CN101940790B - Novel penetration-promoting agent composition and application thereof to transdermal administration system - Google Patents
Novel penetration-promoting agent composition and application thereof to transdermal administration system Download PDFInfo
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- CN101940790B CN101940790B CN2010102082582A CN201010208258A CN101940790B CN 101940790 B CN101940790 B CN 101940790B CN 2010102082582 A CN2010102082582 A CN 2010102082582A CN 201010208258 A CN201010208258 A CN 201010208258A CN 101940790 B CN101940790 B CN 101940790B
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- steroid hormone
- penetrating agent
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- 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
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- 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
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- Veterinary Medicine (AREA)
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- Chemical & Material Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Orthopedic Medicine & Surgery (AREA)
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- Epidemiology (AREA)
- Reproductive Health (AREA)
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Abstract
The invention provides a novel penetration-promoting agent composition and the application thereof to a transdermal administration system. The penetration-promoting agent provided by the invention contains an etheric compound and an alcohol compound and more preferably contains fatty acid having 6 to 18 carbon atoms or fatty alcohol having 6 to 18 carbon atoms. In the penetration-promoting agent of the invention, dimethylsulfoxide (DMSO) with controversial potential toxicity to a human body is not used; and an obtained product has the advantages of high transdermal rate, high adhesion, no potential toxic or side effect to the human body and safe and comfortable use. The transdermal administration system provided by the invention is applied by being stuck to the skin of a woman so as to fulfill the aims of effectively controlling birth and realizing conception control. The novel penetration-promoting agent composition can also be used for preventing and treating osteoporosis, climacteric metancholia of women and the like.
Description
Technical field
The present invention relates to pharmaceutical field, particularly a kind of novel penetrating agent compositions and the application in transdermal drug delivery system thereof.
Background technology
The estrogen of synthetic and the compositions of progestogen often are used to contraception.If the form with OCP is used natural estrogen (17-β estradiol) and progesterone (Progesterone) compositions, these two kinds of hormones can carry out a large amount of first metabolism and need to use very big dosage in liver.The gained metabolite causes undesirable side effect through regular meeting.Therefore, main now artificial synthetic progesterone of use and estrogenic compositions overcome these defectives as oral contraceptive.Wherein, one of the most representative combination is levonorgestrel and ethinylestradiol combination in the oral contraceptive.
Although the progesterone of synthetic and estrogenic compositions are very effective to suppressing ovulation; But use the oral contraceptive of this type still can produce certain side effect: in the women who uses oral contraceptive, thrombosis is higher with the sickness rate of the relevant blood vessel disease that comprises apoplexy and myocardial infarction; Use contraceptive also relevant with the increase of optimum liver tumor symptom and higher gallbladder disease risk; If continuing pills after pregnancy, the women may cause fetal abnormality; Oral contraceptive also can produce human body the intestines and stomach digestive system to stimulate, and some women uses oral contraceptive can produce malaise symptoms; Use the possible complication of oral contraceptive also to comprise breast carcinoma, uterus carcinoma, cervical cancer and cancer of vagina etc.
In the last few years, develop the fertility restraining doser of implantable intrauterine, cervix uteri or intravaginal and subdermal implantation successively, thereby these devices can also controllably provide enough steroid hormone doses to reach the purpose of contraception for a long time to human body.Levonorgestrel is the drug components that these devices the most often use, but these devices use and take out very inconveniently, uses in these doser processes, often brings uncomfortable and misery to sufferer.
Transdermal drug delivery system (transdermal drug delivery system; TDDS) be the transdermal administration novel formulation of the patch dosage form of adhesives; Be in the skin surface administration; Medicine through each layer of skin, gets into the body circulation with constant speed (or near constant speed), produces whole body or local therapeutic effects.Since first transdermal absorption formulation Transderm Scop listing in 1981, existing multiple at present drug transdermal drug-delivery preparation listing.Medicine can reduce many side effect through skin absorbs.Percutaneously administrable prepn has following advantage: avoid intravenous risk and inconvenience and absorption and the metabolic polytropy relevant with oral medication; Successive administration also can use the short medicine of biological half-life; Because reduced the degraded in digestive system, also can play effect even reduced the every day dosage; Preparation is easy to use, if desired, and can be through remove stopped treatment apace from skin surface.
Based on above-mentioned advantage, in recent years, Chinese scholars has been carried out big quantity research to the steroid hormone transdermal drug delivery system.Yet, as the skin of the human body natural cover for defense, hindered medicine and got in the body, most drug, even some medicines that dosage is low, curative effect is high, percutaneous rate also is difficult to satisfy the treatment needs.Overcome the skin barrier effect, promote medicine within a certain period of time transdermal penetration reach therapeutic dose, be one of key issue of transdermal drug delivery system research such as steroid hormone.The exploitation of some penetrating agents and application in recent years promoted the development of transdermal drug delivery system greatly.
U.S. Pat 4,816,258 discloses the system and method that carries out levonorgestrel and estradiol compositions transdermal administration with the form of matrix type patch.What this system framework material used is ethylene-vinyl acetate copolymer (EVA 40) and viscosifier 2,2'-ethylenedioxybis(ethanol). hydrogenated rosins acid esters, and penetrating agent then adopts glycerin mono-fatty acid ester.
U.S. Pat 4; 973,468 and 5,059; 426 disclose a diethylene glycol monoethyl ether (Diethyleneglycol monoethyl ether) oozes combination with methyl laurate (Methyl laurate) binary is short, and this combination can be used to improve the levonorgestrel percutaneous rate.But this patent does not provide bank or shell system with this combination and compatibility.
U.S. Pat 5,296,230 have described the system and method that levonorgestrel and estradiol compositions is carried out transdermal administration with the form of matrix type patch.What this system framework material used is medical grade silicon rubber, and penetrating agent then adopts Polyethylene Glycol aqueous solution (40%V/V) and isopropyl myristate (Isopropylmyristate) respectively.
U.S. Pat 5,560,922 disclose the system and method for new levonorgestrel and estradiol compositions transdermal administration.The patch framework material also expands to use and gathers isoolefine rubber and polyacrylic acid pressure sensitive adhesive except using medical grade silicon rubber, and penetrating agent then adopts the Decanol (n-Decyl alcohol) in the aliphatic alcohol series.
The international monopoly WO9608255 that authorizes people such as DUAN has put down in writing monomer institute polymerization by various variety classes monomers, different proportionings and has generated various acrylic copolymers and be used for levonorgestrel matrix-type transdermal administration situation as pressure sensitive adhesive matrix; Patent disclose glyceryl monolaurate (G1yceryl monolaurate), dimethyl dodecyl amine oxide (N, N-dimethyldodecylamine-N-oxide), tetrahydrofurfuryl carbinol (Tetrahydrofurfuryl alcohol), polyglycol ether (Polyethylene glycol ether), propylene glycol, diisopropyl adipate (Diisopropyl adipate) and methyl laurate (Methyl laurate) and their compositions can be used as the penetrating agent of levonorgestrel transdermal administration in the system.
Authorize people's such as CORDES U.S. Pat 5; 985; 311 disclose diethylene glycol monoethyl ether (Diethylene glycol monoethyl ether) oozes system with oleic acid (Oleic acid) binary is short, can be used to contain levonorgestrel polyacrylic acid matrix-type transdermal drug delivery system.
The U.S. Pat 6,231,885 of authorizing people such as CARRARA discloses oleic acid (Oleic acid) and lauric acid (Lauric acid) binary is short oozes system as penetrating agent in levonorgestrel and the estradiol compositions transdermal drug delivery system.
The U.S. Pat 6,312,715 of authorizing people such as CANTOR is described a kind of synthetic especially polyacrylic binder and can be used for the levonorgestrel transdermal delivery device, and binding agent is the hollow microsphere form.System adopts methanol, isopropyl alcohol, and ethyl acetate is as the levonorgestrel cosolvent, and isopropyl myristate is then as the levonorgestrel penetrating agent.
U.S. Pat 5,762,956 have described levonorgestrel percutaneous contraceptive drugs transporter, and use this device to carry out method of contraception.This system uses two methylene sulfones (DMSO), lactic acid laurate ethyl lactate and capric acid as penetrating agent.
Except the related penetrating agent of above-mentioned relevant levonorgestrel transdermal administration, also have many patent documentation reports to relate to the particularly estradiol transdermal administration of other steroid hormone.
The transdermal administration that is used for estradiol with isopropyl myristate (Isopropyl myristate), ethyl oleate (ethyl oleate), glyceryl monolaurate (Glyceryl monolaurate) as penetrating agent is disclosed in the U.S. Pat 5223261.This patent becomes BERLEX development CLIMARA and contains the basis of levonorgestrel CLIMARA PRO serial therapy women osteoporosis patch product.
