-dose blood samples (08 mL each) were collected at 00.25, 00.50, 00.67, 00.83, 01.00, 01.33, 01.67, 02.00, 02.50, 03.00, 04.00, 05.00, 06.00, 07.00, 08.00, 10.00, 12.00, 18.00, 24.00 and 48.00 hours in labeled K2EDTA—vacutainers via an indwelling cannula placed in one of the forearm veins of the subjects. Each intravenous indwelling cannula was kept in situ as long as possible by injecting about 0.5 mL of 10 IU/mL of heparin in normal saline solution to maintain the cannula for collection of the post-dose samples. In such cases blood samples were collected after discarding the first 0.5 mL of heparin containing blood. Each cannula was removed after the 24.00 hour sample was drawn or earlier or if blocked.
- At the end of the study, the samples were transferred to the bio-analytical facility in a box containing sufficient dry ice to maintain the integrity of the samples. These samples were stored at a temperature of −70° C.±20° C. in the bio-analytical facility until analysis.
- Progesterone (Corrected and Uncorrected) and Estradiol (unconjugated) and estrone (total) in plasma samples is assayed using a validated LC-MS/MS method.
- The pharmacokinetic parameters Cmax, AUC0-t & AUC0-∞ were calculated on data obtained from 24 subjects for the test product and reference product. In general, bioavailability of progesterone and estradiol were similar but bioequivalence was not established.
- Corrected pharmacokinetic profile summaries are presented in Table 18, below, for progesterone.
-
TABLE 18 SUMMARY OF PRIMARY PHARMACOKINETIC PROFILE OF TEST PRODUCT (T) VERSUS REFERENCE PRODUCT (R) FOR PROGESTERONE (CORRECTED) Arithmetic Mean ± Standard Geometric Mean* Deviation Test Reference Test Reference Pharmacokinetic Product Product Product Product Parameter (T) (R) (T) (R) Cmax 47.0 43.0 81.0 ± 82.8 117.7 ± 173.7 AUC0-t 107.6 97.8 163.9 ± 136.5 191.1 ± 241.7 AUC0-∞ 110.7 110.0 173.5 ± 143.0 207.1 ± 250.3 *Estimate of Least Square Mean used to calculate Geometric Mean - Study 351—Progesterone and Estradiol Combination Study under Fasting Conditions.
- Fasted studies using the above protocol and test and reference products were also conducted. However, rather than the high-fat meal prior to administration of the test and reference drug, each subject fasted for a period of at least twelve (12) hours prior to dose administration.
- The pharmacokinetic parameters Cmax, AUC0-t & AUC0-∞ were calculated on data obtained from 23 subjects under fasting conditions for the test product and reference product. In general, bioavailability of progesterone and estradiol were similar, but bioequivalence was not established.
- Corrected pharmacokinetic profile summaries are presented in Table 19, below for progesterone.
-
TABLE 19 SUMMARY OF PRIMARY PHARMACOKINETIC PROFILE OF TEST PRODUCT (T) VERSUS REFERENCE PRODUCT (R) FOR PROGESTERONE (CORRECTED) Arithmetic Mean ± Standard Geometric Mean* Deviation Test Reference Test Reference Pharmacokinetic Product Product Product Product Parameter (T) (R) (T) (R) Cmax 2.3 3.0 2.9 ± 2.3 3.9 ± 3.4 AUC0-t 8.4 10.9 11.2 ± 8.7 14.5 ± 11.0 AUC0-∞ 12.9 17.2 15.1 ± 9.0 19.6 ± 10.2 *Estimate of Least Square Mean used to calculate Geometric Mean - The data indicate good (i.e., low) inter-patient and intra-patient variability relative to Prometrium.
- Method of manufacture in accordance with various embodiments are shown in
FIGS. 1-3 . With reference toFIG. 1 , method offill material 100 is shown. Step 102 comprises heating an oily vehicle carrier to 40° C.±5° C. Heating may be accomplished through any suitable means. The heating may be performed in any suitable vessel, such as a stainless steel vessel. The oily vehicle may be any oily vehicle described herein, for example, Capmul MCM. - Step 104 comprises mixing Gelucire 44/14 with the oily vehicle. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 102 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Mixing may be performed in any suitable vessel, such as a stainless steel vessel.
- Step 106 comprises mixing estradiol into the mixture of the oily vehicle and Gelucire 44/14. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 106 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2.
- Step 108 comprises cooling to room temperature. Cooling may be allowed to occur without intervention or cooling may be aided by application of a cooling system.
- Step 110 comprises mixing micronized progesterone into the mixture of oily vehicle, estradiol and Gelucire 44/14. Mixing may occur in a steel tank or vat. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 110 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Step 112 comprises degasing. The resulting mixture from
step 112 may comprise a fill material suitable for production into a softgel capsule. - With reference to
FIG. 2 , softgel capsule, i.e., gel mass,production 200 is shown. Step 202 comprises mixing glyercin with water. The water used instep 202 may be purified by any suitable means, such as reverse osmosis, ozonation, filtration (e.g., through a carbon column), or the like. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 202 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Heating may be performed until the temperature reaches 80° C.±5° C. - Step 204 comprises the addition of gelatin to the glycerin water mixture. Mixing may be facilitated by an impellor, agitator, or other suitable means. Step 204 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. A vacuum may be drawn in
step 204 to de-aerate. - Step 206 comprises addition of a coloring agent such as a dye. A coloring agent may comprise products sold under the trademark OPATINT or other suitable agent. Step 206 may be performed under an inert or relatively inert gas atmosphere, such as nitrogen gas N2. Step 208 comprises degasing. The resulting mixture from
step 208 may comprise a gel capsule material suitable for use as a gel capsule in production of a softgel capsule. - With reference to
FIG. 3 , softgelcapsule assembly process 300 is shown. Step 302 comprises heating the fill material. The fill material may be heated to any suitable temperature. In various embodiments, the fill material is heated to 30° C.±3° C. Fill material maybe heated in a fill hopper. A fill hopper may comprise a device configured to hold a volume of the fill material and/or to dispense the fill material in controlled volumes. - Step 304 comprises filling a gel mass. A gel mass may be taken from the gel capsule material produced in
step 208 ofFIG. 2 . Filling may be performed by injecting, placing, or otherwise disposing the fill material within a volume defined by the gel capsule material. The filling may occur in an encapsulator. The spreader boxes may be a temperature of 55° C.±10° C. The wedge temperature may be 38° C.±3° C. The drum cooling temperature may be 4° C.±2° C. The encapsulator may be lubricated using MIGLYOL 812 or other suitable lubricant. Step 304 thus produces one or more softgel capsules. Filling may comprise producing a ribbon of thickness 0.85 mm±0.05 mm using spreader box knobs. The fill material may be injected into the gel to produce a fill weight having target weight±5% (i.e., 650±33 mg and 325±16.3 mg). - Step 306 comprises drying the softgel capsules. Drying may be performed in a tumble dryer, tray dryer, or combinations thereof. For example, drying may be performed in a tumble drying basket for between about 10 minutes and about 120 minutes. Drying may continue in a drying room for about 24 hours to about 72 hours. Step 308 may comprise inspection and/or polishing. Polishing may be performed with isopropyl alcohol. Step 310 may comprise packaging. Packaging may be accomplished through any suitable means. Packaging may comprise packing softgel capsules into a blister pack, bottle, box, pouch, or other acceptable packaging.
- Data was obtained visually by making the mixtures described below, sonicating the mixtures, and then seeing if a clear solution resulted. If a clear solution was achieved, it was an indication of solubility at the level studied.
- Procedures and Results:
-
Step 1. - 0.3% of Estradiol suspension in each oil was prepared by adding 30 mg Estradiol to solvent and QS to 10 g. Samples were mixed on vortex for 2 hours, heated @ 50° C. for 30 minutes and then mixed for 1 hour more. All samples were still in suspension form.
-
Step 2. - Each sample was diluted to 0.24% (by adding 2.5 g more oil) and mixed for 2 hours and heated @ 50° C. for 30 min and mixed again for one hour. All the samples were still cloudy. Samples were kept at room temperature overnight to see if they precipitate or if undissolved API settles out. After 20 hours at room temperature, it was observed that all samples still had undissolved API.
-
Step 3. - Each sample was diluted to 0.2% (by adding 2.5 g more oil) and mixed 2 for hours and heated @ 50° C. for 30 min and mixed again for one hour. All the samples were still slightly cloudy, indicating that the estradiol was not completely dissolved.
-
TABLE 20 Estradiol Solubility Estradiol Solubility Ingredient (mg/g) (% w/w) Peanut Oil <2 <0.2 Safflower Oil <2 <0.2 Soy Bean Oil <2 <0.2 - The solubility of estradiol in all three oils was less than 2 mg/g (0.2% w/w). This level of solubility is significantly below the solubility that the present inventors have discovered can be achieved in other oils, e.g., medium chain fatty acid esters, such as the mono/diglycerides, propylene glycol esters, and polyethylene glycol esters discussed above.
- In sum, if no heat is used to dissolve estradiol in safflower oil, it will not go into solution. Given that the estradiol did not dissolve at 50° C., oils such as safflower oil will not be useful in the methods of the invention using medium chain fatty acid esters as described hereinabove.
- Dissolution studies were performed using a formulation of this invention comparing the dissolution of progesterone to the dissolution of Prometrium and comparing the dissolution of estradiol to the dissolution of Estrace. In one study, a formulation of the invention in capsules comprising 200 mg of progesterone and 2 mg estradiol was used. In a second study, a formulation of the invention in capsules comprising 50 mg of progesterone and 2 mg estradiol was used. The two formulations comprised:
- The dissolution study was performed using a USP dissolution apparatus (reciprocating cylinder) (“
USP Apparatus 3”). The apparatus was set to 30 dips per minute. 250 mL of a solution of 0.1 NHCl with 3% sodium lauryl sulfate was used at 37° C. - In both studies, progesterone was dissolved faster, and with smaller standard deviations, from the capsules of the invention than from Prometrium. Dissolution of estradiol was comparable but marginally slower from the capsules of the invention than from Estrace. For illustrative purposes, a graph showing progestrone dissolution from the 200 mg progesterone capsule of the invention and from Prometrium is attached as
FIG. 5 . - Both capsules of the invention were stable on storage in white HDPE bottles. Positive stability data were obtained with the 200 mg progesterone formulation over 6 months (>6 months data unavailable) and with the 50 mg progesterone formulation over 3 months (>3 months data unavailable).
- It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.
- Likewise, numerous characteristics and advantages have been set forth in the preceding description, including various alternatives together with details of the structure and function of the devices and/or methods. This disclosure is intended as illustrative only and as such is not intended to be exhaustive. It will be evident to those skilled in the art that various modifications may be made, especially in matters of structure, materials, elements, components, shape, size and arrangement of parts including combinations within the principles of the disclosure, to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed. To the extent that these various modifications do not depart from the spirit and scope of the appended claims, they are intended to be encompassed therein.
Claims (12)
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/690,955 US20150224118A1 (en) | 2012-06-18 | 2015-04-20 | Natural combination hormone replacement formulations and therapies |
US15/999,040 US11166963B2 (en) | 2012-06-18 | 2018-08-16 | Natural combination hormone replacement formulations and therapies |
US16/520,167 US11529360B2 (en) | 2012-06-18 | 2019-07-23 | Natural combination hormone replacement formulations and therapies |
US16/885,066 US11110099B2 (en) | 2012-06-18 | 2020-05-27 | Natural combination hormone replacement formulations and therapies |
US18/053,120 US20230218636A1 (en) | 2012-06-18 | 2022-11-07 | Natural Combination Hormone Replacement Formulations and Therapies |
US18/077,212 US20230302015A1 (en) | 2012-11-21 | 2022-12-07 | Natural combination hormone replacement formulations and therapies |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261661302P | 2012-06-18 | 2012-06-18 | |
US201261662265P | 2012-06-20 | 2012-06-20 | |
US13/684,002 US8633178B2 (en) | 2011-11-23 | 2012-11-21 | Natural combination hormone replacement formulations and therapies |
US13/843,428 US9301920B2 (en) | 2012-06-18 | 2013-03-15 | Natural combination hormone replacement formulations and therapies |
US14/099,582 US9012434B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/690,955 US20150224118A1 (en) | 2012-06-18 | 2015-04-20 | Natural combination hormone replacement formulations and therapies |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/099,582 Division US9012434B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/999,040 Continuation US11166963B2 (en) | 2012-06-18 | 2018-08-16 | Natural combination hormone replacement formulations and therapies |
Publications (1)
Publication Number | Publication Date |
---|---|
US20150224118A1 true US20150224118A1 (en) | 2015-08-13 |
Family
ID=49756456
Family Applications (13)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/843,428 Active 2033-06-10 US9301920B2 (en) | 2011-11-23 | 2013-03-15 | Natural combination hormone replacement formulations and therapies |
US14/649,818 Abandoned US20150359737A1 (en) | 2012-06-18 | 2013-06-18 | Soluble estradiol capsule for vaginal insertion |
US14/099,598 Active US8987238B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,582 Active US9012434B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,623 Active US9006222B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,612 Active US8933059B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/690,955 Abandoned US20150224118A1 (en) | 2012-06-18 | 2015-04-20 | Natural combination hormone replacement formulations and therapies |
US14/690,913 Abandoned US20150224117A1 (en) | 2012-06-18 | 2015-04-20 | Natural combination hormone replacement formulations and therapies |
US15/090,493 Active US10675288B2 (en) | 2011-11-23 | 2016-04-04 | Natural combination hormone replacement formulations and therapies |
US15/999,040 Active 2033-02-10 US11166963B2 (en) | 2012-06-18 | 2018-08-16 | Natural combination hormone replacement formulations and therapies |
US16/520,167 Active 2033-05-09 US11529360B2 (en) | 2012-06-18 | 2019-07-23 | Natural combination hormone replacement formulations and therapies |
US16/885,066 Active US11110099B2 (en) | 2012-06-18 | 2020-05-27 | Natural combination hormone replacement formulations and therapies |
US18/053,120 Pending US20230218636A1 (en) | 2012-06-18 | 2022-11-07 | Natural Combination Hormone Replacement Formulations and Therapies |
Family Applications Before (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/843,428 Active 2033-06-10 US9301920B2 (en) | 2011-11-23 | 2013-03-15 | Natural combination hormone replacement formulations and therapies |
US14/649,818 Abandoned US20150359737A1 (en) | 2012-06-18 | 2013-06-18 | Soluble estradiol capsule for vaginal insertion |
US14/099,598 Active US8987238B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,582 Active US9012434B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,623 Active US9006222B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
US14/099,612 Active US8933059B2 (en) | 2012-06-18 | 2013-12-06 | Natural combination hormone replacement formulations and therapies |
Family Applications After (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/690,913 Abandoned US20150224117A1 (en) | 2012-06-18 | 2015-04-20 | Natural combination hormone replacement formulations and therapies |
US15/090,493 Active US10675288B2 (en) | 2011-11-23 | 2016-04-04 | Natural combination hormone replacement formulations and therapies |
US15/999,040 Active 2033-02-10 US11166963B2 (en) | 2012-06-18 | 2018-08-16 | Natural combination hormone replacement formulations and therapies |
US16/520,167 Active 2033-05-09 US11529360B2 (en) | 2012-06-18 | 2019-07-23 | Natural combination hormone replacement formulations and therapies |
US16/885,066 Active US11110099B2 (en) | 2012-06-18 | 2020-05-27 | Natural combination hormone replacement formulations and therapies |
US18/053,120 Pending US20230218636A1 (en) | 2012-06-18 | 2022-11-07 | Natural Combination Hormone Replacement Formulations and Therapies |
Country Status (12)
Country | Link |
---|---|
US (13) | US9301920B2 (en) |
EP (2) | EP2861072B1 (en) |
JP (3) | JP6334519B2 (en) |
KR (5) | KR20220080205A (en) |
AU (4) | AU2013277236B2 (en) |
CA (1) | CA2876977A1 (en) |
IL (1) | IL236358B (en) |
MX (2) | MX2014015898A (en) |
PL (1) | PL2861072T3 (en) |
PT (1) | PT2861072T (en) |
RU (2) | RU2015100533A (en) |
WO (1) | WO2013192251A1 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017173191A1 (en) * | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
US10206932B2 (en) | 2014-05-22 | 2019-02-19 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10258630B2 (en) | 2014-10-22 | 2019-04-16 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10675288B2 (en) | 2011-11-23 | 2020-06-09 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10888516B2 (en) | 2012-12-21 | 2021-01-12 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US11103516B2 (en) | 2011-11-23 | 2021-08-31 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
JP6397402B2 (en) * | 2012-06-18 | 2018-09-26 | セラピューティックスエムディー インコーポレーテッドTherapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
MX2016011706A (en) * | 2014-03-28 | 2017-05-01 | Therapeuticsmd Inc | Progesterone formulations. |
AU2015296609A1 (en) | 2014-07-29 | 2016-12-22 | Therapeuticsmd, Inc. | Transdermal cream |
US10467382B2 (en) * | 2014-11-14 | 2019-11-05 | Brazen Incorporated | Conceivable basal body temperatures and menstrual cycle |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
BR112018070199A2 (en) | 2016-04-01 | 2019-01-29 | Therapeuticsmd Inc | pharmaceutical composition of steroid hormone |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
RU2019115913A (en) * | 2016-12-05 | 2021-01-15 | Терапьютиксмд, Инк. | NATURAL COMBINED HORMONE REPLACEMENT FORMULATIONS AND METHODS OF THERAPY |
US20180280410A1 (en) * | 2017-04-03 | 2018-10-04 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10285998B1 (en) | 2018-04-04 | 2019-05-14 | The Menopause Method, Inc. | Composition and method to aid in hormone replacement therapy |
JP2022100558A (en) | 2020-12-24 | 2022-07-06 | 日本碍子株式会社 | Honeycomb filter |
US11298375B2 (en) * | 2021-10-12 | 2022-04-12 | Terry Earl Brady | Halogenated fullerene functionalized as a biocidal and chemotactic spermicide to vaginally harbor and neutralize spermatozoa for use as a safe and effective contraceptive |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8633178B2 (en) * | 2011-11-23 | 2014-01-21 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8933059B2 (en) * | 2012-06-18 | 2015-01-13 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9180091B2 (en) * | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
Family Cites Families (1169)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1967351A (en) | 1930-10-06 | 1934-07-24 | President And Board | Hormone and process of obtaining the same |
US2232438A (en) | 1934-08-04 | 1941-02-18 | Schering Corp | Unsaturated pregnanolones and pregnandiones and a method of producing the same |
GB452238A (en) | 1934-08-24 | 1936-08-19 | Chem Ind Basel | Process for purifying progesterone preparations |
US2379832A (en) | 1936-06-02 | 1945-07-03 | Schering Corp | Process for the manufacture of unsaturated ketones of the cyclopentano polyhydro phenanthrene series |
US2649399A (en) | 1951-02-01 | 1953-08-18 | Ayerst Mckenna & Harrison | Conjugated oestrogenic quaternary ammonium salts and their preparation |
GB720561A (en) | 1952-04-17 | 1954-12-22 | Frederick Victor Wells | Improvements in preparations for application to the hair and scalp |
GB848881A (en) | 1955-12-27 | 1960-09-21 | Upjohn Co | Improvements in or relating to hormone compositions and the preparation thereof |
GB874368A (en) | 1957-12-09 | 1961-08-02 | Irwin Irville Lubowe | Improvements in anti-seborrheic and scalp preparations |
FR1368727A (en) | 1961-05-04 | 1964-08-07 | Roussel Uclaf | Estradiol derivatives and method of preparation |
US3916898A (en) | 1964-05-20 | 1975-11-04 | Searle & Co | Administration of medicaments and the like |
US3755575A (en) | 1965-01-26 | 1973-08-28 | Squibb & Sons Inc | Pharmaceutical compositions |
FR5519M (en) | 1966-06-07 | 1967-11-06 | ||
US3478070A (en) | 1967-12-26 | 1969-11-11 | American Home Prod | Process for selectively acylating the 3-ol group in polyhydroxy 13-alkyl gona-(and 8 - isogona) - 1,3,5 - (10) - trienes and delta - 7 -,delta - 8(9),delta - 9(11) -,and delta - 8(9),14(15) - dehydro derivatives thereof |
GB1261348A (en) | 1968-04-02 | 1972-01-26 | Leo Ab | Treatment of hair and scalp and compositions therefor |
US3755573A (en) | 1970-07-10 | 1973-08-28 | Warner Lambert Co | Fertility control empoying quinestrol and quingestanol acetate |
US3710795A (en) | 1970-09-29 | 1973-01-16 | Alza Corp | Drug-delivery device with stretched, rate-controlling membrane |
US3903880A (en) | 1972-08-17 | 1975-09-09 | Alza Corp | Intrauterine device for managing the reproductive process |
US3923997A (en) | 1971-05-11 | 1975-12-02 | Rhodia | Process for repelling dogs and cats from a selected area or from each other using {65 -n-alkyl-{65 -butyrolactones and {67 -n-alkyl-{67 -valerolactones |
US3729566A (en) | 1971-05-25 | 1973-04-24 | Upjohn Co | Rodent sterilant process |
US3948254A (en) | 1971-11-08 | 1976-04-06 | Alza Corporation | Novel drug delivery device |
US4016251A (en) | 1972-08-17 | 1977-04-05 | Alza Corporation | Vaginal drug dispensing device |
US3971367A (en) | 1972-12-27 | 1976-07-27 | Alza Corporation | Intrauterine device having means for changing from uterine-retentive shape to nonuterine-retentive shape |
US3921636A (en) | 1973-01-15 | 1975-11-25 | Alza Corp | Novel drug delivery device |
US3916899A (en) | 1973-04-25 | 1975-11-04 | Alza Corp | Osmotic dispensing device with maximum and minimum sizes for the passageway |
US4014987A (en) | 1974-06-04 | 1977-03-29 | Alza Corporation | Device for delivery of useful agent |
US3993072A (en) | 1974-08-28 | 1976-11-23 | Alza Corporation | Microporous drug delivery device |
IL48277A (en) | 1974-10-18 | 1978-03-10 | Schering Ag | Vaginal ring |
US4155991A (en) | 1974-10-18 | 1979-05-22 | Schering Aktiengesellschaft | Vaginal ring |
US4093709A (en) | 1975-01-28 | 1978-06-06 | Alza Corporation | Drug delivery devices manufactured from poly(orthoesters) and poly(orthocarbonates) |
