CA1228298A - Compositions and methods for drug delivery involving amphiphilic steroids - Google Patents
Compositions and methods for drug delivery involving amphiphilic steroidsInfo
- Publication number
- CA1228298A CA1228298A CA000455465A CA455465A CA1228298A CA 1228298 A CA1228298 A CA 1228298A CA 000455465 A CA000455465 A CA 000455465A CA 455465 A CA455465 A CA 455465A CA 1228298 A CA1228298 A CA 1228298A
- Authority
- CA
- Canada
- Prior art keywords
- composition
- drug
- agent
- group
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Reproductive Health (AREA)
- Emergency Medicine (AREA)
- Otolaryngology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Compositions and methods useful for the prevention or treatment of a human or animal disorder or for the regulation of a human or animal physiological condition are provided. The compositions used comprise, in admixture, a biologically-effective amount of a drug specific for the disorder or condition and a biocompatible, water-soluble, amphiphilic steroid, other than a natural bile salt, which is capable of increasing drug permeability of the human or animal body surface across which the drug is to be administered, in an amount effective to increase the permeability of the surface to the drug.
Compositions and methods useful for the prevention or treatment of a human or animal disorder or for the regulation of a human or animal physiological condition are provided. The compositions used comprise, in admixture, a biologically-effective amount of a drug specific for the disorder or condition and a biocompatible, water-soluble, amphiphilic steroid, other than a natural bile salt, which is capable of increasing drug permeability of the human or animal body surface across which the drug is to be administered, in an amount effective to increase the permeability of the surface to the drug.
Description
q3~
9~_10/.
Part of the work de~cribed and claimed herein was suppor~ed in part by a grant or award from ~he Uni~ed States Government~ which has certain right~ in the invention.
INTRODUCTION
This invention relates to the administration of drug~ acros8 human or animal body surfaces. (As uæed hereln, the term ~drug" i~ defined a~ any biologically-active chemical or natural ~ubstance u~eful for treating a medical or veterinary disorder~ preventing a medical or veterinary di~order, or regulating the physiology of a human being or animal.) More particularly, the invention relates to an administration method based on the use of biocompat~ble, water-soluble, amphiphilic ~teroids capable of increasing the permeability of human and animal body surfaces to a variety of biologically active substances.
Application of admixtures of ~teroid and drug to mucosal or epithelial surfaces advantageously results in enhanced drug delivery across the body ~urface.
BACKGROUND OF THE INV~NTION
To elicit its characteri~ic biological re~ponse in the body~ a drug must be available in an effective concentration at its site of action~ The concentration of a drug that reaches its reactive si e varies with such factors as the amount of drug administered9 the exten~ and ~r~
32~3~
rate of it6 absorption, distribution, binding or localizaton in tissues, i~s biotransformation, and i~s excretion. (For a review of these topicst see Goodman and Gilman's, The Pharmacoloqical Basis of Therapeutics, 6th edition, MacMillan Publishing Co.~ InC., NeW York, 1980, pp. 1-390) The foregoing factors, and hence the ultimate efficacy of a particular drug, are in turn influenced by ~he route chosen for drug administration.
The common routes of drug administration are enteral (oral ingestion) and parenteral (intravenous, subcutaneous, and intramuscular) routes of administration. To determine the appropriate mode of drug administration, it is necessary to understand some of the advantages and disadvantages of the route used. For example, intravenous drug administration is advantageous for emergency use when very rapid increases in blood levels are necessary. The intravenous route allows for dosage adjustments when required, and is also useful for administration of large volumes of a drug when dilu~ed.
However, there are limitations on the usefulness of intravenous drug administration. One problem is the risk of adverse effects resulting from the rapid accumulation of high co~centrations of the drug in plasma and tissues.
Consequently, intravenously administered drug solutions must generally be continuously moni~ored and injected slowly. The intravenous route is not sui~able for oily or insoluble substances. Furthermore, intravenous administration is restricted to ~rained medical personnel.
Other routes of parental administration are often inconvenient or painful for patients especially if frequent administration i~ required. Subcutaneous 36 injection is used for drugs that are not irritating. This mode o administration is not suitable for delivering --3~
large volumes nor i8 it suitable for adminis~ering irritating substances which may cau~e pain or ~ecrosis at the site of injection~ In~ramuscular administration is generally suitable for moderate volumes, oily substances, and some irritating substances. The intramuscular route cannot be used during anticoagulant medication and may interfere with ~he interpretation of certain diagnostic tests.
Oral administration of drugs is generally more convenient and economical and is most acceptable to humans. Bowever, thi~ route of administration requires patient cooperation. Absorption may be ~nefficient (i.e., 16 incomplete) for poorly soluble, slowly absorbed, or unstable drug preparations, and the time from ingestion to absoptlon may prohibit effective use in emergency situations. Furthermore, peptides and proteins will often be destroyed by the digestive enzymes, acid, and ~urface-active lipids in the gut prior to reaching the site of action.
Certain drugs which need to be administered frequently are not effectively absorbed when administered orally and hence must be delivered by lnjection methodsO
Yet, a number of problems are associated with conventional in~ection therapie~.
By way of illustration, conventional insulin 30 therapy requires frequent insulin injections resulting in discomfort and disruption of the patient's lifestyle.
Hence, many diabetics either refuse insulin therapy altogether or avoid intensive ~reatmen~ regimens such as those which involve injec~ ions with each meal. In 35 addition, certain patients, especially young children, elderly patients, and those who are blind and/or disabled;
9~_10/.
Part of the work de~cribed and claimed herein was suppor~ed in part by a grant or award from ~he Uni~ed States Government~ which has certain right~ in the invention.
INTRODUCTION
This invention relates to the administration of drug~ acros8 human or animal body surfaces. (As uæed hereln, the term ~drug" i~ defined a~ any biologically-active chemical or natural ~ubstance u~eful for treating a medical or veterinary disorder~ preventing a medical or veterinary di~order, or regulating the physiology of a human being or animal.) More particularly, the invention relates to an administration method based on the use of biocompat~ble, water-soluble, amphiphilic ~teroids capable of increasing the permeability of human and animal body surfaces to a variety of biologically active substances.
Application of admixtures of ~teroid and drug to mucosal or epithelial surfaces advantageously results in enhanced drug delivery across the body ~urface.
BACKGROUND OF THE INV~NTION
To elicit its characteri~ic biological re~ponse in the body~ a drug must be available in an effective concentration at its site of action~ The concentration of a drug that reaches its reactive si e varies with such factors as the amount of drug administered9 the exten~ and ~r~
32~3~
rate of it6 absorption, distribution, binding or localizaton in tissues, i~s biotransformation, and i~s excretion. (For a review of these topicst see Goodman and Gilman's, The Pharmacoloqical Basis of Therapeutics, 6th edition, MacMillan Publishing Co.~ InC., NeW York, 1980, pp. 1-390) The foregoing factors, and hence the ultimate efficacy of a particular drug, are in turn influenced by ~he route chosen for drug administration.
The common routes of drug administration are enteral (oral ingestion) and parenteral (intravenous, subcutaneous, and intramuscular) routes of administration. To determine the appropriate mode of drug administration, it is necessary to understand some of the advantages and disadvantages of the route used. For example, intravenous drug administration is advantageous for emergency use when very rapid increases in blood levels are necessary. The intravenous route allows for dosage adjustments when required, and is also useful for administration of large volumes of a drug when dilu~ed.
However, there are limitations on the usefulness of intravenous drug administration. One problem is the risk of adverse effects resulting from the rapid accumulation of high co~centrations of the drug in plasma and tissues.
Consequently, intravenously administered drug solutions must generally be continuously moni~ored and injected slowly. The intravenous route is not sui~able for oily or insoluble substances. Furthermore, intravenous administration is restricted to ~rained medical personnel.