The transdermal administration that is used for estradiol with azone, lauric acid, propylene glycol as penetrating agent is disclosed among the Chinese patent CN1067875A.
WO9832465 has described diethylene glycol monoethyl ether and Arlacel-20 (SPAN-20), diethylene glycol monoethyl ether and Arlacel-80 (SPAN-80) binary are urged the transdermal administration that the system of oozing is used for estradiol.
Ideal steroid hormone penetrating agent must satisfy following requirement: (1) employed penetrating agent has certain dissolubility to steroid hormone; (2) employed penetrating agent has the good short effect of oozing should have rapid-actionly to steroid hormone, and action time is measurable; (3) employed penetrating agent is to skin and human non-toxic, nonirritant, the irritated reaction of nothing and there is not pharmacological action; The compatibility of medicine and other additives comprises not producing physics chemical action, not influencing pharmaceutically active and be complementary with pharmaceutical properties; Can work very soon during application, but not cutaneous normal physiological function after removing; Do not cause the loss of endotrophic material and moisture; Colourless, odorless; Yet up to now, also do not have a kind of promoter to satisfy condition completely, the penetration enhancer of using at present all has pluses and minuses separately.
Because levonorgestrel and estrogen are that the representative steroid hormone all is the extremely low material of dissolubility; And be in the levonorgestrel and the extremely difficult skin that sees through of estrogen of dissolved state not; Therefore; When making levonorgestrel and estrogen transdermal delivery device, it is very crucial and important selecting the short system of oozing of appropriate hydrotropy.For solving levonorgestrel and estrogen problems of dissolution; The short system of oozing of some hydrotropy has adopted two methylene sulfones (DMSO) to urge to ooze to increase the levonorgestrel dissolving and to increase levonorgestrel; Publication number is the Chinese patent of CN1399533, discloses a kind of percutaneous contraceptive drugs delivery system, and this system enhancer of cutaneous penetration compositions has been used dimethyl sulfoxide (DMSO); This system has percutaneous rate preferably to human body skin; But because at present still there is bigger dispute in dimethyl sulfoxide to the genotoxic potential of human body, for safety, the penetrating agent compositions should avoid the use of dimethyl sulfoxide (DMSO).Also have many fatty esters penetrating agents to be proved to be levonorgestrel is had the good short effect of oozing; For example; Methyl laurate (Methyl laurate), polyethylene glycol monolaurate (Polyethyleneglycol monolaurate); Polypropylene glycol monolaurate (Polypropylene glycolmonolaurate) but these penetrating agents have serious destruction as plasticiser to the viscosity or the cohesiveness of acrylic matrix system, and very limited to the levonorgestrel dissolving.In order to guarantee the short effect of oozing; Often need high concentration levonorgestrel and estrogen to be in the adhesive matrix of transdermal delivery device with the over-saturation dissolved state; Need to use the hydrotropy penetrating agent of height ratio; When the above-mentioned height ratio fat of use in making levonorgestrel and estrogen transdermal delivery device esters penetrating agent, often cause serious cold flow or lose viscosity, can't practical application.
In addition; Existing disclosed transdermal administration technical scheme all be with Corium Mus as experimental subject, realize that institute's medicine of giving can and reach certain transdermal amount through Corium Mus, seeing that people's skin and Corium Mus structure have a great difference; The permeability of Corium Mus is higher than the skin of human body far away; Given percutaneous rate is very high, but and impracticable, prepared based on this patch often can't really be realized on human body, using and reach medically needed therapeutic dose.
The inventor has unexpectedly found to overcome in-problem desirable penetrating agent compositions in the prior art.Enhancer of cutaneous penetration compositions of the present invention not only can improve the dissolubility of steroid hormone effectively, and obtains better percutaneous permeability, the cohesiveness of patch is not destroyed.Penetrating agent provided by the invention; Do not having under dimethyl sulfoxide (DMSO) condition; Fell equally also there is very high percutaneous rate; The steroid hormone transdermal dosage compositions that treatment is expected can be provided, thereby avoid life-time service genotoxic potential to be had the short potential danger that to bring of oozing of dimethyl sulfoxide of dispute.And transdermal drug delivery system is easy to easy means manufacturing, avoids complicated processing technology such as MULTILAYER COMPOSITE.
Summary of the invention
One object of the present invention is to provide a kind of penetrating agent compositions, and it does not comprise the dimethyl sulfoxide (DMSO) that the human body genotoxic potential is had dispute.Penetrating agent provided by the invention is applied to prepare transdermal drug delivery system (patch), and resulting product cohesiveness is good, human body is not had potential toxic and side effects, safety and comfort, and preparation is simple.
Penetrating agent provided by the invention contains ether compound and alcohol compound, perhaps is made up of ether compound and alcohol compound.What need special instruction is: used term alcohol compound all is meant and does not comprise C among the present invention
6-C
18The alcohol compound of aliphatic alcohol, alcohol compound promptly according to the invention is meant non-C
6-C
18The alcohol compound of aliphatic alcohol.
In the penetrating agent of ether compound provided by the invention and alcohol compound composition, the consumption of ether compound and alcohol compound is counted with weight portion: ether compound accounts for 1-30 part, and alcohol compound accounts for 1-30 part; Be preferably: ether compound accounts for 1-20 part, and alcohol compound accounts for 1-20 part; More preferably be: ether compound accounts for 1-10 part, and alcohol compound accounts for 1-10 part; Be most preferably: ether compound accounts for 1-4 part, and alcohol compound accounts for 1-4 part.In penetrating agent of the present invention, said ether compound preferably is selected from isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether.
In penetrating agent of the present invention, said alcohol compound preferably is selected from propylene glycol, Polyethylene Glycol (PEG400, PEG600, PEG1000 or PEG2000) or benzyl alcohol.
In embodiment preferred of the present invention, penetrating agent of the present invention also contains C simultaneously
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol.
At ether compound, alcohol compound and the C of comprising provided by the invention
6-C
18Fatty acid or C
6-C
18The penetrating agent of aliphatic alcohol in, the consumption of these three kinds of materials is counted with weight portion:
Ether compound accounts for 1-30 part, alcohol compound accounts for 1-30 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-30 part;
Be preferably: ether compound accounts for 1-20 part, alcohol compound accounts for 1-20 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-20 part;
More preferably be: ether compound accounts for 1-10 part, alcohol compound accounts for 1-10 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-10 part.
Be most preferably: ether compound accounts for 1-4 part, alcohol compound accounts for 1-4 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-4 part.
In penetrating agent of the present invention, C
6-C
18Fatty acid preferably is selected from capric acid, lauric acid or oleic acid.C
6-C
18Aliphatic alcohol preferably is selected from decanol, lauryl alcohol or oleyl alcohol.
In penetrating agent compositions of the present invention, most preferred scheme is: penetrating agent is diethylene glycol monoethyl ether, propylene glycol and lauric compositions; Or isosorbide dimethyl ether, propylene glycol and lauric compositions; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol; Or the compositions of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol; Or the compositions of isosorbide dimethyl ether, propylene glycol and oleyl alcohol; Or the compositions of diethylene glycol monoethyl ether, propylene glycol and decanol; Or the compositions of isosorbide dimethyl ether, propylene glycol and decanol.Wherein in weight portion, the ether compound in the above-mentioned composition accounts for 1-4 part, alcohol compound accounts for 1-4 part, C
6-C
18Fatty acid or aliphatic alcohol account for 1-4 part.
Another object of the present invention has been to provide the application of above-mentioned penetrating agent in the preparation transdermal drug delivery system.
Penetrating agent of the present invention is particularly useful for making the transdermal drug delivery system (transdermal patch) that on human body skin, pastes usefulness.Be particularly useful for making steroid hormone and compound recipe steroid hormone transdermal drug delivery system, it can make progestogen and estrogen bi-component well penetrate skin simultaneously.The prepared steroid hormone transdermal drug delivery system that obtains is applied on the female skin, can be used for birth control or treatment female osteoporosis, associated conditions such as climacteric syndrome.Steroid hormone transdermal drug delivery system of the present invention is specially adapted to female contraception.
In one embodiment, steroid hormone transdermal drug delivery system provided by the invention comprises protective layer 1, drug storing layer 2 and backing layer 3;
Components contents is counted with weight portion in the sticky polymers matrix solution: penetrating agent of the present invention accounts for 5-50 weight portion, sticky polymers and accounts for that 20-90 weight portion, viscosity modifier account for the 0.1-20 weight portion, steroid hormone accounts for the 0.1-5 weight portion; More preferably be: penetrating agent of the present invention accounts for 10-40 weight portion, sticky polymers and accounts for that 50-90 weight portion, viscosity modifier account for the 0.5-5 weight portion, steroid hormone accounts for the 0.1-3 weight portion; Be most preferably: penetrating agent of the present invention accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion.