NL7506407A (en) | 1975-05-30 | 1976-12-02 | Akzo Nv | PROCESS FOR PREPARING AN ORAL ACTIVE PHARMACEUTICAL PREPARATION. |
US3977404A (en) | 1975-09-08 | 1976-08-31 | Alza Corporation | Osmotic device having microporous reservoir |
US4014334A (en) | 1976-02-02 | 1977-03-29 | Alza Corporation | Laminated osmotic system for dispensing beneficial agent |
US4008719A (en) | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US4154820A (en) | 1976-02-23 | 1979-05-15 | Akzona Incorporated | Compositions containing alkali metal sulfate salts of conjugated estrogens and antioxidants as stabilizers |
FR2408345A1 (en) | 1976-11-30 | 1979-06-08 | Besins Jean Louis | NEW COMPOSITION WITH ANTI-CONCEPTIONAL ACTION |
US4310510A (en) | 1976-12-27 | 1982-01-12 | Sherman Kenneth N | Self administrable anti-fertility composition |
US4393871A (en) | 1977-06-27 | 1983-07-19 | Vli Corporation | Vaginal device |
GB1589946A (en) | 1977-12-14 | 1981-05-20 | Kali Chemie Pharma Gmbh | Enterally absorbable preparations and process for the production thereof |
US4215691A (en) | 1978-10-11 | 1980-08-05 | Alza Corporation | Vaginal contraceptive system made from block copolymer |
US4732763A (en) | 1978-10-17 | 1988-03-22 | Stolle Research And Development Corporation | Active/passive immunization of the internal female reproductive organs |
US4756907A (en) | 1978-10-17 | 1988-07-12 | Stolle Research & Development Corp. | Active/passive immunization of the internal female reproductive organs |
US4237885A (en) | 1978-10-23 | 1980-12-09 | Alza Corporation | Delivery system with mated members for storing and releasing a plurality of beneficial agents |
US4384096A (en) | 1979-08-27 | 1983-05-17 | The Dow Chemical Company | Liquid emulsion polymers useful as pH responsive thickeners for aqueous systems |
US4372951A (en) | 1979-10-11 | 1983-02-08 | Nichols Vorys | Vaginal delivery for physiologic follicular-luteal steroid treatment |
US4402695A (en) | 1980-01-21 | 1983-09-06 | Alza Corporation | Device for delivering agent in vagina |
GB2079158B (en) | 1980-06-09 | 1985-01-09 | Ahi Operations Ltd | Intra-vaginal devices |
DE3040978A1 (en) | 1980-10-28 | 1982-05-27 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | VAGINAL RING |
US4327725A (en) | 1980-11-25 | 1982-05-04 | Alza Corporation | Osmotic device with hydrogel driving member |
US4423151A (en) | 1981-09-24 | 1983-12-27 | Peter S. Brune | Process for preparation of control for use in estrogen receptor tests |
US4961931A (en) | 1982-07-29 | 1990-10-09 | Alza Corporation | Method for the management of hyperplasia |
US4629449A (en) | 1982-07-29 | 1986-12-16 | Alza Corporation | Vaginal dispenser for dispensing beneficial hormone |
US4826831A (en) | 1983-08-05 | 1989-05-02 | Pre Jay Holdings Limited | Method of hormonal treatment for menopausal or post-menopausal disorders involving continuous administration of progestogens and estrogens |
US6309669B1 (en) | 1984-03-16 | 2001-10-30 | The United States Of America As Represented By The Secretary Of The Army | Therapeutic treatment and prevention of infections with a bioactive materials encapsulated within a biodegradable-biocompatible polymeric matrix |
US4610687A (en) | 1984-08-06 | 1986-09-09 | Board Of Trustees Operating Michigan State University | Method for breeding control in female bovines |
DE3510555A1 (en) | 1985-03-21 | 1986-09-25 | Schering AG, 1000 Berlin und 4709 Bergkamen | ESTRIOLESTER |
US4816257A (en) | 1985-09-20 | 1989-03-28 | Research & Education Institute, Harbor-Ucla Medical Center Inc. | Method for producing an in vivo environment suitable for human embryo transfer |
US5208225A (en) | 1986-02-27 | 1993-05-04 | Warner-Lambert Company | Compositions containing fixed combinations |
US4762717A (en) | 1986-03-21 | 1988-08-09 | The General Hospital Corporation | Continuous delivery of luteinizing hormone releasing hormone compositions in combination with sex steroid delivery for use as a contraceptive |
US5140021A (en) | 1986-04-16 | 1992-08-18 | Genesis Systems Corporation | Method and dosage form for treatment of premenstrual syndrome |
US5145682A (en) | 1986-05-30 | 1992-09-08 | Rutgers, The State University Of New Jersey | Transdermal absorption dosage unit for postmenopausal syndrome treatment and process for administration |
US4908389A (en) | 1986-08-27 | 1990-03-13 | Warner-Lambert Company | Penetration enhancement system |
US6139868A (en) | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
CN1021196C (en) | 1986-12-29 | 1993-06-16 | 新泽西州州立大学(鲁杰斯) | Prepn. method of progestin unit and system |
US4876249A (en) | 1987-01-12 | 1989-10-24 | Rajadhyaksha Vithal J | Compositions and method comprising heterocyclic compounds containing two heteroatoms |
US4788062A (en) | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
US4865848A (en) | 1987-02-26 | 1989-09-12 | Alza Corporation | Skin permeation enhancer compositions using sucrose esters |
US5538736A (en) | 1987-04-28 | 1996-07-23 | Lts Lohmann Therapie-Systeme Gmbh | Active substance-containing plaster for the controlled administration of active substances to the skin |
US4900734A (en) | 1987-08-27 | 1990-02-13 | Maxson Wayne S | Novel pharmaceutical composition containing estradiol and progesterone for oral administration |
US5276022A (en) | 1987-09-24 | 1994-01-04 | Jencap Research Ltd. | Hormone preparation and method |
US5108995A (en) | 1987-09-24 | 1992-04-28 | Jencap Research Ltd. | Hormone preparation and method |
US5064654A (en) | 1989-01-11 | 1991-11-12 | Ciba-Geigy Corporation | Mixed solvent mutually enhanced transdermal therapeutic system |
US4906475A (en) | 1988-02-16 | 1990-03-06 | Paco Pharmaceutical Services | Estradiol transdermal delivery system |
US5656286A (en) | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US5719197A (en) | 1988-03-04 | 1998-02-17 | Noven Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
US5474783A (en) | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
US4942158A (en) | 1988-10-13 | 1990-07-17 | Eastman Kodak | Transdermal steroid penetrant compositions and methods utilizing isopropanol and isobutanol |
WO1990004397A1 (en) | 1988-10-27 | 1990-05-03 | Schering Aktiengesellschaft Berlin Und Bergkamen | Preparation for transdermal application containing gestodene |
JP2651616B2 (en) | 1989-02-03 | 1997-09-10 | リンテック株式会社 | Transdermal formulation |
US5164416A (en) | 1989-02-03 | 1992-11-17 | Lintec Corporation | Transdermal therapeutic formulation containing a limonene |
US4973468A (en) | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
US5059426A (en) | 1989-03-22 | 1991-10-22 | Cygnus Therapeutic Systems | Skin permeation enhancer compositions, and methods and transdermal systems associated therewith |
JP2910857B2 (en) | 1989-04-04 | 1999-06-23 | ニチバン株式会社 | Prostaglandin E1 transdermal preparation |
DE3916112A1 (en) | 1989-05-16 | 1990-11-22 | Schering Ag | DIHYDROSPIRORENONE AS AN ANTIANDROGEN |
ATE107517T1 (en) | 1989-05-25 | 1994-07-15 | Takeda Chemical Industries Ltd | TRANSDERMAL THERAPEUTIC AGENT. |
US5043331A (en) | 1989-06-15 | 1991-08-27 | Orion-Yhtyma Oy | Treatment of postmenopausal disorders |
DE69007886T2 (en) | 1989-07-21 | 1994-11-17 | Izhak Blank | Oestradiol containing agents and methods for topical use. |
US5130137A (en) | 1989-08-09 | 1992-07-14 | The General Hospital Corporation | Continuous delivery of luteinizing hormone releasing hormone compositions in combination with sex steroid delivery for use in treating benign ovarian secretory disorders |
US5252334A (en) | 1989-09-08 | 1993-10-12 | Cygnus Therapeutic Systems | Solid matrix system for transdermal drug delivery |
CA1340994C (en) | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
DE3933460A1 (en) | 1989-10-06 | 1991-04-18 | Lohmann Therapie Syst Lts | OSTROGEN-ACTIVE PLASTER |
US5288496A (en) | 1990-05-15 | 1994-02-22 | Stolle Research & Development Corporation | Growth promoters for animals |
AU653156B2 (en) | 1990-06-14 | 1994-09-22 | Dermamed | Transdermal administration to humans and animals |
DE4104385C1 (en) | 1991-02-09 | 1992-08-13 | Marika Dr.Med. 6509 Framersheim De Ehrlich | |
FR2673840A1 (en) | 1991-03-14 | 1992-09-18 | Lvmh Rech | COSMETIC OR PHARMACEUTICAL COMPOSITION, PARTICULARLY DERMATOLOGICAL, CONTAINING OXYACANTHIN, PARTICULARLY FOR STIMULATING THE PUSH OF HAIR OR FOR DELAYING THEIR FALL. |
US5340585A (en) | 1991-04-12 | 1994-08-23 | University Of Southern California | Method and formulations for use in treating benign gynecological disorders |
US5211952A (en) | 1991-04-12 | 1993-05-18 | University Of Southern California | Contraceptive methods and formulations for use therein |
US5340586A (en) | 1991-04-12 | 1994-08-23 | University Of Southern California | Methods and formulations for use in treating oophorectomized women |
US6342491B1 (en) | 1991-05-21 | 2002-01-29 | American Home Products Corporation | Method of treating estrogen receptor positive carcinoma with 17 α-dihydroequilin |
GB9113726D0 (en) | 1991-06-25 | 1991-08-14 | Inst Of Animal Physiology And | Artificial animal foster mothers |
US5653983A (en) | 1991-07-19 | 1997-08-05 | Lvmh Recherche | Compositions for the pigmentation of the skin or of the hair containing an extract of Marrubium vulgare, the process for it's manufacture and it's |
US5676968A (en) | 1991-10-31 | 1997-10-14 | Schering Aktiengesellschaft | Transdermal therapeutic systems with crystallization inhibitors |
DK0615445T3 (en) | 1991-12-05 | 1996-06-03 | Alfatec Pharma Gmbh | Pharmaceutically manageable nanosol and method of preparation thereof |
MX9301121A (en) | 1992-03-02 | 1993-09-01 | Schering Ag | METHOD AND EQUIPMENT FOR ORAL CONTRACEPTION AND REGULATION OF MENSTRUATION WITH ESTROGEN / PROGESTIN / ANIPROGESTIN. |
US7704983B1 (en) | 1992-03-02 | 2010-04-27 | Eastern Virginia Medical School | Antiprogestin method for reducing side effects associated with low dosage HRT and oral contraception |
US6010715A (en) | 1992-04-01 | 2000-01-04 | Bertek, Inc. | Transdermal patch incorporating a polymer film incorporated with an active agent |
US5453279A (en) | 1992-04-21 | 1995-09-26 | Tbs Laboratories, Inc. | Enhancing transdermal absorption compositions; transdermal dosage form; and process |
US5393528A (en) | 1992-05-07 | 1995-02-28 | Staab; Robert J. | Dissolvable device for contraception or delivery of medication |
US5607691A (en) | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
US5295945A (en) | 1992-08-03 | 1994-03-22 | Beth Israel Hospital Assoc. Inc. | Garment and method for positioning and securing a radioactive implant internally within the female genital organs |
FR2695561B1 (en) | 1992-09-17 | 1994-12-02 | Lvmh Rech Gie | Cosmetic or dermatological composition containing at least one ginsenoside-type saponin, and its applications, in particular for hair care. |
WO1994008238A1 (en) | 1992-09-28 | 1994-04-14 | Biex, Inc. | Method for prediction of premature labor |
US5811547A (en) | 1992-10-14 | 1998-09-22 | Nippon Shinyaju Co., Ltd. | Method for inducing crystalline state transition in medicinal substance |
AU5541594A (en) | 1992-10-21 | 1994-05-09 | Gynetech Laboratories, Inc. | Vaginal sponge delivery system |
US5639743A (en) | 1992-11-13 | 1997-06-17 | University Of Georgia Research Foundation | Compositions and methods for treating exocrine gland atrophy |
FR2699406B1 (en) | 1992-12-21 | 1995-03-10 | Commissariat Energie Atomique | Films based on copolymers, their applications in transdermal systems and their preparation processes. |
MY113268A (en) | 1992-12-29 | 2002-01-31 | Insite Vision Incorporated | Plasticized bioerodible controlled delivery system |
DE4301783C1 (en) | 1993-01-23 | 1994-02-03 | Lohmann Therapie Syst Lts | Transdermal system per admin. of galanthamine - esp. for treatment of Alzheimer's disease and alcohol addiction |
US5468736A (en) | 1993-02-25 | 1995-11-21 | The Medical College Of Hampton Road | Hormone replacement therapy |
US5843979A (en) | 1993-02-25 | 1998-12-01 | Bristol-Myers Squibb Company | Transdermal treatment with mast cell degranulating agents for drug-induced hypersensitivity |
SE9301171D0 (en) | 1993-04-07 | 1993-04-07 | Ab Astra | PHARMACEUTICAL COMPOSITION CONTAINING LIPOPHILIC DRUGS |
US5762952A (en) | 1993-04-27 | 1998-06-09 | Hercon Laboratories Corporation | Transdermal delivery of active drugs |
DE4336557C2 (en) | 1993-05-06 | 1997-07-17 | Lohmann Therapie Syst Lts | Estradiol-containing transdermal therapeutic system, process for its preparation and its use |
FI95768C (en) | 1993-06-17 | 1996-03-25 | Leiras Oy | Intravaginal dosing system |
US5595970A (en) | 1993-07-16 | 1997-01-21 | Schering Aktiengesellschaft | Treatment of climacteric disorders with nitric oxide synthase substrates and/or donors |
DK95093D0 (en) | 1993-08-20 | 1993-08-20 | Novo Nordisk As | PHARMACEUTICAL FORMULA CONTAINING A HORMON |
DE4329242A1 (en) | 1993-08-26 | 1995-03-02 | Schering Ag | Agent for transdermal application containing gestodenester |
US5543150A (en) | 1993-09-15 | 1996-08-06 | Columbia Laboratories, Inc. | Method of progesterone delivery and affect thereof |
CA2165802A1 (en) | 1993-09-29 | 1995-04-06 | Eun Soo Lee | Monoglyceride/lactate ester permeation enhancer for oxybutynin |
DE4341444C2 (en) | 1993-12-04 | 1996-03-14 | Lohmann Therapie Syst Lts | Active substance-containing plaster and process for its production |
DE4344463A1 (en) | 1993-12-22 | 1995-06-29 | Schering Ag | Combination product for contraception |
DE4344405C2 (en) | 1993-12-24 | 1995-12-07 | Marika Dr Med Ehrlich | Anti-ovulation agent and method for hormonal contraception |
DE4400770C1 (en) | 1994-01-13 | 1995-02-02 | Lohmann Therapie Syst Lts | Plaster containing an active substance for delivery of oestradiol with at least one penetration enhancer, method of producing it and its use |
DE4405898A1 (en) | 1994-02-18 | 1995-08-24 | Schering Ag | Transdermal therapeutic systems containing sex steroids |
US6228383B1 (en) | 1994-03-03 | 2001-05-08 | Gs Development Ab | Use of fatty acid esters as bioadhesive substances |
AU676430B2 (en) | 1994-03-07 | 1997-03-06 | Theratech, Inc. | Drug-containing adhesive composite transdermal delivery device |
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
FR2717688B1 (en) | 1994-03-28 | 1996-07-05 | Lhd Lab Hygiene Dietetique | Transdermal matrix system for administration of an estrogen and / or an EVA-based progestin. |
FR2717689B1 (en) | 1994-03-28 | 1996-07-05 | Lhd Lab Hygiene Dietetique | Transdermal matrix system for the administration of an estrogen and / or a progestin based on a styrene-isoprene-styrene copolymer. |
BR9507313A (en) | 1994-04-08 | 1997-10-07 | Atrix Lab Inc | Liquid-release composition suitable for the formation of a controlled-release implant biodegradable microporous film dressing polymeric controlled-release implant precursor for implantation in an individual thermoplastic polymer organic solvent liquid pre-polymer composition controlled-release component active agent use of liquid release composition and processes to form an extended release microporous implant and to release an active agent in an individual |
AU1958295A (en) | 1994-04-13 | 1995-11-10 | Novartis Ag | Temporally controlled drug delivery systems |
US6538039B2 (en) | 1994-04-29 | 2003-03-25 | Laboratoire L. Lafon | Pharmaceutical dosage form for transdermal administration |
JPH09512562A (en) | 1994-05-05 | 1997-12-16 | メルク フロスト カナダ インコーポレーテツド | Localized polymer drug delivery system |
US5811416A (en) | 1994-06-06 | 1998-09-22 | Board Of Regents The University Of Texas System | Endothelin antagonist and/or endothelin synthase inhibitor in combination with a progestin, an estrogen, a cyclooxygenase inhibitor, or a nitric acid donor or substrate |
US5709844A (en) | 1994-06-09 | 1998-01-20 | The Regents Of The University Of California | Transgenic mice expressing HPV early region oncogene develop progressive cervico-vaginal neoplasia |
US5869084A (en) | 1994-06-20 | 1999-02-09 | K-V Pharmaceuticals Co. | Multi-vitamin and mineral supplements for women |
EP0729363B1 (en) | 1994-06-27 | 2003-02-19 | Neutron Therapies Inc. | Boron-containing hormone analogs and methods of their use in imaging or killing cells having hormone receptors |
FR2722102B1 (en) | 1994-07-11 | 1996-08-23 | Cird Galderma | USE OF DEFORMABLE HOLLOW PARTICLES IN A COSMETIC AND / OR DERMATOLOGICAL COMPOSITION CONTAINING FAT MATERIALS |
FR2722984B1 (en) | 1994-07-26 | 1996-10-18 | Effik Lab | PROCESS FOR THE PREPARATION OF DRY PHARMACEUTICAL FORMS AND THE PHARMACEUTICAL COMPOSITIONS THUS PRODUCED |
US5633011A (en) | 1994-08-04 | 1997-05-27 | Alza Corporation | Progesterone replacement therapy |
US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
DE4429374C1 (en) | 1994-08-12 | 1996-02-01 | Jenapharm Gmbh | Pharmaceutical preparations for contraception / hormone substitution with biogenic estrogen component |
US5762614A (en) | 1994-08-25 | 1998-06-09 | Caillouette; James C. | Estrogen or estradiol need determination by vaginal acidity determination |
US6402705B1 (en) | 1994-08-25 | 2002-06-11 | James C. Caillouette | Body moisture test apparatus and method |
US5916176A (en) | 1994-08-25 | 1999-06-29 | Caillouette; James C. | Estrogen or estradiol need determination by vaginal or urethral acidity determination |
US5735801A (en) | 1994-08-25 | 1998-04-07 | Caillouette; James C. | Estrogen or estradiol need determination by vaginal acidity determination |
US5827200A (en) | 1997-01-27 | 1998-10-27 | Caillouette; James C. | Method and apparatus for detecting amine producing organisms in the vagina |
EP0781122B1 (en) | 1994-09-14 | 2000-07-05 | Minnesota Mining And Manufacturing Company | Matrix for transdermal drug delivery |
US6613757B1 (en) | 1994-09-22 | 2003-09-02 | Board Of Regents, The University Of Texas System | Combination of prostacyclin with an estrogen or progestin for the prevention and treatment of atherosclerotic vascular disease including preeclampsia and for the treatment of hypertension, and for hormone replacement therapy |
US6716454B2 (en) | 1994-09-23 | 2004-04-06 | Laboratorie Innothera, Société Anonyme | Therapeutic combination of vitamin and calcium in unitary galenic tablet form, a method of obtaining it, and the use thereof |
CA2159419C (en) | 1994-10-17 | 2006-07-04 | Pieter De Haan | Solid pharmaceutical composition comprising an excipient capable of binding water |
FR2725623A1 (en) | 1994-10-18 | 1996-04-19 | Flamel Tech Sa | MEDICINAL AND / OR NUTRITION MICROCAPSULES FOR PER OS ADMINISTRATION |
US5595759A (en) | 1994-11-10 | 1997-01-21 | Alza Corporation | Process for providing therapeutic composition |
US5571933A (en) | 1994-11-17 | 1996-11-05 | Duquesne University Of The Holy Ghost | Derivatives of estra 1,3,5(10)triene-17-one, 3-amino compounds and their use |
AU692944B2 (en) | 1994-11-18 | 1998-06-18 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbable patch |
US5686100A (en) | 1994-11-22 | 1997-11-11 | E.R. Squibb & Sons, Inc. | Prophylactic and therapeutic treatment of skin sensitization and irritation |
US5885974A (en) | 1994-12-06 | 1999-03-23 | Michael M. Danielov | Therapeutic methods utilizing naturally derived bio-active complexes and delivery systems therefor |
FR2728463A1 (en) | 1994-12-21 | 1996-06-28 | Lhd Lab Hygiene Dietetique | TRANSDERMIC SYSTEM FOR SIMULTANEOUS DELIVERY OF SEVERAL ACTIVE PRINCIPLES |
FR2728464B1 (en) | 1994-12-22 | 1997-04-30 | Innothera Lab Sa | UNITAL GALENIC FORM, PROCESS FOR OBTAINING SAME AND USES THEREOF |
DE4446600A1 (en) | 1994-12-24 | 1996-06-27 | Lohmann Therapie Syst Lts | Transdermal absorption of active ingredients from supercooled melts |
US6344211B1 (en) | 1994-12-24 | 2002-02-05 | Lts Lohmann Therapie-Systeme Gmbh | Transdermal absorption of active substances from subcooled melts |
US6024974A (en) | 1995-01-06 | 2000-02-15 | Noven Pharmaceuticals, Inc. | Composition and methods for transdermal delivery of acid labile drugs |
DE19500662C2 (en) | 1995-01-12 | 2001-04-26 | Lohmann Therapie Syst Lts | Plaster containing estradiol and its use |
US5516528A (en) | 1995-01-13 | 1996-05-14 | Wake Forest University | Dietary phytoestrogen in estrogen replacement therapy |
US5547948A (en) | 1995-01-17 | 1996-08-20 | American Home Products Corporation | Controlled release of steroids from sugar coatings |
FR2729854A1 (en) | 1995-01-26 | 1996-08-02 | Oreal | USE OF DEHYDROEPI-ANDROSTERONE SULFATE IN A COSMETIC OR DERMATOLOGICAL COMPOSITION |
US5629021A (en) | 1995-01-31 | 1997-05-13 | Novavax, Inc. | Micellar nanoparticles |
US5565199A (en) | 1995-02-07 | 1996-10-15 | Page; Elliot W. | Systems and methods for the synthesis of natural base steroidal hormones and more especially estrogens and progesterone and estrogen-like and progesterone-like compounds and their derivatives derived as phytohormones from herbaceous plants |
US5609617A (en) | 1995-02-21 | 1997-03-11 | C. Norman Shealy | Method for enhancement of dehydroepiandrosterone |
FR2732223B1 (en) | 1995-03-30 | 1997-06-13 | Sanofi Sa | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL ADMINISTRATION |
MY118354A (en) | 1995-05-01 | 2004-10-30 | Scarista Ltd | 1,3-propane diol derivatives as bioactive compounds |
US6262115B1 (en) | 1995-05-22 | 2001-07-17 | Alza Coporation | Method for the management of incontinence |
US5912268A (en) | 1995-05-22 | 1999-06-15 | Alza Corporation | Dosage form and method for treating incontinence |
US5882676A (en) | 1995-05-26 | 1999-03-16 | Alza Corporation | Skin permeation enhancer compositions using acyl lactylates |
US5693335A (en) | 1995-06-07 | 1997-12-02 | Cygnus, Inc. | Skin permeation enhancer composition for use with sex steroids |
US5747058A (en) | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
US5785991A (en) | 1995-06-07 | 1998-07-28 | Alza Corporation | Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate |
US7833543B2 (en) | 1995-06-07 | 2010-11-16 | Durect Corporation | High viscosity liquid controlled delivery system and medical or surgical device |
US5780050A (en) | 1995-07-20 | 1998-07-14 | Theratech, Inc. | Drug delivery compositions for improved stability of steroids |
DE19526864A1 (en) | 1995-07-22 | 1997-01-23 | Labtec Gmbh | Hormone patches |
US5679573A (en) | 1995-07-27 | 1997-10-21 | Abbott Laboratories | Stabilized aqueous steroid immunoassay standards with cyclodextrins |
US6245347B1 (en) | 1995-07-28 | 2001-06-12 | Zars, Inc. | Methods and apparatus for improved administration of pharmaceutically active compounds |
US5567831A (en) | 1995-08-16 | 1996-10-22 | Duguesne University Of The Holy Ghost | Non-steroidal sulfatase inhibitor compounds and their method of use |
US5840327A (en) | 1995-08-21 | 1998-11-24 | Alza Corporation | Transdermal drug delivery device having enhanced adhesion |
US5906830A (en) | 1995-09-08 | 1999-05-25 | Cygnus, Inc. | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same |
US5902603A (en) | 1995-09-14 | 1999-05-11 | Cygnus, Inc. | Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use |
FR2739031B1 (en) | 1995-09-27 | 1997-11-21 | Lhd Lab Hygiene Dietetique | TRANSDERMAL MATRIX SYSTEM FOR ADMINISTRATION OF AN ESTROGEN AND / OR A PROGESTIVE BASED ON STYRENE-ISOPRENE-STYRENE COPOLYMER, PREPARATION METHOD AND THERAPEUTIC USE |
FR2739032B1 (en) | 1995-09-27 | 1997-11-21 | Lhd Lab Hygiene Dietetique | TRANSDERMAL MATRIX SYSTEM FOR ADMINISTRATION OF AN ESTROGEN AND / OR AN EVA-BASED PROGESTIVE, PROCESS FOR PREPARATION AND THERAPEUTIC USE |
US6551611B2 (en) | 1995-09-28 | 2003-04-22 | Schering Aktiengesellschaft | Hormone replacement therapy method |