Other routes of parental administration are often inconvenient or painful for patients especially if frequent administration i~ required. Subcutaneous 36 injection is used for drugs that are not irritating. This mode o administration is not suitable for delivering --3~
large volumes nor i8 it suitable for adminis~ering irritating substances which may cau~e pain or ~ecrosis at the site of injection~ In~ramuscular administration is generally suitable for moderate volumes, oily substances, and some irritating substances. The intramuscular route cannot be used during anticoagulant medication and may interfere with ~he interpretation of certain diagnostic tests.
Oral administration of drugs is generally more convenient and economical and is most acceptable to humans. Bowever, thi~ route of administration requires patient cooperation. Absorption may be ~nefficient (i.e., 16 incomplete) for poorly soluble, slowly absorbed, or unstable drug preparations, and the time from ingestion to absoptlon may prohibit effective use in emergency situations. Furthermore, peptides and proteins will often be destroyed by the digestive enzymes, acid, and ~urface-active lipids in the gut prior to reaching the site of action.
Certain drugs which need to be administered frequently are not effectively absorbed when administered orally and hence must be delivered by lnjection methodsO
Yet, a number of problems are associated with conventional in~ection therapie~.
By way of illustration, conventional insulin 30 therapy requires frequent insulin injections resulting in discomfort and disruption of the patient's lifestyle.
Hence, many diabetics either refuse insulin therapy altogether or avoid intensive ~reatmen~ regimens such as those which involve injec~ ions with each meal. In 35 addition, certain patients, especially young children, elderly patients, and those who are blind and/or disabled;
2~
often have difficulty with insulin self-administration by injection. Furthermore, insulin absorption after subcutaneous injection is variable in ~erms of rate and amount depending upon factors such as exercise, local blood flow, dep~h and volume of injection, the presence of local proteases which degrade insulin, and perhaps other, unknown factors. Even presently available short acting and long acting preparations of insulin or mixtures thereof cannot mimic the daily glucose and insulin excursions of non-diabetic individuals. Portable infusion pumps have now been employed to increase the ease of delivering subcutaneously meal-related insulin boluses.
~oweverV these devices are externally worn and are therefore cumbersome. They require regular needle replacement, are complicated by local infections at the site of needle placement, are expensive, and are not acceptable to many patients.
It is clear that a reproducible~ reliable, and non-invasive means for delivering drugs 6uch as insulin would be highly desirable. What is needed especially in ~he case of insulin is a delivery sys~em that would permit easy~ rapid, and non-invasive administration of insulin at meal times when blood glucose concentration rises to peak levels. Since the discovery of insulin six decades ago, there have been many attempts to develop alternate means of in~ulin delivery. For instance, insulin has been administered enterally, either alone or encapsulated in 30 liposomes (microcapsules), sublin~ually, vaginally, and rectally, with and without surfactants~
In addition to the preceding routes of administration, the nasal route has been ~he subject of investigation for the delivery not only of insulin but of other drugs as wellO It is known that certain very small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution withou~ an adjuvant. Examples of pep ides which can ~ometimes be administered by ~his rou~e are adrenocorticotrophic hormone (ACTH), lu~einizlng hormone releasing hormone (LHRH), oxytocin and vasopressin. Indeed, for patients with diabetes insipidus9 the intranasal route is frequently the means for vasopressin delivery~
Xn ~ontrast to these directly administrable compounds, many drugs such as insulin are inefficiently absorbed across mucous membranes at physiological pH in the absence of adjuvants. Several workers have attempted to mix insulin with adjuvants that might enhance nasal insulin absorption. ~irai et al., IntO J. Pharmaceutics (1981) g:l65-184; Hirai et al., Diabetes (1978) 27-2~6-299; British Pat7 No. 1,527,605; and U.S. Pat~ No.
4,153,689; and Pontiroli et al. (1982~ Br. Med. 3.
284:303-386~ have described the use of various bile salts to enhance absorption of insulin by he nasal mucosaO
While the nasal mucosal route has received considerable attention for systemic drug deli~ery, it has also hitherto been known that drugs may be applied to mucous membranes of th~ conjunctiva, nasopharynx, oropharynx, ear canalr respiratory tract, vagina, rectum, colon, and urinary bladder for their local effectsO
SUMMARY OF THE INVENTION
We have discovered an effective means of administering a drug to a human being or animal which avoids many of the problems associated with other modes of administration such as injectionO The invention provides methods and compositions useful for ~he prevention and/or treatment of human or animal disorders ~nd for ~h regulatio~ of a$pect8 of human or animal physiology, e.g., ~ertility. The compo~itions employed ~re admixtures comprising: (a) as act~ve ingredient, a drug specific for a g~ven di~order or condition ln a biologically-effective amoun~t ~nd (~3 a~ adjuvant, a biocompat~ble, water~oluble, amphiph~lic ~teroid, other than a natural bile salt, capable of increasing drug permeability of a human or a~imal body surface acro~s which the drug i6 to be adminlstered, in an amount effective to increase the permeability of said ~urface to said drug. The admixtures can be applied advantageou~ly to ~uch body surfaces as mucosal and epithelial ~urfaces to achieve improved drug transport across the ~urfaGes, there~y enhancing ~he delivery of the drug to its ultimate site of action in the body.
Preferably the steroid adjuvant is one of the naturally occurring steroids, fu6idic acid or P p in Pl~P2' P3- P4 or P5 or a derivative of ~ny of these. The eteroid may have the following formula:
133t: ~C~H3 . 25 a3 ~
~c~
often have difficulty with insulin self-administration by injection. Furthermore, insulin absorption after subcutaneous injection is variable in ~erms of rate and amount depending upon factors such as exercise, local blood flow, dep~h and volume of injection, the presence of local proteases which degrade insulin, and perhaps other, unknown factors. Even presently available short acting and long acting preparations of insulin or mixtures thereof cannot mimic the daily glucose and insulin excursions of non-diabetic individuals. Portable infusion pumps have now been employed to increase the ease of delivering subcutaneously meal-related insulin boluses.
~oweverV these devices are externally worn and are therefore cumbersome. They require regular needle replacement, are complicated by local infections at the site of needle placement, are expensive, and are not acceptable to many patients.
It is clear that a reproducible~ reliable, and non-invasive means for delivering drugs 6uch as insulin would be highly desirable. What is needed especially in ~he case of insulin is a delivery sys~em that would permit easy~ rapid, and non-invasive administration of insulin at meal times when blood glucose concentration rises to peak levels. Since the discovery of insulin six decades ago, there have been many attempts to develop alternate means of in~ulin delivery. For instance, insulin has been administered enterally, either alone or encapsulated in 30 liposomes (microcapsules), sublin~ually, vaginally, and rectally, with and without surfactants~
In addition to the preceding routes of administration, the nasal route has been ~he subject of investigation for the delivery not only of insulin but of other drugs as wellO It is known that certain very small peptides can be absorbed through the nasal mucosa as a "snuff" or directly from aqueous solution withou~ an adjuvant. Examples of pep ides which can ~ometimes be administered by ~his rou~e are adrenocorticotrophic hormone (ACTH), lu~einizlng hormone releasing hormone (LHRH), oxytocin and vasopressin. Indeed, for patients with diabetes insipidus9 the intranasal route is frequently the means for vasopressin delivery~
Xn ~ontrast to these directly administrable compounds, many drugs such as insulin are inefficiently absorbed across mucous membranes at physiological pH in the absence of adjuvants. Several workers have attempted to mix insulin with adjuvants that might enhance nasal insulin absorption. ~irai et al., IntO J. Pharmaceutics (1981) g:l65-184; Hirai et al., Diabetes (1978) 27-2~6-299; British Pat7 No. 1,527,605; and U.S. Pat~ No.
4,153,689; and Pontiroli et al. (1982~ Br. Med. 3.