Sticky polymers among the present invention can be selected biological acceptable sticky polymers, for example crosslinked or uncrosslinked polyacrylate sticky polymers, silicone sticky polymers or the polyisobutylene sticky polymers etc. for use.Preferred crosslinked or uncrosslinked polyacrylate sticky polymers.
The further explain and the example that are appropriate to the polyacrylate sticky polymers of embodiment of the present invention have been described in Satas " Acrylic Adhesives, " Handbook of Pressure Sensitive-Adhesive Technology.2
NdEd.pp 396 1 456 (D.Satas, ed.) Ban NostrandReinhole, New York (1989).The polyacrylate sticky polymers preferably can be for having the chemical compound of following general formula (I):
-(CH
2-CH-COOR)n-
(I)
Wherein n representes the number of repeat unit of polymer monomer, and R is hydrogen or rudimentary (C
1-C
10) alkyl, said rudimentary (C
1-C
10) alkyl can be selected from ethyl, butyl and ethylhexyl etc. 1 in a preferred embodiment of the invention, said polyacrylate sticky polymers is preferably and gathers (2-EHA/acrylic copolymer), gathers (the own ester/acrylic acid of acrylic acid 2-hydroxyl/methyl acrylate copolymer), gathers (2-EHA/acrylic acid/methyl acrylate copolymer) or gather (2-EHA/acrylic acid/butylacrylate/vinyl acetate copolymer).GMS 737,788,1753 like Cytec Surface Specialties Inc company; DUROTAK 87-4098,87-2287,87-4297,87-900A, the 87-2677 of National Starch Chemical Company; The RODERM 607 of Rohm Haas company or 610 etc.
Described silicone sticky polymers can for: suitable polysiloxanes comprises the siloxanes pressure sensitive adhesive, and it is based on two kinds of main components, polymer and elastomer or and tacky resin.The preparation of this silicone gums generally ties up in the appropriate organic solvent, utilizes condensation reaction with this elastomer (typically being a high-molecular weight polydiorganosiloxanepolyurea) and resin interlinkage key knot, to produce three-dimensional polysiloxane structure.This resin is one can controlled important factor to elastomeric ratio, to modify the physical characteristic of this polysiloxanes.Sobieski, et al., " Silocone Pressure SensitiveAdhesives; " Handbok ofPressure-Sensitive AdhesiveTechnology, 2nd ed., pp.508 one 517 (D.Satas; Ed.), Van Nostrand Reinhold, New York (1989).Suitable polysiloxanes pressure sensitive adhesive comprises that the brand name that Dow Coring Corporation company sells is BIO-PSA X7-3027; X7-4203; Q7-4503, the polysiloxanes pressure sensitive adhesive of X7-4603, X7-4301, X7-4303, X7-4919, X7-2685 and X7-3122.BI0 one PSA X7-4203, X7-4301 and X7-4303.
Said polyisobutylene sticky polymers can be hydrocarbon polymer; The for example natural or synthetic polymer that gathers 2 monomethyl butadiene, polybutene and polyisobutylene, phenylethylene/butadiene polymer, styrene one 2 monomethyl butadiene one styrene block copolymer, hydrocarbyl polymers (for example butyl rubber), polyacrylonitrile, contains halogen (for example politef, polrvinyl chloride, gather vinylidene chloride and polychlorobutadiene) and their other copolymer.
Sticky polymers substrate of the present invention also comprises the viscosity modifier that is dispersed in the substrate.Can use pharmaceutical polymers commonly used in pharmaceuticals industry as viscosity modifier.Using viscosity modifier is the viscosity for controlling polymers substrate.In sticky polymers substrate, adding viscosity modifier can increase the comfort of percutaneous contraceptive drugs delivery system (patch) when wearing, and helps reducing scytitis, and comes off when preventing the life-time service transdermal patch.Wherein said viscosity modifier is polyvinylpyrrolidone//vinyl acetate copolymers, polyvinylpyrrolidone, polybutyl methacrylate/methylmethacrylate copolymer or ethyl cellulose.The employed polyvinylpyrrolidone of embodiment of the present invention is selected from K12, K17, K25, the K30 that BASF (BASF) company produces.Employed polybutyl methacrylate/the methyl methacrylate of embodiment of the present invention is selected from moral and fills in the Plastoid B that (DEGUSSA) company produces admittedly.The employed ethyl cellulose of embodiment of the present invention is selected from the Ethocel 7,10,14,20 that Dow Chemical (DOW CHEMICAL) company produces.Viscosity modifier preferably polyethylene ketopyrrolidine/vinyl acetate copolymer, polyvinylpyrrolidone or ethyl cellulose.Viscosity modifier is most preferably the polyvinylpyrrolidone/vinyl acetate of molecular weight 50,000, and the weight ratio of polyvinylpyrrolidone and vinyl acetate is 6: 4.Polyvinylpyrrolidone//vinyl acetate copolymers S-630 like the production of the U.S. international special article company; The polyvinylpyrrolidone//vinyl acetate copolymers VA64 that BASF Aktiengesellschaft produces.
Said steroid hormone is selected from one or more in progestogen and the estrogen.In weight portion, steroid hormone preferably is made up of the estrogen of 1-30 weight portion progestogen and 1-10 weight portion; More preferably form by the progestogen of 1-20 weight portion and the estrogen of 1-5 part.
Progestogen in the said steroid hormone can be selected from: the diacetate esters of levonorgestrel, methylnorethindron, norgestimate variant, gestodene, norethindrone, norethynodrel, hydrogen progesterone, gestodene, etynodiol, hydroxyprogesterone acetas, gestogen, other is biocompatible and can be through the progestogen of skin absorbs; Can pass through skin absorbs, and skin absorbs can change into the biocompatible progestogen derivant of original progestogen etc. afterwards.
Estrogen in the said steroid hormone can be selected from ethinylestradiol, 17 beta estradiols and biocompatible derivant thereof etc.If if absorbtivity meets the requirement and the hormone component of estrogenic component daily dose is compatible, what also can use 17 beta estradiol biocompatibility can be the derivant of 17 beta estradiols by Transdermal absorption and preferred biotransformation.Such derivatives of estradiol comprises ester, monoesters or diester.Monoesters can be 3-or 17-ester.Estradiol ester can be, for example, and estradiol-3,17-diacetate esters; Estradiol-3-acetas; Estradiol 17-acetas; Estradiol-3,17-two valerates; Estradiol-3-valerate; Estradiol l7-valerate; 3-is single-, 17-is single and 3,17-dipivilateesters; The 3-list-, the 17-list-with 3, the 17-dipropionate; The 3-list-, the 17-list-and 3,17 1 two cyclopenta-propionic esters; Corresponding cypionate, heptanoate, benzoate and similar ester; The thinyl estradiol; Estrone; But estrogens sterin and derivant thereof with other Transdermal absorption.
Progestogen in the steroid hormone are levonorgestrel most preferably, and estrogen is ethinylestradiol most preferably.
For steroid hormone transdermal drug delivery system provided by the invention; Special optimized technical scheme is following: in a preferred embodiment; Be used for preparing the sticky polymers matrix solution of drug storing layer 2, the consumption of component is counted with weight portion: penetrating agent 10-20 weight portion of the present invention, sticky polymers 70-90 weight portion, viscosity modifier 0.5-3 weight portion, steroid hormone 0.1-1 weight portion; Said steroid hormone is made up of the progestogen of 1-20 weight portion and the estrogen of 1-5 weight portion; Said penetrating agent is by the alcohol compound of the ether compound of 1-4 weight portion, 1-4 weight portion, the C of 1-4 weight portion
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol is formed; Said ether compound is selected from diethylene glycol monoethyl ether or isosorbide dimethyl ether; Said alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; Said C
6-C
18Fatty acid is selected from lauric acid, oleic acid or capric acid; Said C
6-C
18Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.
Adopt the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, preferably processing area is the circle of 10-30 square centimeter, the patch of square or rectangular; More preferably process area and be the patch of round, the square or rectangular of 15-25 square centimeter.
Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, the thickness of drug storing layer 2 can be between the 50-200 micron; Preferably between the 80-150 micron.
Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, do not limit backing layer is concrete, preferably to impermeable basically backing layer such as medicines; In other words be such backing layer, it loses from the back side through stoping medicine as the active component in the hypothallus, additive etc. to pass it, does not allow the content of medicine, additive etc. to reduce.The material of backing layer 3 can be selected the laminated product of the polymeric film that contains or do not contain metal formings such as aluminium foil for use.Being suitable for the present invention is comprised by the material of lining: polyethylene, and polypropylene gathers ammonia phenol, and polrvinyl chloride gathers (O-phthalic vinyl acetate), tinsel etc.Scotchpak1109 that the preferred 3M of the present invention company produces or Cotran9720 are as back lining materials.The thickness of backing layer 3 can be between 10 to 300 microns; Preferred thickness is between 20 to 100 microns, and more preferably thickness is between 30 to 50 microns.