US5922349A (en) | 1995-09-28 | 1999-07-13 | Schering Aktiengesellschaft | Hormone replacement therapy method and hormone dispenser |
FR2739558B1 (en) | 1995-10-05 | 1997-11-28 | Innothera Lab Sa | UNITAL GALENIC FORM FOR LOCAL HORMONOTHERAPY OF VAGINAL DROUGHT |
FR2739559B1 (en) | 1995-10-05 | 1997-11-28 | Innothera Lab Sa | GEL FOR LOCAL HORMONOTHERAPY OF VAGINAL DROUGHT |
US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
DE19540253C2 (en) | 1995-10-28 | 1998-06-04 | Jenapharm Gmbh | Multi-phase preparation for contraception based on natural estrogens |
GB9522403D0 (en) | 1995-11-01 | 1996-01-03 | Hoechst Roussel Ltd | Intravaginal drug delivery device |
US5612051A (en) | 1995-11-17 | 1997-03-18 | Yue; Samuel K. | Method of treating involuntary muscle dysfunction with relaxin hormone |
US5770176A (en) | 1995-12-08 | 1998-06-23 | Chiron Diagnostics Corporation | Assays for functional nuclear receptors |
DE19549264A1 (en) | 1995-12-23 | 1997-06-26 | Schering Ag | Contraception procedure and kit |
DE19548332A1 (en) | 1995-12-22 | 1997-07-10 | Rotta Res Bv | hormone patches |
US5789442A (en) | 1996-01-18 | 1998-08-04 | Schering Aktiengesellschaft | Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents |
EP0785212A1 (en) | 1996-01-22 | 1997-07-23 | Laboratoire Theramex | New 19-nor-pregnene derivatives |
EP0785211A1 (en) | 1996-01-22 | 1997-07-23 | Laboratoire Theramex | New substituted 19-nor-pregnane derivatives |
AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
US5898038A (en) | 1996-03-19 | 1999-04-27 | Board Of Regents, The University Of Texas System | Treatment of osteoporosis and metabolic bone disorders with nitric oxide substrate and/or donors |
FR2747042B1 (en) | 1996-04-05 | 1998-06-05 | Besins Iscovesco Lab | PROGESTERONE AND OESTRADIOL-BASED MEDICINE |
GB9608719D0 (en) | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
NZ286492A (en) | 1996-05-01 | 1998-02-26 | Dec International Nz Ltd Subst | Intra vaginal devices for synchronising oestrus of animals is made up of cured silicone rubber material with 5% by weight of progesterone |
US6040340A (en) | 1996-05-07 | 2000-03-21 | Schering Aktiengesellschaft | Implantation rates after in vitro fertilization, treatment of infertility and early pregnancy loss with a nitric oxide donor alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors |
DE69731473T2 (en) | 1996-05-09 | 2005-10-27 | Amrad Operations Pty. Ltd., Richmond | USE OF STEROIDS FOR THE TREATMENT OF ASTHMA AND RESPIRATORY DISEASES |
EP0954260A1 (en) | 1996-05-22 | 1999-11-10 | Diversified Pharmaceuticals, Inc. | Compositions, methods and devices for the transdermal delivery of drugs |
US5744463A (en) | 1996-06-03 | 1998-04-28 | Bair; Glenn O. | Treatment of side effects of progestins and progesterone analogues used for birth control |
IT1283102B1 (en) | 1996-06-06 | 1998-04-07 | Permatec Nv | THERAPEUTIC COMPOSITION FOR THE TRANSDERMAL ADMINISTRATION OF AN ESTROGENIC OR PROGESTINIC ACTIVE SUBSTANCE OR OF THEIR MIXTURES |
US6506390B2 (en) | 1996-06-25 | 2003-01-14 | Akzo Nobel | Progestogen-anti-progestogen regimens |
US6139873A (en) | 1996-07-10 | 2000-10-31 | Cedars-Sinai Medical Center | Combined pharmaceutical estrogen-androgen-progestin |
DE19629468A1 (en) | 1996-07-11 | 1998-01-15 | Schering Ag | Transdermal therapeutic systems |
US6228852B1 (en) | 1996-07-12 | 2001-05-08 | Carolyn V. Shaak | Transdermal application of naturally occurring steroid hormones |
DK0930876T3 (en) | 1996-07-22 | 2005-02-14 | Renovo Ltd | Use of compounds that promote estrogenic activity in the treatment of wounds |
US5972372A (en) | 1996-07-31 | 1999-10-26 | The Population Council, Inc. | Intravaginal rings with insertable drug-containing core |
US6227202B1 (en) | 1996-09-03 | 2001-05-08 | Maulana Azad Medical College | Method of organogenesis and tissue regeneration/repair using surgical techniques |
WO1998010293A1 (en) | 1996-09-06 | 1998-03-12 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Method of screening for side effects of anticonceptives or estrogen and/or progesterone replacements or supplements |
US6028064A (en) | 1996-09-13 | 2000-02-22 | New Life Pharmaceuticals Inc. | Prevention of ovarian cancer by administration of progestin products |
FR2753626B1 (en) | 1996-09-20 | 1998-11-06 | Centre International De Rech Dermatologiques Galderma Cird Galderma | NOVEL TOPICAL COMPOSITIONS IN THE FORM OF A FLUID O / W EMULSION WITH A HIGH PRO-PENETRATING GLYCOL CONTENT |
JP2002516619A (en) | 1996-10-18 | 2002-06-04 | ユニオン キャンプ コーポレイション | Ester-terminated polyamide gel |
JP2001503062A (en) | 1996-10-30 | 2001-03-06 | セラテック・インコーポレーテッド | Salts of fatty acid esters of lactic acid as permeation enhancers |
US5985861A (en) | 1996-11-04 | 1999-11-16 | Columbia Laboratories, Inc. | Progesterone for treating or reducing ischemia |
US5928666A (en) | 1996-11-12 | 1999-07-27 | Cygnus Inc. | Crystalline form of estradiol and pharmaceutical formulations comprising same |
US5942243A (en) | 1996-11-12 | 1999-08-24 | Polytherapeutics, Inc. | Mucoadhesive compositions for administration of biologically active agents to animal tissue |
US5814329A (en) | 1996-11-12 | 1998-09-29 | Polytherapeutics, Inc. | Hydrophilic polystyrene graft copolymer vehicle for intravaginal administration of pharmacologically active agents |
US20060014728A1 (en) | 1996-11-21 | 2006-01-19 | Kristof Chwalisz | Hormone replacement therapy |
DE19654609A1 (en) | 1996-12-20 | 1998-06-25 | Schering Ag | Therapeutic progestogens for the treatment of premenstrual dysphoric disorder |
DE19701949A1 (en) | 1997-01-13 | 1998-07-16 | Jenapharm Gmbh | Transdermal therapeutic system |
DE19700913C2 (en) | 1997-01-14 | 2001-01-04 | Lohmann Therapie Syst Lts | Transdermal therapeutic system for the delivery of hormones |
US5993856A (en) | 1997-01-24 | 1999-11-30 | Femmepharma | Pharmaceutical preparations and methods for their administration |
US6416778B1 (en) | 1997-01-24 | 2002-07-09 | Femmepharma | Pharmaceutical preparations and methods for their regional administration |
KR100215027B1 (en) | 1997-01-27 | 1999-08-16 | 성재갑 | Composition for transdermal administration of steroid drugs and formulation containing same |
US20010023261A1 (en) | 1997-01-27 | 2001-09-20 | Lg Chemical Limited. | Novel composition for the transdermal administration of drugs |
FR2759292B1 (en) | 1997-02-10 | 2000-08-11 | Cird Galderma | USE OF RETINOIDS AS PIGMENTATION INDUCING AGENTS |
DE19705229C2 (en) | 1997-02-12 | 1999-04-15 | Hesch Rolf Dieter Prof Dr Med | Use of three hormonal components for hormonal contraception for the treatment and / or prophylaxis of tumors of the mammary glands |
US6056972A (en) | 1997-02-26 | 2000-05-02 | Dimera, Llc | Method for reducing coronary artery reactivity |
FR2760639B1 (en) | 1997-03-14 | 2000-09-22 | Innothera Lab Sa | MINERALO-VITAMIN THERAPEUTIC ASSOCIATION IN THE FORM OF A UNITABLE ORAL LIQUID PREPARATION |
US6093394A (en) | 1997-04-11 | 2000-07-25 | Gynelogix, Inc. | Vaginal lactobacillus medicant |
DE19718012C1 (en) | 1997-04-29 | 1998-10-08 | Jenapharm Gmbh | Process for the production of orally applicable solid pharmaceutical forms with controlled release of active substances |
IT1291362B1 (en) | 1997-05-13 | 1999-01-07 | Vectorpharma Int | BIPHASIC MULTICOMPONENT PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTANCES SUITABLE TO MODIFY THE PARTITION OF THE ACTIVE SUBSTANCES |
JP4202431B2 (en) | 1997-05-28 | 2008-12-24 | インターエージー | Pig cage equipment |
DE69833254T2 (en) | 1997-06-23 | 2006-11-02 | Cellegy Pharmaceuticals, Inc., Brisbane | MICRODOSIS THERAPY OF VASCULAR EXPOSURE BY NO-DONORS |
US6039968A (en) | 1997-06-24 | 2000-03-21 | Hoechst Marion Roussel | Intravaginal drug delivery device |
DE19728516C2 (en) | 1997-07-04 | 1999-11-11 | Sanol Arznei Schwarz Gmbh | TTS for administration of levonorgestrel and possibly estradiol |
DE19728517C2 (en) | 1997-07-04 | 1999-11-11 | Sanol Arznei Schwarz Gmbh | TTS for the administration of sex steroid hormones and process for its preparation |
US6217886B1 (en) | 1997-07-14 | 2001-04-17 | The Board Of Trustees Of The University Of Illinois | Materials and methods for making improved micelle compositions |
DE19739916C2 (en) | 1997-09-11 | 2001-09-13 | Hesch Rolf Dieter | Use of a combination of a progestogen and an estrogen for the continuous inhibition of ovulation and possibly simultaneous treatment and / or prophylaxis of tumors of the mammary glands |
US8765177B2 (en) | 1997-09-12 | 2014-07-01 | Columbia Laboratories, Inc. | Bioadhesive progressive hydration tablets |
US20040234606A1 (en) | 1997-09-12 | 2004-11-25 | Levine Howard L. | Localized vaginal delivery without detrimental blood levels |
GB9720470D0 (en) | 1997-09-25 | 1997-11-26 | Ethical Pharmaceuticals South | Inhibition of crystallization in transdermal devices |
US8257725B2 (en) | 1997-09-26 | 2012-09-04 | Abbott Laboratories | Delivery of highly lipophilic agents via medical devices |
US6201072B1 (en) | 1997-10-03 | 2001-03-13 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co- glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US5968919A (en) | 1997-10-16 | 1999-10-19 | Macrochem Corporation | Hormone replacement therapy drug formulations for topical application to the skin |
US6306914B1 (en) | 1997-10-21 | 2001-10-23 | Columbia Laboratories, Inc. | Progestin therapy for maintaining amenorrhea |
CA2306837C (en) | 1997-10-28 | 2007-05-08 | Asivi, Llc. | Treatment of female sexual dysfunction |
US20020099003A1 (en) | 1997-10-28 | 2002-07-25 | Wilson Leland F. | Treatment of female sexual dysfunction with vasoactive agents, particularly vasoactive intestinal polypeptide and agonists thereof |
US20040044080A1 (en) | 1997-10-28 | 2004-03-04 | Place Virgil A. | Treatment of dyspareunia with topically administered nitroglycerin formulations |
US6193991B1 (en) | 1997-10-29 | 2001-02-27 | Atul J. Shukla | Biodegradable delivery systems of biologically active substances |
WO1999022680A1 (en) | 1997-11-03 | 1999-05-14 | Deschutes Medical Products, Inc. | Pessary with medicated cartridge |
CA2310632A1 (en) | 1997-11-19 | 1999-05-27 | Humanetics Corporation | Use of .delta.5-androstene-3.beta.-ol-7,17-dione in the treatment of lupus erythematosus |
US5891868A (en) | 1997-11-21 | 1999-04-06 | Kaiser Foundation Health Plan, Inc. | Methods for treating postmenopausal women using ultra-low doses of estrogen |
NZ330596A (en) | 1998-06-05 | 2001-02-23 | Dec Res | Intravaginal devices allowing for increased uptake of active ingredients |
US6692763B1 (en) | 1998-11-19 | 2004-02-17 | The Regents Of The University Of California | Methods for treating postmenopausal women using ultra-low doses of estrogen |
US20020031513A1 (en) | 1997-11-24 | 2002-03-14 | Shamir Leibovitz | Method and pharmaceutical composition for inhibiting premature rapture of fetal membranes, ripening of uterine cervix and preterm labor in mammals |
US6030948A (en) | 1997-12-19 | 2000-02-29 | Mann; Morris A. | Hair regeneration compositions for treatment of alopecia and methods of application related thereto |
FR2772617B1 (en) | 1997-12-19 | 2001-03-09 | Besins Iscovesco Lab | PROGESTERONE TABLET AND PROCESS FOR THE PREPARATION THEREOF |
AU1728099A (en) | 1997-12-22 | 1999-07-12 | Alza Corporation | Monoglyceride and ethyl palmitate permeation enhancer compositions |
US6054446A (en) | 1997-12-24 | 2000-04-25 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
US6503896B1 (en) | 1997-12-24 | 2003-01-07 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
US6548491B2 (en) | 1997-12-24 | 2003-04-15 | Sri International | Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use |
FR2774291B1 (en) | 1998-02-03 | 2000-04-21 | Innothera Lab Sa | PHARMACEUTICAL SPECIALTY IN UNITAL GALENIC FORM OF CHEWABLE OR SUGAR TABLETS, INCLUDING AS ACTIVE INGREDIENT OF IRON ELEMENT |
US6312703B1 (en) | 1998-02-06 | 2001-11-06 | Lecigel, Llc | Compressed lecithin preparations |
IT1298575B1 (en) | 1998-02-06 | 2000-01-12 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF NANOPARTICLES INCLUDING LIPID SUBSTANCES AND ANTIPHILIC SUBSTANCES AND RELATED PROCESS OF |
US6001846A (en) | 1998-02-17 | 1999-12-14 | Ligand Pharmaceuticals Incorporated | Process for the preparation of 1,2-dihydroquinolines |
DE19807791A1 (en) | 1998-02-19 | 1999-08-26 | Schering Ag | Combination preparation of estrogen with 7-aminoalkyl-estratriene antiestrogen, useful in hormone replacement therapy, e.g. for treatment osteoporosis, Alzheimer's disease and hot flushes |
US6028057A (en) | 1998-02-19 | 2000-02-22 | Thorn Bioscience, Llc | Regulation of estrus and ovulation in gilts |
US6287693B1 (en) | 1998-02-25 | 2001-09-11 | John Claude Savoir | Stable shaped particles of crystalline organic compounds |
US20010056068A1 (en) | 1998-03-04 | 2001-12-27 | Kristof Chwalisz | Method of treatment and prevention of nitric oxide deficiency-related disorders with citrulline and citrulline derivatives |
FR2775599B1 (en) | 1998-03-09 | 2001-08-17 | Besins Iscovesco Lab | PHARMACEUTICAL COMPOSITION BASED ON SYNTHESIS NATURAL PROGESTERONE AND OESTRADIOL AND PROCESS FOR PREPARING THE SAME |
FR2776191B1 (en) | 1998-03-23 | 2002-05-31 | Theramex | TOPICAL HORMONAL COMPOSITION WITH SYSTEMIC EFFECT |
JP2002510336A (en) | 1998-04-11 | 2002-04-02 | エレカッパ・ユウロテラピッチ・ソシエタ・ペル・アチオニ | Pharmaceutical preparations containing water-soluble ketoprofen salts and methods of using the same |
US20030040790A1 (en) | 1998-04-15 | 2003-02-27 | Furst Joseph G. | Stent coating |
WO1999053910A2 (en) | 1998-04-17 | 1999-10-28 | Ortho-Mcneil Pharmaceutical, Inc. | Folic acid-containing pharmaceutical compositions, and related methods and delivery systems |
FR2777783A1 (en) | 1998-04-24 | 1999-10-29 | Innothera Lab Sa | Pharmaceutical composition for treatment of infectious vulvovaginitis and vaginosis |
FR2777784B1 (en) | 1998-04-27 | 2004-03-19 | Arepa | PHARMACEUTICAL COMPOSITION BASED ON ESTROGEN AND PROGESTERONE |
US6277418B1 (en) | 1998-06-02 | 2001-08-21 | Baylor College Of Medicine | Corn extract contraceptive |
AU3951399A (en) | 1998-06-03 | 1999-12-20 | Jean-Marc Aiache | Stable gel mixture in the form of a mixture of oleogel and aqueous gel |
FR2779438B1 (en) | 1998-06-03 | 2004-12-24 | Jean Marc Aiache | STABLE GEL, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME |
DE19825591A1 (en) | 1998-06-09 | 1999-12-23 | Jenapharm Gmbh | Pharmaceutical combinations to compensate for a testosterone deficit in men while protecting the prostate |
US6465445B1 (en) | 1998-06-11 | 2002-10-15 | Endorecherche, Inc. | Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors |
NZ330726A (en) | 1998-06-18 | 2000-10-27 | Dec Res | Intra-vaginal delivery unit or composition containing a cyclodextrin which improves absorbtion of 17-beta oestradiol or oestradiol benzoate |
DE19827732A1 (en) | 1998-06-22 | 1999-12-23 | Rottapharm Bv | Transdermal patch useful for hormone replacement therapy used for treatment of menopausal symptoms |
WO2000001351A1 (en) | 1998-07-07 | 2000-01-13 | Transdermal Technologies, Inc. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
US6294188B1 (en) | 1998-07-09 | 2001-09-25 | Aviana Biopharm Inc. | Methods involving changing the constitutive and stimulated secretions of the local reproductive system of women |
US6124362A (en) | 1998-07-17 | 2000-09-26 | The Procter & Gamble Company | Method for regulating hair growth |
DE19834931A1 (en) | 1998-07-28 | 2000-02-24 | Jenapharm Gmbh | Use of biogenic estrogens for hormone replacement therapy |
DE19834007C1 (en) | 1998-07-29 | 2000-02-24 | Lohmann Therapie Syst Lts | Estradiol-containing patch for the transdermal application of hormones and its use |
US20070015698A1 (en) | 1998-07-30 | 2007-01-18 | United States Of America As Represented By The Secretary Of Health | Treatment of skin, and wound repair, with thymosin beta 4 |
US20030181353A1 (en) | 1998-08-03 | 2003-09-25 | Nyce Jonathan W. | Composition & use as analgesic, anti-inflammatory, wound healing agent, for treatment of heart conditions, assessment of heart function & tissue & cell protection & healing & reperfusion, mood disorders & symptoms & sequelae of menopause & for inducing unconsciousness, sleep & anesthesia |
ES2255294T3 (en) | 1998-08-07 | 2006-06-16 | Chiron Corporation | ISOXAZOL DERIVATIVES REPLACED AS MODULATORS OF THE STROGEN RECEPTOR. |
WO2000009113A1 (en) | 1998-08-17 | 2000-02-24 | Trout William E | Use of zeranol to modulate reproductive cycles |
US8257724B2 (en) | 1998-09-24 | 2012-09-04 | Abbott Laboratories | Delivery of highly lipophilic agents via medical devices |
US20020169205A1 (en) | 1998-09-29 | 2002-11-14 | Krzysztof Chwalisz | Implantation rates after in vitro fertilization, and treatment of infertility and early pregnancy loss with a nitric oxide donor or substrate alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors in combination with antiprogestins or other agents |
JP2002526397A (en) | 1998-10-05 | 2002-08-20 | ザ ペン ステイト リサーチ ファンデーション | Compositions and methods for enhancing receptor-mediated cell internalization |
JP4399044B2 (en) | 1998-10-14 | 2010-01-13 | 久光製薬株式会社 | Absorption enhancer and transdermal absorption preparation comprising the absorption enhancer |
US6372246B1 (en) | 1998-12-16 | 2002-04-16 | Ortho-Mcneil Pharmaceutical, Inc. | Polyethylene glycol coating for electrostatic dry deposition of pharmaceuticals |
US20040120891A1 (en) | 1998-12-21 | 2004-06-24 | Craig Hill | Compounds for intracellular delivery of therapeutic moieties to nerve cells |
ATE272391T1 (en) | 1998-12-23 | 2004-08-15 | Idea Ag | IMPROVED FORMULATION FOR TOPICAL, NON-INVASIVE USE IN VIVO |
GB9828480D0 (en) | 1998-12-24 | 1999-02-17 | Dermatech Limited | Transdermal drug delivery system |
US6117446A (en) | 1999-01-26 | 2000-09-12 | Place; Virgil A. | Drug dosage unit for buccal administration of steroidal active agents |
NZ513208A (en) | 1999-02-05 | 2003-05-30 | Cipla Ltd | Topical sprays comprising a film forming composition |
US7919109B2 (en) | 1999-02-08 | 2011-04-05 | Intarcia Therapeutics, Inc. | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicles |
US6080118A (en) | 1999-02-25 | 2000-06-27 | Blythe; Cleveland | Vaginal probe and method of using same |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6294192B1 (en) | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US20030104048A1 (en) | 1999-02-26 | 2003-06-05 | Lipocine, Inc. | Pharmaceutical dosage forms for highly hydrophilic materials |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
DE19911799A1 (en) | 1999-03-17 | 2000-09-28 | Lohmann Therapie Syst Lts | Multipack for the removal of filled bags in the specified order |
CA2267743C (en) | 1999-03-30 | 2011-07-26 | Robert F. Casper | Low dose estrogen interrupted hormone replacement therapy |
US6287588B1 (en) | 1999-04-29 | 2001-09-11 | Macromed, Inc. | Agent delivering system comprised of microparticle and biodegradable gel with an improved releasing profile and methods of use thereof |
US6649155B1 (en) | 1999-05-03 | 2003-11-18 | The Procter & Gamble Company | Anti-dandruff and conditioning shampoos containing certain cationic polymers |
US6974569B2 (en) | 1999-05-03 | 2005-12-13 | The Procter & Gamble Company | Shampoos providing a superior combination anti-dandruff efficacy and condition |
US6451300B1 (en) | 1999-05-03 | 2002-09-17 | The Procter & Gamble Company | Anti-dandruff and conditioning shampoos containing polyalkylene glycols and cationic polymers |
US8663692B1 (en) | 1999-05-07 | 2014-03-04 | Pharmasol Gmbh | Lipid particles on the basis of mixtures of liquid and solid lipids and method for producing same |
WO2000069422A1 (en) | 1999-05-13 | 2000-11-23 | Hisamitsu Pharmaceutical Co., Inc. | Patch |
US6962691B1 (en) | 1999-05-20 | 2005-11-08 | U & I Pharmaceuticals Ltd. | Topical spray compositions |
US6645947B1 (en) | 1999-05-20 | 2003-11-11 | Chitogenics, Inc. | Adhesive N, O-carboxymethylchitosan coatings which inhibit attachment of substrate-dependent cells and proteins |
US6395300B1 (en) | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US7919119B2 (en) | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
RU2271196C2 (en) | 1999-06-04 | 2006-03-10 | Элзэ Копэрейшн | Implantable composition (variants) and method for production thereof |
AU5325000A (en) | 1999-06-05 | 2000-12-28 | David Houze | Solubility enhancement of drugs in transdermal drug delivery systems and methodsof use |
MXPA01012769A (en) | 1999-06-11 | 2003-06-24 | Watson Pharmaceuticals Inc | Administration of non-oral androgenic steroids to women. |
GB9914648D0 (en) | 1999-06-24 | 1999-08-25 | Univ Birmingham | Control of infra-ocular pressure |
US20030236236A1 (en) | 1999-06-30 | 2003-12-25 | Feng-Jing Chen | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US6303132B1 (en) | 1999-07-16 | 2001-10-16 | Ardell H. Nelson | Administering progesterone using EMU oil |
KR20010010393A (en) | 1999-07-20 | 2001-02-05 | 김윤 | Biodegradable Block Copolymer of Hydrophobic and Hydrophilic Polymers, and Composition for Drug Delivery Comprising Same |
NZ337318A (en) | 1999-08-18 | 2002-07-26 | Interag | Dispensing apparatus for dispensing same or different materials for at least two reservoirs |
US20010036481A1 (en) | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
US6526980B1 (en) | 1999-08-26 | 2003-03-04 | West Virginia University | Cervical drug delivery system |
CN1223350C (en) | 1999-08-31 | 2005-10-19 | 先灵公司 | Pharmaceutical combination of ethinylestradiol and drospirenone for use as contraceptive |
US6787531B1 (en) | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
CA2384679A1 (en) | 1999-09-08 | 2001-03-15 | Srinivasan Venkateshwaran | Using quaternary ammonium salts for transdermal drug delivery |
US6610674B1 (en) | 1999-09-28 | 2003-08-26 | University Of Pennsylvania | Method of treating inflammatory conditions with progesterone analogs |
US6479545B1 (en) | 1999-09-30 | 2002-11-12 | Drugtech Corporation | Formulation for menopausal women |
US6720001B2 (en) | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
US6436633B1 (en) | 1999-10-22 | 2002-08-20 | The Pennsylvania State University | Human xenografts for microbicide testing and anatomical modeling |
US6958327B1 (en) | 1999-11-02 | 2005-10-25 | Schering, Ag | 18 Norsteroids as selectively active estrogens |
US20030180352A1 (en) | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
AUPQ419099A0 (en) | 1999-11-23 | 1999-12-16 | Ko, Thomas Sai Ying | Novel compositions and methods |
US7384650B2 (en) | 1999-11-24 | 2008-06-10 | Agile Therapeutics, Inc. | Skin permeation enhancement composition for transdermal hormone delivery system |
US20020012710A1 (en) | 1999-11-29 | 2002-01-31 | Rimonest Ltd. | Pomegranate products useful in improving health and methods of use thereof |
US6708822B1 (en) | 1999-11-30 | 2004-03-23 | Cutispharma, Inc. | Compositions and kits for compounding pharmaceuticals |
US20040191276A1 (en) | 1999-11-30 | 2004-09-30 | Cutispharma, Inc. | Compositions and kits for compounding pharmaceuticals |
US7250174B2 (en) | 1999-12-07 | 2007-07-31 | Schott Ag | Cosmetic, personal care, cleaning agent, and nutritional supplement compositions and methods of making and using same |
US6562370B2 (en) | 1999-12-16 | 2003-05-13 | Dermatrends, Inc. | Transdermal administration of steroid drugs using hydroxide-releasing agents as permeation enhancers |
US20010032125A1 (en) | 1999-12-20 | 2001-10-18 | Sundeep Bhan | Activation of coupons based on quiz or questionnaire |
US6544553B1 (en) | 1999-12-28 | 2003-04-08 | Watson Pharmaceuticals, Inc. | Dosage forms and methods for oral delivery of progesterone |