284:303-386~ have described the use of various bile salts to enhance absorption of insulin by he nasal mucosaO
While the nasal mucosal route has received considerable attention for systemic drug deli~ery, it has also hitherto been known that drugs may be applied to mucous membranes of th~ conjunctiva, nasopharynx, oropharynx, ear canalr respiratory tract, vagina, rectum, colon, and urinary bladder for their local effectsO
SUMMARY OF THE INVENTION
We have discovered an effective means of administering a drug to a human being or animal which avoids many of the problems associated with other modes of administration such as injectionO The invention provides methods and compositions useful for ~he prevention and/or treatment of human or animal disorders ~nd for ~h regulatio~ of a$pect8 of human or animal physiology, e.g., ~ertility. The compo~itions employed ~re admixtures comprising: (a) as act~ve ingredient, a drug specific for a g~ven di~order or condition ln a biologically-effective amoun~t ~nd (~3 a~ adjuvant, a biocompat~ble, water~oluble, amphiph~lic ~teroid, other than a natural bile salt, capable of increasing drug permeability of a human or a~imal body surface acro~s which the drug i6 to be adminlstered, in an amount effective to increase the permeability of said ~urface to said drug. The admixtures can be applied advantageou~ly to ~uch body surfaces as mucosal and epithelial ~urfaces to achieve improved drug transport across the ~urfaGes, there~y enhancing ~he delivery of the drug to its ultimate site of action in the body.
Preferably the steroid adjuvant is one of the naturally occurring steroids, fu6idic acid or P p in Pl~P2' P3- P4 or P5 or a derivative of ~ny of these. The eteroid may have the following formula:
133t: ~C~H3 . 25 a3 ~
~c~
3~ 1 20 D ~ 1 ) ~ E
1~ 111 131 16 G/~O
C9~3 ~
wherein each dashed line, independently, repre~ents a single or a double bond; D is a group which renders an effective amount of the s~eroid water soluble wi~hin the range of about pH 2 to about pH 12; E and G are individually OAc, OH, or a lowex alkyl or lower heteroalkyl; W is OAc or H; and Q, V and X are individually OH or H. Most preferably the &teroids of formula (1) have functional groups as follows: E is 1G OAc, ~ OH, or a lower (3 or fewer carbons~ alkyl or heteroalkyl group in ~ position; G is ~ OAc, OH, lower alkyl, or lower heteroalkyl; W is ~ OAc or H; Q is OH or H, provided that, when W is ~ OAc and Q is ~ OH, Q must be ~-axial; V is H or ~ OH, and X is H or ~ OH, provided that the steroid contains two or three polar functions exclusive of D. Three O~ groups are allowed provided that one is C16 ~-axial, replacing OAc at th~t position. (As used herein, the symbol "OAcW refers to the acetoxyl radical OCOCH3,) The steroid of formula (1~ can be unconjugated, i~e., D is O Na , O K , O Rb , O Cs ~ or some other ionic configuration, or it can be conjugated, eO~ D is an organic group containing at least one carbon atom.
Preferably group D has a molecular weight below about 600 daltons and is one of the following groups:
(a) a peptide of one, two, or three amino acids and containing an ionic function which is dissociated within the range of about pH 2 to about pH 12;
(b) a heteroalkyl group of about three or fewer carbon atoms which contains an ionic func1:ion which is dissociated within the range of about p~ 2 to about pH 12 (c~ a uronlc acid of about six or fewer carbon atoms which contains an ionic function which i5 dissociated wi~hin ~he range of abou~ pH 2 to about pH 12;
(d) a polyether containing between abou~ six and about fourteen carbon atoms, inclusive, which terminates in an ionic function which is dissociated within the range of about pH 2 to about pH 12~ or (e) a polyether containing between about sixteen and about twenty-four carbon atoms, inclusive, and optionally terminatin~ in an ionic function which is dissociated within the range of about pH 2 to about pH 12u Group D i~ preferably bonded to C21 via an amide or ester linkage.
Preferably the steroid used in the invention is characterized in that the unconjugated derlvative of the steroid is retained on a hydrophobic cslumn for a length of time sufficient to produce a k~ factor value of at least about 4~ the k' factor value being obtained by subjecting a monomeric solution of 1 mg/mQ of such steroid 2 derivative to high-performance liquid column chromatoyraphy at 3,000 pSi9 using a ~50 x 4.6 mm column having octadecylsilane coated 5 ~m silica particles as the stationary pha~e and a mobile phase, delivered at 1.0 mQ/min., consisting of 75% methanol in water, v/v, bu~ered wi~h 00005 M KH2P04/H3P04 ~o give a~
apparent pH value, as measured using a glass electrode, of 5. 0, the k ' factor value being def ined b~,7 k '= t~ - to ~0 where to is the reten~ion Jcime in the column of ~he 35 solvent front and tr is the r~tention time in the column of the steroid derivative as measured by obtaining the elution profile of the sterQid derivative by absorbance at 210 nm.
Pre~er~bly the steroid is further characterized in that the critical micellar temperature (CMT) (the temperature at which the 3teroid ceases to be an insoluble crystal or gel and begins to go into solution and self-associate in ~olution) of an aqueous 1~ solution, w/v, of the ateroid is below human or animal body temperature, and optimally below about ODC within the range of abou~ pH 2 to about pH 12 (a measure of solubility); and the critical micellar concen~ration (CMC) (the concentration at which the steroid ceases to be an ideal solution and begins to self-associate) is as high as 8 m~501ar but preferably less than 4 mM and more preferably less than 2 mMolar at 37C in 0.15 M NaCl as measured by surface tension.
Preferred steroids are ionized or partially ionized alkali ~alt~ of fusidlc acid, 24,25-dihydrofusidic acid, cephalosporin Pl and C21 conjugates of these; and tauro-24y25-dihydrofusidate and glyco-24,25-dihydrofusidateO Other preferred steroids may be 17,20-24,25-tetrahydrofusidic acid, 3-acetoxyl-fusidic acid, cephalo5porin P2-P5, and C21 conju~ates of these; and tauro-17,20-24,25~tetrahydrofusidate~ tauro-16-OH-24,25-dihydrofusidate, tauro~l6~-OH-17,20-24,25-tetrahydrofusidate, tauro 16-0-methyl-ether-24,25-3~ dihydrofusidate, tauro-16-0-methyl-ether-17,20 24,25-tetrahydrofusidate. The foregoing preferred steroids must be freely soluble in water at the pH of the composition to be administered. A broad spectrum of drugs may be used including but not limlted to (a) peptides and polypeptides which have a molecular weight between about 100 and about 3009000 daLtons, (b) non-peptides, and (c~ other drugs~
~ 3~
The invention permits more effective, safer and convenient adminis~ration across a body surface of a human being or animal, e.q., any mucosal surface, including but not limited to oropharynx, ear canal, respiratory tract, nasopharynx, conjunctiva, rectal, gastric, intestinal, endometrial, cervical, vaginal, colon~ urethra7 urinary bladder, and tympanic membranet of a wide range of drugs, some of which normally cannot be so administered. For example, in contrast to intravenous in jection, the invention allows for convenient patient self-administration of drugs, making it more likely that the patient will adhere to prescribed treatment schedules.
The invention will deliver drugs more quickly than oral, subcutaneous, or intramuscular administration and i5 potentially more effective in delivering drugs to a localized site than is intravenous administration. In contrast to oral administration, drugs administered by the method oE the present invention do not need ~o pass through the liver where they might be metabolized in order to reach the site of action, in some cases reducing liver toxicity. Because drugs can be delivered more efficiently to the site of action or into the blood stream, in many cases a higher percentage of a given drug will reach the site than when administered by other means, thereby reducing the quantity of the drug that needs to be administered. Administration of reduced quantities of drug can be more cost effective than administration of he same drug by a conventional method. Alternatively, this method provides a means of delivering increased amounts of drug to a site, if desired or necessaryO In addition, administration, accsrding to the present invention/ does not have deleterious toxic side effects. In particular, the s~eroids of the invention are able to potentiate ~he tran.sport and enhance absorption of drugs across mucosal surfaces into the circulation while causing less irritation, burning sensation or other local ~11-toxicity than i5 a characteri3tic by-product of transport facilitation by other carrier molecule~.
The invention al~o allows drug admini~ration to be tallored much more cl~sely to cyclic disease ~tates than i~ possible with otheL forms of administration. This is of particular importance with diseases (such as diabetes) in which drug requirements vary during the course of a day.