Adopt in the steroid hormone transdermal drug delivery system of penetrating agent preparation of the present invention, do not limit protective layer 1 is concrete, as long as fully guarantee the release characteristics of transdermal drug delivery system.The material of said protective layer 1 can be selected for use and gather the vinegar film; Polychloroethylene film, the polyvinylidene chloride film gathers (ethylene glycol terephthalate) film etc.; High quality paper; Cellophane etc., laminated film of polyolefin and paper such as high quality paper, cellophane etc. or the like, that one side that they contact with hypothallus is carried out release treatment through applying silicone resin, fluororesin or corona etc.The Scotchpak1022 that the preferred 3M of the present invention company produces is as protective layer material.The thickness of protective layer 1 can be between 10 to 300 microns; Preferred thickness is between 30 to 200 microns, and more preferably thickness is between 50 to 100 microns.
In preparation steroid hormone transdermal drug delivery system process,, can add optional cosolvent for increasing the dissolubility of active constituent (steroid hormone).These cosolvents can be selected from: acetone, methanol, ethanol, isopropyl alcohol, formic acid second fat, ethyl acetate, oxolane and any mixture thereof.In case of necessity, can promote medicine dissolution through physical means such as heating or sonic oscillations.Cosolvent can remove in preparation process subsequently.
The present invention also provides the method for preparing that adopts penetrating agent of the present invention to prepare the steroid hormone transdermal drug delivery system, comprises the steps:
(a) take by weighing steroid hormone (active component), add viscosity modifier, penetrating agent, cosolvent, stir and make dissolving; Add sticky polymers again, stir, make abundant mixing; Leave standstill, promptly get sticky polymers substrate;
(b) on protective layer 1, drying must be attached to the drug storing layer 2 on the protective layer 1 with the sticky polymers substrate of step (a) gained coating (spraying, solution casting);
(c) will be placed on as the material of backing layer 3 on the drug storing layer 2, together lamination;
(d) behind the lamination, according to required form and area, cutting gets the transdermal administration patch; Can cut into circle, square, rectangle or other desirable shape.
(e) the gained transdermal drug delivery system is put into the packing that is used for storing, be saved in skin-penetrating therapeutic.
In prepared patch, in the sticky polymers substrate the amount of dispersive steroid hormone (active component), can make it greater than the dosage sent of hope, for example doubly than the excessive 10-50 of the hope accumulated dose of sending; Preferred excessive 20-30 doubly.
Transdermal drug delivery system provided by the invention is bonded on the female skin to be used, and can effectively control birth, and realizes the purpose of contraception.
Those skilled in the art, the composition of the steroid hormone that can confirm to be selected for use according to therapeutic purposes.As can select for use estradiol to prevent and treat osteoporosis, climacteric syndrome.Those skilled in the art all are included within the present invention according to the determined active ingredient of therapeutic purposes.
In the present invention, " C
6-C
18Fatty acid " be meant to have 6 acid to 18 carbon atom carbochains; " C
6-C
18Aliphatic alcohol " be meant to have 6 alcohol to 18 carbon atom carbochains; " sticky polymers " is meant when it is applied to surface and drying with the solution form, the polymer formation film, and as understood by one of ordinary skill in the art, this film will have bonding and cohesive strength; " viscosity modifier " refers to change the material of viscosity; " steroid hormone " is meant the hormone of steroidal compounds class, for example estrogen, progestogen etc.In the present invention, " penetrating agent " is meant and can quickens or promote drug osmotic to get into the for example reagent of skin, and this area also can be called " penetration enhancer " etc.
In this article, if not explanation especially, content or consumption are all in weight portion; If there is not special explanation; The device that is adopted, instrument, raw material, material, consumption, method, time, temperature and other condition etc. all are well-known in the art, or those skilled in the art combine prior art to obtain according to the application's description.
Enhancer of cutaneous penetration compositions of the present invention not only can improve the dissolubility of steroid hormone in the transdermal drug delivery system (such as steroid hormone transdermal drug delivery system of the present invention) effectively, and obtains better percutaneous permeability, the cohesiveness of patch is not destroyed.And; Because penetrating agent compositions of the present invention can produce extraordinary collaborative promotion Absorption; Have and urge efficiently to ooze effect, can improve the percutaneous rate of institute's transdermal thing (active constituent) significantly, do not having under dimethyl sulfoxide (DMSO) condition; The transdermal drug delivery system Chinese medicine dosage that (such as levonorgestrel and the contraception of estrogen transdermal) expected can be provided equally, thereby avoid the short potential danger of bringing of oozing of life-time service dimethyl sulfoxide (DMSO).In addition, penetrating agent of the present invention is compatible with many acrylic compounds pressure sensitive adhesive matrixs system, and to the inherent cohesiveness of matrix system, viscosity and rheological property destroy less.In addition, transdermal drug delivery system method for preparing provided by the invention is simple, has avoided complicated technologies such as MULTILAYER COMPOSITE.The resulting product initial bonding strength of the present invention with hold viscous force, heat stability, non-oxidizability, rate of release, safety etc. all are superior to the prior art level.The transdermal drug delivery system that adopts penetrating agent preparation of compositions of the present invention to obtain, therapeutic effect is good, and is safe and convenient to use.
Description of drawings
Fig. 1: transdermal drug delivery system schematic cross-section of the present invention
1, protective layer 2, drug storing layer 3, backing layer
The specific embodiment
" method for preparing " is the general method for preparing of the steroid hormone transdermal drug delivery system of the embodiment of the invention as follows, and " vitro skin permeability test " is the experimental technique of measuring the transdermal infiltration rate of transdermal drug delivery system Chinese medicine of each embodiment.
Method for preparing:
By the consumption that each embodiment provides, take by weighing active component (steroid hormone), put into vial, add viscosity modifier, cosolvent, penetrating agent, be stirred to solubilization of active ingredient.Add viscous polymer solution,, form homogeneous solution to stir 6 hours under the 200rpm speed.Left standstill 3 hours.Get the sticky polymers matrix solution.
The sticky polymers matrix solution that obtains is coated on the protective layer material (like 3M Co., the Scotch Pak 1022 that St.Paul Minn. produces), and applied thickness is about 600 microns, subsequently 65 ℃ of oven dryings 30 minutes.After the drying, about 120 microns of the thickness of sticky polymers hypothallus (drug storing layer).(like 3M Co., Scotch Pak 1109 or Cotran 9720 that St.Paul Minn. produces) is placed on the sticky polymers hypothallus with the release liner (backing layer) of a slice same size, and lamination together obtains the patch of transdermal drug delivery system.Patch cut into 20 square centimeters round patch.Patch is put into the appropriate packaging (like paper bag and/or metallic foil bag) that is used for storing to be preserved subsequent use.
The vitro skin permeability test:
The skin that fresh human body skin is cut into a certain size is tight respectively between two Room of VALIA-CHIEN osmotic cell; Skin corium is towards receiving chamber; Stratum corneum side is sticked the transdermal contraception patch behind the removal protective layer, fixes the twoport of two Room with alligator clamp, in receiving chamber, adds 40% (v/v) PEG400 normal saline solution 3.4ml; Water temperature in the control osmotic cell interlayer is at 32 ± 0.5 ℃; Electromagnetic agitation rotating speed 500r/min by stipulating 4,8,24,32,48 hour blanking time, takes out the penetrating fluid of 100 μ l respectively from receiving chamber; Replenish equivalent 40% (v/v) PEG400 normal saline solution blank solution simultaneously, with LNG in the HPLC method mensuration penetrating fluid and the transdermal cumulative release amount of EE.The amount of linear regression analysis drug accumulation is over time calculated the transdermal infiltration rate of 48 h drug thus.
Embodiment 1
Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.05g;
Viscosity modifier: PVP/VA copolymer (VA64) 0.1g;
Penetrating agent 5g: propylene glycol 2.5g, diethylene glycol monoethyl ether 2.5g;
Sticky polymers: GMS737 20g
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm
2/ h.
Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (VA64) 1.5g;
Penetrating agent 6g: propylene glycol 2g, diethylene glycol monoethyl ether 4g;
Sticky polymers: GMS737 30g;
Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.3g;
Penetrating agent 8g: propylene glycol 2g, isosorbide dimethyl ether 6g;
Sticky polymers: GMS737 40g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Steroid hormone: levonorgestrel 0.4g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.4g;
Penetrating agent 10g: propylene glycol 2g, diethylene glycol monoethyl ether 8g;
Sticky polymers: GMS737 50g;
Recording the levonorgestrel percutaneous rate is 0.18 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 5
Steroid hormone: levonorgestrel 0.6g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 18g: propylene glycol 3g, diethylene glycol monoethyl ether 15g;
Sticky polymers: GMS737 60g;
Recording the levonorgestrel percutaneous rate is 0.18 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 6
Steroid hormone: levonorgestrel 0.5g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.6g;
Penetrating agent 21g: propylene glycol 3g, diethylene glycol monoethyl ether 18g;
Sticky polymers: GMS737 70g;
Recording the levonorgestrel percutaneous rate is 0.18 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 7
Steroid hormone: levonorgestrel 0.7g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.7g;
Penetrating agent 24g: propylene glycol 3g, isosorbide dimethyl ether 21g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 8
Steroid hormone: levonorgestrel 0.8g, ethinylestradiol 0.2g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.8g;
Penetrating agent 20g: propylene glycol 10g, diethylene glycol monoethyl ether 10g;
Sticky polymers: DUROTAK 87-4098 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm
2/ h.
Embodiment 9
Steroid hormone: levonorgestrel 0.9g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.9g;
Penetrating agent 30g: propylene glycol 3g, diethylene glycol monomethyl ether 27g;
Sticky polymers: GMS 1753 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 10
Steroid hormone: levonorgestrel 0.10g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.0g;
Penetrating agent 33g: propylene glycol 3g, isosorbide dimethyl ether 30g;
Sticky polymers: GMS737 75g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.08 μ g/cm
2/ h.
Embodiment 11
Steroid hormone: levonorgestrel 0.15g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.1g;
Penetrating agent 36g: propylene glycol 3g, diethylene glycol monoethyl ether 33g;
Sticky polymers: GMS 788 60g;
Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.08 μ g/cm
2/ h.
Embodiment 12
Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.2g;
Penetrating agent 39g: propylene glycol 3g, diethylene glycol monomethyl ether 36g;
Sticky polymers: GMS737 65g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.08 μ g/cm
2/ h.
Embodiment 13
Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.3g;
Penetrating agent 45g: propylene glycol 3g, diethylene glycol monoethyl ether 42g;
Sticky polymers: GMS 788 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.04 μ g/cm
2/ h.
Embodiment 14
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.2g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.4g;
Penetrating agent 42g: propylene glycol 3g, isosorbide dimethyl ether 39g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm
2/ h.
Embodiment 15
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.02g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.5g;
Penetrating agent 45g: propylene glycol 3g, diethylene glycol monoethyl ether 42g;
Sticky polymers: 6MS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.06 μ g/cm
2/ h.
Embodiment 16
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.04g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.6g;
Penetrating agent 48g: propylene glycol 3g, isosorbide dimethyl ether 45g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 17
Steroid hormone: levonorgestrel 2g, ethinylestradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.7g;
Penetrating agent 17g: propylene glycol 1g, diethylene glycol monoethyl ether 16g;
Sticky polymers: 6MS737 70g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm
2/ h.
Embodiment 18
Steroid hormone: levonorgestrel 1g, ethinylestradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.8g;
Penetrating agent 19g: propylene glycol 1g, isosorbide dimethyl ether 18g;
Sticky polymers: GMS737 75g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.21 μ g/cm
2/ h.
Embodiment 19
Steroid hormone: levonorgestrel 1.5g, ethinylestradiol 1.0g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.9g;
Penetrating agent 20g: propylene glycol 1g, isosorbide dimethyl ether 19g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.21 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm
2/ h.
Embodiment 20
Steroid hormone: levonorgestrel 0.1g, the female 0.08g of alkynes;
Viscosity modifier: PVP/VA copolymer (S-630) 2.0g;
Penetrating agent 21g: propylene glycol 1g, diethylene glycol monoethyl ether 20g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 21
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.09g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.1g;
Penetrating agent 22g: propylene glycol 1g, diethylene glycol monoethyl ether 21g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 22
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.2g;
Penetrating agent 23g: propylene glycol 1g, diethylene glycol monoethyl ether 22g;
Sticky polymers: DUROTAK87-2287 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.04 μ g/cm
2/ h.
Embodiment 23
Steroid hormone: levonorgestrel 0.01g, ethinylestradiol 0.10g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.3g;
Penetrating agent 25g: propylene glycol 1g, isosorbide dimethyl ether 24g;
Sticky polymers: DUROTAK87-4297 80g;
Recording the levonorgestrel percutaneous rate is 0.06 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm
2/ h.
Embodiment 24
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.20g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.4g;
Penetrating agent 26g: propylene glycol 1g, diethylene glycol monoethyl ether 25g;
Sticky polymers: DUROTAK87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.21 μ g/cm
2/ h.
Embodiment 25
Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.25g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.5g;
Penetrating agent 27g: propylene glycol 1g, diethylene glycol monoethyl ether 26g;
Sticky polymers: GMS737 90g;
Recording the levonorgestrel percutaneous rate is 0.04 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm
2/ h.
Embodiment 26
Steroid hormone: levonorgestrel 1g, ethinylestradiol 3g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.6g;
Penetrating agent 25g: propylene glycol 1g, diethylene glycol monoethyl ether 28g;
Sticky polymers: DUROTAK87-2677 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 27
Steroid hormone: levonorgestrel 1g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 10g, isosorbide dimethyl ether 10g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm
2/ h.
Embodiment 28
Steroid hormone: levonorgestrel 0.02g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.8g;
Penetrating agent 31g: propylene glycol 1g, diethylene glycol monoethyl ether 30g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.06 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.14 μ g/cm
2/ h.
Embodiment 29
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.9g;
Penetrating agent 31g: propylene glycol 30g, diethylene glycol monoethyl ether 1g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm
2/ h.
Embodiment 30
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.0g;
Penetrating agent 26g: propylene glycol 25g, isosorbide dimethyl ether 1g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.13 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm
2/ h.
Embodiment 31
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;
Penetrating agent 21g: propylene glycol 20g, diethylene glycol monoethyl ether 1g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm
2/ h.
Embodiment 32
Steroid hormone: levonorgestrel 0.01g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.2g;
Penetrating agent 16g: propylene glycol 15g, diethylene glycol monoethyl ether 1g;
Sticky polymers: GMS737 90g;
Recording the levonorgestrel percutaneous rate is 0.04 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm
2/ h.
Embodiment 33
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.3g;
Penetrating agent 22g: propylene glycol 20g, diethylene glycol monoethyl ether 2g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.13 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.03 μ g/cm
2/ h.
Embodiment 34
Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.01g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.4g;
Penetrating agent 18g: propylene glycol 15g, isosorbide dimethyl ether 3g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm
2/ h.
Embodiment 35
Steroid hormone: levonorgestrel O.1g, ethinylestradiol 0.3g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.5g;
Penetrating agent 15g: benzyl alcohol 12g, diethylene glycol monoethyl ether 3g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.16 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 36
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.4g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.6g;
Penetrating agent 20g:PEG40015g, diethylene glycol monoethyl ether 5g;
Sticky polymers: RODERM 607 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 37
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.5g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.7g;
Penetrating agent 15g: propylene glycol 10g, diethylene glycol monoethyl ether 5g;
Sticky polymers: RODERM 610 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.27 μ g/cm
2/ h.
Embodiment 38
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.6g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.8g;
Penetrating agent 41g: propylene glycol 5g, isosorbide dimethyl ether 36g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.28 μ g/cm
2/ h.
Embodiment 39
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.7g;
Viscosity modifier: PVP/VA copolymer (S-630) 4.1g;
Penetrating agent 42g: propylene glycol 10g, diethylene glycol monoethyl ether 32g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.30 μ g/cm
2/ h.
Embodiment 40
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.8g;
Viscosity modifier: PVP/VA copolymer (S-630) 4.2g;
Penetrating agent 43g: propylene glycol 13g, diethylene glycol monoethyl ether 20g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.30 μ g/cm
2/ h.
Embodiment 41
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 0.9g;
Viscosity modifier: PVP/VA copolymer (S-630) 4.3g;
Penetrating agent 44g: propylene glycol 10g, diethylene glycol monoethyl ether 44g;
Sticky polymers: 6MS737 90g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.29 μ g/cm
2/ h.
Embodiment 42
Steroid hormone: levonorgestrel 0.1g, ethinylestradiol 1.0g;
Viscosity modifier: PVP/VA copolymer (S-630) 4.5g;
Penetrating agent 45g: propylene glycol 5g, isosorbide dimethyl ether 40g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.08 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm
2/ h.
Embodiment 43
Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 1.0g;
Viscosity modifier: PVP/VA copolymer (S-630) 5.0g;
Penetrating agent 50g: propylene glycol 20g, diethylene glycol monoethyl ether 30g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 44
Steroid hormone: levonorgestrel 3.5g, ethinylestradiol 1.5g;
Viscosity modifier: PVP/VA copolymer (S-630) 5.0g;
Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm
2/ h.