GB0000313D0 (en) | 2000-01-10 | 2000-03-01 | Astrazeneca Uk Ltd | Formulation |
US6967023B1 (en) | 2000-01-10 | 2005-11-22 | Foamix, Ltd. | Pharmaceutical and cosmetic carrier or composition for topical application |
US7335650B2 (en) | 2000-01-14 | 2008-02-26 | Sterix Limited | Composition |
US6653298B2 (en) | 2000-01-14 | 2003-11-25 | Sterix Limited | Composition |
US20020132801A1 (en) | 2001-01-11 | 2002-09-19 | Schering Aktiengesellschaft | Drospirenone for hormone replacement therapy |
US20020004065A1 (en) | 2000-01-20 | 2002-01-10 | David Kanios | Compositions and methods to effect the release profile in the transdermal administration of active agents |
CA2395730A1 (en) | 2000-01-28 | 2001-08-02 | Endorecherche, Inc. | Selective estrogen receptor modulators in combination with estrogens |
FR2804603B1 (en) | 2000-02-04 | 2004-01-23 | Rhodia Chimie Sa | CONTINUOUS PROCESS FOR FORMULATING IN THE FORM OF GRANULES ONE OR MORE PHARMACEUTICAL ACTIVE SUBSTANCES |
US6562790B2 (en) | 2000-02-05 | 2003-05-13 | Chein Edmund Y M | Hormone therapy methods and hormone products for abating coronary artery blockage |
KR20030016227A (en) | 2000-02-16 | 2003-02-26 | 벤트레이 파마슈티칼스, 인코포레이티드 | Pharmaceutical composition |
AU3982601A (en) | 2000-02-23 | 2001-09-03 | Orentreich Foundation For The | Methods and compositions for the treatment of alopecia and other disorders of the pilosebaceous apparatus |
US7989436B2 (en) | 2003-07-23 | 2011-08-02 | Duramed Pharmaceuticals, Inc. | Estrogenic compounds and pharmaceutical formulations comprising the same |
US6855703B1 (en) | 2000-03-10 | 2005-02-15 | Endeavor Pharmaceuticals | Pharmaceutical compositions of conjugated estrogens and methods of analyzing mixtures containing estrogenic compounds |
US6660726B2 (en) | 2000-03-10 | 2003-12-09 | Endeavor Pharmaceuticals | Estrogenic compounds, pharmaceutical compositions thereof, and methods of using same |
US7459445B2 (en) | 2000-03-10 | 2008-12-02 | Duramed Pharmaceuticals, Inc. | Estrogenic compounds and topical pharmaceutical formulations of the same |
US20010034340A1 (en) | 2000-03-20 | 2001-10-25 | American Home Products Corporation | Hormone replacement therapy |
US20040176336A1 (en) | 2000-03-21 | 2004-09-09 | Rodriguez Gustavo C. | Prevention of ovarian cancer by administration of products that induce biologic effects in the ovarian epithelium |
IL135335A (en) | 2000-03-29 | 2013-12-31 | Lycored Natural Prod Ind Ltd | Use of carotenoids in the preparation of medicaments for preventing hormone induced adverse effects and pharmaceutical compositions comprising carotenoids |
EP1272196B1 (en) | 2000-03-31 | 2006-08-02 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Methods of making the 4-n-butylcyclohexanoic and the undecanoic acid esters of (7 alpha,11 beta)-dimethyl-17 beta-hydroxy-4-estren-3-one and their medical use |
IL152248A0 (en) | 2000-04-12 | 2003-05-29 | Schering Ag | 8beta-HYDROCARBYL-SUBSTITUTED ESTRATRIENES FOR USE AS SELECTIVE ESTROGENS |
US20020013327A1 (en) | 2000-04-18 | 2002-01-31 | Lee Andrew G. | Compositions and methods for treating female sexual dysfunction |
US7758888B2 (en) | 2000-04-21 | 2010-07-20 | Sol-Gel Technologies Ltd. | Composition exhibiting enhanced formulation stability and delivery of topical active ingredients |
US6589549B2 (en) | 2000-04-27 | 2003-07-08 | Macromed, Incorporated | Bioactive agent delivering system comprised of microparticles within a biodegradable to improve release profiles |
US7018645B1 (en) | 2000-04-27 | 2006-03-28 | Macromed, Inc. | Mixtures of various triblock polyester polyethylene glycol copolymers having improved gel properties |
US8119138B2 (en) | 2000-05-10 | 2012-02-21 | Signe Biopharma Inc. | Anti-estrogen and immune modulator combinations for treating breast cancer |
US6495534B2 (en) | 2000-05-15 | 2002-12-17 | Pharmacia & Upjohn Spa | Stabilized aqueous suspensions for parenteral use |
KR100452972B1 (en) | 2000-05-16 | 2004-10-14 | 주식회사 삼양사 | Hydrogel composition for transdermal drug |
KR20030003769A (en) | 2000-05-31 | 2003-01-10 | 니찌방 가부시기가이샤 | Percutaneous absorption type steroid preparation for external use |
GB0015617D0 (en) | 2000-06-26 | 2000-08-16 | Vectura Ltd | Improved preparations for dermal delivery of active substances |
US7001911B2 (en) | 2000-06-28 | 2006-02-21 | Bristol-Myers Squibb Company | Fused cyclic modulators of nuclear hormone receptor function |
US20030114420A1 (en) | 2000-06-28 | 2003-06-19 | Salvati Mark E. | Fused cyclic modulators of nuclear hormone receptor function |
US20040077605A1 (en) | 2001-06-20 | 2004-04-22 | Salvati Mark E. | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
US20040176324A1 (en) | 2000-09-19 | 2004-09-09 | Salvati Mark E. | Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
US20040047910A1 (en) | 2000-07-07 | 2004-03-11 | Christian Beckett | Suppository and composition comprising at least one polyethylene glycol |
US6420352B1 (en) | 2000-07-19 | 2002-07-16 | W. Roy Knowles | Hair loss prevention |
WO2002007712A2 (en) | 2000-07-24 | 2002-01-31 | Pharmacia & Upjohn Company | Self-emulsifying drug delivery systems for extremely water-insoluble, lipophilic drugs |
US20020035070A1 (en) | 2000-07-26 | 2002-03-21 | The Procter & Gamble Company | Method of regulating hair growth using metal complexes of oxidized carbohydrates |
US20020119174A1 (en) | 2000-07-26 | 2002-08-29 | Gardlik John Michael | Compositions useful for regulating hair growth containing metal complexes of oxidized carbohydrates |
US8980290B2 (en) | 2000-08-03 | 2015-03-17 | Antares Pharma Ipl Ag | Transdermal compositions for anticholinergic agents |
US7198801B2 (en) | 2000-08-03 | 2007-04-03 | Antares Pharma Ipl Ag | Formulations for transdermal or transmucosal application |
WO2002011768A1 (en) | 2000-08-03 | 2002-02-14 | Antares Pharma Ipl Ag | Novel composition for transdermal and/or transmucosal administration of active compounds that ensures adequate therapeutic levels |
US20040198706A1 (en) | 2003-03-11 | 2004-10-07 | Carrara Dario Norberto R. | Methods and formulations for transdermal or transmucosal application of active agents |
US7163681B2 (en) | 2000-08-07 | 2007-01-16 | Centocor, Inc. | Anti-integrin antibodies, compositions, methods and uses |
US20040092494A9 (en) | 2000-08-30 | 2004-05-13 | Dudley Robert E. | Method of increasing testosterone and related steroid concentrations in women |
GB0021317D0 (en) | 2000-08-30 | 2000-10-18 | Queen Mary & Westfield College | Transdermal pharmaceutical delivery composition |
DE10045380A1 (en) | 2000-09-14 | 2002-04-04 | Schering Ag | Contraception procedure and dosage form |
FR2814074B1 (en) | 2000-09-15 | 2003-03-07 | Theramex | NOVEL TOPICAL ESTRO-PROGESTIVE COMPOSITIONS WITH SYSTEMIC EFFECT |
DE60131862D1 (en) | 2000-09-20 | 2008-01-24 | Nycomed Pharma As | PREPARATION OF VITAMIN EMULSIONS AND CONCENTRATES THEREOF |
US20020119187A1 (en) | 2000-09-29 | 2002-08-29 | Cantor Adam S. | Composition for the transdermal delivery of fentanyl |
AU2001282617A1 (en) | 2000-10-16 | 2002-04-29 | Hisamitsu Pharmaceutical Co. Inc. | Compositions for external preparations |
US6635274B1 (en) | 2000-10-27 | 2003-10-21 | Biochemics, Inc. | Solution-based transdermal drug delivery system |
ATE303156T1 (en) | 2000-10-30 | 2005-09-15 | Univ Zuerich | USE OF GNRH ANALOGUE TO TREAT URINARY INCONTINENCE |
US6328987B1 (en) | 2000-11-03 | 2001-12-11 | Jan Marini Skin Research, Inc. | Cosmetic skin care compositions containing alpha interferon |
US20030113268A1 (en) | 2000-11-10 | 2003-06-19 | Mina Buenafae | Degradation-resistant glucocorticosteroid formulations |
US6605605B2 (en) | 2000-11-13 | 2003-08-12 | Milton Hammerly | Estrogenic substances combined with cruciferous indole compounds |
US6682757B1 (en) | 2000-11-16 | 2004-01-27 | Euro-Celtique, S.A. | Titratable dosage transdermal delivery system |
FR2816838B1 (en) | 2000-11-17 | 2004-12-03 | Oreal | USE OF DERIVATIVES OF 2-OXOTHIAZOLIDINE-4-CARBOXYLIC ACID AS PRODESQUAMANTS |
JP2004522710A (en) | 2000-11-17 | 2004-07-29 | ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー | Treatment of sexual dysfunction |
AUPR184500A0 (en) | 2000-12-01 | 2001-01-04 | Drug Delivery Solutions Pty Ltd | Dispensing device |
AU2002245104B2 (en) | 2000-12-11 | 2006-08-17 | Testocreme, Llc | Topical testosterone formulations and associated methods |
DK1361881T3 (en) | 2000-12-14 | 2006-02-20 | Ortho Mcneil Pharm Inc | Steroidal hormone products and methods for their preparation |
US7018992B2 (en) | 2000-12-15 | 2006-03-28 | Novo Nordisk A/S | Hormone composition |
EP1216712A1 (en) | 2000-12-20 | 2002-06-26 | Schering Aktiengesellschaft | Cyclodextrin-drospirenone inclusion complexes |
EP1216699A1 (en) | 2000-12-21 | 2002-06-26 | Schering Aktiengesellschaft | Transdermal system comprising a highly potent progestin |
US20020107230A1 (en) | 2000-12-22 | 2002-08-08 | Waldon R. Forrest | Methods and formulations for the treatment of female sexual dysfunction |
US20020151530A1 (en) | 2000-12-22 | 2002-10-17 | Leonard Thomas W. | Method of treating hormonal deficiencies in women undergoing estrogen replacement therapy |
FR2818905A1 (en) | 2000-12-28 | 2002-07-05 | Cll Pharma | MICELLAR COLLOIDAL PHARMACEUTICAL COMPOSITIONS COMPRISING A LIPOPHILIC ACTIVE INGREDIENT |
EP1351678A2 (en) | 2001-01-02 | 2003-10-15 | Elizabeth Shanahan-Prendergast | Treatment for inhibiting neoplastic lesions using incensole and/or furanogermacrens |
US20020197286A1 (en) | 2001-01-16 | 2002-12-26 | Jane Brandman | Method for preventing and treating skin aging |
FR2820320B1 (en) | 2001-02-02 | 2003-04-04 | Oreal | SUSPENSION OF LIPOPHILIC ACTIVE INGREDIENT NANOSPHERES STABILIZED BY WATER-DISPERSIBLE POLYMERS |
AU2002240312A1 (en) | 2001-02-08 | 2002-08-19 | Pankaj Paranjp | Enhanced oral and transcompartmental delivery of therapeutic or diagnostic agents using polymer conjugates |
US7381427B2 (en) | 2001-02-09 | 2008-06-03 | Mickey Miller | Seborrheic keratosis treatment |
NZ509894A (en) | 2001-02-09 | 2002-11-26 | Interag | A "T" or "Y" shaped intravaginal device suitable for delivery of pharmaceuticals such as progesterone |
US7303763B2 (en) | 2001-02-12 | 2007-12-04 | Watson Laboratories, Inc. | Compositions for conjugated estrogens and associated methods |
US20040087548A1 (en) | 2001-02-27 | 2004-05-06 | Salvati Mark E. | Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function |
US6756208B2 (en) | 2001-02-28 | 2004-06-29 | John H. Griffin | Plasma glucosylceramide deficiency as risk factor for thrombosis and modulator of anticoagulant protein C |
FR2821555B1 (en) | 2001-03-01 | 2003-05-16 | Besins Int Lab | PROGESTIVE CO-MICRONIZED WITH A SURFACTANT, PHARMACEUTICAL COMPOSITION COMPRISING SAME, METHODS OF MAKING SAME AND USES THEREOF |
WO2002069906A2 (en) | 2001-03-06 | 2002-09-12 | Cellegy Pharmaceuticals, Inc. | Compounds and methods for the treatment of urogenital disorders |
EA200301022A1 (en) | 2001-03-16 | 2004-02-26 | Уайт | HORMONAL REPLACEMENT THERAPY |
FR2828102B1 (en) | 2001-03-28 | 2004-07-09 | Ifc Sa | USE OF LIPOAMINOACIDS IN A PHARMACEUTICAL COMPOSITION AS A PROMOTER AND DISPERSE SYSTEM FOR PHARMACEUTICAL USE CONTAINING SUCH COMPOUNDS |
WO2002078604A2 (en) | 2001-03-30 | 2002-10-10 | Elan Transdermal Technologies, Inc. | Transdermal delivery of bioactive material |
US20020142941A1 (en) | 2001-03-30 | 2002-10-03 | Pro Duct Health, Inc. | Intraductal treatment targeting methylated promoters in breast cancer |
EP1385459A2 (en) | 2001-03-30 | 2004-02-04 | Elan Pharmaceuticals, Inc. | Transdermal delivery of pergolide |
US20040131670A1 (en) | 2001-04-17 | 2004-07-08 | Ping Gao | Pellicle-resistant gelatin capsule |
US6860859B2 (en) | 2001-04-20 | 2005-03-01 | Monsanto Technology Llc | Apparatus and method for detection of estrus and/or non-pregnancy |
WO2002085308A2 (en) | 2001-04-24 | 2002-10-31 | Epigenesis Pharmaceuticals, Inc. | Antisense and anti-inflammatory based compositions to treat respiratory disorders |
US6936599B2 (en) | 2001-04-25 | 2005-08-30 | The Regents Of The University Of California | Estriol therapy for multiple sclerosis and other autoimmune diseases |
US20050209208A1 (en) | 2001-04-25 | 2005-09-22 | The Regents Of The University Of California | Use of estriol and other estranes, estrogens and estrogen receptor active compositions in the treatment of psoriasis and other autoimmune disorders |
US20120322779A9 (en) | 2001-04-25 | 2012-12-20 | Rhonda Voskuhl | Estriol Therapy for Autoimmune and Neurodegenerative Diseases and Disorders |
WO2002092102A2 (en) | 2001-05-16 | 2002-11-21 | Endeavor Pharmaceuticals | Treatment of conditions relating to hormone deficiencies by administration of progestins |
WO2002094276A1 (en) | 2001-05-18 | 2002-11-28 | Pantarhei Bioscience B.V. | Pharmaceutical composition for use in hormone replacement therapy |
JP4865958B2 (en) | 2001-05-23 | 2012-02-01 | 株式会社トクホン | Analgesic anti-inflammatory patch with local action |
US20020193356A1 (en) | 2001-05-23 | 2002-12-19 | Van Beek Agatha Antonia Magdalena | Means and method for hormonal contraception |
FR2825277B1 (en) | 2001-05-30 | 2004-10-15 | Oreal | COSMETIC AND / OR DERMATOLOGICAL AND / OR PHARMACEUTICAL COMPOSITION CONTAINING AT LEAST ONE ENZIME 3, B-HSD IHNIBITOR COMPOUND |
EP1406633B1 (en) | 2001-06-18 | 2011-10-05 | Noven Pharmaceuticals, Inc. | Enhanced drug delivery in transdermal systems |
US20020193758A1 (en) | 2001-06-18 | 2002-12-19 | Sca Hygiene Products Ab | Product |
JP2005504032A (en) | 2001-07-31 | 2005-02-10 | ファイザー・プロダクツ・インク | Pharmaceutical compositions, kits and methods comprising estrogen agonist / antagonist, estrogen and progestin combinations |
US7094228B2 (en) | 2001-07-31 | 2006-08-22 | Zars, Inc. | Methods and formulations for photodynamic therapy |
DE10141652B4 (en) | 2001-08-24 | 2011-04-07 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system based on polyacrylate pressure-sensitive adhesives without functional groups and its use |
ATE429947T1 (en) | 2001-08-29 | 2009-05-15 | Pharmakodex Ltd | DEVICE FOR TOPICAL ADMINISTRATION |
US6911438B2 (en) | 2001-09-12 | 2005-06-28 | Jonathan V. Wright | Hormone replacement formulation |
DE10146541A1 (en) | 2001-09-21 | 2003-04-17 | Kade Pharma Fab Gmbh | Medicinal products based on progestogens for dermal use |
US7393696B2 (en) | 2001-09-28 | 2008-07-01 | Aspenbio Pharma, Inc. | Bovine pregnancy test |
DE10294402D2 (en) | 2001-09-29 | 2004-11-11 | Solvay Pharm Gmbh | Estrogen-progestogen combination preparation and application |
US20030175329A1 (en) | 2001-10-04 | 2003-09-18 | Cellegy Pharmaceuticals, Inc. | Semisolid topical hormonal compositions and methods for treatment |
US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
AR026386A1 (en) | 2001-10-24 | 2003-02-12 | Massara Julio Eduardo | AN INTRAVAGINAL DEVICE CONTAINING PROGESTERONE, USEFUL AS A HAIR INDUCTOR IN MEAT AND MILK PRODUCING BOVES, AND THE PROCEDURE FOR PARAPREPARATION |
US7815936B2 (en) | 2001-10-30 | 2010-10-19 | Evonik Degussa Gmbh | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
FR2832065B1 (en) | 2001-11-13 | 2004-11-05 | Besins Int Belgique | PHARMACEUTICAL COMPOSITION BASED ON MICRONIZED PROGESTERONE, PREPARATION METHOD THEREOF AND USES THEREOF |
US20070196415A1 (en) | 2002-11-14 | 2007-08-23 | Guohua Chen | Depot compositions with multiple drug release rate controls and uses thereof |
ATE356635T1 (en) | 2001-11-15 | 2007-04-15 | Pantarhei Bioscience Bv | METHOD FOR PREVENTING OR TREATING BENIGUS GYNECOLOGICAL DISORDERS |
PT1446128E (en) | 2001-11-15 | 2007-03-30 | Pantarhei Bioscience Bv | Use of estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy |
WO2003043586A2 (en) | 2001-11-20 | 2003-05-30 | Advanced Inhalation Research, Inc. | Compositions for sustained action product delivery |
FR2832311B1 (en) | 2001-11-21 | 2004-04-16 | Besins Int Belgique | FILM-FORMING POWDER, COMPOSITIONS COMPRISING SAME, PREPARATION METHODS AND USES THEREOF |
US20040022820A1 (en) | 2001-11-28 | 2004-02-05 | David Anderson | Reversed liquid crystalline phases with non-paraffin hydrophobes |
DE10159120B4 (en) | 2001-12-01 | 2006-08-17 | Lts Lohmann Therapie-Systeme Ag | Steroid hormone-containing transdermal therapeutic systems containing propylene glycol monocaprylate and its use |
AU2002353118A1 (en) | 2001-12-11 | 2003-07-24 | Dor Biopharma, Inc. | Lipid particles and suspensions and uses thereof |
ES2188426B1 (en) | 2001-12-12 | 2004-11-16 | Rosalia Pidal Fernandez | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PSORIASIS AND OTHER DERMOPATIAS. |
TWI332400B (en) | 2001-12-14 | 2010-11-01 | Solvay Pharm Gmbh | Preformulation for the tableting of natural mixtures of conjugated estrogens |
ES2310622T3 (en) | 2001-12-19 | 2009-01-16 | Bristol-Myers Squibb Company | CONDENSED HETEROCICLICAL COMPOUNDS AND ANALOGS OF THE SAME, MODULATORS OF THE FUNCTION OF NUCLEAR HORMONE RECEPTORS. |
US7329654B2 (en) | 2001-12-19 | 2008-02-12 | Janssen Pharmaceutica N.V. | Heteroatom containing tetracyclic derivatives as selective estrogen receptor modulators |
US6962908B2 (en) | 2001-12-21 | 2005-11-08 | Warner Chilcott Company Inc. | Oral pharmaceutical products containing 17 β-estradiol-3-lower alkanoate, method of administering the same and process of preparation |
JP2005531495A (en) | 2001-12-21 | 2005-10-20 | シャイア ラボラトリーズ,インコーポレイテッド | Oral capsule formulation with high physical stability |
FR2834212B1 (en) | 2001-12-27 | 2004-07-09 | Besins Int Belgique | USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS |
US6878518B2 (en) | 2002-01-22 | 2005-04-12 | The Trustees Of The University Of Pennsylvania | Methods for determining steroid responsiveness |
US6901278B1 (en) | 2002-01-29 | 2005-05-31 | Morris Notelovitz | Methods for reducing the risk of breast cancer in and improving the health of women |
AU2003210787B2 (en) | 2002-02-01 | 2009-04-23 | Medinol Ltd. | Phosphorus-containing compounds & uses thereof |
EP1474069A1 (en) | 2002-02-08 | 2004-11-10 | Advanced Animal Technology Limited | Control of a biological function |
NZ517094A (en) | 2002-02-08 | 2005-03-24 | Advanced Animal Technology Ltd | Improvements in and relating to substance delivery device |
GB0203276D0 (en) | 2002-02-12 | 2002-03-27 | Novartis Ag | Organic compounds |
CA2475388A1 (en) | 2002-02-14 | 2003-08-21 | William J. Rutter | Chimeric molecules for cleavage in a treated host |
DE10206390A1 (en) | 2002-02-15 | 2003-08-28 | Bionorica Ag | Use of phytoestrogen-containing extracts that selectively modulate the estrogen receptor beta |
RS50909B (en) | 2002-02-21 | 2010-08-31 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical compositions comprising one or more steroids one or more tetrahydrofolate components and vitamin b12 |
US7741116B2 (en) | 2002-03-06 | 2010-06-22 | University Of Cincinnati | Surgical device for skin therapy or testing |
US20030175333A1 (en) | 2002-03-06 | 2003-09-18 | Adi Shefer | Invisible patch for the controlled delivery of cosmetic, dermatological, and pharmaceutical active ingredients onto the skin |
US20030225047A1 (en) | 2002-03-11 | 2003-12-04 | Caubel Patrick Michel | Sulfatase inhibiting progestogen-only contraceptive regimens |
DE60307602T2 (en) | 2002-03-11 | 2007-10-04 | Janssen Pharmaceutica N.V. | CONTINUOUS SULFATASE-INHIBITING PROGESTOGENIC HORMONIC SUBSTITUTION THERAPY |
CA2478206A1 (en) | 2002-03-11 | 2003-09-25 | Patrick Michel Caubel | Sulfatase inhibiting continuous progestogen contraceptive regimens |
MXPA04008881A (en) | 2002-03-11 | 2004-12-07 | Schering Ag | 5-}2 -hydroxy-3-`1 -(3- trifluoromethylphenyl) -cyclopropyl! -propionylamino}- phtalide and related compounds with progesterone receptor modulating activity for use in fertility control and hormone replacement therapy. |
AU2002242339A1 (en) | 2002-03-14 | 2003-09-29 | Watson Pharmaceuticals, Inc. | Progesterone oral drug delivery system |
DE10211832A1 (en) | 2002-03-16 | 2003-10-02 | Lohmann Therapie Syst Lts | Hormone-containing transdermal therapeutic system with a drug reservoir based on vinyl acetate-vinylpyrrolidone copolymer with improved cohesion |
FR2837100B1 (en) | 2002-03-18 | 2004-07-23 | Flamel Tech Sa | MODIFIED RELEASE MICROCAPSULE-BASED TABLETS |
EP2087882A1 (en) | 2002-03-26 | 2009-08-12 | Teva Pharmaceutical Industries Ltd. | Drug microparticles |
US7300926B2 (en) | 2002-04-01 | 2007-11-27 | University Of Florida Research Foundation, Inc. | Steroidal quinols and their use for estrogen replacement therapy |
US20040235812A1 (en) | 2002-04-03 | 2004-11-25 | Caspers Robert F | Pharmaceutical composition comprisng an aromatase inhibitor and an estrogen suitable for hormone replacement therapy for a male |
US20030191096A1 (en) | 2002-04-03 | 2003-10-09 | Leonard Thomas W. | Method of hormonal therapy |
IL164163A0 (en) | 2002-04-09 | 2005-12-18 | Pharmacia Corp | Process for preparing a finely self-emulsifiable pharmaceutical composition |
US6750291B2 (en) | 2002-04-12 | 2004-06-15 | Pacific Corporation | Film-forming agent for drug delivery and preparation for percutaneous administration containing the same |
DE10218109A1 (en) | 2002-04-23 | 2003-11-20 | Jenapharm Gmbh | Process for the production of crystals, then available crystals and their use in pharmaceutical formulations |
US20050214384A1 (en) | 2002-04-23 | 2005-09-29 | Vijaya Juturu | Chromium compositions and methods for using the same for inhibiting drug-induced insulin resistance |
PL372055A1 (en) | 2002-04-26 | 2005-07-11 | Schering Aktiengesellschaft | Treatment of hypertension in women receiving hormone replacement therapy |
AU2003223754B2 (en) | 2002-04-30 | 2007-08-16 | Merck Sharp & Dohme Corp. | 4-azasteroid derivatives as androgen receptor modulators |
ATE353632T1 (en) | 2002-05-03 | 2007-03-15 | Pr Pharmaceuticals Inc | ESTRADIOL METABOLITE COMPOSITIONS WITH CONTROLLED RELEASE |
US7727720B2 (en) | 2002-05-08 | 2010-06-01 | Ravgen, Inc. | Methods for detection of genetic disorders |
US8591951B2 (en) | 2002-05-15 | 2013-11-26 | Joachim B. Kohn | Tri-block copolymers for nanosphere-based drug delivery |
US6821524B2 (en) | 2002-06-03 | 2004-11-23 | Jan Marini Skin Research, Inc. | Cosmetic skin care compositions |
US6943021B2 (en) | 2002-06-07 | 2005-09-13 | Mattek Corporation | Three dimensional vaginal tissue model containing immune cells |
WO2003103685A1 (en) | 2002-06-11 | 2003-12-18 | Pantarhei Bioscience B.V. | A method of treating human skin and a skin care composition for use in such a method |
US7414043B2 (en) | 2002-06-11 | 2008-08-19 | Schering Ag | 9-α-substituted estratrienes as selectively active estrogens |
US20040048900A1 (en) | 2002-06-17 | 2004-03-11 | Pamela Flood | Nicotine and/or nicotine agonists for the treatment of general anesthetic effects and side effects |
FR2841138B1 (en) | 2002-06-25 | 2005-02-25 | Cll Pharma | SOLID PHARMACEUTICAL COMPOSITION COMPRISING A LIPOPHILIC ACTIVE INGREDIENT, ITS PREPARATION PROCESS |
US20050186141A1 (en) | 2002-06-25 | 2005-08-25 | Acrux Dds Pty Ltd. | Transdermal aerosol compositions |
KR100533458B1 (en) | 2002-07-20 | 2005-12-07 | 대화제약 주식회사 | Composition for solubilization of paclitaxel and preparation method thereof |
CN1671394A (en) | 2002-07-25 | 2005-09-21 | 舍林股份公司 | Composition containing an androgenous 11beta-halogen steroid and a progestational hormone, and male contraceptive based on said composition |
US6960337B2 (en) | 2002-08-02 | 2005-11-01 | Balance Pharmaceuticals, Inc. | Methods and compositions for treating benign gynecological disorders |