It is ~ontemplated tha~ ~he adjuvants and me~hods of the instant invention can be used to admini~ter agents useful for vaccination (both active immunization with antigens and immunogenic fragments thereof as well as passive immunization with antibodies and neutralizing fragments thereof) and to administer agents u~eful for birth control.
It is further con~emplated that the adjuvants and methods of the instant invention may potentially b~ useful for the delivery across plant surfaces of antivir~l agents, systemic insecticides and herbicides; and across arthropod surfaces of contact insecticides and miticides.
Other fea~ures and advantages of ~he invention will be apparent from the following description of the preferred embodiments thereof, and from ~he claims.
DE5CRIPTION OF TE~E INVENTION
-- - .
The steroid which i5 admixed with a drug to be administered is preferably an ionized or partially ionized, wat~r-soluble derivative of fusidic acid or cephalosporin Pl-P5, preferably a derivative having formula (l), above. These ~teroid molecules are all characterized in tha~ they have the specific four-ring ~L~2~
structure of fusidis acid and cephalo porin Pl-P5, including the boat conformation of ~he B ring (in contrast to cholesterol derivatives such as bile salts, which have he B ring in the lower energy, more stable chair s::onf ormation) O
The ~tructure of the steroid molecule affect~ its chemical properties and thus its functioning as a drug transportirlg molecule. We believe that all of the steroid molecules u~ed in the invention facilitate transport by self-associating to form reversed micelles within the membrane across which the drug is being transported; these reversed micelles, it is believed, function as pores, 15 allowing the drug to pass throughA measure o a given steroid mole¢ule's ability to form such reversed micelles is the hydrophobicity of the uncon~ugated form of the molecule, a prQperty which can be quantified using the k' factor value, which is computed by observing the steroid's retention timP in a high-performance liquid chromatography (HPLC) column under the conditions described above. As mentioned above, the k' value of the unconjugated derivative of the steroid ~hould be at least about 4 for the ~teroid to be suitable in the therapeutic compositions of the invention.
Critical micellar temperature (CMT) is an additional measure of a steroid's utility in the compositions of the invention. CMT is the temperature at which the ~teroid molecules abruptly become soluble and self-associate into micelles from the gel or crystalline staten This change i~ a reflec ion of the colligative properties of the system, and the ~icelles for~ed at a temperature just above the CMT can be ~mall, e.g. dimers.
The steroid molecules used in ~he invention should have a great enough tendency to self~associate to give a CMT at or below human or animal body temper~ture and op~imally below abou~ 0C, for a 1~ aqueous solution, w/v, within ~he range of about pH 2 ~o ~bout p~ 12.
The steroids of formula (1) can be conjugated or unconjugated at C2l0 The conjugating group can be any organic group which does no~ raise the critical micellar temperature of a 1% solution of ~he steroid above human or animal ~ody temperature and preferably does not raise the CMT above about 0C within the range of about pH 2 to about pH 12 and does not raise the CMC above about 8 mMolar ~t 37C in 0.15 M NaCl as mea~ured by ~urface tension. Pre~erably, the C~C is less than ~ mMolar under similar conditionsO
The conjugating group can be, e.g. 9 any ionic function-containing ~traight or branch-chained amino acid. The amino acid can be aliphatic or aromatic, and can also be a homo- or a dihomo~amino acid, ~
homotaurine or homoglycine, or an amphoteric amino acid, e~., sulfobetaine or phosphobetaine. A strai~ht or branched chain di- or tripeptide which terminates in an ionic function which is dissociated within the range of about p~ 2 to about pH 12 can also be employ~dO Peptides larger than tripeptide~ generally should not be used because they can lead to unaccep~ably lower solubility, Any ~u~table uronic acid, e.~. glucuronic acid, can also be used.
Preferred conjugating amino acids are glycine and taurine. Preferred ~traight-chain peptides are diglyclne and glutathione, and preferred branched chain peptides are sarcosylcysteine, hydroxyprolinetaurine~ and 35 ~arcosyltaurine~, When the conjugating group is a polye~her of at least ~ixteen carbon a~oms, the group need not (al~hough it may) ~ontain an ionic unction; the ionic func:tion is unnecessary b~cause such ~roups are highly polar and thus confer solubility without ionization. For smaller polyether groups, an ionic function is generally necessary, although it can be weakly ionizable since the smaller polyethers are polar themselves~
The group bsnded to each of C6 and C16, independently, (W and E in formula (1)~ can be OAc (OCOCH3) as in naturally occurring fusidic acid and cephalosporin Pl. Alternatively, E can be 0~, an alkyl ~ , me~hyl or ethyl) or a different heteroalkyl (e.qq alkyloxy, alkylthio, or ether derivative) group of three or fewer carbon atoms; larger groups can unacceptably lower ~olubility. Group G~ bonded to C3~ can be OH, as in naturally occurring fusidic acid and cephalosporin P1-P5. G can also be OAc, a lower alkyl group, or a different lower heteroalkyl group. Group W, if OAc, preferably should be in the B-axial orientatio~.
The molecule should possess two or three polar ~unctions, exclusiYe of any side chains at C21, at the positions indicated above where acetoxyl and hydroxyl groups can b~ located.
The k' and CMT of ~he steroids used in the compositionx of the invention are influenced by whether the steroid is conjugated at C21 and, if S07 by th~
nature of the conjugating group~ Additionally, a polar group at position 16 i8 essential for solubility (See position E on formula 1)~ Because the k' factor value is influenced by the polarity of any conjugating group, unconjugat~d derivatives must be used in numerical comparisons involving ~teroids which are conjugated with different group8, or comparisons involving both conjuga~ed and unconjugated steroid~. Ov0rall hydrophobicity and k' factor ~alue generally decrease as the polarity of the conjugating group increases~ However, 6uch decrease is not a reflection of the hydrophobicity of the steroid nucleus. It is this hydrsphobicity which is the important parameter for purposes of rever ed micelle formation.
As discussed supra, the k' factor value of the uncon~ugated derivative of any such steroid hould be at least about 4. For example some k' values of some unconjugated steroids useful in the invention are:
cephalosporin Pl (k'=9~5)~ fusidic acid (k'=2007);
3-acetoxyl-fusidic ~cid (k'=26~4); 24,25-dihydrofusidic acid lki=27.1). To give a few minimum k' values of conjugated steroids, the k' factor value of a glycine-conjugated steroid should be at least about 2 to be useful in the invention. For a ~aurine-conjugated steroid, ~he kS actor value should be at least about 1.
It is desirable that conjugated steroids have strongly ionized ~onjugating groups which are capable of forming micelles at low pH and concentrations (the critical mic211ar concentration, CMC, is a measure of this latter proper~y). As me~tioned above, examples of such desirable conjugating groups include but are not limited to taurine, homotaurine, sarcosyltaurine, and ~ulfobetaine. 5teroids conjugated with such groups al~n have the advantages of s~ability and ease of synthesis.
Conjugation has additional effects as well, which provide the opportunity to tailor the conjugated steroid to a given clinical ~ituation. For example, if the steroid is to be used to transport a drug across a mucosal membrane, ~ the nasal mucosa, relatively long l~
homotaurine), branched (~ sarcosyl~aurine~, bulky (~
glucuronic acid), and amphoteric (e.q. sulfob~tain2) groups are desirable, ~ince they may cause ~he steroid to be held in the nasal membrane somewhat longer than unconjugated steroids or steroids conjugated with smaller conjugating groups.
Conjugation alsot in some instances, lowers the CMC, ~o that only a small amount of steroid need be used.
Strong acidic conjugating group~ render the ~teroid resistant to being taken out of solution by variations in pH, ionic s~rength, and by the presence of other ~ons (e.g. Ca ) and other macromoleculesO Conjugation further prevents retention by the body, promotes rapid exsretion, and prevents hepatic metabolism to potentially toxic metabolites (Beauaboin et al., J. Clin. Invest.
(1975) 56:1431-1~41).
As mentiorled above, conjugating groups are bonded to C21 via any suitable linkage, e~q. amide or ester~
Conjugation is carried out using conventional techniques.