Embodiment 45
Steroid hormone: levonorgestrel 0.05g, ethinylestradiol 0.05g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.1g;
Penetrating agent 6g: propylene glycol 2g, diethylene glycol monoethyl ether 2g, lauric acid 2g;
Sticky polymers: GMS737 20g;
Recording the levonorgestrel percutaneous rate is 0.17 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.17 μ g/cm
2/ h.
Embodiment 46
Steroid hormone: levonorgestrel 0.07g, ethinylestradiol 0.13g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.2g;
Penetrating agent 10g: propylene glycol 8.0g, diethylene glycol monoethyl ether 1.0g, lauric acid 1g;
Sticky polymers: GMS737 30g;
Recording the levonorgestrel percutaneous rate is 0.14 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm
2/ h.
Embodiment 47
Steroid hormone: levonorgestrel 0.2g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.3g;
Penetrating agent 7g: benzyl alcohol 5g, diethylene glycol monoethyl ether 1g, lauric acid 1g;
Sticky polymers: GMS737 40g;
Recording the levonorgestrel percutaneous rate is 0.22 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 48
Steroid hormone: levonorgestrel 0.3g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.4g;
Penetrating agent 12g: propylene glycol 10g, diethylene glycol monoethyl ether 1g, lauric acid 1g;
Sticky polymers: GMS737 50g;
Recording the levonorgestrel percutaneous rate is 0.28 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 49
Steroid hormone: levonorgestrel 0.4g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 17g: propylene glycol 15g, diethylene glycol monoethyl ether 1g, lauric acid 1g;
Sticky polymers: GMS737 60g;
Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 50
Steroid hormone: levonorgestrel 0.5g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.6g;
Penetrating agent 22g: propylene glycol 20g, isosorbide dimethyl ether 1g, lauric acid 1g;
Sticky polymers: GMS737 70g;
Recording the levonorgestrel percutaneous rate is 0.32 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 51
Steroid hormone: levonorgestrel 0.6g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.7g;
Penetrating agent 32g: propylene glycol 30g, diethylene glycol monoethyl ether 1g, lauric acid 1g;
Sticky polymers: GMS737 80g;
Recording the levonorgestrel percutaneous rate is 0.34 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 52
Steroid hormone: levonorgestrel 0.7g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.8g;
Penetrating agent 40g: propylene glycol 10g, isosorbide dimethyl ether 20g, lauric acid 10g;
Sticky polymers: GMS 788 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 53
Steroid hormone: levonorgestrel 0.8g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.9g;
Penetrating agent 16g: propylene glycol 6g, diethylene glycol monoethyl ether 6g, lauric acid 4g;
Sticky polymers: GMS 1753 78g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 54
Steroid hormone: levonorgestrel 0.9g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.0g;
Penetrating agent 35g: propylene glycol 5g, diethylene glycol monoethyl ether 25g, lauric acid 5g;
Sticky polymers: GMS 788 80g;
Recording the levonorgestrel percutaneous rate is 0.24 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 55
Steroid hormone: levonorgestrel 1.0g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.1g;
Penetrating agent 40g: propylene glycol 5g, diethylene glycol monoethyl ether 30g, lauric acid 5g;
Sticky polymers: GMS 1753 90g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 56
Steroid hormone: levonorgestrel 1.1g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.2g;
Penetrating agent 39g: propylene glycol 3g, isosorbide dimethyl ether 30g, lauric acid 3g;
Sticky polymers: GMS 1753 80g;
Recording the levonorgestrel percutaneous rate is 0.26 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 57
Steroid hormone: levonorgestrel 1.2g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.3g;
Penetrating agent 34g: propylene glycol 2g, diethylene glycol monomethyl ether 30g, lauric acid 2g;
Sticky polymers: GMS 1753 80g;
Recording the levonorgestrel percutaneous rate is 0.26 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 58
Steroid hormone: levonorgestrel 1.3g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.4g;
Penetrating agent 44g: propylene glycol 2g, diethylene glycol monoethyl ether 40g, lauric acid 2g;
Sticky polymers: GMS 1753 80g;
Recording the levonorgestrel percutaneous rate is 0.27 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 59
Steroid hormone: levonorgestrel 1.4g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.5g;
Penetrating agent 32g: propylene glycol 1g, diethylene glycol monomethyl ether 30g, oleic acid 1g;
Sticky polymers: DUROTAK 87-4098 80g;
Recording the levonorgestrel percutaneous rate is 0.28 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 60
Steroid hormone: levonorgestrel 1.5g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.6g;
Penetrating agent 15g: propylene glycol 3g, isosorbide dimethyl ether 6g, lauric acid 6g;
Sticky polymers: DUROTAK 87-4098 70g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 61
Steroid hormone: levonorgestrel 1.6g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.7g;
Penetrating agent 21g: propylene glycol 3g, diethylene glycol monoethyl ether 9g, oleic acid 9g;
Sticky polymers: DUROTAK 87-4098 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 62
Steroid hormone: levonorgestrel 1.7g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.8g;
Penetrating agent 27g: propylene glycol 3g, diethylene glycol monoethyl ether 12g, oleic acid 12g;
Sticky polymers: DUROTAK 87-2287 80g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 63
Steroid hormone: levonorgestrel 1.8g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1.9g;
Penetrating agent 33g: propylene glycol 3g, isosorbide dimethyl ether 15g, oleic acid 15g;
Sticky polymers: DUROTAK 87-2287 80g;
Recording the levonorgestrel percutaneous rate is 0.29 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 64
Steroid hormone: levonorgestrel 1.9g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.0g;
Penetrating agent 26g: propylene glycol 2g, diethylene glycol monoethyl ether 12g, oleic acid 12g;
Sticky polymers: DUROTAK 87-2287 80g;
Recording the levonorgestrel percutaneous rate is 0.29 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 65
Steroid hormone: levonorgestrel 2.0g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.1g;
Penetrating agent 28g: propylene glycol 2g, diethylene glycol monoethyl ether 12g, capric acid 14g;
Sticky polymers: DUROTAK 87-2287 80g;
Recording the levonorgestrel percutaneous rate is 0.29 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 66
Steroid hormone: levonorgestrel 2.1g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.2g;
Penetrating agent 34g: propylene glycol 2g, diethylene glycol monomethyl ether 12g, capric acid 20g;
Sticky polymers: DUROTAK 87-4297 80g;
Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 67
Steroid hormone: levonorgestrel 2.2g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.3g;
Penetrating agent 23g: propylene glycol 1g, diethylene glycol monoethyl ether 6g, capric acid 15g;
Sticky polymers: DUROTAK 87-4297 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 68
Steroid hormone: levonorgestrel 2.3g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.4g;
Penetrating agent 27g: propylene glycol 1g, isosorbide dimethyl ether 6g, lauric acid 20g;
Sticky polymers: DUROTAK 87-4297 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 69
Steroid hormone: levonorgestrel 2.4g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.5g;
Penetrating agent 36g: propylene glycol 1g, diethylene glycol monomethyl ether 10g, lauric acid 25g;
Sticky polymers: DUROTAK 887-2677 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 70
Steroid hormone: levonorgestrel 2.5g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.6g;
Penetrating agent 46g: propylene glycol 1g, diethylene glycol monoethyl ether 15g, lauric acid 30g;
Sticky polymers: DUROTAK 87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 71
Steroid hormone: levonorgestrel 2.6g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.7g;
Penetrating agent 41g: propylene glycol 1g, diethylene glycol monoethyl ether 10g, capric acid 30g;
Sticky polymers: DUROTAK 87-2677 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Embodiment 72
Steroid hormone: levonorgestrel 2.7g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.8g;
Penetrating agent 40g: propylene glycol 15g, diethylene glycol monoethyl ether 15g, lauric acid 10g;
Sticky polymers: DUROTAK 87-2677 80g;
Recording left alkynes W norgesterone percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Embodiment 73
Steroid hormone: levonorgestrel 2.8g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 2.9g;
Penetrating agent 30g: propylene glycol 10g, isosorbide dimethyl ether 10g, lauric acid 10g;
Sticky polymers: DUROTAK 87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Embodiment 74
Steroid hormone: levonorgestrel 2.9g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.0g;
Penetrating agent 50g: propylene glycol 20g, diethylene glycol monoethyl ether 20g, lauric acid 10g;
Sticky polymers: DUROTAK 87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Embodiment 75
Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;
Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g, capric acid 10g;
Sticky polymers: DUROTAK 87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Embodiment 76
Steroid hormone: levonorgestrel 4.0g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid 10g;
Sticky polymers: GMS 737 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm
2/ h.
Embodiment 77
Steroid hormone: levonorgestrel 0.50g, ethinylestradiol 0.05g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, lauric acid 10g;
Sticky polymers: GMS 737 80g;
Recording the levonorgestrel percutaneous rate is 0.20 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm
2/ h.