US8268352B2 (en) | 2002-08-05 | 2012-09-18 | Torrent Pharmaceuticals Limited | Modified release composition for highly soluble drugs |
TR200201966A2 (en) | 2002-08-07 | 2004-02-23 | Edko Pazarlama Tanitim Ti̇caret Li̇mi̇ted Şi̇rketi̇ | Pharmaceutical composition. |
AU2002950713A0 (en) | 2002-08-09 | 2002-09-12 | Vital Health Sciences Pty Ltd | Carrier |
US20030049307A1 (en) | 2002-08-15 | 2003-03-13 | Gyurik Robert J. | Pharmaceutical composition |
US20060068045A1 (en) | 2002-08-20 | 2006-03-30 | Yong Eu L | Method for the preparation of phytoprogestogenic extracts from rhizoma ligusticum chuanxiong and uses thereof |
CN1678324A (en) | 2002-08-28 | 2005-10-05 | 罗伯特·卡斯珀 | Estrogen replacement regimen |
US7497855B2 (en) | 2002-09-04 | 2009-03-03 | Microchips, Inc. | Method and device for the controlled delivery of parathyroid hormone |
CN101785775B (en) | 2002-09-05 | 2015-03-25 | 潘塔希生物科学股份有限公司 | Pharmaceutical application of 15- or 16- substituted testosterone analogues |
US6967194B1 (en) | 2002-09-18 | 2005-11-22 | Susan Matsuo | Bio-identical hormones and method of use |
GB0222522D0 (en) | 2002-09-27 | 2002-11-06 | Controlled Therapeutics Sct | Water-swellable polymers |
CA2500713C (en) | 2002-10-04 | 2012-07-03 | Photokinetix, Inc. | Photokinetic delivery of biologically active substances using pulsed incoherent light |
DE10247399A1 (en) | 2002-10-08 | 2004-04-29 | Schering Ag | Pharmaceutical preparations, use of this preparation and methods for increasing the bioavailability of drugs to be administered orally |
FR2845597B1 (en) | 2002-10-11 | 2005-03-11 | Innothera Lab Sa | DRY ORAL FORMULATION CONTAINING DIOSMINE AS A PHARMACEUTICAL FORM OF A TABLET TO BE CROQUERED |
US20040146894A1 (en) | 2002-10-14 | 2004-07-29 | Warrington Janet A. | Methods of diagnosing and treating stress urinary incontinence |
GB0224415D0 (en) | 2002-10-21 | 2002-11-27 | Medical Res Council | Compositions |
WO2004037269A1 (en) | 2002-10-23 | 2004-05-06 | Pantarhei Bioscience B.V. | Pharmaceutical compositions comprising estetrol derivatives for use in cancer therapy |
IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
US20070292461A1 (en) | 2003-08-04 | 2007-12-20 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
US20060018937A1 (en) | 2002-10-25 | 2006-01-26 | Foamix Ltd. | Steroid kit and foamable composition and uses thereof |
AU2003278565A1 (en) | 2002-10-25 | 2004-05-13 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Steroid compounds comprising superoxide dismutase mimic groups and nitric oxide donor groups, and their use in the preparation of medicaments |
US20060193789A1 (en) | 2002-10-25 | 2006-08-31 | Foamix Ltd. | Film forming foamable composition |
MXPA05004278A (en) | 2002-10-25 | 2005-10-05 | Foamix Ltd | Cosmetic and pharmaceutical foam. |
US20080206161A1 (en) | 2002-10-25 | 2008-08-28 | Dov Tamarkin | Quiescent foamable compositions, steroids, kits and uses thereof |
US20070292359A1 (en) | 2002-10-25 | 2007-12-20 | Foamix Ltd. | Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof |
DE10249853A1 (en) | 2002-10-25 | 2004-05-13 | Liedtke, Rainer K., Dr. | Flexible, plaster-type chip heating system, for thermodynamic control of topical (trans)dermal systems, including supporting matrix, electrical energy source, controlling microprocessor and electric heater |
US20040087564A1 (en) | 2002-10-31 | 2004-05-06 | Wright D. Craig | Delivery composition and method |
US20040138103A1 (en) | 2002-11-07 | 2004-07-15 | Procyte Corporation | Compositions containing peptide copper complexes and metalloproteinase inhibitors and methods related thereto |
US20040093261A1 (en) | 2002-11-08 | 2004-05-13 | Vivek Jain | Automatic validation of survey results |
US20040089308A1 (en) | 2002-11-13 | 2004-05-13 | Welch Robert A. | Cervical ring to deliver medication |
US20040097468A1 (en) | 2002-11-20 | 2004-05-20 | Wimalawansa Sunil J. | Method of treating osteoporosis and other bone disorders with upfront loading of bisphosphonates, and kits for such treatment |
US7674783B2 (en) | 2002-11-22 | 2010-03-09 | Dimera Inc. | Estrogen beta receptor agonists to prevent or reduce the severity of cardiovascular disease |
US8088605B2 (en) | 2002-12-04 | 2012-01-03 | Technologies Biolactics Inc. | Exopolysaccharides delivery system for active molecules |
FR2848112B1 (en) | 2002-12-10 | 2007-02-16 | Besins Int Belgique | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL OR TRANSMUCTIVE DELIVERY COMPRISING AT LEAST ONE PROGESTATIVE AND / OR AT LEAST ONE OESTROGEN, PREPARATION METHOD AND USES THEREOF |
US20040115226A1 (en) | 2002-12-12 | 2004-06-17 | Wenji Li | Free-flowing solid formulations with improved bio-availability of poorly water soluble drugs and process for making the same |
EP1428526A1 (en) | 2002-12-13 | 2004-06-16 | Rijksuniversiteit Groningen | Formulation for fast dissolution of lipophilic compounds |
US20040115287A1 (en) | 2002-12-17 | 2004-06-17 | Lipocine, Inc. | Hydrophobic active agent compositions and methods |
WO2004054576A1 (en) | 2002-12-18 | 2004-07-01 | Ferrer Internacional, S.A. | Pharmaceutical compositions of sertaconazole for vaginal use |
US20040121003A1 (en) | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
US20050031651A1 (en) | 2002-12-24 | 2005-02-10 | Francine Gervais | Therapeutic formulations for the treatment of beta-amyloid related diseases |
FR2849380A1 (en) | 2002-12-27 | 2004-07-02 | Ernest Loumaye | Treating sterility in female mammals, especially women, by administration of gonadotrophin-releasing hormone agonist in composition adapted for supporting the luteal phase |
CA2552690C (en) | 2002-12-31 | 2014-12-09 | Ultra-Sonic Technologies, L.L.C. | Transdermal delivery using encapsulated agent activated by ultrasound and/or heat |
FR2849597B1 (en) | 2003-01-08 | 2006-12-08 | Oreal | COSMETIC COMPOSITION FOR THE CARE OF OIL SKIN CONTAINING A CARBOXYLIC FATTY ACID OR ONE OF ITS DERIVATIVES |
US7572780B2 (en) | 2003-01-21 | 2009-08-11 | Dimera, Incorporated | Method and kit for reducing the symptoms of peripheral vascular disease |
US20040146539A1 (en) | 2003-01-24 | 2004-07-29 | Gupta Shyam K. | Topical Nutraceutical Compositions with Selective Body Slimming and Tone Firming Antiaging Benefits |
US20090318558A1 (en) | 2003-02-12 | 2009-12-24 | Jae-Hwan Kim | Solvent system of hardly soluble drug with improved dissolution rate |
US20040161435A1 (en) | 2003-02-14 | 2004-08-19 | Gupta Shyam K. | Skin Firming Anti-Aging Cosmetic Mask Compositions |
US20060194775A1 (en) | 2003-02-20 | 2006-08-31 | University Of Pittsburgh | Estradiol metabolites for the treatment of pulmonary hypertension |
FR2851470B1 (en) | 2003-02-20 | 2007-11-16 | Besins Int Belgique | PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL OR TRANSMUCTIVE DELIVERY |
ATE333271T1 (en) | 2003-02-21 | 2006-08-15 | Schering Ag | UV-STABLE TRANSDERMAL PLASTER |
FR2851918B1 (en) | 2003-03-06 | 2006-06-16 | IMPREGNATED POWDER ENHANCING BIOAVAILABILITY AND / OR SOLUBILITY AND METHOD OF MANUFACTURE | |
US7858607B2 (en) | 2003-03-14 | 2010-12-28 | Mamchur Stephen A | System for use by compounding pharmacists to produce hormone replacement medicine customized for each consumer |
US6956099B2 (en) | 2003-03-20 | 2005-10-18 | Arizona Chemical Company | Polyamide-polyether block copolymer |
US20040191207A1 (en) | 2003-03-31 | 2004-09-30 | Lipari John M. | Alpha-hydroxy acid ester drug delivery compositions and methods of use |
AU2003288644A1 (en) | 2003-03-31 | 2004-10-25 | Council Of Scientific And Industrial Research | Mercapto-phenyl-naphthyl-methane derivatives and preparation thereof |
AU2004233997C1 (en) | 2003-04-29 | 2014-01-30 | Massachusetts Institiute Of Technology | Methods and devices for the sustained release of multiple drugs |
WO2004097002A2 (en) | 2003-04-29 | 2004-11-11 | The Miriam Hospital | SELECTIVE TESTICULAR 11β-HSD INHIBITORS AND METHODS OF USE THEREOF |
BRPI0409860A (en) | 2003-04-29 | 2006-05-16 | Akzo Nobel Nv | anti-solvent solidification process |
US20040219124A1 (en) | 2003-05-01 | 2004-11-04 | Gupta Shyam K. | Cosmetic and Pharmaceutical Masks Based on Ion-Pair Delivery System |
JP4422430B2 (en) | 2003-05-14 | 2010-02-24 | 帝國製薬株式会社 | External patch containing estrogen and / or progestogen |
US7925519B2 (en) | 2003-05-20 | 2011-04-12 | Medencentive, Llc | Method and system for delivery of healthcare services |
EP1624878B1 (en) | 2003-05-22 | 2006-09-27 | Pantarhei Bioscience B.V. | Use of compositions comprising an estrogenic component for the treatment and prevention of musculoskeletal pain |
US20060165744A1 (en) | 2003-05-22 | 2006-07-27 | Neopharm, Inc | Combination liposomal formulations |
TWI336627B (en) | 2003-05-23 | 2011-02-01 | Organon Nv | Drug delivery system,and use and manufacturing method thereof |
US7668735B2 (en) | 2003-05-30 | 2010-02-23 | Mdrxdirect Inc. | Compensated electronic consults |
US20040243437A1 (en) | 2003-05-30 | 2004-12-02 | Grace Joseph P. | Compensated electronic consults |
US20090227025A1 (en) | 2003-06-06 | 2009-09-10 | The Board Of Regents Of The University Of Texas System | Ex vivo human lung/immune system model using tissue engineering for studying microbial pathogens with lung tropism |
US20040253319A1 (en) | 2003-06-11 | 2004-12-16 | Shrirang Netke | Pharmaceutical compositions and method for alleviating side-effects of estrogen replacement therapy |
AU2004246870B2 (en) | 2003-06-13 | 2009-07-23 | Skendi Finance Ltd | Slow release estradiol-progesterone formulation for contraception and hormone replacement therapy |
EP1488785A1 (en) | 2003-06-18 | 2004-12-22 | B. Braun Melsungen Ag | Oil emulsion for postnatal substitution of hormones |
US20040259852A1 (en) | 2003-06-18 | 2004-12-23 | White Hillary D. | Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US20110318405A1 (en) | 2003-06-25 | 2011-12-29 | Charles Erwin | Chemical Combination and Method for Increasing Delivery of Coenzyme Q10 |
JP2007521081A (en) | 2003-06-27 | 2007-08-02 | エイエムエス・リサーチ・コーポレーション | Method and apparatus for occlusion of body lumens and / or delivery of therapeutic agents |
US7074779B2 (en) | 2003-07-02 | 2006-07-11 | Ortho-Mcneil Pharmaceutical, Inc. | Estrieno[3,2-b]/[3,4-c]pyrrole derivatives useful as modulators of the estrogen receptors |
AU2004255340B2 (en) | 2003-07-08 | 2008-05-01 | Novartis Ag | Use of rapamycin and rapamycin derivatives for the treatment of bone loss |
WO2005007100A2 (en) | 2003-07-11 | 2005-01-27 | Macrochem Corporation | Pharmaceutical compositions for topical application |
US20050020552A1 (en) | 2003-07-16 | 2005-01-27 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
US20050042268A1 (en) | 2003-07-16 | 2005-02-24 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
US20050025833A1 (en) | 2003-07-16 | 2005-02-03 | Chaim Aschkenasy | Pharmaceutical composition and method for transdermal drug delivery |
ES2237298B1 (en) | 2003-07-16 | 2006-11-01 | Italfarmaco, S.A. | SEMISOLID MUCOADHESIVE FORMULATIONS. |
WO2005009342A2 (en) | 2003-07-16 | 2005-02-03 | Pharmacia Corporation | Method for the treatment or prevention of dermatological disorders with a cyclooxygenase-2 inhibitor alone and in combination with a dermatological treatment agent and compositions therewith |
US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
US20080069779A1 (en) | 2003-08-04 | 2008-03-20 | Foamix Ltd. | Foamable vehicle and vitamin and flavonoid pharmaceutical compositions thereof |
CN102349927A (en) | 2003-08-29 | 2012-02-15 | Hdac默克研究有限责任公司 | Combination methods of treating cancer |
PT1660009E (en) | 2003-09-03 | 2015-05-18 | Miscon Trading S A | Methods for the treatment of endometriosis |
ATE416761T1 (en) | 2003-09-22 | 2008-12-15 | Onepharm Res & Dev Gmbh | PREVENTION AND TREATMENT OF INFLAMMATORY AND/OR IMMUNE-MEDIATED BONE LOSS |
JP2005104862A (en) | 2003-09-29 | 2005-04-21 | Meiji Milk Prod Co Ltd | Aged macular degeneration therapeutic agent |
EP2295041A3 (en) | 2003-09-29 | 2012-01-04 | Novo Nordisk Femcare AG | HRT formulations |
EP2409690B1 (en) | 2003-09-29 | 2022-11-09 | Novo Nordisk Health Care AG | Improved stability of progestogen formulations |
US7247625B2 (en) | 2003-10-09 | 2007-07-24 | Wyeth | 6-amino-1,4-dihydro-benzo[d][1,3] oxazin-2-ones and analogs useful as progesterone receptor modulators |
HUP0303313A2 (en) | 2003-10-09 | 2005-07-28 | Richter Gedeon Vegyészeti Gyár Rt. | Transdermal pharmaceutical compositions |
TW200517114A (en) | 2003-10-15 | 2005-06-01 | Combinatorx Inc | Methods and reagents for the treatment of immunoinflammatory disorders |
WO2005039490A2 (en) | 2003-10-16 | 2005-05-06 | The Administrators Of The Tulane Educational Fund | Methods and compositions for treating cancer |
WO2005039537A1 (en) | 2003-10-22 | 2005-05-06 | Lidds Ab | Composition comprising biodegradable hydrating ceramics for controlled drug delivery |
ATE544460T1 (en) | 2003-10-24 | 2012-02-15 | Nora Therapeutics Inc | COMPOSITIONS AND METHODS FOR A HEALTHY PREGNANCY |
US20050101579A1 (en) | 2003-11-06 | 2005-05-12 | Shippen Eugene R. | Endometriosis treatment protocol |
ATE319426T1 (en) | 2003-11-11 | 2006-03-15 | Mattern Udo | NASAL FORMULATION WITH CONTROLLED RELEASE OF SEXUAL HORMONES |
WO2005049142A2 (en) | 2003-11-14 | 2005-06-02 | Warner Chilcott Company, Inc. | Graduated estrogen contraceptive |
US7517994B2 (en) | 2003-11-19 | 2009-04-14 | Array Biopharma Inc. | Heterocyclic inhibitors of MEK and methods of use thereof |
EP1535618A1 (en) | 2003-11-26 | 2005-06-01 | Schering Aktiengesellschaft | Pharmaceutical preparation for continuous hormonal treatment over a period of longer than 21-28 days comprising two estrogen and/or progestin compositions |
US20050113350A1 (en) | 2003-11-26 | 2005-05-26 | Bernd Duesterberg | Extended use combination comprising estrogens and progestins |
US20050186183A1 (en) | 2003-12-08 | 2005-08-25 | Deangelo Joseph | Stabilized products, processes and devices for preparing same |
US20050129756A1 (en) | 2003-12-10 | 2005-06-16 | Hans-Peter Podhaisky | UV-stable, liquid or semisolid transdermal pharmaceutical preparation with light sensitive active ingredient |
CN1889994A (en) | 2003-12-10 | 2007-01-03 | 艾克若克斯Dds有限公司 | Method of treatment for undesired effect following transdermal or topical drug delivery |
MXPA06006810A (en) | 2003-12-17 | 2006-08-23 | Pfizer Prod Inc | Continuous combination therapy with selective prostaglandin ep4, receptor agonists and an estrogen for the treatment of conditions that present with low bone mass. |
CA2550811C (en) | 2003-12-24 | 2012-05-01 | Jane Hirsh | Temperature-stable formulations, and methods of development thereof |
US20080069791A1 (en) | 2003-12-29 | 2008-03-20 | Universitaetsklinikum Muenster | Means for stimulation and activation of hair growth by il-15 |
IL159729A0 (en) | 2004-01-06 | 2004-06-20 | Doron I Friedman | Non-aqueous composition for oral delivery of insoluble bioactive agents |
ES2702607T3 (en) | 2004-01-07 | 2019-03-04 | E L Man Corporation | Cosmetic composition and hair growth retardation method |
US20060084704A1 (en) | 2004-01-28 | 2006-04-20 | Charles Shih | Methods and compositions for enhancing degradation of nuclear receptor transcription factors and uses thereof |
US7820702B2 (en) | 2004-02-04 | 2010-10-26 | Bristol-Myers Squibb Company | Sulfonylpyrrolidine modulators of androgen receptor function and method |
US20050182105A1 (en) | 2004-02-04 | 2005-08-18 | Nirschl Alexandra A. | Method of using 3-cyano-4-arylpyridine derivatives as modulators of androgen receptor function |
US20050271597A1 (en) | 2004-02-13 | 2005-12-08 | Keith Alec D | Prostate hypertrophy treatment composition and method |
DE602005013490D1 (en) | 2004-02-23 | 2009-05-07 | Euro Celtique Sa | MISSIBLE TRANSDERMAL DISTRIBUTION DEVICE FOR OPIOIDE, CONTAINING OPIOIDANT AGONIST IN THE FORM OF MICRO BEAMS |
US8052669B2 (en) | 2004-02-25 | 2011-11-08 | Femasys Inc. | Methods and devices for delivery of compositions to conduits |
US8147561B2 (en) | 2004-02-26 | 2012-04-03 | Endosphere, Inc. | Methods and devices to curb appetite and/or reduce food intake |
US7378426B2 (en) | 2004-03-01 | 2008-05-27 | Bristol-Myers Squibb Company | Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
US7417040B2 (en) | 2004-03-01 | 2008-08-26 | Bristol-Myers Squibb Company | Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
US20050196434A1 (en) | 2004-03-04 | 2005-09-08 | Brierre Barbara T. | Pharmaceutical composition and method for the transdermal delivery of magnesium |
US20050220825A1 (en) | 2004-03-10 | 2005-10-06 | Adrian Funke | Molecular dispersions of drospirenone |
MY142989A (en) | 2004-03-10 | 2011-02-14 | Bayer Schering Pharma Ag | Stabilised supersaturated solids of lipophilic drugs |
PL1748756T3 (en) | 2004-03-10 | 2009-10-30 | Bayer Schering Pharma Ag | Compositions comprising drospirenone molecularly dispersed |
US20050222106A1 (en) | 2004-04-01 | 2005-10-06 | Stefan Bracht | Drospirenone-containing preparations for transdermal use |
US20080138390A1 (en) | 2004-04-07 | 2008-06-12 | Tsung-Min Hsu | Transdermal Delivery System For Use With Basic Permeation Enhancers |
US20050228692A1 (en) | 2004-04-08 | 2005-10-13 | Hodgdon Darren W | Incentive based health care insurance program |
US20050228718A1 (en) | 2004-04-13 | 2005-10-13 | Pop Insights Inc. | Point of purchase research device |
US20050239747A1 (en) | 2004-04-21 | 2005-10-27 | Pharmaceutical Industry Technology And Development Center | Compositions and methods of enhanced transdermal delivery of steroid compounds and preparation methods |
WO2005105107A2 (en) | 2004-04-21 | 2005-11-10 | Roby Russell R | Hormone treatment of multiple sclerosis |
RU2275930C2 (en) | 2004-04-26 | 2006-05-10 | ООО "РусГен" | Composition for correction of human endocrine system age-related changes (variants) and method for production of pharmaceutical formulation based on the same |
US20050244522A1 (en) | 2004-04-30 | 2005-11-03 | Carrara Dario Norberto R | Permeation enhancer comprising genus Curcuma or germacrone for transdermal and topical administration of active agents |
US20050250746A1 (en) | 2004-05-06 | 2005-11-10 | Matthew Iammatteo | Premenstrual dysphoric disorder medication |
EP1744750A2 (en) | 2004-05-06 | 2007-01-24 | Sandoz AG | Pharmaceutical composition comprising hydrophobic drug having improved solubility |
PT1750766E (en) | 2004-05-11 | 2013-09-30 | Emotional Brain Bv | Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction |
FR2870125B1 (en) | 2004-05-12 | 2010-03-26 | Dermaconcept Jmc | FORMULATION OF THE SPOT-ON TYPE USEFUL IN COSMETOLOGY AND DERMATOLOGY |
US7899527B2 (en) | 2004-05-13 | 2011-03-01 | Palo Alto Investors | Treatment of conditions through modulation of the autonomic nervous system during at least one predetermined menstrual cycle phase |
US7534780B2 (en) | 2004-05-21 | 2009-05-19 | Bayer Schering Pharma Aktiengesellschaft | Estradiol prodrugs |
US7101342B1 (en) | 2004-05-24 | 2006-09-05 | Caillouette James C | Detection of menopause status and treatment thereof |
EP1755618A1 (en) | 2004-05-26 | 2007-02-28 | Wyeth a Corporation of the State of Delaware | Compositions and methods for treatment of premenstrual dysphoric disorder |
US20070196453A1 (en) | 2004-06-07 | 2007-08-23 | Jie Zhang | Two or more non-volatile solvent-containing compositions and methods for dermal delivery of drugs |
WO2005120517A1 (en) | 2004-06-07 | 2005-12-22 | Strides Arcolab Limited | Stable liquid suspension formulation comprising synthetic steroids and process for producing the same |
DE102004028284A1 (en) | 2004-06-11 | 2006-01-05 | Hexal Ag | Matrix-controlled transdermal therapeutic system based on a hotmelt adhesive for the application of norelgestromin |
US7485666B2 (en) | 2004-06-17 | 2009-02-03 | Kimberly-Clark Worldwide, Inc. | Vaginal health products |
US7235563B2 (en) | 2004-06-21 | 2007-06-26 | Bristol-Myers Squibb Company | Spirocyclic compounds useful as modulators of nuclear hormone receptor function |
EP1773344A1 (en) | 2004-07-07 | 2007-04-18 | Wyeth a Corporation of the State of Delaware | Cyclic progestin regimens and kits |
FR2873585B1 (en) | 2004-07-27 | 2006-11-17 | Aventis Pharma Sa | NEW GALENIC FORMULATIONS OF ACTIVE PRINCIPLES |
US8541400B2 (en) | 2004-08-04 | 2013-09-24 | Camurus Ab | Compositions forming non-lamellar dispersions |
GT200500183A (en) | 2004-08-09 | 2006-04-10 | PROGESTERONE RECEIVER MODULATORS UNDERSTANDING PIRROL-OXINDOL DERIVATIVES AND THEIR USES | |
GT200500185A (en) | 2004-08-09 | 2006-04-10 | PROGESTERONE RECEIVER MODULATORS UNDERSTANDING PIRROL-OXINDOL DERIVATIVES AND THEIR USES | |
US20060034889A1 (en) | 2004-08-16 | 2006-02-16 | Macromed, Inc. | Biodegradable diblock copolymers having reverse thermal gelation properties and methods of use thereof |
US20060040904A1 (en) | 2004-08-17 | 2006-02-23 | Ahmed Salah U | Vaginal cream compositions, kits thereof and methods of using thereof |
TW200616604A (en) | 2004-08-26 | 2006-06-01 | Nicholas Piramal India Ltd | Nitric oxide releasing prodrugs containing bio-cleavable linker |
US7879830B2 (en) | 2004-09-02 | 2011-02-01 | Wiley Teresa S | Hormone replacement composition and method |
US20070167418A1 (en) | 2004-09-07 | 2007-07-19 | Ferguson Steven W | Progesterone/testosterone cream for erectile dysfunction |
AR043476A1 (en) | 2004-09-09 | 2005-08-03 | Dvoskin Victor Oscar | REGULATED SUBSTANCE ADMINISTRATION DEVICE FOR INSERTION IN A BODY CAVITY AND PROCEDURE FOR MANUFACTURING A SUPPORT MEDIA FOR SUCH SUBSTANCES |
PL1796692T3 (en) | 2004-09-09 | 2012-08-31 | Warburton Technology Ltd | Trace elements |
CA2580264A1 (en) | 2004-09-13 | 2006-03-23 | Pr Pharmaceuticals, Inc. | Long acting injectable crystal formulations of estradiol metabolites and methods of using same |
US8252321B2 (en) | 2004-09-13 | 2012-08-28 | Chrono Therapeutics, Inc. | Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like |
US20060058238A1 (en) | 2004-09-15 | 2006-03-16 | Lee Laurent-Applegate | Fetal skin cell protein compositions for the treatment of skin conditions, disorders or diseases and methods of making and using the same |
US20070254314A1 (en) | 2004-09-16 | 2007-11-01 | Geier Mark R | Methods of treating autism and autism spectrum disorders |
ES2366193T3 (en) | 2004-09-20 | 2011-10-18 | Janssen Pharmaceutica Nv | NEW DERIVATIVES CONTAINING TETRACYCLIC HETEROATOMS USEFUL AS MODULATORS OF SEXUAL STEROID HORMONE RECEPTORS. |
US20060062758A1 (en) | 2004-09-21 | 2006-03-23 | Nastech Pharmaceutical Comapny Inc. | Tight junction modulator peptide PN159 for enhanced mucosal delivery of therapeutic compounds |
ATE401913T1 (en) | 2004-09-27 | 2008-08-15 | Pantarhei Bioscience Bv | TREATMENT OR PREVENTION OF UNSCHEDULED BLEEDING IN WOMEN ON PROGESTOGEN-CONTAINING MEDICATION |
WO2006036899A2 (en) | 2004-09-27 | 2006-04-06 | Corium International, Inc. | Transdermal systems for the delivery of estrogens and progestins |
US20070111975A1 (en) | 2004-10-07 | 2007-05-17 | Duramed Pharmaceuticals, Inc. | Methods of Hormonal Treatment Utilizing Ascending-Dose Extended Cycle Regimens |
RS20070166A (en) | 2004-10-20 | 2008-09-29 | Endorecherche Inc., | Sex steroid precursors alone or in combination with a selective estrogen receptor modulator... |
US7569725B2 (en) | 2004-10-21 | 2009-08-04 | Britsol-Myers Squibb Company | Anthranilic acid derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
US8022053B2 (en) | 2004-11-02 | 2011-09-20 | Bayer Schering Pharma Aktiengesellschaft | Oral solid dosage forms containing a low dose of estradiol |
WO2006051818A1 (en) | 2004-11-10 | 2006-05-18 | Hisamitsu Pharmaceutical Co., Inc. | Drug for external use and adhesive patch |