As an example) taurine bonded to C21 via an amide 1 nkage is shown below (the presence of a cation, e.
K or Na, is indicated in the parentheses):
C-N-CH2-CH2-S03 (K or Na ) 21 ~1 The properties of the steroid are also affected by the nature of the substituents at C3~ C6 and Cl60 Generally9 OAc groups at ~hese positions tend to aid solubility; howaver, OAc groups are also quite labile, and tend to decrease stability and shelf-life.
The fusidlc acid or cephalosporin P1P5 derivatives can be made by ~ppropria~ely modifying commercially available fu~idic acid or cephalo~porin Pl~P5. Such techni~ues are known in the art.
The drugs which are admixed with a st~roid carrier preferably have a molecular weight of between ~bout 100 daltons and about 300,000 daltons~ The drug may be either water soluble or lipid soluble, and may be peptide, e.~7 a peptide hormone such as insulin or a peptide hormone precursor ~uch as proinsulin. Water soluble dru~s, ~ some peptides and vi~amins, can also be transported across mucosal membranes by any of the steroids of the invention, including ~hose whose unconjugated deriva~ives have relatively low k' values (between about 7 and about 15)~ E'or hydrophobic, lipid-soluble drugs, e.~. the lipid-soluble vitamins, the unconjugated derivative of the steroid should have a higher k' value, preferably above about 20~
Drugs for which the method of administration of the invention is par~icularly important are peptides.
Suitable pepti~es include but are not limited to insulin, proinsulin, glucagon, parathyroid hormone and an~agonists of it, calcitonin, vasopressin, renin, prolactin, growth hormone, thyroid s~imula~ing hormone~ corticotropin, follicle stimulating hormone, luteinizing hormone, chorionic gonadotropin~ atrial peptides (a natriuretic factor), interferon, tissue plasminogen ac~ivator, gammaglobulin, ~actor VIII~ and chemical modifications of these peptides~
The invention can al~o be used to administer hormone releasing hormones, ~ growth hormone relea~ing hormone, corticotropin releasing factor~ lu~einizing hormone releasing hormone, growth hormone release ...~ . . _ r inhibiting hormone ~somatostatin) and thyrotropin releas~ng hormone.
Other suitable drugs include the physiologically active enzymes: transferases, hydrola6es, isomerases, proteases, ligases, and oxidoreductases such as esterases, phosphata3es, glycosidases and peptidases; enzyme inhibitors such as leupeptinp chymostatin and pepstatin;
and growth factors such as tumor angiogenesis factor, epidexmal growth factor, nerve growth factor and insulin-like growth factors~ Other ~uitable drugs are those normally absorbed to a limited extent across the gastrointes~inal mucosa after oral administration; e.q.
antihistamines (~ diphenhydramine and chlorpheniramine), and drugs affecting the cardiovascular (e.q., antihypertensives), renal, hepatic and immune systems (including vaccines). Additionally, sympathomimetic drugs, such as the catecholamines (e.q.
epinephrine~ and non-catecholamines (e.q. phenylephrine and pseudoephedrine) ~ay be administered according to the method of the present invention.
Drugs such as anti-infectiv~ agents, including antibacterial, antiviral and antifungal agents may also be administered according to the method of the present invention. For example, antibiotics such as the aminoglycosides (~ g~, streptomycin~ gentamicin, kanamycin, etc.) are generally not adequately absorbed after oral administration, and may therefore be advantageously admini~tered by the method o~ the invention, Many other drugs may also be adminis~ered according to the inventiont ~ the many drugs currently used to treat arthritis such ~s narcotic pain relievers.
An~i-inflammatory agents (e g. indomethacin, dexamethasone and triamcinolone), anti-tumor agents (~ 5-fluorouracil ~2~ 3~
and methotrexa~e) and tranquilizer~ such as diazepam may also be administered according to khe invention.
Other suitable drugs are the water lnsoluble, fat-soluble hydrophobic drugs, ~ ~ s'ceroids æuch as progesterone, ~strogen~ ~including con~raceptives suc:h as ethinyl estradiol~ and androgen~ and ~heir analogs, and the fat-soluble YitaminS~ ~ vitamins A~ D, E and K, and their analogs, qlhe ~urf ace across which transpor~ occurs may be any mucosal ~urface such as the nasopharynx, conjunctiva~
oropharynx, ear canal~ rectal, in~estinal (enteral)~
15 respiratory tract, en~ometrial, cervical vaginal, urethra, urinary bladder or, in ~ome circumstances, a skin surface ~uch as the axilla, the gluteal cleft, ympanic membrane, between the toes, and the groin. Additionally, transport of the drug according to the method of the present invention may enhance penetration into the skin for increased l~cal effects7 The ratio of drug and steroid present in a therapeutic composition will vary depending on a number of factors, including khe k' and CMC of the steroid, the dosage of the drug to be adminis~ered, and the chemical characteristics, e.q. hydrophobicity, of the drug~
Generally, the steroid is provided in an aqueous physiological buffer solu~ion which i3 ~hen mixed with the drugO The 601ution generally contain~ about n. 1% to about 2.5~, W/v9 steroid in a physiologically acceptable carrier, ~ sodium phosph~te buffered NaCl; pH 5-8, having a NaCl concentration of about 0.05 M to about 006 M.
The concentration of ~he drug in the ~olution will of course vary widely, depending on the nature of the drug, and on the extent to which absorption is facilitated by the steroid. In some cases, administration according to the invention will enable ~he delivery of a higher dosage of the drug where needed than if the conventional mode of administration i~ used; in other cases, a much smaller do~age can be used becau~e of efficient administration to a site. For instance~ the amount of drug potentially can be decreased to one ~housandth the amount or increased to ten times the amount of the drug normally used with conventional administration methods.
The therap2utic composition may con~ain, in addition to steroid and drug~ any other desired non-toxic, pharmaceutically acceptable substance~, ~ a preservative such a phenol or cresol or stabilizing agents.
The dosage given a~ any one time will depend on a number of factors including, in addition to those mentioned above, the frequency of administration.
The compositi.ons of the present inventi4n may be administered to human and animal body surfaces in a variety of forms, including bu not limited to~ sprays, 2~ drops, ~uppositorie~, douches, salves, ointments, and creamsO Some composi~ion~ may be advantageously applied in long term release dosage forms such as slow rel ase, continuous xelease and intermittent release dosage forms~
These long term release dosage forms include but are not limited to polymers, microcapsules~ microspheres, osmotic diffusion devices and membrane release devices.
~X_ The following exam21es are intended to illust~ate the invention, without actlng as a limitation upon its scope.
Examples 1-14 demonstrate the effec~iveness of using various u~idic acid derivatives (Leo Pharmaceutical~, Ballerup, Denmark~ and cephalosporin ~s adjuvants for the delivery of insulin, glucagon, human chorionic gonado'cropin (hCG), proinsuli~, corticotropin releasing-f~ctor (CRF) and epinephrine across nasal mucosal membranes or conjunctival membrane~ in humans or sheep. A~says of insulin~ glucagon, and hCG across nasal 0 mucosal membranes and conjunctlval membranes were accomplished by highly specific radioimmuno2ssay (R~A).
(Protocol~ for RIA of insulin followed the procedures given in ~GammaCoat ~125I~ Insulin Radioimmunoassay Kit,~ Cat. No. CA 532, Clinical Assays Division of Travenol Laboratories, Inc., Cambridge; MA and for glucagon, the procedures given in ~Protocol for the Radioimmunoassay of Glucagon [ I], Cat. No. 520, Cambridge Medical Diagnostics, ~iddle Billerica, MA) In the case of proin~ulin, an insulin immunoassay with signiicant cross~reactivity for proinsulin was adapted to e~timate the amounts of proin~ulin absorbad. (The protocol is given in ~Insulin [125I] Radioimmunoassay,~
Corning Medical and Scientific, Medfield, MAo~ The values obtained for ins~lin were ad~usted to correlate with known cross-reactivity (i.~., 36%) of proinsulin in $he assay.