Embodiment 78
Steroid hormone: levonorgestrel 2g, ethinylestradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, oleyl alcohol 10g;
Sticky polymers: RODERM 607 80g;
Recording the levonorgestrel percutaneous rate is 0.33 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.20 μ g/cm
2/ h.
Embodiment 79
Steroid hormone: estradiol 0.2g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, oleic acid 10g;
Sticky polymers: RODERM 610 80g;
Recording estradiol transdermal speed is 0.23 μ g/cm
2/ h.
Embodiment 80
Steroid hormone: estradiol 8g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauryl alcohol 10g;
Sticky polymers: RODERM 610 80g;
Recording estradiol transdermal speed is 0.35 μ g/cm
2/ h.
Embodiment 81
Steroid hormone: estradiol 5g,
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 34g: propylene glycol 12g, isosorbide dimethyl ether 12g, lauric acid 10g;
Sticky polymers: RODERM 610 80g;
Recording estradiol transdermal speed is 0.35 μ g/cm
2/ h.
Embodiment 82
Steroid hormone: levonorgestrel 0.2g estradiol 0.04g;
Viscosity modifier: PVP/VA copolymer (S-630) 0.5g;
Penetrating agent 12g: propylene glycol 4g, isosorbide dimethyl ether 4g, lauric acid 4g;
Sticky polymers: GMS 737 72g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.05 μ g/cm
2/ h.
Embodiment 83
Steroid hormone: levonorgestrel 0.2g estradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 12g, diethylene glycol monoethyl ether 12g, lauric acid 10g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.22 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.12 μ g/cm
2/ h.
Embodiment 84
Steroid hormone: levonorgestrel 0.1g estradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g: propylene glycol 5g, diethylene glycol monoethyl ether 5g, oleic acid 4g;
Sticky polymers: GMS 737 75g;
Recording the levonorgestrel percutaneous rate is 0.24 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 85
Steroid hormone: levonorgestrel 0.02g estradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 15g: propylene glycol 6g, diethylene glycol monoethyl ether 6g, oleic acid 3g;
Sticky polymers: GMS 737 75g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 86
Steroid hormone: levonorgestrel 0.1g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 13g: propylene glycol 5g, diethylene glycol monoethyl ether 5g, oleic acid 3g;
Sticky polymers: GMS 737 75g;
Recording the levonorgestrel percutaneous rate is 0.12 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 87
Steroid hormone: levonorgestrel 0.5g estradiol 0.2g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, lauric acid 6g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.25 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.10 μ g/cm
2/ h.
Embodiment 88
Steroid hormone: levonorgestrel 4g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, lauric acid 6g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 89
Steroid hormone: levonorgestrel 3g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 10g: propylene glycol 4g, diethylene glycol monoethyl ether 4g, lauric acid 2g;
Sticky polymers: GMS 737 80g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.18 μ g/cm
2/ h.
Embodiment 90
Steroid hormone: levonorgestrel 0.8g estradiol 0.2g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g: propylene glycol 5g, diethylene glycol monoethyl ether 5g, lauryl alcohol 4g;
Sticky polymers: GMS 737 86g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.15 μ g/cm
2/ h.
Embodiment 91
Steroid hormone: levonorgestrel 2g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g:PEG1000 5g, diethylene glycol monoethyl ether 5g, oleic acid 4g;
Sticky polymers: GMS 737 86g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.35 μ g/cm
2/ h.
Embodiment 92
Steroid hormone: levonorgestrel 1g estradiol 2g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, capric acid 4g;
Sticky polymers: GMS 737 86g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.40 μ g/cm
2/ h.
Embodiment 93
Steroid hormone: levonorgestrel 1g estradiol 3g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g: propylene glycol 5g, isosorbide dimethyl ether 5g, decanol 4g;
Sticky polymers: GMS 737 86g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.40 μ g/cm
2/ h.
Embodiment 94
Steroid hormone: levonorgestrel 1g estradiol 2g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 14g: benzyl alcohol 5g, isosorbide dimethyl ether 5g, capric acid 4g;
Sticky polymers: GMS 737 86g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.40 μ g/cm
2/ h.
Embodiment 95
Steroid hormone: levonorgestrel 4g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, lauryl alcohol 6g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 96
Steroid hormone: levonorgestrel 4g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 7g, diethylene glycol monoethyl ether 7g, oleyl alcohol 6g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 97
Steroid hormone: levonorgestrel 4g estradiol 1g;
Viscosity modifier: PVP/VA copolymer (S-630) 1g;
Penetrating agent 20g: propylene glycol 7g, isosorbide dimethyl ether 7g, oleyl alcohol 6g;
Sticky polymers: GMS 737 90g;
Recording the levonorgestrel percutaneous rate is 0.35 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.25 μ g/cm
2/ h.
Embodiment 98
Steroid hormone: levonorgestrel 3.0g, ethinylestradiol 0.1g;
Viscosity modifier: PVP/VA copolymer (S-630) 3.1g;
Penetrating agent 40g: propylene glycol 10g, diethylene glycol monoethyl ether 30g, decanol 10g;
Sticky polymers: DUROTAK 87-900A 80g;
Recording the levonorgestrel percutaneous rate is 0.30 μ g/cm
2/ h, ethinyl estradiol gas permeable speed are: 0.09 μ g/cm
2/ h.
Resulting transdermal drug delivery system is bonded on the female skin uses, can reach contraception or prevent and treat osteoporotic ideal effect.Through tests such as skin toxicity, sensitivity, prove that patch of the present invention is superior to the prior art level greatly.
The as above embodiment purpose that is only used for setting forth, and and limit protection scope of the present invention never in any form.Those skilled in the art can make multiple modification or change to embodiment of the present invention under spirit of the present invention and purport under the instruction of this description, these all will comprise within the scope of the invention.
Claims (32)
1. steroid hormone transdermal drug delivery system, it is characterized in that: it comprises protective layer (1), drug storing layer (2) and backing layer (3); Drug storing layer (2) is attached between strippable protective layer (1) and the backing layer (3), is to be prepared from the sticky polymers matrix solution; The sticky polymers matrix solution composition of preparation drug storing layer (2) comprising: steroid hormone, sticky polymers, penetrating agent and viscosity modifier; Said penetrating agent is made up of ether compound and alcohol compound; The content of ether compound and alcohol compound is counted with weight portion in the penetrating agent: ether compound accounts for 1-30 part; Alcohol compound accounts for 1-30 part; Ether compound is selected from isosorbide dimethyl ether, diethylene glycol monoethyl ether or diethylene glycol monomethyl ether; Alcohol compound is selected from propylene glycol, Polyethylene Glycol or benzyl alcohol, and in the said sticky polymers matrix solution, the consumption of component is counted with parts by weight: penetrating agent accounts for 5-50 weight portion, sticky polymers and accounts for that 20-90 weight portion, viscosity modifier account for the 0.1-20 weight portion, steroid hormone accounts for the 0.1-5 weight portion.
2. steroid hormone transdermal drug delivery system according to claim 1; It is characterized in that the consumption of component is counted with parts by weight in the said sticky polymers matrix solution: penetrating agent accounts for 10-40 weight portion, sticky polymers and accounts for that 50-90 weight portion, viscosity modifier account for the 0.5-5 weight portion, steroid hormone accounts for the 0.1-3 weight portion.
3. steroid hormone transdermal drug delivery system according to claim 2; It is characterized in that the consumption of component is counted with parts by weight in the said sticky polymers matrix solution: penetrating agent accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion.
4. steroid hormone transdermal drug delivery system according to claim 1, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion in the penetrating agent: ether compound accounts for 1-20 part, and alcohol compound accounts for 1-20 part.
5. steroid hormone transdermal drug delivery system according to claim 4, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion in the penetrating agent: ether compound accounts for 1-10 part, and alcohol compound accounts for 1-10 part.
6. steroid hormone transdermal drug delivery system according to claim 5, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion in the penetrating agent: ether compound accounts for 1-4 part, and alcohol compound accounts for 1-4 part.
7. steroid hormone transdermal drug delivery system according to claim 1 is characterized in that described penetrating agent also contains C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol, ether compound, alcohol compound and C in the penetrating agent
6-C
18Fatty acid or C
6-C
18The content of aliphatic alcohol is counted with weight portion: ether compound accounts for 1-30 part, alcohol compound accounts for 1-30 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-30 part.
8. steroid hormone transdermal drug delivery system according to claim 7 is characterized in that ether compound in the penetrating agent, alcohol compound and C
6-C
18Fatty acid or C
6-C
18The content of aliphatic alcohol is counted with weight portion: ether compound accounts for 1-20 part, alcohol compound accounts for 1-20 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol accounts for 1-20 part.