US20060106004A1 (en) | 2004-11-12 | 2006-05-18 | Brody Steven A | Unique methods and formulations of bio-identical sex steroids for the treatment of pathophysiologic aberrations of menopause |
US20060110415A1 (en) | 2004-11-22 | 2006-05-25 | Bioderm Research | Topical Delivery System for Cosmetic and Pharmaceutical Agents |
US8121886B2 (en) | 2004-12-03 | 2012-02-21 | Ryma Technology Solutions Inc. | Confidence based selection for survey sampling |
US7465587B2 (en) | 2004-12-03 | 2008-12-16 | Genzyme Corporation | Diagnostic assay device |
AT501408B1 (en) | 2004-12-07 | 2011-03-15 | Physikalisches Buero Steinmueller Gmbh | BIOLOGICAL SURFACES |
CA2588566A1 (en) | 2004-12-17 | 2006-06-22 | Bionovo, Inc. | Estrogenic extracts of morus alba and uses thereof |
US20060134188A1 (en) | 2004-12-20 | 2006-06-22 | Hans-Peter Podhaisky | Transdermal pharmaceutical preparation with a progesterone A-specific ligand (PRASL) as active ingredient |
US20070060589A1 (en) | 2004-12-21 | 2007-03-15 | Purandare Ashok V | Inhibitors of protein arginine methyl transferases |
WO2006081518A2 (en) | 2005-01-28 | 2006-08-03 | Collegium Pharmaceutical, Inc. | Non-ionic non-aqueous vehicles for topical and oral administration of carrier-complexed active agents |
ITMI20050262A1 (en) | 2005-02-21 | 2006-08-22 | Carlo Ghisalberti | SUBSTANCES COMPOSITIONS AND METHODS OF TREATMENT OF ALOPECIA |
US8703198B2 (en) | 2005-03-02 | 2014-04-22 | Aquatrove Biosciences | Water-based personal moisturizers and lubricants, in particular vaginal lubricants, and uses thereof |
US7473687B2 (en) | 2005-03-24 | 2009-01-06 | Emory University | Methods for the treatment of a traumatic central nervous system injury |
US7405186B2 (en) | 2005-03-25 | 2008-07-29 | Chemsil Silicones, Inc. | Lubricant compositions, condom products and methods of making same |
CN101227892B (en) | 2005-04-08 | 2013-06-05 | 舌交付有限公司 | Buccal delivery system |
KR20080016552A (en) | 2005-04-13 | 2008-02-21 | 유니메드 파마슈티칼스, 인크. | Method of increasing testosterone and related steroid concentrations in women |
WO2006113505A2 (en) | 2005-04-15 | 2006-10-26 | Clarus Therapeutics, Inc. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
WO2006113458A1 (en) | 2005-04-15 | 2006-10-26 | Bristol-Myers Squibb Company | Heterocyclic inhibitors of protein arginine methyl transferases |
WO2007124250A2 (en) | 2006-04-21 | 2007-11-01 | Antares Pharma Ipl Ag | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
US9205047B2 (en) | 2005-04-25 | 2015-12-08 | The Governing Council Of The University Of Toronto | Tunable sustained release of a sparingly soluble hydrophobic therapeutic agent from a hydrogel matrix |
US7767656B2 (en) | 2005-04-25 | 2010-08-03 | Molly S Shoichet | Blends of temperature sensitive and anionic polymers for drug delivery |
US8962013B2 (en) | 2005-05-02 | 2015-02-24 | Bayer Intellectual Property Gmbh | Multi-layered transdermal system with triazine UV absorber |
US20060252049A1 (en) | 2005-05-04 | 2006-11-09 | Shuler Richard O | Growth-promoting and immunizing subcutaneous implant |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
US20060251581A1 (en) | 2005-05-09 | 2006-11-09 | Mcintyre Jon T | Method for treatment of uterine fibroid tumors |
US8048017B2 (en) | 2005-05-18 | 2011-11-01 | Bai Xu | High-aspect-ratio microdevices and methods for transdermal delivery and sampling of active substances |
EP1893182B8 (en) | 2005-05-26 | 2012-04-04 | Teva Women's Health, Inc. | Oral dosage forms comprising progesterone and method of making and using the same |
ES2607454T3 (en) | 2005-06-03 | 2017-03-31 | Acrux Dds Pty Ltd | Method and composition for transdermal testosterone delivery |
ITBO20050388A1 (en) | 2005-06-06 | 2006-12-07 | Alfa Wassermann Spa | USEFUL FORMULATION OF MUCOADESIVES IN MEDICAL DEVICES IN PHARMACEUTICAL PREPARATIONS |
US20060280795A1 (en) | 2005-06-08 | 2006-12-14 | Dexcel Pharma Technologies, Ltd. | Specific time-delayed burst profile delivery system |
JP5339903B2 (en) | 2005-06-09 | 2013-11-13 | ワイス・エルエルシー | Tanaproget composition comprising ethinylestradiol |
EP1904028A1 (en) | 2005-06-16 | 2008-04-02 | Warner Chilcott Company Inc. | Estrogen compositions for vaginal administration |
CA2612456C (en) | 2005-06-16 | 2017-06-06 | Warner Chilcott Company, Inc. | Gel compositions for topical administration |
CA2612415A1 (en) | 2005-06-16 | 2006-12-28 | Warner Chilcott Company, Inc. | Estrogen compositions for vaginal administration |
TW200726473A (en) | 2005-06-28 | 2007-07-16 | Wyeth Corp | Compositions and methods for treatment of cycle-related symptoms |
EP1898953B1 (en) | 2005-06-29 | 2012-12-05 | Warner Chilcott Company, LLC | Quadraphasic continuous graduated estrogen contraceptive |
US20070010550A1 (en) | 2005-07-08 | 2007-01-11 | The Board Of Regents Of The University Of Texas | Scopolamine to Reduce or Eliminate Hot Flashes, Night Sweats, and Insomnia |
US20070014839A1 (en) | 2005-07-18 | 2007-01-18 | Stefan Bracht | Decomposer film for transdermal patches |
DE102005034498A1 (en) | 2005-07-20 | 2007-01-25 | Grünenthal GmbH | Oral contraception with Trimegeston |
US8195403B2 (en) | 2005-07-21 | 2012-06-05 | The Invention Science Fund I, Llc | Selective resonance of bodily agents |
PE20070341A1 (en) | 2005-07-29 | 2007-04-13 | Wyeth Corp | PIRROL DERIVATIVES AS PROGESTERONE RECEPTOR MODULATORS |
US20070027107A1 (en) | 2005-07-29 | 2007-02-01 | Curt Hendrix | Compositions and methods for treating estrogen-dependent diseases and conditions |
US10137135B2 (en) | 2005-08-15 | 2018-11-27 | Allergan Sales, Llc | Formulations and methods for providing progestin-only contraception while minimizing adverse side effects associated therewith |
CA2622721A1 (en) | 2005-09-16 | 2007-03-22 | Cereuscience Ab | Method and means of preventing and treating sleep disordered breathing |
US20070066628A1 (en) | 2005-09-19 | 2007-03-22 | Wyeth | 5-Aryl-indan-1-ol and analogs useful as progesterone receptor modulators |
US7319152B2 (en) | 2005-09-19 | 2008-01-15 | Wyeth | 5-Aryl-indan-1-one and analogs useful as progesterone receptor modulators |
US7414142B2 (en) | 2005-09-19 | 2008-08-19 | Wyeth | 5-aryl-indan-1-one oximes and analogs useful as progesterone receptor modulators |
AU2006297041A1 (en) | 2005-09-27 | 2007-04-05 | Stem Cell Therapeutics Corp. | Oligodendrocyte precursor cell proliferation regulated by prolactin |
US8372806B2 (en) | 2005-10-06 | 2013-02-12 | Pantec Biosolutions Ag | Transdermal delivery system for treating infertility |
US7550458B2 (en) | 2005-10-18 | 2009-06-23 | Bristol-Myers Squibb Company | Tricycloundecane compounds useful as modulators of nuclear hormone receptor function |
US20090215731A1 (en) | 2005-10-19 | 2009-08-27 | Chavah Pty Ltd. | Reduction of Side Effects From Aromatase Inhibitors Used for Treating Breast Cancer |
CA2626518A1 (en) | 2005-10-19 | 2007-04-26 | Scott Josephson | Improved reproductive management |
US8096940B2 (en) | 2005-10-19 | 2012-01-17 | Iversync Ii Llc | Reproductive management |
DE102005050729A1 (en) | 2005-10-19 | 2007-04-26 | Schering Ag | Method of preventive on-demand hormonal contraception |
CA2627315A1 (en) | 2005-10-24 | 2007-05-03 | Manawatu Biotech Investments, Ltd. | Ovulation cycle monitoring and management |
US20070093548A1 (en) | 2005-10-25 | 2007-04-26 | Wyeth | Use of progesterone receptor modulators |
IE20050723A1 (en) | 2005-10-28 | 2007-05-30 | Patrick T Prendergast | Anti-mineralocorticoid therapy of infection |
US8158152B2 (en) | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
JP2009516694A (en) | 2005-11-22 | 2009-04-23 | スミスクライン ビーチャム コーポレーション | Compound |
WO2007062190A2 (en) | 2005-11-22 | 2007-05-31 | Smithkline Beecham Corporation | Chemical compounds |
US20080234199A1 (en) | 2005-11-22 | 2008-09-25 | Smithkline Beecham Corporation | Chemical Compounds |
EP1951043A2 (en) | 2005-11-22 | 2008-08-06 | SmithKline Beecham Corporation | Chemical compounds |
WO2007062151A2 (en) | 2005-11-22 | 2007-05-31 | Smithkline Beecham Corporation | Chemical compounds |
US20070116829A1 (en) | 2005-11-23 | 2007-05-24 | The Coca-Cola Company | Pharmaceutical Composition with High-Potency Sweetener |
TWI389709B (en) | 2005-12-01 | 2013-03-21 | Novartis Ag | Transdermal therapeutic system |
GB0524961D0 (en) | 2005-12-07 | 2006-01-18 | Pharmakodex Ltd | Transdermal administration of active agents for systemic effect |
CA2631493A1 (en) | 2005-12-15 | 2007-06-21 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration |
US8337814B2 (en) | 2005-12-15 | 2012-12-25 | Topical Sinus Therapeutics, Inc. | Treatment of active infections, sinusitis, rhinitis, and related neurological disorders and related compositions |
US20090093440A1 (en) | 2005-12-20 | 2009-04-09 | Howard Murad | Fragranced Therapeutic Delivery System |
US20090047357A1 (en) | 2005-12-22 | 2009-02-19 | Otsuka Pharmaceutical Co., Ltd. | Method of producing drug-containing wax matrix particles, extruder to be used in the method and sustained-release preparation containing cilostazol |
CN101374860A (en) | 2005-12-23 | 2009-02-25 | 技术转让合伙人公司 | Synthetic peptides for use as inhibitors of neurotransmitter secretion and as inducers of cellular relaxation |
US9393218B2 (en) | 2005-12-23 | 2016-07-19 | Epinamics Gmbh | Use of film-forming hair care polymers from the group of polyurethanes and pharmaceutical preparations and patches that contain these polymers |
WO2007076144A2 (en) | 2005-12-27 | 2007-07-05 | Duramed Pharmaceuticals, Inc. | Conjugated estrogen compositions, applicators, kits, and methods of making and use thereof |
KR20130116954A (en) | 2005-12-28 | 2013-10-24 | 프레세니어스 카비 온콜로지 리미티드 | A biocompatible, non-biodegradable, non-toxic polymer useful for nanoparticle pharmaceutical compositions |
KR100750320B1 (en) | 2006-01-04 | 2007-08-17 | 학교법인 포항공과대학교 | Gel comprising cucurbitril |
EA018606B1 (en) | 2006-01-05 | 2013-09-30 | Велоксис Фармасьютикалз А/С | Disintegrating loadable tablets |
KR100784485B1 (en) | 2006-01-18 | 2007-12-11 | 한국과학기술연구원 | Biodegradable and thermosensitive polyorganophosphazene hydrogel, preparation method thereof and use thereof |
BRPI0706925A2 (en) | 2006-01-20 | 2011-04-19 | Pera Tree Pharmaceuticals Inc | pharmaceutical composition for vaginal administration in a subject and method for treating urogenital symptoms of atrophic vaginitis |
JP2009508852A (en) | 2006-01-23 | 2009-03-05 | クワンジュ インスティチュート オブ サイエンス アンド テクノロジー | Conjugate in which pharmacologically active substance and mucoadhesive polymer are covalently bonded, and method for transmucosal delivery of pharmacologically active substance using the same |
WO2007117352A2 (en) | 2006-02-08 | 2007-10-18 | Howard Murad | Topical therapeutic delivery system |
CA2638124A1 (en) | 2006-02-24 | 2007-08-30 | Axelar Ab | Use of cyclolignans for the treatment of type 2 diabetes and as contraceptives |
CA2640520C (en) | 2006-03-02 | 2014-04-22 | Warner Chilcott Company, Inc. | Extended cycle multiphasic oral contraceptive method |
US20070207225A1 (en) | 2006-03-03 | 2007-09-06 | Francesco Squadrito | Genistein modulated reduction of cardiovascular risk factors |
GB0604535D0 (en) | 2006-03-07 | 2006-04-12 | Sndv Sprl | Betulonic acid derivatives |
AU2007224006A1 (en) | 2006-03-07 | 2007-09-13 | Novavax, Inc. | Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same |
KR100746962B1 (en) | 2006-04-04 | 2007-08-07 | 한국과학기술연구원 | Thermosensitive polyphosphazene-bioactive molecule conjugates, preparation method thereof and use thereof |
AU2007234841A1 (en) | 2006-04-05 | 2007-10-18 | Wyeth | Methods for prevention and treatment of conditions arising from local estrogen deficiency |
US20100048523A1 (en) | 2006-04-07 | 2010-02-25 | Bachman Kurtis E | Compounds, Compositions and Methods for Treating Hormone-Dependent Maladies |
AU2007240983A1 (en) | 2006-04-07 | 2007-11-01 | Novavax, Inc. | Nanostructured compositions having antibacterial, anti-fungal, anti-yeast, and/or anti-viral properties |
WO2007120868A2 (en) | 2006-04-14 | 2007-10-25 | Stanley Kepka | Bioavailability enhancement of lipophilic drug by use solvent system |
US8399012B2 (en) | 2006-04-17 | 2013-03-19 | Kimberly-Clark Worldwide, Inc. | Degradable therapeutic delivery device |
FR2900052B1 (en) | 2006-04-19 | 2011-02-18 | Galderma Sa | COMPOSITION COMPRISING AT LEAST ONE AQUEOUS PHASE AND AT LEAST ONE FATTY PHASE COMPRISING IVERMECTIN |
WO2007127158A2 (en) | 2006-04-25 | 2007-11-08 | Croda, Inc | Modification of percutaneous absorption of topically active materials |
US20070254858A1 (en) | 2006-04-27 | 2007-11-01 | Cronk Peter J | Contraceptive and Acne Medication Combination and Treatment of Acne and Other Diseases with Reduced Side Effects |
WO2007128349A1 (en) | 2006-05-10 | 2007-11-15 | Evonik Degussa Gmbh | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
JP5193196B2 (en) | 2006-06-02 | 2013-05-08 | ペア ツリー ウーマンズ ヘルス ケア | Methods of treatment for atrophic vaginitis |
US20070281008A1 (en) | 2006-06-05 | 2007-12-06 | Lin Shun Y | Personal lubricant compositions and kits for providing personal lubrication |
US20070287789A1 (en) | 2006-06-07 | 2007-12-13 | Stephen Ray Jones | Bleed-resistant colored microparticles |
US20080113953A1 (en) | 2006-06-08 | 2008-05-15 | Warner Chilcott Company, Inc. | Methods to administer solid dosage forms of ethinyl estradiol and prodrugs thereof with improved bioavailability |
US20070286819A1 (en) | 2006-06-08 | 2007-12-13 | Warner Chilcott Company, Inc. | Methods to administer ethinyl estradiol and prodrugs thereof with improved bioavailability |
US20080021003A1 (en) * | 2006-06-13 | 2008-01-24 | Vladimir Hanes | Extended step-down estrogen regimen |
US20070292493A1 (en) | 2006-06-15 | 2007-12-20 | Brierre Barbara T | Pharmaceutical composition and method for the transdermal delivery of calcium |
US8288366B2 (en) | 2006-06-20 | 2012-10-16 | Chochinov Ronald H | Formulation for hair growth |
EP1872775A1 (en) | 2006-06-29 | 2008-01-02 | Polichem S.A. | Use of a hydrophilic matrix comprising a polyacrylic acid derivative, a cellulose ether and a disintegrant for the manufacture of a medicament for treating female genital disorders |
US7989487B2 (en) | 2006-07-06 | 2011-08-02 | University Of Medicine And Dentistry Of New Jersey | Estrogen receptor modulators and uses thereof |
US8617597B2 (en) | 2006-07-06 | 2013-12-31 | Bayer Intellectual Property Gmbh | Pharmaceutical composition containing a tetrahydrofolic acid |
EP1880715A1 (en) | 2006-07-19 | 2008-01-23 | Abbott GmbH & Co. KG | Pharmaceutically acceptable solubilizing composition and pharmaceutical dosage form containing same |
JP5270542B2 (en) | 2006-07-22 | 2013-08-21 | オキサジェン リミテッド | Compound having CRTH2 antagonist activity |
DE102006035549A1 (en) | 2006-07-27 | 2008-01-31 | Evonik Röhm Gmbh | Pharmaceutical form with at least two-layer separating layer |
US20080026062A1 (en) | 2006-07-31 | 2008-01-31 | Isaac Farr | Pharmaceutical compositions including nano-sized active agent |
US20080026040A1 (en) | 2006-07-31 | 2008-01-31 | Isaac Farr | Active agent-releasing dosage forms |
US20080038219A1 (en) | 2006-08-07 | 2008-02-14 | Calgenex Corporation | Novel Composition for a Topical Skin Treatment Base and Medicated Applications Thereof |
US20080095831A1 (en) | 2006-08-10 | 2008-04-24 | Mc Graw Thomas L | Topical formulation of multilamellar vesicles composition for percutaneous absorption of pharmaceutically active agent |
US20080085877A1 (en) | 2006-08-10 | 2008-04-10 | Drugtech Corporation | Therapeutic methods of using estrogen compositions |
US20080038350A1 (en) | 2006-08-10 | 2008-02-14 | Hagen Gerecke | Low-dosage peroral medication for contraception containing crystalline dienogest and ethinyl estradiol |
WO2008032212A2 (en) | 2006-09-08 | 2008-03-20 | Foamix Ltd. | Colored or colorable foamable composition and foam |
CA2664315C (en) | 2006-09-15 | 2016-01-19 | Echo Pharmaceuticals B.V. | Dosage unit for sublingual, buccal or oral administration of water-insoluble pharmaceutically active substances |
EP2063870A2 (en) | 2006-09-16 | 2009-06-03 | Bayer Schering Pharma Aktiengesellschaft | Oral modified release formulations |
AU2007304471B2 (en) | 2006-10-04 | 2012-09-06 | M & P Patent Aktiengesellschaft | Controlled release delivery system for nasal application of neurotransmitters |
US20080175814A1 (en) | 2006-10-12 | 2008-07-24 | Supergen, Inc. | Quinoline derivatives for modulating dna methylation |
WO2008062466A2 (en) | 2006-10-13 | 2008-05-29 | Reliance Life Sciences Pvt. Ltd. | Cinnamic acid, vanillic acid and benzofuran derivatives for use in the treatment of inflammation and cancer |
EP1930010A1 (en) | 2006-10-20 | 2008-06-11 | Bayer Schering Pharma Aktiengesellschaft | Application of estradiol valerate or 17ß-estradiol in combination with dienogest for oral therapy to maintain and/or increase the female libido |
EP1915986A1 (en) | 2006-10-23 | 2008-04-30 | BIOPHARM GESELLSCHAFT ZUR BIOTECHNOLOGISCHEN ENTWICKLUNG VON PHARMAKA mbH | Lipid growth factor formulations |
US8636787B2 (en) | 2006-10-25 | 2014-01-28 | Arterial Remodeling Technologies, S.A. | Method for expansion and deployment of polymeric structures including stents |
DE102006050558B4 (en) | 2006-10-26 | 2009-03-26 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing norelgestromin for contraception and hormone replacement |
US20080103116A1 (en) | 2006-11-01 | 2008-05-01 | Jennings-Spring Barbara L | Method of treatment and compositions of D-chiro inositol and phosphates thereof |
US20090214474A1 (en) | 2006-11-01 | 2009-08-27 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
WO2008063910A2 (en) | 2006-11-08 | 2008-05-29 | Novavax, Inc. | Method of preparing solid dosage forms of multi-phasic pharmaceutical compositions |
US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US7829116B2 (en) | 2006-11-14 | 2010-11-09 | Momentive Performance Materials Inc. | Adhesive-forming composition and blend of adhesives obtained therefrom |
DE102006054731B4 (en) | 2006-11-21 | 2013-02-28 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system for administration of the active ingredient buprenorphine and use thereof in pain therapy |
EP2097065A2 (en) | 2006-11-29 | 2009-09-09 | Foamix Ltd. | Foamable waterless compositions with modulating agents |
US20080175905A1 (en) | 2006-11-29 | 2008-07-24 | Wyeth | Estrogen/serm and estrogen/progestin bi-layer tablets |
US20080132475A1 (en) | 2006-12-05 | 2008-06-05 | Charles Gerald Connor | Treatment for dry eye |
US9918934B2 (en) | 2006-12-12 | 2018-03-20 | Edgar Joel Acosta-Zara | Linker-based lecithin microemulsion delivery vehicles |
US20080145423A1 (en) | 2006-12-14 | 2008-06-19 | Ajmal Ali Khan | Chewable tablet and method of formulating |
ATE498620T1 (en) | 2006-12-20 | 2011-03-15 | Bayer Healthcare Llc | 4-Ä4-Ä(Ä3-TERT-BUTYL-1-Ä3-(HYDROXYMETHYL)-PHENY Ü-1H-PYRAZOLE-5-YLÜ-CARBAMOYL)-AMINOÜ-3- FLUOROPHENOXYÜ -N-METHYLPYRIDINE-2-CARBOXAMIDE AND PRODRUGS AND SALTS THEREOF FOR THE TREATMENT OF CANCER |
WO2008079898A1 (en) | 2006-12-20 | 2008-07-03 | Pharmwest, Inc. | Methods and topical formulations comprising colloidal metal for treating or preventing skin conditions |
CA2674078C (en) | 2006-12-26 | 2012-03-20 | Femmepharma Holding Company, Inc. | Topical administration of danazol |
TWI433674B (en) | 2006-12-28 | 2014-04-11 | Infinity Discovery Inc | Cyclopamine analogs |
GB2445539A (en) | 2006-12-29 | 2008-07-16 | Ardana Bioscience Ltd | Bigel composition |
US20090203658A1 (en) | 2007-01-08 | 2009-08-13 | Duke University | Neuroactive steroid compositions and methods of use therefor |
EP2106272A4 (en) | 2007-01-11 | 2011-05-04 | Acrux Dds Pty Ltd | Spreading implement |
AU2008206476A1 (en) | 2007-01-12 | 2008-07-24 | Wyeth | Tablet-in-tablet compositions |
EP2051702A1 (en) | 2007-01-22 | 2009-04-29 | Novavax, Inc. | Multi-phasic pharmaceutical formulations of poorly water-soluble drugs for reduced fed/fasted variability and improved oral bioavailability |
US8828981B2 (en) | 2007-02-06 | 2014-09-09 | George Creasy | Progesterone for the treatment or prevention of spontaneous preterm birth |
IL181217A0 (en) | 2007-02-08 | 2007-07-04 | Haim Levy | Pharmaceuticalcompositions based on a microemulsion |
WO2008121447A1 (en) | 2007-02-14 | 2008-10-09 | Northwestern University | Self-assembling membranes and related methods thereof |
CA2678496A1 (en) | 2007-02-20 | 2008-08-28 | Galderma Research & Development | A method for delivery of a therapeutic substance into the skin |
US20080206156A1 (en) | 2007-02-22 | 2008-08-28 | Cronk Peter J | Continuous spray scalp therapy and dispensing systems for same |
US20100105071A1 (en) | 2007-02-28 | 2010-04-29 | Children's Medical Center Corporation | Methods for predicting the onset of menarche |
US20080214512A1 (en) | 2007-03-01 | 2008-09-04 | Christian Seitz | Pharmaceutical preparation containing a gestagen, and kit and method for treating endometriosis using the preparation |
DE102007011486A1 (en) | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Medicament comprising at least one progestin |
US20080226698A1 (en) | 2007-03-16 | 2008-09-18 | Mylan Technologies, Inc. | Amorphous drug transdermal systems, manufacturing methods, and stabilization |
CA2680825C (en) | 2007-03-22 | 2013-10-29 | Cytotech Labs, Llc | Topical formulations having enhanced bioavailability |
US20090017120A1 (en) | 2007-03-23 | 2009-01-15 | Humco Holding Group, Inc. | Phase stable lecithin organogel composition |
PL2148681T3 (en) | 2007-04-20 | 2016-09-30 | Selective progesterone modulators in the treatment of uterine bleeding | |
EP1988098A1 (en) | 2007-04-27 | 2008-11-05 | AEterna Zentaris GmbH | Novel Tetrahydrocarbazole Derivatives as Ligands of G-protein Coupled Receptors |
WO2008140794A1 (en) | 2007-05-11 | 2008-11-20 | The Texas A & M University System | Hormone normalization therapy and uses thereof |
EP2164498A4 (en) | 2007-06-04 | 2010-09-08 | Univ California | Pregnancy hormone combination for treatment of autoimmune diseases |
US20080312197A1 (en) | 2007-06-14 | 2008-12-18 | Rodriguez Gustavo C | Pharmaceutical products containing hormones and a 25-hydroxy vitamin d compound |
KR100968591B1 (en) | 2007-06-14 | 2010-07-08 | 한국과학기술연구원 | Polyorganophosphazene hydrogels for drug delivery, preparation method thereof and use thereof |
US20080312198A1 (en) | 2007-06-14 | 2008-12-18 | Rodriguez Gustavo C | Pharmaceutical products containing hormones and a 25-hydroxy vitamin d compound |
ES2378117T3 (en) | 2007-06-21 | 2012-04-09 | Pantarhei Bioscience B.V. | Treatment of meconium aspiration syndrome with estrogens |
ES2310968B1 (en) | 2007-06-25 | 2010-02-08 | Italfarmaco, S.A. | USE OF ESTRIOL IN LOW DOSE. |
CN101827581A (en) | 2007-06-26 | 2010-09-08 | 沃纳奇尔科特有限责任公司 | Intravaginal drug delivery devices for the delivery of macromolecules and water-soluble drugs |
CA2691777A1 (en) | 2007-06-27 | 2008-12-31 | Samos Pharmaceuticals, Llc | Multi-day delivery of biologically active substances |
FR2918277B1 (en) | 2007-07-06 | 2012-10-05 | Coretecholding | NOVEL PROCESS FOR THE PRODUCTION OF HYDRODISPERSIBLE DRY PHARMACEUTICAL FORMS AND THE HYDRODISPERSIBLE COMPOSITIONS THUS OBTAINED |
US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US8268806B2 (en) | 2007-08-10 | 2012-09-18 | Endorecherche, Inc. | Pharmaceutical compositions |
KR100937625B1 (en) | 2007-08-10 | 2010-01-20 | 주식회사 제닉 | Dissolvable Web Porous Film and Preparing Method Thereof |
US20090060997A1 (en) | 2007-08-27 | 2009-03-05 | Christian Seitz | Process for producing a pharmaceutical preparation for therapeutic treatment of endometriosis containing a combination of a gestagen and (6s)-5-methyltetrahydrofolate |