The "Ga~maDab [ I] ~-HCG ~adioimmunoassay Rit,~
Clinical Assays Cat. No. 589, Clinical Assays Division of Travenol Laboratories, Inc., CambridgeO MA was used ~o evaluate hCG levels in serum.
INTRANASAL ADMINISTRATION OF INSULIN TO HUMANS
The final concentration of insulin varied for each ~ubject since they were of different weights.
Sodium ~auro-24,25-dihydrofusida~e was dissolved in 0.15 M NaCl, pH 7~4 to form a 5~ solution, w/v~
Commercially ~vailable porcine regular insulin ~U-500) (Eli Lilly & Co~, Xndianapolis, IN) was mixed in a ~otal volume of 2.0 mQ wlth 0.15 M NaCl, p~ 7.~ and the 5~
~olution of sodium tauro-24,25-dihydrofusidate to give final concentrations of 216 U/mQ insuli~ and 1% (w/v) ~odium tauro-24,25-dihydrofusidate~ A normal human subject (subjec~ 40) wa~ administered at time 0, by nasal spray, two 75 microliter aliquots, 50 that the dosage of in~ulin administered to the subject was 0.5 Units/kg body weight, For subjects 92 and 93, sodium tauro-24,25-dihydrofusidate was dissolved in 0.15 M NaCl, 0.05 M
sodium phosphate bu~fert pH 7~ to form a 2% solution, w/v. Insulin was mixed in a total volume of 7.0 m~ with ~he 0.15 M NaCl, 0.05 M sodium phosphate buffer and the 2%
solution of ~odium tauro-24,25-dihydrofusidate to give final concentrations of 220 Units/mQ for subject 92 and 233 Units/mQ for sub]ect 93~
As shown in Table I, below, five minutes after nasal administra~ion, subject 4~'s serum insulin level had increased more than twenty-fold~ demonstrating that the insulin had been rapidly and effectively absorbed across the nasal ~ucosa. After ten minutes serum insulin levels for subjects 92 and 93 had increased more than ten-fold, indicating rapid absorption across the nasal mucosa.
Furthermore, as is ~hown in Table I~ each subjects' blood glucose was lowered significantly after twenty minutes, and was reduced more than fifty percent after thirty minutes for subjects 40 and 92.
~23-._ ~
TABBE I
STUDY OF NASALLY ADMINISTERED INSULIN IN
SODIUM TAUR0~24,25-DI~YDROFUSIDATE TO ~UMANS
Blood Serum Insulin Time Glucose Insulin l~U/mQ
~ (mg/dQ) (~U/mQ) above basal) SUBJECT 40 -20 8909 5~6 1.1 -~0 88 ~5 115 110.5 82 100 95.5 90.5 54~5 62 57.5 31.5 ~ 17.5 ~0 3705 10 5.5 6.~ 1.9 72 B.8 4.3 7~ 85 5 gO 89 3.5 SUBJECT 92 -20 81 5.0 03 0 80 4.7 0 ~5 79~5 52 ~7,3 7~0~ 68 63.3 61~5 55 50.3 47 35 30.3 34.5 53.5 ~.4 1~7 67 3.2 71.5 2.8 0 SUBJECT 93 -20 91.5 7.2 1.8 O ~9 5.4 0 ~5 89.5 54 ~8.6 ~5 58 52.~
75~5 28~5 23~1 ~S 19.5 14.1 3~ 6505 7.2 108 ~0 75 4.7 0 8~1o5 9~4 4~t) 84.5 6.2 O.B
2~-_X~
Unconjugated ~odium fus~da~e was dis~olved in 0.15 M NaCl, pH 7.4 to form a 3% ~olution w/v.
Commercially avallable insulin (U-500) wa~ mixed in ~
total volume of 3 mQ with 0.15 M NaCl, pH 7.4 and the 3%
solution of 60dium fusidate to give final concentrations of 210 Units/mQ insulin and 1% (w~v) sodium fu~idate. A
normal human subject was administered the in~ulin preparation by na~al spray at time 0 as described in Exampl~ 1. The results obtained are ~hown in Tabl~ II
below. Twenty minutes after nasal adminis~ration the ~ubjectls ~erum insulin level had increased more than fifteen-foldO Additionally, a~ i~ shown in Table II, the ~ubject's blood glucose was reduced more than fifty percent after thirty minutes.
.. . . .. .. . . . . . _ .
TABLE II
STUDY OF NASALLY ADMINISTE~E~ INSULIN IN
UNCONJUGATED SODIUM FUSIDATE, pH 7.4 TO HUMANS
~5 Blood Serum Insulin T~me Gluco~e Insulin(~U/m~
~ L (mg/dQ ~ (~U~m~)above basal) SUBJECT 33 -20 75,5 3~7 -.8 0 79 4~5 0 ~5 16 11.5 77 60 55.5 75.5 59.5 85 B0.5 3~ 28 23.5 ~0 ~3.~ 10.5 6 56.5 7 2.5 68.5 4.5 _.. , ...... . . _ . __ ._ _ _ . . .
~X~
-~5-The insulin preparatlon was obtained by the same procedure as described in Example 2. ~owever, the pH of the solution was adju~ted to pM 7.95 and the final insulin concentration ~as 267 Unit~/m~. A normal human ~ubject was administered the insulin preparation by nasal spray at time 0 as described in Example l. As shown in ~able III
below the subject's eeru~ in~ulin level had increased more than thirty-~ive fold after fifteen minutes. Furthermore the patient's blood glucose was lowered ~ignificantly after thirty minutefi.
15 ~ e__ TABLE I I I
STUDY OF NASALLY ADMINISTERED INSULIN IN
UNCONJUGATED SODIUM FUSIDATE ~ pE~ 7 0 9 5 TO HUMANS
BloodSerumInsulin Time GlucoseInsu:i int~lU/mQ
(minutesl ~ U/m~)abo~re basal~
SUBJECT 3 5 - 2 0 1~, 7 O
0 80 1,7 ~5 ~5 43 0 3 ~ 6~ 58. 3 3~ 32. 3 ~0 64 20 1~. 3 ~ 10 8. 3 56 4.5 ~.8 73~,514 1203 84 7 5. 3 Sodium glyco-2~,25-dihydrousidate was di~solved in Q.15 M NaCl, p~ 7.6 to form a 3% 801ution W/V.
Commercially available porcine insulin (U-500) was mixed in a total volume of 3.9 mQ with 0.15 M NaCl, pH 7.S and the 3% solution of sodium glyco 24,25-dihydrofusidate to give final concentrations of 216 Units/mQ insulin and 1 (w/v) sodium glyco-24,25-dihydrofu~idate. Subject 40 wa~
adminis~ered ~he insulin preparation by nasal spray at time O as described ln Example 1. As shown in Table IV
below, five minutes after nasal administration~ subject 409S ~erum insulin had ~ncreased more than twenty-fold, indicating that the insulin had been rapidly and effectively absorbed through the nasal mucosa.
Furthermore, ~he ~ubject's blood glucose was lowered significantly after tw~nty minutes.
~~~
T~BLE IV
STUDY OF NASALLY ADMINISTERED INSULIN IN
SODIUM GLYCO-24,25-DIHYDROFUSIDATE TO HUMANS
~5 Blood Serum Insulin Time GlucoseInsulin (~U/m~
(minutes~ (m~dQ)~U/mQ) above basal) SUBJECT 40 -20 90 3.5 ,8 0 ~6.S 2.7 0 +5 66 63~3 81 58 55.3 38 35.3 23 20~3 51 6 3~3 6705 4.5 1 78.5 506 209 82~5 2.4 -.3 ~,,r~d ~
-~7-For subject 34, sodium 24~25-dihydrofusldate was dissolved in 0,15 M NaCl, pH 8.1 ~o form a 3% solution w/v. Commercially available porcine insulin tU-5003 was mixed in a total volume of 3 mQ with 0.15 M NaCl~ pH 8.1 and the 3% ~olution of sodium 24,25-dihydrofusidate to give final concentrations of 190 Units/m~ insulin and 1%
(w/v) ~odium 2~,25-dihydrofusidateO For ~ubject 35, the in~ulin preparation was made in the s~me manner as described above except that tha initial sodium 24, 25-dihydrofusidate concentration was 3.75% (w/v) and the final insulin concentration was 267 Units/mQ~ The two normal human subj~cts were administer~d the insulin preparat$on by na al ~pray at time 0 as described in Example 1. As shown in Table V below, fif~een minute~
after nasal administration su~ject 34's ~erum insulin level had increased thirty-fold and the subject's blood glucose was lowered significantly after thirty minutes.