9. steroid hormone transdermal drug delivery system according to claim 8 is characterized in that ether compound in the penetrating agent, alcohol compound and C
6-C
18Fatty acid or C
6-C
18The content of aliphatic alcohol count with weight portion: ether compound accounts for 1-10 part, alcohol compound accounts for 1-10 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol account for 1-10 part.
10. steroid hormone transdermal drug delivery system according to claim 9, it is characterized in that the content of ether compound and alcohol compound is counted with weight portion in the penetrating agent: ether compound accounts for 1-4 part, and alcohol compound accounts for 1-4 part, C
6-C
18Fatty acid or C
6-C
18Aliphatic alcohol account for 1-4 part.
11. according to each described steroid hormone transdermal drug delivery system of claim 7-10, C
6-C
18Fatty acid is selected from capric acid, lauric acid or oleic acid; C
6-C
18Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.
12. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is diethylene glycol monoethyl ether, propylene glycol and lauric compositions.
13. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is isosorbide dimethyl ether, propylene glycol and lauric compositions.
14. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and lauryl alcohol.
15. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of diethylene glycol monoethyl ether, benzyl alcohol and lauryl alcohol.
16. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and oleyl alcohol.
17. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of isosorbide dimethyl ether, propylene glycol and oleyl alcohol.
18. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of diethylene glycol monoethyl ether, propylene glycol and decanol.
19. steroid hormone transdermal drug delivery system according to claim 11 is characterized in that said penetrating agent is the compositions of isosorbide dimethyl ether, propylene glycol and decanol.
20. according to the arbitrary described steroid hormone transdermal drug delivery system of claim 1-19, wherein said sticky polymers is selected from crosslinked or uncrosslinked polyacrylate, silicone or polyisobutylene.
21. steroid hormone transdermal drug delivery system according to claim 20, wherein said sticky polymers are crosslinked or uncrosslinked polyacrylate.
22. steroid hormone transdermal drug delivery system according to claim 20, wherein said polyacrylate are selected from and gather (2-EHA/acrylic copolymer), gather (the own ester/acrylic acid of acrylic acid 2-hydroxyl/methyl acrylate copolymer), gather (2-EHA/acrylic acid/methyl acrylate copolymer) or gather (2-EHA/acrylic acid/butylacrylate/vinyl acetate copolymer).
23. according to the described steroid hormone transdermal drug delivery system of claim 1-19, wherein said viscosity modifier is polyvinylpyrrolidone//vinyl acetate copolymers, polyvinylpyrrolidone, polybutyl methacrylate/methylmethacrylate copolymer or ethyl cellulose.
24. steroid hormone transdermal drug delivery system according to claim 23, wherein said viscosity modifier are molecular weight is polyvinylpyrrolidone/vinyl acetate of 50,000, and the weight ratio of polyvinylpyrrolidone and vinyl acetate is 6: 4.
25. according to each described steroid hormone transdermal drug delivery system among the claim 1-24, wherein said steroid hormone is one or more in progestogen and the estrogen.
26. steroid hormone transdermal drug delivery system according to claim 25, wherein said steroid hormone is made up of the progestogen of 1-30 weight portion and the estrogen of 1-10 weight portion.
27. steroid hormone transdermal drug delivery system according to claim 26, wherein said steroid hormone is made up of the progestogen of 1-20 weight portion and the estrogen of 1-5 part.
28. according to each described steroid hormone transdermal drug delivery system among the claim 25-27, the progestogen in the wherein said steroid hormone are selected from: the diacetate esters of levonorgestrel, methylnorethindron, norgestimate variant, gestodene, norethindrone, norethynodrel, hydrogen progesterone, gestodene, etynodiol, hydroxyprogesterone acetas, gestogen.
29. according to each described steroid hormone transdermal drug delivery system among the claim 25-27, the estrogen in the wherein said steroid hormone is selected from ethinylestradiol, 17 beta estradiols.
30. according to each described steroid hormone transdermal drug delivery system among the claim 25-27, the progestogen in the wherein said steroid hormone are that levonorgestrel, estrogen are ethinylestradiols.
31. steroid hormone transdermal drug delivery system according to claim 1; It is characterized in that components contents is counted with parts by weight in the said sticky polymers substrate: penetrating agent accounts for 10-20 weight portion, sticky polymers and accounts for that 70-90 weight portion, viscosity modifier account for the 0.5-3 weight portion, steroid hormone accounts for the 0.1-1 weight portion;
Wherein, said steroid hormone is made up of the levonorgestrel of 1-20 weight portion and the ethinylestradiol of 1-5 part; Said penetrating agent is by the alcohol compound of the ether compound of 1-4 weight portion, 1-4 weight portion, the C of 1-4 weight portion
6-C
16Fatty acid or C
6-C
18Aliphatic alcohol form; Said ether compound is selected from diethylene glycol monoethyl ether or isosorbide dimethyl ether; Said alcohol compound is propylene glycol, benzyl alcohol, PEG400, PEG600 or PEG1000; Said C
6-C
18Fatty acid is selected from lauric acid, oleic acid or capric acid; Said C
6-C
18Aliphatic alcohol is selected from decanol, lauryl alcohol or oleyl alcohol.
32. the described steroid hormone transdermal drug delivery system of claim 1-31 is in preparation birth control or treatment female osteoporosis, the application of climacteric syndrome Chinese medicine.
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| CN2010102082582A CN101940790B (en) | 2009-07-01 | 2010-06-24 | Novel penetration-promoting agent composition and application thereof to transdermal administration system |
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Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2715000T3 (en) | 2011-09-12 | 2019-05-31 | Merial Inc | Parasiticidal compositions comprising an active isoxazoline agent, methods and uses thereof |
| HUE055562T2 (en) | 2011-11-23 | 2021-11-29 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
| US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US10537581B2 (en) | 2012-12-21 | 2020-01-21 | 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 |
| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
| 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 |
| 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
| US20040101551A1 (en) * | 2000-08-30 | 2004-05-27 | Thorsten Selzer | Transdermal therapeutic system for releasing venlafaxine |
| US20060153905A1 (en) * | 2003-10-10 | 2006-07-13 | Carrara R D N | Transdermal pharmaceutical formulation for minimizing skin residues |
| CN101426475A (en) * | 2006-04-21 | 2009-05-06 | 安塔雷斯制药Ipl股份公司 | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
-
2010
- 2010-06-24 CN CN2010102082582A patent/CN101940790B/en active Active
- 2010-06-24 WO PCT/CN2010/000935 patent/WO2011000210A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
| US20040101551A1 (en) * | 2000-08-30 | 2004-05-27 | Thorsten Selzer | Transdermal therapeutic system for releasing venlafaxine |
| US20060153905A1 (en) * | 2003-10-10 | 2006-07-13 | Carrara R D N | Transdermal pharmaceutical formulation for minimizing skin residues |
| CN101426475A (en) * | 2006-04-21 | 2009-05-06 | 安塔雷斯制药Ipl股份公司 | Methods of treating hot flashes with formulations for transdermal or transmucosal application |
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| CN101940790A (en) | 2011-01-12 |
| WO2011000210A1 (en) | 2011-01-06 |
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Address after: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee after: Guangzhou Iconas Biomedical Technology Co.,Ltd. Patentee after: Yang Mingjing Address before: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee before: Guangzhou Iconas Biomedical Technology Co.,Ltd. Patentee before: Yang Mingjing |
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Address after: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee after: Guangzhou Iconas Biomedical Technology Co.,Ltd. Patentee after: Yang Mingjing Address before: 515063 in Rongsheng science and Technology Park, University Road, Shantou City, Guangdong Province Patentee before: RUNBIO BIOTECH Co.,Ltd. Patentee before: Yang Mingjing |
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Correction item: Patentee|Address Correct: RUNBIO BIOTECH Co.,Ltd.|515063 in Rongsheng science and Technology Park, University Road, Shantou City, Guangdong Province False: Guangzhou Iconas Biomedical Technology Co.,Ltd.|Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Number: 07-01 Volume: 39 |
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Address after: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee after: Guangdong Iconas Biomedical Technology Co.,Ltd. Patentee after: Yang Mingjing Address before: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee before: Guangdong Iconas Biomedical Technology Co.,Ltd. Patentee before: Yang Mingjing |
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Address after: Room 116, Floor 1, Transportation Bureau Building, No. 95, Yingbin Avenue, Huacheng Street, Huadu District, Guangzhou, Guangdong Province, 510801 Patentee after: Guangdong Iconas Biomedical Technology Co.,Ltd. Patentee after: Yang Mingjing Address before: 515063 in Rongsheng science and Technology Park, University Road, Shantou City, Guangdong Province Patentee before: RUNBIO BIOTECH Co.,Ltd. Patentee before: Yang Mingjing |
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