US8617100B2 (en) | 2007-09-04 | 2013-12-31 | Foamix Ltd. | Device for delivery of a foamable composition |
US20100204326A1 (en) | 2007-09-06 | 2010-08-12 | Regain Biotechnology Pvt Ltd | Novel agents for treatment of ailments and dysfunctions |
AR068409A1 (en) | 2007-09-14 | 2009-11-18 | Drugtech Corp | PHARMACEUTICAL, TRANSDERMIC COMPOSITIONS WITHOUT ALCOHOL |
US8507467B2 (en) | 2007-09-20 | 2013-08-13 | Shiseido Company, Ltd. | Transdermally absorbable preparation |
AR066166A1 (en) | 2007-09-21 | 2009-07-29 | Organon Nv | DRUG SUPPLY SYSTEM |
AU2008303129B2 (en) | 2007-09-25 | 2013-08-01 | Formulex Pharma Innovations Ltd. | Compositions comprising lipophilic active compounds and method for their preparation |
EP2195033A1 (en) | 2007-10-08 | 2010-06-16 | Fovea Pharmaceuticals SA | Aqueous ophthalmic formulations |
US20090099149A1 (en) | 2007-10-11 | 2009-04-16 | Wyeth | Bioadhesive film |
US7939546B2 (en) | 2007-10-12 | 2011-05-10 | Supergen, Inc. | Quinoline derivatives for modulating DNA methylation |
US7790746B2 (en) | 2007-10-12 | 2010-09-07 | Supergen, Inc. | Quinoline derivatives for modulating DNA methylation |
AU2008315319A1 (en) | 2007-10-25 | 2009-04-30 | Lupin Limited | Antiemetic-oral contraceptive combination |
PL2214643T3 (en) | 2007-11-02 | 2014-09-30 | Acrux Dds Pty Ltd | Transdermal delivery system for hormones and steroids |
US20090130029A1 (en) | 2007-11-21 | 2009-05-21 | Foamix Ltd. | Glycerol ethers vehicle and pharmaceutical compositions thereof |
WO2009070794A1 (en) | 2007-11-29 | 2009-06-04 | Jackson Gregg A | Progesterone-containing compositions and devices |
WO2009069006A2 (en) | 2007-11-30 | 2009-06-04 | Foamix Ltd. | Foam containing benzoyl peroxide |
US8420624B2 (en) | 2007-12-04 | 2013-04-16 | Yung Shin Pharm. Ind. Co., Ltd. | Methods for treating or preventing symptoms of hormonal variations |
WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
FR2924942B1 (en) | 2007-12-14 | 2012-06-15 | Pf Medicament | TRANSCUTANEOUS PHARMACEUTICAL COMPOSITIONS CONTAINING STEROIDAL HORMONE |
US8762865B2 (en) | 2007-12-19 | 2014-06-24 | The Iams Company | Interactive survey feedback tool |
EP2242476A2 (en) | 2008-01-14 | 2010-10-27 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
US20090181068A1 (en) | 2008-01-14 | 2009-07-16 | Dunn Richard L | Low Viscosity Liquid Polymeric Delivery System |
GB0801876D0 (en) | 2008-02-01 | 2008-03-12 | Vectura Group Plc | Suspension formulations |
GB0802403D0 (en) | 2008-02-08 | 2008-03-12 | Probiox Sa | Compositions for the treatment of oxidative stress |
EP2265629B1 (en) | 2008-03-05 | 2015-06-24 | Evestra, Inc. | Bismethylene-17 carbolactones and related uses |
US20090232897A1 (en) | 2008-03-14 | 2009-09-17 | Bijayananda Sahoo | Pharmaceutical compositions comprising conjugated estrogens |
WO2009126926A2 (en) | 2008-04-11 | 2009-10-15 | Bionovo, Inc. | Anticancer methods employing extracts of gleditsia sinensis lam |
CA2721509A1 (en) | 2008-04-14 | 2009-10-22 | Posi Visionary Solutions Llp | Method and pharmaceutical composition for obtaining the plasmatic progesterone levels required for different therapeutic indications |
ES2327201B1 (en) | 2008-04-23 | 2010-07-23 | Ignacio Umbert Millet | PERSONALIZED PHARMACEUTICAL COMPOSITION FOR THE REJUVENATION OF SKIN CONTAINING RETINOIC ACID. |
EP2293779A1 (en) | 2008-04-24 | 2011-03-16 | Evestra, Inc. | Oral contraceptive dosage forms comprising a progestogen dispersed in an enteric polymer and further comprising an estrogen |
TWI477276B (en) | 2008-04-28 | 2015-03-21 | Repros Therapeutics Inc | Antiprogestin dosing regimens |
GB0807605D0 (en) | 2008-04-28 | 2008-06-04 | Diurnal Ltd | Lipid composition |
US20090285869A1 (en) | 2008-05-14 | 2009-11-19 | Humco Holding Group, Inc. | Salt stable lecithin organogel composition |
WO2009142742A1 (en) | 2008-05-20 | 2009-11-26 | Cantimer, Inc. | Methods, systems and devices for analyzing a biological fluid sample following ion exchange |
EP2283363A1 (en) | 2008-05-20 | 2011-02-16 | Cantimer Incorporated | Methods, systems and devices for analyzing a surfactant-treated biological fluid sample |
EP2285350B1 (en) | 2008-06-16 | 2017-11-15 | Pfizer Inc | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic nanoparticles |
WO2010005726A2 (en) | 2008-06-16 | 2010-01-14 | Bind Biosciences Inc. | Therapeutic polymeric nanoparticles with mtor inhibitors and methods of making and using same |
WO2009158584A1 (en) | 2008-06-27 | 2009-12-30 | Wyeth | Dual adhesive technology |
EP2140860A1 (en) | 2008-07-03 | 2010-01-06 | Bayer Schering Pharma Oy | An improved method of contraception |
US20110190201A1 (en) | 2008-07-24 | 2011-08-04 | Searete Llc | Method, device, and kit for maintaining physiological levels of steroid hormone in a subject |
US20100028360A1 (en) | 2008-07-26 | 2010-02-04 | Craig Stephen Atwood | Methods for the modulation of brain progestagen signaling in the prevention and treatment of neurological disorders and neurodegenerative diseases |
IT1392903B1 (en) | 2008-07-29 | 2012-04-02 | Marino Salin | COMPOSITION INCLUDING AN ASSOCIATION OF ACTIVE PRINCIPLES FOR USE IN THE TOPIC TREATMENT OF CALVIZIE |
TW201008569A (en) | 2008-08-08 | 2010-03-01 | Bayer Schering Pharma Ag | Progestin-containing drug delivery system |
US20100040671A1 (en) | 2008-08-12 | 2010-02-18 | Ahmed Salah U | Intravaginal Devices With a Rigid Support, Methods of Making, and Uses Thereof |
EP2331707A4 (en) | 2008-08-28 | 2012-06-06 | Dermtech Int | Determining age ranges of skin samples |
EP2599497A3 (en) | 2008-09-08 | 2013-09-25 | Hoffman/Barrett, L.L.C. | Porphyrazine-chemotherapeutic agents conjugates |
WO2010030763A2 (en) | 2008-09-10 | 2010-03-18 | Bind Biosciences, Inc. | High throughput fabrication of nanoparticles |
WO2010029374A1 (en) | 2008-09-12 | 2010-03-18 | Critical Pharmaceuticals Limited | Improvements in the absorption of therapeutic agents across mucosal membranes or the skin |
US20100120707A1 (en) | 2008-09-16 | 2010-05-13 | Playtex Products, Llc | Dosages for menstrual suppression, contraception, and hormone replacement therapy, and methods of administering same |
WO2010033832A2 (en) | 2008-09-19 | 2010-03-25 | Evestra, Inc. | Estriol formulations |
EP2174650A1 (en) | 2008-10-08 | 2010-04-14 | Polichem SA | Modified release emulsions for application to skin or vaginal mucosa |
CA2740509A1 (en) | 2008-10-30 | 2010-05-06 | Medlite A/S | Formulation for treatment of vaginal dryness |
WO2010053548A2 (en) | 2008-11-04 | 2010-05-14 | Anchor Therapeutics, Inc. | Pthr1 receptor compounds |
CN102202678A (en) | 2008-11-04 | 2011-09-28 | 安科治疗公司 | CXCR4 receptor compounds |
EP2218447B1 (en) | 2008-11-04 | 2017-04-19 | PharmaSol GmbH | Compositions containing lipid micro- or nanoparticles for the enhancement of the dermal action of solid particles |
WO2010053547A2 (en) | 2008-11-04 | 2010-05-14 | Anchor Therapeutics, Inc. | Cxcr5 receptor compounds |
CN103396474A (en) | 2008-11-04 | 2013-11-20 | 安科治疗公司 | APJ receptor compound |
US20110301087A1 (en) | 2008-11-04 | 2011-12-08 | Mcbride Edward | Crf1 receptor compounds |
CN102209531B (en) | 2008-11-14 | 2014-08-27 | 梨花女子大学校产学协力团 | Method for preparing microspheres and microspheres produced thereby |
US8394759B2 (en) | 2008-11-21 | 2013-03-12 | Cymbiotics, Inc. | Transdermal delivery of medicaments with combinations of cetylated fatty ester penetrant complexes |
EP2367808A4 (en) | 2008-11-25 | 2012-05-09 | Evestra Inc | PROGESTATIONAL 3-(6,6-ETHYLENE-17b-HYDROXY-3-OXO-17a-PREGNA-4-ENE-17a-YL) PROPIONIC ACID g-LACTONES |
US8603999B2 (en) | 2008-12-05 | 2013-12-10 | Commonwealth Scientific And Industrial Research Organisation | Amphiphile prodrugs |
EA201170773A1 (en) | 2008-12-06 | 2012-01-30 | Интра-Селлулар Терапиз, Инк. | ORGANIC COMPOUNDS |
JP5813511B2 (en) | 2008-12-06 | 2015-11-17 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | Organic compounds |
PE20120209A1 (en) | 2008-12-06 | 2012-03-18 | Intra Cellular Therapies Inc | DERIVATIVES OF IMIDAZO- [1,2-a] -PIRAZOLO [4,3-e] PYRIMIDINE OR PYRIMIDO- [1,2-a] -PIRAZOLO [4,3-e] PYRIMIDINE AS INHIBITORS OF PHOSPHODIESTERASE 1 (PDE1) |
EP2358204B1 (en) | 2008-12-06 | 2015-08-05 | Intra-Cellular Therapies, Inc. | 4,5,7,8-tetrahydro-4-oxo-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine compounds as PDE1 inhibitors. |
SG171775A1 (en) | 2008-12-06 | 2011-07-28 | Intra Cellular Therapies Inc | Organic compounds |
PE20110834A1 (en) | 2008-12-06 | 2011-12-14 | Intra Cellular Therapies Inc | PYRROL [3,4-d] PYRIMIDINE DERIVATIVES AS PHOSPHODIESTERASE 1 (PDE1) INHIBITORS |
WO2010066203A1 (en) | 2008-12-10 | 2010-06-17 | Anhui Zhongren Technology Co., Ltd. | Controlled releasing composition |
EP2378872A4 (en) | 2008-12-18 | 2012-05-16 | B Eugene Guthery | Acne vulgaris treatment regimen |
EP2384198A4 (en) | 2008-12-30 | 2012-08-08 | Endogenx Inc | Pharmaceutical compositions and methods of treating neurological insults |
EP2381957B1 (en) | 2009-01-13 | 2015-01-07 | Lubris LLC | Therapeutic modulation of vaginal epithelium boundary lubrication |
CN102291992A (en) | 2009-01-26 | 2011-12-21 | 哈尔·维特 | Estrus synchronization preparations and effective cidr-less protocols |
EP2391358A1 (en) | 2009-01-27 | 2011-12-07 | Wisconsin Alumni Research Foundation | Therapeutic treatment of cancer and dysplasia of the cervix or vagina using estrogen antagonists |
US20110306579A1 (en) | 2009-01-30 | 2011-12-15 | Emory University | Methods of neuroprotection using neuroprotective steroids and a vitamin d |
WO2010093834A2 (en) | 2009-02-12 | 2010-08-19 | Incube Labs, Llc | Skin penetrating device and method for subcutaneous solid drug delivery |
WO2010099508A1 (en) | 2009-02-26 | 2010-09-02 | Theraquest Biosciences, Inc. | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
US8202736B2 (en) | 2009-02-26 | 2012-06-19 | The Governing Council Of The University Of Toronto | Method of hormone extraction using digital microfluidics |
WO2010104937A2 (en) | 2009-03-10 | 2010-09-16 | Northwestern University | Lateral flow strip and uses thereof |
US20120142645A1 (en) | 2009-03-17 | 2012-06-07 | Marx Christine E | Neuroactive steroid compositions and methods of use for lowering cholesterol |
AU2010224957B2 (en) | 2009-03-17 | 2016-07-21 | Intervet International B.V. | Zoo-technical drug delivery device |
US9005608B2 (en) | 2009-03-24 | 2015-04-14 | Adds Pharmaceuticals Llc | Stabilized solubility-enhanced formulations for oral delivery |
WO2010111488A1 (en) | 2009-03-27 | 2010-09-30 | Agile Therapeutics, Inc. | Transdermal delivery |
WO2010117873A2 (en) | 2009-04-06 | 2010-10-14 | Banner Pharmacaps, Inc. | Progesterone solutions for increased bioavailability |
WO2010120232A1 (en) | 2009-04-14 | 2010-10-21 | Yki, Ytkemiska Institutet Ab | A prodrug comprising beta-keto carboxylic acid, beta-keto carboxylic acid salt or beta-keto carboxylic acid ester for drug delivery |
US8694358B2 (en) | 2009-04-14 | 2014-04-08 | Vital Insights Inc. | Systems, methods, and media for survey management |
US20120129819A1 (en) | 2009-04-14 | 2012-05-24 | Medortus (Uk) Ltd | Gel compositions for administration of pharmaceutically active compounds |
US8344007B2 (en) | 2009-04-23 | 2013-01-01 | The Hong Kong Polytechnic University | Water-soluble polymer-based cantharimides as potentially selective anti-tumor agents |
EP2421367A4 (en) | 2009-04-23 | 2012-05-23 | Univ Cincinnati | Allantoin administration for the treatment of neurodegenerative disease and neurotrauma |
US20100273730A1 (en) | 2009-04-27 | 2010-10-28 | Innopharmax, Inc. | Self-emulsifying pharmaceutical compositions of hydrophilic drugs and preparation thereof |
US20120087872A1 (en) | 2009-04-28 | 2012-04-12 | Foamix Ltd. | Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof |
EP2424356B1 (en) | 2009-04-29 | 2017-08-23 | Amarin Pharmaceuticals Ireland Limited | Stable pharmaceutical composition and methods of using same |
US8568374B2 (en) | 2009-05-04 | 2013-10-29 | Merck Sharp & Dohme B.V. | Intrauterine system |
EP2429292B1 (en) | 2009-05-08 | 2019-04-03 | Georgia State University Research Foundation | Compounds and compositions comprising cdk inhibitors and their use in the treatment of cancer |
GB0908129D0 (en) | 2009-05-12 | 2009-06-24 | Innovata Ltd | Composition |
WO2013170052A1 (en) | 2012-05-09 | 2013-11-14 | Sio2 Medical Products, Inc. | Saccharide protective coating for pharmaceutical package |
WO2010144943A1 (en) | 2009-05-20 | 2010-12-23 | Ozpharma Pty Ltd | Buccal and/or sublingual therapeutic formulation |
US8658628B2 (en) | 2009-06-18 | 2014-02-25 | Karan Y. Baucom | Hormone delivery system and method |
US8815261B2 (en) | 2009-06-19 | 2014-08-26 | Medrx Co., Ltd. | Composition for external application comprising aripiprazole and organic acid as active ingredients |
KR20120044307A (en) | 2009-06-23 | 2012-05-07 | 바이엘 파마 악티엔게젤샤프트 | Pharmaceutical composition for emergency contraception |
FR2947178B1 (en) | 2009-06-29 | 2012-07-06 | Effik | PHARMACEUTICAL COMPOSITION BASED ON MICRONIZED PROGESTERONE AND USES THEREOF |
CN101940790B (en) | 2009-07-01 | 2012-07-25 | 润和生物医药科技(汕头)有限公司 | Novel penetration-promoting agent composition and application thereof to transdermal administration system |
PL2451279T3 (en) | 2009-07-06 | 2019-09-30 | Aerpio Therapeutics, Inc. | Benzosulfonamide derivatives, compositions thereof, and their use in preventing metastasis of cancer cells |
DE102009034368A1 (en) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-acyloxyalkylenephenyl derivatives, process for their preparation and their use for the treatment of diseases |
DE102009034366A1 (en) | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluoroethyl-estra-4,9 (10) -diene-11-methyleneoxyalkylene aryl derivatives, process for their preparation and their use for the treatment of diseases |
US8618083B2 (en) | 2009-07-31 | 2013-12-31 | Duquesne University Of The Holy Spirit | Combination hormone replacement therapy (HRT) and melatonin to prevent and treat mammary cancer |
KR101118587B1 (en) | 2009-08-17 | 2012-06-12 | 포항공과대학교 산학협력단 | Responsive polymer capsule, and method for preparing thereof |
US8577716B2 (en) | 2009-09-17 | 2013-11-05 | Therapeuticsmd, Inc. | System and method of ongoing evaluation reporting and analysis |
MX359879B (en) | 2009-10-02 | 2018-10-12 | Foamix Pharmaceuticals Ltd | Topical tetracycline compositions. |
US8882748B2 (en) | 2009-10-08 | 2014-11-11 | Palo Alto Research Center Incorporated | Transmucosal drug delivery device and method including chemical permeation enhancers |
WO2011046842A1 (en) | 2009-10-12 | 2011-04-21 | The Regents Of The University Of California | Targeted nanoclusters and methods of their use |
US20110086825A1 (en) | 2009-10-13 | 2011-04-14 | Chatroux Sylvia S | Therapeutic vaginal emollient |
US20120329738A1 (en) | 2009-10-15 | 2012-12-27 | Zhijun Liu | Water Soluble Drug-Solubilizer Powders and Their Uses |
EP2461842A1 (en) | 2009-10-16 | 2012-06-13 | Hemoteq AG | Use of compositions to coat catheter balloons and coated catheter balloons |
EP2490680B1 (en) | 2009-10-19 | 2018-04-04 | The Population Council, Inc. | Neuroprotection and myelin repair using nestorone® |
US8637569B2 (en) | 2009-10-22 | 2014-01-28 | Api Genesis, Llc | Methods of increasing solubility of poorly soluble compounds and methods of making and using formulations of such compounds |
US10080760B2 (en) | 2009-10-27 | 2018-09-25 | Besins Healthcare Luxembourg Sarl | Transdermal pharmaceutical compositions comprising active agents |
EP2506867B1 (en) | 2009-12-02 | 2014-10-08 | Cardio3 Biosciences S.A. | Pharmaceutical compositions for the stimulation of stem cells. |
WO2011073995A2 (en) | 2009-12-14 | 2011-06-23 | Lincoln Pharmaceuticals Limited | Liquid vaginal spray of progesterone |
AU2010339867B2 (en) | 2009-12-17 | 2014-07-24 | The Population Council, Inc. | Nestorone/estradiol transdermal gel |
CA2784847C (en) | 2009-12-18 | 2017-11-21 | Molly Sandra Shoichet | Injectable polymer composition for use as a cell delivery vehicle |
WO2011079047A1 (en) | 2009-12-23 | 2011-06-30 | Drugtech Corporation | Methods for reducing the occurrence of preterm delivery and other pregnancy-related conditions |
BRPI1001367A2 (en) | 2010-01-04 | 2012-07-17 | Theraskin Farmaceutica Ltda | composition for topical application |
TWI482645B (en) | 2010-01-07 | 2015-05-01 | Teikoku Seiyaku Kk | External oily plaster containing diclofenac hydroxyethylpyrrolidine |
US8709451B2 (en) | 2010-01-20 | 2014-04-29 | University Of Utah Research Foundation | Stable nanoemulsions for ultrasound-mediated drug delivery and imaging |
CA2787002A1 (en) | 2010-01-25 | 2011-07-28 | Concept Medical Research Private Limited | A method and an insertable medical device for delivering one or more pro-healing agents to a target site within a blood vessel post-deployment of a stent |
EP2533799B8 (en) | 2010-02-08 | 2019-12-25 | Shenzhen Evergreen Therapeutics Co., Ltd. | Methods for the use of progestogen as a glucocorticoid sensitizer |
WO2011098262A2 (en) | 2010-02-09 | 2011-08-18 | Universität Bremen | P19arf, hmga2 and mdm2 for use in the diagnosis and treatment of aberrant cell growth |
WO2011102684A2 (en) | 2010-02-22 | 2011-08-25 | 영남대학교 산학협력단 | Composition containing placenta extracts |
WO2011109809A2 (en) | 2010-03-05 | 2011-09-09 | New Agriculture, Inc | A novel composition of matter for delivering lipid-soluble materials, and a method for producing it |
CA2789238C (en) | 2010-03-09 | 2020-05-12 | Dignity Health | Methods for inhibiting preterm labor and uterine contractility disorders and preventing cervical ripening |
WO2011112822A2 (en) | 2010-03-10 | 2011-09-15 | University Of Florida Research Foundation. Inc. | Implantable therapeutic device and methods of making |
ES2384060B1 (en) | 2010-03-24 | 2013-09-23 | Lipotec S.A. | LIPID NANOPARTICLES CAPSULES. |
US20130245253A1 (en) | 2010-03-26 | 2013-09-19 | Department Of Veterans Affairs | Conjugated Neuroactive Steroid Compositions And Methods Of Use |
RU2553350C2 (en) | 2010-03-30 | 2015-06-10 | Фосфейдженикс Лимитед | Transdermal plaster |
DE102010003494A1 (en) | 2010-03-31 | 2011-10-06 | Bayer Schering Pharma Aktiengesellschaft | Parenteral delivery system that releases aromatase inhibitors and progestins for the treatment of endometriosis |
US20110250259A1 (en) | 2010-04-12 | 2011-10-13 | Kevin Buckman | Method of treating and preventing breast diseases and breast cancer with medicated formula |
US10688096B2 (en) | 2010-04-13 | 2020-06-23 | The University Of Chicago | Methods for treatment of sleep-related breathing disorders |
KR20180018827A (en) | 2010-04-15 | 2018-02-21 | 바이엘 인텔렉쳐 프로퍼티 게엠베하 | Very low-dosed solid oral dosage forms for hrt |
TW201138782A (en) | 2010-04-26 | 2011-11-16 | Besins Healthcare Lu Sarl | Low-oil pharmaceutical emulsion compositions comprising progestogen |
US8653129B2 (en) | 2010-05-28 | 2014-02-18 | M. Alphabet 1, Llc | Combination therapy for skin disorders |
CN102258455B (en) | 2010-05-28 | 2014-09-17 | 上海市计划生育科学研究所 | Film coating agent containing steroid hormone and its preparation method |
JP5911854B2 (en) | 2010-05-31 | 2016-04-27 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | Organic compounds |
US9434730B2 (en) | 2010-05-31 | 2016-09-06 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
JP5894148B2 (en) | 2010-05-31 | 2016-03-23 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | Organic compounds |
TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
BRPI1002601E2 (en) | 2010-06-01 | 2020-06-30 | Embrapa Pesquisa Agropecuaria | nanostructured composition for veterinary use for drug administration |
JP2012020991A (en) | 2010-06-16 | 2012-02-02 | Takasago Internatl Corp | Transdermal absorption promoter, and external skin formulation thereof |
JP5905455B2 (en) | 2010-06-17 | 2016-04-20 | モメンタ ファーマシューティカルズ インコーポレイテッド | Methods and compositions for promoting hair growth |
US9375437B2 (en) | 2010-06-18 | 2016-06-28 | Lipocine Inc. | Progesterone containing oral dosage forms and kits |
US20110312928A1 (en) | 2010-06-18 | 2011-12-22 | Lipocine Inc. | Progesterone Containing Oral Dosage Forms and Related Methods |
US20110312927A1 (en) | 2010-06-18 | 2011-12-22 | Satish Kumar Nachaegari | Progesterone Containing Oral Dosage Forms and Related Methods |
WO2011162802A1 (en) | 2010-06-21 | 2011-12-29 | Virun, Inc. | Compositions containing non-polar compounds |
EP2399566A1 (en) | 2010-06-28 | 2011-12-28 | Laboratoire HRA Pharma | Once-a-month method of contraception |
US10849857B2 (en) | 2010-07-28 | 2020-12-01 | Laboratorios Leon Farma Sa | Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same |
KR101209266B1 (en) | 2010-06-30 | 2012-12-06 | 한국과학기술연구원 | Biodegradable and thermosensitive poly(phosphazene)-superparamagnetic nano-particle complex, preparation method and use thereof |
EP2407157A1 (en) | 2010-07-13 | 2012-01-18 | Koninklijke Philips Electronics N.V. | Lipid bilayer carrier for drugs or imaging agents |
KR20120011344A (en) | 2010-07-21 | 2012-02-08 | 에스케이케미칼주식회사 | Method for preparing microspheres and microspheres produced thereby |
BRPI1002486B1 (en) | 2010-07-22 | 2017-07-18 | Evidence Soluções Farmacêuticas Ltda Epp | STABILIZED TOPICAL COMPOSITION AND PROCESS OF OBTAINING COMPOSITION STABLE TOPIC |
US20120046264A1 (en) | 2010-08-17 | 2012-02-23 | Biosante Pharmaceuticals, Inc. | Commercial scale production methods for transdermal hormone formulations |
ES2377616B1 (en) | 2010-09-01 | 2013-02-13 | M. Cristina Fernández Rodríguez | STABILIZING COMPOSITION FOR TOPICAL APPLICATION FORMULATIONS AND USING THE SAME. |
US8435972B2 (en) | 2010-09-02 | 2013-05-07 | Emory University | Method for the treatment of central nervous system cancers and compositions related thereto |
BRPI1003661A2 (en) | 2010-09-15 | 2013-01-08 | Libbs Farmaceutica Ltda | pharmaceutical combination to treat and / or prevent fibroid and / or endometriosis, use of resveratrol and progestogen, pharmaceutical composition for treatment and / or prevention of fibroid and / or endometriosis drug for treatment and / or prevention of fibroid and / or endometriosis, kit and Method for the treatment and / or prevention of fibroid and / or endometriosis |
US20120064135A1 (en) | 2010-09-15 | 2012-03-15 | Norac Pharma | Benzoyl Peroxide Composition, Methods for Making Same, and Pharmaceutical or Cosmetic Formulations Comprising Same, and Uses Thereof |
ES2386177B1 (en) | 2010-09-21 | 2013-09-23 | Lipotec, S.A. | NANOCAPSULES CONTAINING MICROEMULSIONS |
EP2434285A1 (en) | 2010-09-22 | 2012-03-28 | IMBA-Institut für Molekulare Biotechnologie GmbH | Breast cancer diagnostics |
EP2433644A1 (en) | 2010-09-22 | 2012-03-28 | IMBA-Institut für Molekulare Biotechnologie GmbH | Breast cancer therapeutics |
DE102010047714A1 (en) | 2010-10-06 | 2012-04-12 | Justus-Liebig-Universität | Derivatives of steroid benzylamines with antiparasitic, antibacterial, antifungal and / or antiviral activity |
US20120101073A1 (en) | 2010-10-22 | 2012-04-26 | Galleon Pharmaceutical, Inc. | Novel Method For Treating Breathing Disorders or Diseases |
WO2012055814A1 (en) | 2010-10-25 | 2012-05-03 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Compound inducing lbpa accumulation for inhibiting cell-to-cell transmission of hiv |
JP5927121B2 (en) | 2010-10-26 | 2016-05-25 | 小松精練株式会社 | Porous ceramic sintered body and method for producing the same |
WO2012055840A1 (en) | 2010-10-28 | 2012-05-03 | Bayer Pharma Aktiengesellschaft | Composition and preparation for treatment of dysmenorrhea and menstrual pain and use of a hormonal agent and a zinc salt for treatment of menstrual disorders |