Subject 35 showed a dramatic increase in ~erum insulin (6305-fold) after ten minutes, demonstrating that the insulin had been rapidly and effectively absorbed through the nasal ~ucosa. Additionally, ~he subjects' blood glucose was lowered mor~ than fifty percent after thirty minutes.
TABL~ V
STUDY OF NAS~LLY ADMI~ISTERED INSULIN
IN SODIUM 24,25-DI~YDROFUSIDATE TO HUMANS
BloodSerumInsulin Time Gluco~eIn~ulin(~U/mQ
(minutes) ~mg/dQ~(UU/mQ)above basal~
SU~JECT 34 -20 76 2.2 .3 76.5 1.9 0 ~5 9.6 7.7 7~ 36 34.1 38 36.1 65.5 28 26.1 49 9.~ 7.7 44.5 7 5.1 52.5 3 1.1 SUBJECT 35 -20 75.5 1.6 ~1 0 76.5206 0 ~5 94 9~.4 72 165 162.4 130 127.4
1~ 111 131 16 G/~O
C9~3 ~
wherein each dashed line, independently, repre~ents a single or a double bond; D is a group which renders an effective amount of the s~eroid water soluble wi~hin the range of about pH 2 to about pH 12; E and G are individually OAc, OH, or a lowex alkyl or lower heteroalkyl; W is OAc or H; and Q, V and X are individually OH or H. Most preferably the &teroids of formula (1) have functional groups as follows: E is 1G OAc, ~ OH, or a lower (3 or fewer carbons~ alkyl or heteroalkyl group in ~ position; G is ~ OAc, OH, lower alkyl, or lower heteroalkyl; W is ~ OAc or H; Q is OH or H, provided that, when W is ~ OAc and Q is ~ OH, Q must be ~-axial; V is H or ~ OH, and X is H or ~ OH, provided that the steroid contains two or three polar functions exclusive of D. Three O~ groups are allowed provided that one is C16 ~-axial, replacing OAc at th~t position. (As used herein, the symbol "OAcW refers to the acetoxyl radical OCOCH3,) The steroid of formula (1~ can be unconjugated, i~e., D is O Na , O K , O Rb , O Cs ~ or some other ionic configuration, or it can be conjugated, eO~ D is an organic group containing at least one carbon atom.
Preferably group D has a molecular weight below about 600 daltons and is one of the following groups:
(a) a peptide of one, two, or three amino acids and containing an ionic function which is dissociated within the range of about pH 2 to about pH 12;
(b) a heteroalkyl group of about three or fewer carbon atoms which contains an ionic func1:ion which is dissociated within the range of about p~ 2 to about pH 12 (c~ a uronlc acid of about six or fewer carbon atoms which contains an ionic function which i5 dissociated wi~hin ~he range of abou~ pH 2 to about pH 12;
(d) a polyether containing between abou~ six and about fourteen carbon atoms, inclusive, which terminates in an ionic function which is dissociated within the range of about pH 2 to about pH 12~ or (e) a polyether containing between about sixteen and about twenty-four carbon atoms, inclusive, and optionally terminatin~ in an ionic function which is dissociated within the range of about pH 2 to about pH 12u Group D i~ preferably bonded to C21 via an amide or ester linkage.
Preferably the steroid used in the invention is characterized in that the unconjugated derlvative of the steroid is retained on a hydrophobic cslumn for a length of time sufficient to produce a k~ factor value of at least about 4~ the k' factor value being obtained by subjecting a monomeric solution of 1 mg/mQ of such steroid 2 derivative to high-performance liquid column chromatoyraphy at 3,000 pSi9 using a ~50 x 4.6 mm column having octadecylsilane coated 5 ~m silica particles as the stationary pha~e and a mobile phase, delivered at 1.0 mQ/min., consisting of 75% methanol in water, v/v, bu~ered wi~h 00005 M KH2P04/H3P04 ~o give a~
apparent pH value, as measured using a glass electrode, of 5. 0, the k ' factor value being def ined b~,7 k '= t~ - to ~0 where to is the reten~ion Jcime in the column of ~he 35 solvent front and tr is the r~tention time in the column of the steroid derivative as measured by obtaining the elution profile of the sterQid derivative by absorbance at 210 nm.
Pre~er~bly the steroid is further characterized in that the critical micellar temperature (CMT) (the temperature at which the 3teroid ceases to be an insoluble crystal or gel and begins to go into solution and self-associate in ~olution) of an aqueous 1~ solution, w/v, of the ateroid is below human or animal body temperature, and optimally below about ODC within the range of abou~ pH 2 to about pH 12 (a measure of solubility); and the critical micellar concen~ration (CMC) (the concentration at which the steroid ceases to be an ideal solution and begins to self-associate) is as high as 8 m~501ar but preferably less than 4 mM and more preferably less than 2 mMolar at 37C in 0.15 M NaCl as measured by surface tension.
Preferred steroids are ionized or partially ionized alkali ~alt~ of fusidlc acid, 24,25-dihydrofusidic acid, cephalosporin Pl and C21 conjugates of these; and tauro-24y25-dihydrofusidate and glyco-24,25-dihydrofusidateO Other preferred steroids may be 17,20-24,25-tetrahydrofusidic acid, 3-acetoxyl-fusidic acid, cephalo5porin P2-P5, and C21 conju~ates of these; and tauro-17,20-24,25~tetrahydrofusidate~ tauro-16-OH-24,25-dihydrofusidate, tauro~l6~-OH-17,20-24,25-tetrahydrofusidate, tauro 16-0-methyl-ether-24,25-3~ dihydrofusidate, tauro-16-0-methyl-ether-17,20 24,25-tetrahydrofusidate. The foregoing preferred steroids must be freely soluble in water at the pH of the composition to be administered. A broad spectrum of drugs may be used including but not limlted to (a) peptides and polypeptides which have a molecular weight between about 100 and about 3009000 daLtons, (b) non-peptides, and (c~ other drugs~
~ 3~
The invention permits more effective, safer and convenient adminis~ration across a body surface of a human being or animal, e.q., any mucosal surface, including but not limited to oropharynx, ear canal, respiratory tract, nasopharynx, conjunctiva, rectal, gastric, intestinal, endometrial, cervical, vaginal, colon~ urethra7 urinary bladder, and tympanic membranet of a wide range of drugs, some of which normally cannot be so administered. For example, in contrast to intravenous in jection, the invention allows for convenient patient self-administration of drugs, making it more likely that the patient will adhere to prescribed treatment schedules.
The invention will deliver drugs more quickly than oral, subcutaneous, or intramuscular administration and i5 potentially more effective in delivering drugs to a localized site than is intravenous administration. In contrast to oral administration, drugs administered by the method oE the present invention do not need ~o pass through the liver where they might be metabolized in order to reach the site of action, in some cases reducing liver toxicity. Because drugs can be delivered more efficiently to the site of action or into the blood stream, in many cases a higher percentage of a given drug will reach the site than when administered by other means, thereby reducing the quantity of the drug that needs to be administered. Administration of reduced quantities of drug can be more cost effective than administration of he same drug by a conventional method. Alternatively, this method provides a means of delivering increased amounts of drug to a site, if desired or necessaryO In addition, administration, accsrding to the present invention/ does not have deleterious toxic side effects. In particular, the s~eroids of the invention are able to potentiate ~he tran.sport and enhance absorption of drugs across mucosal surfaces into the circulation while causing less irritation, burning sensation or other local ~11-toxicity than i5 a characteri3tic by-product of transport facilitation by other carrier molecule~.