US9149537B2 (en) | 2010-11-04 | 2015-10-06 | Board Of Regents Of The University Of Nebraska | Compositions and methods for the treatment of traumatic brain injury |
DK2640389T3 (en) | 2010-11-17 | 2015-03-09 | Hexal Ag | Transdermal therapeutic system comprising buprenorphine |
US20120295911A1 (en) | 2010-11-29 | 2012-11-22 | Galleon Pharmaceuticals, Inc. | Novel Compounds and Compositions for Treatment of Breathing Control Disorders or Diseases |
WO2012075319A2 (en) | 2010-12-03 | 2012-06-07 | Allergan, Inc. | Pharmaceutical cream compositions and methods of use |
WO2012078649A1 (en) | 2010-12-06 | 2012-06-14 | Follica, Inc. | Methods for treating baldness and promoting hair growth |
KR101424163B1 (en) | 2010-12-24 | 2014-08-01 | 주식회사 삼양바이오팜 | Polymeric microparticles containing a hydrophobic drug for sustained release thereof and method for preparing the same |
DE102011002934A1 (en) | 2011-01-20 | 2012-07-26 | Bayer Schering Pharma Ag | CB2 agonists for the treatment and prevention of endometriosis |
EP2667842A1 (en) | 2011-01-24 | 2013-12-04 | Anterios, Inc. | Surfactant compositions |
EP2667945A1 (en) | 2011-01-24 | 2013-12-04 | Anterios, Inc. | Oil compositions |
EP2478898B1 (en) | 2011-01-25 | 2016-03-23 | Industrial Cooperation Foundation Chonbuk National University | Method of regulating fertilizing ability using cyclic ADP-ribose and CD38 |
TW201309670A (en) | 2011-01-25 | 2013-03-01 | Kissei Pharmaceutical | Indole derivative and pharmacologically acceptable salt of same |
WO2012102254A1 (en) | 2011-01-25 | 2012-08-02 | キッセイ薬品工業株式会社 | Indole derivative, and pharmacologically acceptable salt thereof |
US20140031323A1 (en) | 2011-02-15 | 2014-01-30 | Ramiro M. Perez | Transdermal hormone composition and combined static-cyclic delivery |
WO2012112883A1 (en) | 2011-02-18 | 2012-08-23 | Yale University | The kras-variant and endometriosis |
WO2012116277A1 (en) | 2011-02-25 | 2012-08-30 | Arena Pharmaceuticals, Inc. | Cannabinoid receptor modulators |
CA2828877A1 (en) | 2011-03-03 | 2012-09-07 | Vanderbilt University | 6-alkyl-n-(pyridin-2-yl)-4-aryloxypicolinamide analogs as mglur5 negative allosteric modulators and methods of making and using the same |
EP2680862B1 (en) | 2011-03-04 | 2016-07-20 | Wake Forest University Health Sciences | Encapsulated cells for hormone replacement therapy |
WO2012120365A1 (en) | 2011-03-07 | 2012-09-13 | Aurobindo Pharma Limited | Stable pharmaceutical composition comprising ethinyl estradiol |
WO2012127501A2 (en) | 2011-03-11 | 2012-09-27 | Sanzyme Limited | Composition for improving endometrial thickness during ovarian stimulation |
EP2691114A1 (en) | 2011-03-29 | 2014-02-05 | Principium Europe S.r.l. | Delivery of large molecular weight biologically active substances |
CA2834262C (en) | 2011-04-28 | 2020-08-25 | Borje S. Andersson | Improved parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same |
AR082266A1 (en) | 2011-05-13 | 2012-11-28 | Univ Nac Del Litoral | INJECTABLE CONTROLLED LIBERATION MICROPARTICLE |
CA2836405C (en) | 2011-05-15 | 2021-09-07 | Trimel Biopharma Srl | Controlled release nasal testosterone gels, methods and pre-filled multi-dose applicator systems for pernasal administration |
EP2710085B1 (en) | 2011-05-16 | 2018-09-26 | Avery Dennison Corporation | Adhesive containing microparticles |
KR101481859B1 (en) | 2011-05-20 | 2015-01-14 | 에스케이케미칼주식회사 | Method for preparing microparticles with reduced initial drug release and microparticles prepare thereby |
US9084797B2 (en) | 2011-05-23 | 2015-07-21 | Besins Healthcare Luxembourg Sarl | Progesterone treatment for improving sleep quality |
WO2012166909A1 (en) | 2011-06-03 | 2012-12-06 | Galleon Pharmaceuticals, Inc. | Compositions and methods for treating breathing control disorders or diseases |
JP6068454B2 (en) | 2011-06-06 | 2017-01-25 | オーク・クレスト・インスティテュート・オブ・サイエンスOak Crest Institute Of Science | Drug delivery device using wicking release window |
JP6051210B2 (en) | 2011-06-10 | 2016-12-27 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | Organic compounds |
WO2012171793A1 (en) | 2011-06-13 | 2012-12-20 | Parthenogen Sagl | Selective cns delivery of mifepristone (ru486) to modulate the timing of the spontaneous lh surge during follicular stimulation cycles |
US20130004619A1 (en) | 2011-06-28 | 2013-01-03 | Kemin Industries, Inc. | Method of Forming Encapsulated Compositions with Enhanced Solubility and Stability |
US9724324B2 (en) | 2011-07-20 | 2017-08-08 | Perrigo Israel Pharmaceuticals Ltd. | Topical oily foam compositions |
US8951996B2 (en) | 2011-07-28 | 2015-02-10 | Lipocine Inc. | 17-hydroxyprogesterone ester-containing oral compositions and related methods |
WO2013025449A1 (en) | 2011-08-16 | 2013-02-21 | Merck Sharp & Dohme Corp. | Use of inorganic matrix and organic polymer combinations for preparing stable amorphous dispersions |
KR101302557B1 (en) | 2011-08-16 | 2013-09-02 | 충북대학교 산학협력단 | Method For Preparing Polymeric Biomaterials Having Immobilized Drug Delivery System Comprising Bioactive Molecules Loaded Particulate Carrier |
US20140227184A1 (en) | 2011-08-19 | 2014-08-14 | The Trustees Of Princeton University | C-halogen bond formation |
WO2013032934A1 (en) | 2011-08-26 | 2013-03-07 | Aegis Therapeutics, Llc | Compositions and methods thereof for oral administration of drugs |
KR101494594B1 (en) | 2011-08-30 | 2015-02-23 | 주식회사 종근당 | Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same |
EP2741757B1 (en) | 2011-09-11 | 2018-05-16 | Minovia Therapeutics Ltd. | Compositions of functional mitochondria and uses thereof |
WO2013044067A1 (en) | 2011-09-23 | 2013-03-28 | Trustees Of Tufts College | Methods for treatment of cervical insufficiency |
DE102011083595A1 (en) | 2011-09-28 | 2013-03-28 | Bayer Pharma AG | Inhibition of the effect of interleukin 1 beta for the treatment of endometriosis |
WO2013052889A1 (en) | 2011-10-07 | 2013-04-11 | Florida State University Research Foundation | Nasal delivery mechanism for prophylactic and post-acute use for progesterone and/or its enantiomer for use in treatment of mild traumatic brain injuries |
US8721331B2 (en) | 2011-10-11 | 2014-05-13 | Puthalath Koroth Raghuprasad | Oral transmucosal drug delivery device |
CA2888213A1 (en) | 2011-10-17 | 2013-04-25 | Temple University - Of The Commonwealth System Of Higher Education | Silica particles coated with beta-cyclodextrin for the removal of emerging contaminants from wastewater |
US9120766B2 (en) | 2011-10-21 | 2015-09-01 | Amri Ssci, Llc | Methods of making cocrystals |
US20140271884A1 (en) | 2011-10-25 | 2014-09-18 | The Trustees Of Princeton University | High-loading nanoparticle-based formulation for water-insoluble steroids |
US20130116215A1 (en) | 2011-10-28 | 2013-05-09 | Mireia Coma | Combination therapies for treating neurological disorders |
AR088622A1 (en) | 2011-11-04 | 2014-06-25 | Bayer Pharma AG | 18-METHYL-6,7-METHYLENE-3-OXO-17-PREGN-4-EN-21,17b-CARBOLACTONE, PHARMACEUTICAL PREPARATIONS CONTAINING THE MENTIONED COMPOUNDS AND THEIR USE IN THE THERAPY OF ENDOMETRIOSIS |
CN103957899A (en) | 2011-11-04 | 2014-07-30 | 敏捷治疗公司 | Dermal delivery compositions and methods |
CA2856235A1 (en) | 2011-11-13 | 2013-05-16 | Blanchette Rockefeller Neurosciences Institute | Esters of dcpla for the treatment of neurodegenerative disorders |
US20130122051A1 (en) | 2011-11-15 | 2013-05-16 | Pharmaceutics International, Inc. | Methods of preparing progesterone pharmaceutical compositions |
US20120128683A1 (en) | 2011-11-22 | 2012-05-24 | Shantha Totada R | Autism treatment |
US9334538B2 (en) | 2011-12-06 | 2016-05-10 | Annabelle Rodriguez Oquendo | Method for pre-screening and correlation of underlying SCARB1 gene variation to infertility in women and therapeutic use of progestational and other medications in treatment |
EP2788028B1 (en) | 2011-12-08 | 2019-03-27 | Rigel Pharmaceuticals, Inc. | Topical formulation for administering a compound |
SG11201403162XA (en) | 2011-12-12 | 2014-10-30 | Lohmann Therapie Syst Lts | Transdermal delivery system comprising buprenorphine |
US9282995B2 (en) | 2011-12-22 | 2016-03-15 | Previvo Genetics, Llc | Recovery and processing of human embryos formed in vivo |
KR101278204B1 (en) | 2011-12-22 | 2013-06-27 | 경북대학교 산학협력단 | Method for preparing biomedical metal/alloy material with multi-drug delivery system |
GB201200062D0 (en) | 2012-01-04 | 2012-02-15 | Innotesto Bvba | Estradiol oromucosal liquid compositions |
CA2860740A1 (en) | 2012-01-09 | 2013-07-18 | Anchor Therapeutics, Inc. | Apj receptor compounds |
JP6342334B2 (en) | 2012-01-26 | 2018-06-13 | セラピューティックスエムディー インコーポレーテッドTherapeuticsmd, Inc. | Transdermal hormone replacement therapy |
US20130211351A1 (en) | 2012-01-31 | 2013-08-15 | Gruenenthal Gmbh | Pharmaceutical patch for transdermal administration of (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine |
EP2630952A1 (en) | 2012-02-23 | 2013-08-28 | Novagali Pharma S.A. | Self-preserved oil dispersions comprising boric acid |
WO2013130535A1 (en) | 2012-02-27 | 2013-09-06 | Newgen Biopharma Corporation | Topical delivery of hormonal and non hormonal nano formulations, methods of making and using the same |
US20130225412A1 (en) | 2012-02-28 | 2013-08-29 | Soroush Sardari Lodriche | Silicon nanocarrier for delivery of drug, pesticides and herbicides , and for waste water treatment |
MX2014010445A (en) | 2012-02-29 | 2014-10-13 | Braun Melsungen Ag | Hormone containing emulsion comprising krill phospholipids. |
FR2988610B1 (en) | 2012-03-30 | 2014-10-31 | Effik | PROGESTATIVE CO-MICRONIZED WITH A POLYMER CARRYING THE PYRROLIDONE GROUP, COMPOSITION AND USES |
US9682093B2 (en) | 2012-03-30 | 2017-06-20 | Charles R. Drew University Of Medicine And Science | Compositions and methods for treating or preventing metabolic syndrome disorders |
FR2988609B1 (en) | 2012-03-30 | 2015-09-04 | Commissariat Energie Atomique | FORMULATION FOR HORMONOTHERAPY |
ES2671294T3 (en) | 2012-04-18 | 2018-06-05 | Siemens Healthcare Diagnostics Inc. | Compounds and procedures for the preparation of conjugated reagents |
US20130317315A1 (en) | 2012-05-22 | 2013-11-28 | Tony V. Lu | Method of age management |
US9346978B2 (en) | 2012-05-22 | 2016-05-24 | Hitachi Chemical Company, Ltd. | Slurry, polishing-solution set, polishing solution, substrate polishing method, and substrate |
ITMI20120913A1 (en) | 2012-05-28 | 2013-11-29 | Nicoletta Maxia | USE OF N-ACETHYL-5-METHOXY-RIPTAMIN OR ITS ANALOGUES TO ENCOURAGE THE EMBRYO PLANT MECHANISM, AND RELATIVE COMPOSITIONS AND MEANS OF CULTURE |
JP6341910B2 (en) | 2012-05-31 | 2018-06-13 | レプロス セラピューティクス インコーポレイティド | Formulation for vaginal delivery of antiprogestin and delivery method thereof |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
JP6397402B2 (en) | 2012-06-18 | 2018-09-26 | セラピューティックスエムディー インコーポレーテッドTherapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
WO2014004424A1 (en) | 2012-06-26 | 2014-01-03 | Temple University - Of The Commonwealth System Of Higher Education | Method for detecting injury to the brian |
BR112014031773B1 (en) | 2012-06-27 | 2020-10-13 | Medincell | hydrophobic biodegradable drug release composition |
WO2014009434A1 (en) | 2012-07-11 | 2014-01-16 | Sandoz Ag | Self-microemulsifying drug delivery system of abiraterone or abiraterone acetate |
US9220680B2 (en) | 2012-07-13 | 2015-12-29 | South Dakota State University | Compositions and methods for localized drug delivery through mammary papillae |
AR091858A1 (en) | 2012-07-25 | 2015-03-04 | Sova Pharmaceuticals Inc | CISTATIONIN-g-LIASA INHIBITORS (CSE) |
AR091857A1 (en) | 2012-07-25 | 2015-03-04 | Sova Pharmaceuticals Inc | CISTATIONIN-g-LIASA INHIBITORS (CSE) |
EP2877175A4 (en) | 2012-07-25 | 2016-07-13 | Sova Pharmaceuticals Inc | Use of cse inhibitors for the treatment of cutaneous injuries or conditions and sleep-related breathing disorders |
CA2880236C (en) | 2012-07-27 | 2022-09-13 | Antonius Martinus Gustave Bunt | Efflux inhibitor compositions and methods of treatment using the same |
US20150216877A1 (en) | 2012-07-27 | 2015-08-06 | Rhodes Technologies | Compositions and treatment for eye diseases and disorders |
KR101480363B1 (en) | 2012-07-30 | 2015-01-09 | 한국과학기술연구원 | Poly(organophosphazene) containing degradation-controllable ionic group, preparation method thereof and use thereof |
CA2882870C (en) | 2012-08-24 | 2020-12-15 | Integurx Therapeutics, Llc | Chemical compositions and methods for enhancing transdermal delivery of therapeutic agents |
EP2708213A1 (en) | 2012-09-13 | 2014-03-19 | PAT&Co bvba | Multipurpose ethylene vinyl acetate fibrous drug delivery systems for long-term implantation or insertion |
WO2014052792A1 (en) | 2012-09-28 | 2014-04-03 | Sio2 Medical Products, Inc. | Halogenated or parylene polymer coating |
PT2716291T (en) | 2012-10-08 | 2020-03-04 | Univ Ulm | Combination of opioids and anticancer drugs for cancer treatment |
US9381231B2 (en) | 2012-10-09 | 2016-07-05 | University Of Florida Research Foundation, Inc. | Use of relaxin to restore maternal physiology in pregnancies conceived by assisted reproductive technologies |
WO2014066442A2 (en) | 2012-10-24 | 2014-05-01 | Emory University | Methods of managing childhood cerebral injury |
US20140127185A1 (en) | 2012-11-02 | 2014-05-08 | Emory University | Methods and compositions using neuroprotective steroids and thrombolytic agents |
JP2015536991A (en) | 2012-11-09 | 2015-12-24 | セルジーン コーポレイション | How to treat bone loss |
WO2014076569A2 (en) | 2012-11-14 | 2014-05-22 | Trimel Biopharma Srl | Controlled release topical testosterone formulations and methods |
EP2732824A1 (en) | 2012-11-16 | 2014-05-21 | Ceva Sante Animale | Compositions and methods for increasing reproduction performance in non human mammals using alpha-beta-linked follicle stimulating hormone |
US9651561B2 (en) | 2012-11-20 | 2017-05-16 | The Brigham And Womens's Hospital, Inc. | Diagnosis and treatment of endometriosis and related conditions |
US20180221389A1 (en) | 2016-12-05 | 2018-08-09 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
UA115576C2 (en) | 2012-12-06 | 2017-11-27 | Байєр Фарма Акцієнгезелльшафт | BENZIMIDASOL DERIVATIVES AS ER4 ANGAGONES |
EP2931274A1 (en) | 2012-12-11 | 2015-10-21 | Metabolic Solutions Development Company LLC | Ppar-sparing thiazolidinediones and combinations for the treatment of neurodegenerative diseases |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US20200155465A9 (en) | 2012-12-21 | 2020-05-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9498539B2 (en) | 2012-12-27 | 2016-11-22 | Molly Sandra Shoichet | Affinity-based controlled release system |
KR101586789B1 (en) | 2012-12-28 | 2016-01-19 | 주식회사 종근당 | Sustained-release lipid pre-concentrate of cationic pharmacologically active substance and pharmaceutical composition comprising the same |
US20140186332A1 (en) | 2012-12-28 | 2014-07-03 | NX Pharmagen | Biomarkers of preterm birth |
US8992951B2 (en) | 2013-01-09 | 2015-03-31 | Sapna Life Sciences Corporation | Formulations, procedures, methods and combinations thereof for reducing or preventing the development, or the risk of development, of neuropathology as a result of trauma |
US20140370084A1 (en) | 2013-06-18 | 2014-12-18 | Therapeuticsmd, Inc. | Estradiol formulations and therapies |
CA2926342A1 (en) | 2013-10-10 | 2015-05-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositons and methods |
EP3145489A1 (en) | 2014-05-22 | 2017-03-29 | TherapeuticsMD, Inc. | Natural combination hormone replacement formulations and therapies |
AU2015296609A1 (en) | 2014-07-29 | 2016-12-22 | Therapeuticsmd, Inc. | Transdermal cream |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
BR112018070199A2 (en) | 2016-04-01 | 2019-01-29 | Therapeuticsmd Inc | pharmaceutical composition of steroid hormone |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
CA3019375A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
WO2017173191A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
US20180280410A1 (en) | 2017-04-03 | 2018-10-04 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
WO2018227172A1 (en) | 2017-06-08 | 2018-12-13 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
-
2013
- 2013-03-15 US US13/843,428 patent/US9301920B2/en active Active
- 2013-06-18 PL PL13806855.6T patent/PL2861072T3/en unknown
- 2013-06-18 JP JP2015518529A patent/JP6334519B2/en active Active
- 2013-06-18 US US14/649,818 patent/US20150359737A1/en not_active Abandoned
- 2013-06-18 EP EP13806855.6A patent/EP2861072B1/en active Active
- 2013-06-18 RU RU2015100533A patent/RU2015100533A/en unknown
- 2013-06-18 CA CA2876977A patent/CA2876977A1/en not_active Abandoned
- 2013-06-18 AU AU2013277236A patent/AU2013277236B2/en not_active Ceased
- 2013-06-18 WO PCT/US2013/046445 patent/WO2013192251A1/en active Application Filing
- 2013-06-18 MX MX2014015898A patent/MX2014015898A/en unknown
- 2013-06-18 KR KR1020227018561A patent/KR20220080205A/en not_active Application Discontinuation
- 2013-06-18 EP EP23198869.2A patent/EP4309646A1/en active Pending
- 2013-06-18 KR KR1020157001189A patent/KR102177782B1/en active IP Right Grant
- 2013-06-18 RU RU2019142696A patent/RU2019142696A/en unknown
- 2013-06-18 PT PT138068556T patent/PT2861072T/en unknown
- 2013-06-18 KR KR1020207032034A patent/KR20200128214A/en not_active Application Discontinuation
- 2013-06-18 KR KR1020237003285A patent/KR20230021170A/en not_active Application Discontinuation
- 2013-06-18 KR KR1020217027152A patent/KR20210107915A/en not_active Application Discontinuation
- 2013-12-06 US US14/099,598 patent/US8987238B2/en active Active
- 2013-12-06 US US14/099,582 patent/US9012434B2/en active Active
- 2013-12-06 US US14/099,623 patent/US9006222B2/en active Active
- 2013-12-06 US US14/099,612 patent/US8933059B2/en active Active
-
2014
- 2014-12-18 MX MX2020013533A patent/MX2020013533A/en unknown
- 2014-12-18 IL IL236358A patent/IL236358B/en unknown
-
2015
- 2015-04-20 US US14/690,955 patent/US20150224118A1/en not_active Abandoned
- 2015-04-20 US US14/690,913 patent/US20150224117A1/en not_active Abandoned
-
2016
- 2016-04-04 US US15/090,493 patent/US10675288B2/en active Active
-
2017
- 2017-07-20 AU AU2017206262A patent/AU2017206262A1/en not_active Abandoned
- 2017-09-14 JP JP2017176379A patent/JP2018024688A/en active Pending
-
2018
- 2018-08-16 US US15/999,040 patent/US11166963B2/en active Active
-
2019
- 2019-06-28 AU AU2019204655A patent/AU2019204655B2/en active Active
- 2019-07-23 US US16/520,167 patent/US11529360B2/en active Active
- 2019-08-15 JP JP2019149172A patent/JP7198177B2/en active Active
-
2020
- 2020-05-27 US US16/885,066 patent/US11110099B2/en active Active
-
2021
- 2021-09-30 AU AU2021240253A patent/AU2021240253A1/en not_active Abandoned
-
2022
- 2022-11-07 US US18/053,120 patent/US20230218636A1/en active Pending
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8633178B2 (en) * | 2011-11-23 | 2014-01-21 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8846649B2 (en) * | 2011-11-23 | 2014-09-30 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8846648B2 (en) * | 2011-11-23 | 2014-09-30 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8987237B2 (en) * | 2011-11-23 | 2015-03-24 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8993548B2 (en) * | 2011-11-23 | 2015-03-31 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9114145B2 (en) * | 2011-11-23 | 2015-08-25 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9114146B2 (en) * | 2011-11-23 | 2015-08-25 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8933059B2 (en) * | 2012-06-18 | 2015-01-13 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US8987238B2 (en) * | 2012-06-18 | 2015-03-24 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9006222B2 (en) * | 2012-06-18 | 2015-04-14 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9012434B2 (en) * | 2012-06-18 | 2015-04-21 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9180091B2 (en) * | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
Cited By (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10675288B2 (en) | 2011-11-23 | 2020-06-09 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11793819B2 (en) | 2011-11-23 | 2023-10-24 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11103516B2 (en) | 2011-11-23 | 2021-08-31 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11110099B2 (en) | 2012-06-18 | 2021-09-07 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11166963B2 (en) | 2012-06-18 | 2021-11-09 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11529360B2 (en) | 2012-06-18 | 2022-12-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US11622933B2 (en) | 2012-12-21 | 2023-04-11 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US11065197B2 (en) | 2012-12-21 | 2021-07-20 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11304959B2 (en) | 2012-12-21 | 2022-04-19 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11497709B2 (en) | 2012-12-21 | 2022-11-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10888516B2 (en) | 2012-12-21 | 2021-01-12 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11351182B2 (en) | 2012-12-21 | 2022-06-07 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10835487B2 (en) | 2012-12-21 | 2020-11-17 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11116717B2 (en) | 2012-12-21 | 2021-09-14 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US11123283B2 (en) | 2012-12-21 | 2021-09-21 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11241445B2 (en) | 2012-12-21 | 2022-02-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11103513B2 (en) | 2014-05-22 | 2021-08-31 | TherapeuticsMD | Natural combination hormone replacement formulations and therapies |
US10206932B2 (en) | 2014-05-22 | 2019-02-19 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US10668082B2 (en) | 2014-10-22 | 2020-06-02 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10398708B2 (en) | 2014-10-22 | 2019-09-03 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10258630B2 (en) | 2014-10-22 | 2019-04-16 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
WO2017173191A1 (en) * | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11110099B2 (en) | Natural combination hormone replacement formulations and therapies | |
US20240115584A1 (en) | Natural combination hormone replacement formulations and therapies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: MIDCAP FINANCIAL TRUST, AS AGENT, MARYLAND Free format text: SECURITY INTEREST;ASSIGNORS:THERAPEUTICSMD, INC.;VITAMEDMD, LLC;BOCAGREENMD, INC.;AND OTHERS;REEL/FRAME:046053/0723 Effective date: 20180501 |
|
AS | Assignment |
Owner name: THERAPEUTICSMD, INC., FLORIDA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BERNICK, BRIAN A.;CACACE, JANICE LOUISE;PERSICANER, PETER H.R.;AND OTHERS;SIGNING DATES FROM 20130611 TO 20130613;REEL/FRAME:045897/0557 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: VITACARE PRESCRIPTION SERVICES, INC., FLORIDA Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST, AS AGENT;REEL/FRAME:049012/0215 Effective date: 20190424 Owner name: BOCAGREENMD, INC., FLORIDA Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST, AS AGENT;REEL/FRAME:049012/0215 Effective date: 20190424 Owner name: THERAPEUTICSMD, INC., FLORIDA Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST, AS AGENT;REEL/FRAME:049012/0215 Effective date: 20190424 Owner name: VITAMEDMD, LLC, FLORIDA Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:MIDCAP FINANCIAL TRUST, AS AGENT;REEL/FRAME:049012/0215 Effective date: 20190424 |