The invention al~o allows drug admini~ration to be tallored much more cl~sely to cyclic disease ~tates than i~ possible with otheL forms of administration. This is of particular importance with diseases (such as diabetes) in which drug requirements vary during the course of a day.
It is ~ontemplated tha~ ~he adjuvants and me~hods of the instant invention can be used to admini~ter agents useful for vaccination (both active immunization with antigens and immunogenic fragments thereof as well as passive immunization with antibodies and neutralizing fragments thereof) and to administer agents u~eful for birth control.
It is further con~emplated that the adjuvants and methods of the instant invention may potentially b~ useful for the delivery across plant surfaces of antivir~l agents, systemic insecticides and herbicides; and across arthropod surfaces of contact insecticides and miticides.
Other fea~ures and advantages of ~he invention will be apparent from the following description of the preferred embodiments thereof, and from ~he claims.
DE5CRIPTION OF TE~E INVENTION
-- - .
The steroid which i5 admixed with a drug to be administered is preferably an ionized or partially ionized, wat~r-soluble derivative of fusidic acid or cephalosporin Pl-P5, preferably a derivative having formula (l), above. These ~teroid molecules are all characterized in tha~ they have the specific four-ring ~L~2~
structure of fusidis acid and cephalo porin Pl-P5, including the boat conformation of ~he B ring (in contrast to cholesterol derivatives such as bile salts, which have he B ring in the lower energy, more stable chair s::onf ormation) O
The ~tructure of the steroid molecule affect~ its chemical properties and thus its functioning as a drug transportirlg molecule. We believe that all of the steroid molecules u~ed in the invention facilitate transport by self-associating to form reversed micelles within the membrane across which the drug is being transported; these reversed micelles, it is believed, function as pores, 15 allowing the drug to pass throughA measure o a given steroid mole¢ule's ability to form such reversed micelles is the hydrophobicity of the uncon~ugated form of the molecule, a prQperty which can be quantified using the k' factor value, which is computed by observing the steroid's retention timP in a high-performance liquid chromatography (HPLC) column under the conditions described above. As mentioned above, the k' value of the unconjugated derivative of the steroid ~hould be at least about 4 for the ~teroid to be suitable in the therapeutic compositions of the invention.
Critical micellar temperature (CMT) is an additional measure of a steroid's utility in the compositions of the invention. CMT is the temperature at which the ~teroid molecules abruptly become soluble and self-associate into micelles from the gel or crystalline staten This change i~ a reflec ion of the colligative properties of the system, and the ~icelles for~ed at a temperature just above the CMT can be ~mall, e.g. dimers.
The steroid molecules used in ~he invention should have a great enough tendency to self~associate to give a CMT at or below human or animal body temper~ture and op~imally below abou~ 0C, for a 1~ aqueous solution, w/v, within ~he range of about pH 2 ~o ~bout p~ 12.
The steroids of formula (1) can be conjugated or unconjugated at C2l0 The conjugating group can be any organic group which does no~ raise the critical micellar temperature of a 1% solution of ~he steroid above human or animal ~ody temperature and preferably does not raise the CMT above about 0C within the range of about pH 2 to about pH 12 and does not raise the CMC above about 8 mMolar ~t 37C in 0.15 M NaCl as mea~ured by ~urface tension. Pre~erably, the C~C is less than ~ mMolar under similar conditionsO
The conjugating group can be, e.g. 9 any ionic function-containing ~traight or branch-chained amino acid. The amino acid can be aliphatic or aromatic, and can also be a homo- or a dihomo~amino acid, ~
homotaurine or homoglycine, or an amphoteric amino acid, e~., sulfobetaine or phosphobetaine. A strai~ht or branched chain di- or tripeptide which terminates in an ionic function which is dissociated within the range of about p~ 2 to about pH 12 can also be employ~dO Peptides larger than tripeptide~ generally should not be used because they can lead to unaccep~ably lower solubility, Any ~u~table uronic acid, e.~. glucuronic acid, can also be used.
Preferred conjugating amino acids are glycine and taurine. Preferred ~traight-chain peptides are diglyclne and glutathione, and preferred branched chain peptides are sarcosylcysteine, hydroxyprolinetaurine~ and 35 ~arcosyltaurine~, When the conjugating group is a polye~her of at least ~ixteen carbon a~oms, the group need not (al~hough it may) ~ontain an ionic unction; the ionic func:tion is unnecessary b~cause such ~roups are highly polar and thus confer solubility without ionization. For smaller polyether groups, an ionic function is generally necessary, although it can be weakly ionizable since the smaller polyethers are polar themselves~
The group bsnded to each of C6 and C16, independently, (W and E in formula (1)~ can be OAc (OCOCH3) as in naturally occurring fusidic acid and cephalosporin Pl. Alternatively, E can be 0~, an alkyl ~ , me~hyl or ethyl) or a different heteroalkyl (e.qq alkyloxy, alkylthio, or ether derivative) group of three or fewer carbon atoms; larger groups can unacceptably lower ~olubility. Group G~ bonded to C3~ can be OH, as in naturally occurring fusidic acid and cephalosporin P1-P5. G can also be OAc, a lower alkyl group, or a different lower heteroalkyl group. Group W, if OAc, preferably should be in the B-axial orientatio~.
The molecule should possess two or three polar ~unctions, exclusiYe of any side chains at C21, at the positions indicated above where acetoxyl and hydroxyl groups can b~ located.
The k' and CMT of ~he steroids used in the compositionx of the invention are influenced by whether the steroid is conjugated at C21 and, if S07 by th~
nature of the conjugating group~ Additionally, a polar group at position 16 i8 essential for solubility (See position E on formula 1)~ Because the k' factor value is influenced by the polarity of any conjugating group, unconjugat~d derivatives must be used in numerical comparisons involving ~teroids which are conjugated with different group8, or comparisons involving both conjuga~ed and unconjugated steroid~. Ov0rall hydrophobicity and k' factor ~alue generally decrease as the polarity of the conjugating group increases~ However, 6uch decrease is not a reflection of the hydrophobicity of the steroid nucleus. It is this hydrsphobicity which is the important parameter for purposes of rever ed micelle formation.
As discussed supra, the k' factor value of the uncon~ugated derivative of any such steroid hould be at least about 4. For example some k' values of some unconjugated steroids useful in the invention are:
cephalosporin Pl (k'=9~5)~ fusidic acid (k'=2007);
3-acetoxyl-fusidic ~cid (k'=26~4); 24,25-dihydrofusidic acid lki=27.1). To give a few minimum k' values of conjugated steroids, the k' factor value of a glycine-conjugated steroid should be at least about 2 to be useful in the invention. For a ~aurine-conjugated steroid, ~he kS actor value should be at least about 1.
It is desirable that conjugated steroids have strongly ionized ~onjugating groups which are capable of forming micelles at low pH and concentrations (the critical mic211ar concentration, CMC, is a measure of this latter proper~y). As me~tioned above, examples of such desirable conjugating groups include but are not limited to taurine, homotaurine, sarcosyltaurine, and ~ulfobetaine. 5teroids conjugated with such groups al~n have the advantages of s~ability and ease of synthesis.
Conjugation has additional effects as well, which provide the opportunity to tailor the conjugated steroid to a given clinical ~ituation. For example, if the steroid is to be used to transport a drug across a mucosal membrane, ~ the nasal mucosa, relatively long l~
homotaurine), branched (~ sarcosyl~aurine~, bulky (~
glucuronic acid), and amphoteric (e.q. sulfob~tain2) groups are desirable, ~ince they may cause ~he steroid to be held in the nasal membrane somewhat longer than unconjugated steroids or steroids conjugated with smaller conjugating groups.
Conjugation alsot in some instances, lowers the CMC, ~o that only a small amount of steroid need be used.
Strong acidic conjugating group~ render the ~teroid resistant to being taken out of solution by variations in pH, ionic s~rength, and by the presence of other ~ons (e.g. Ca ) and other macromoleculesO Conjugation further prevents retention by the body, promotes rapid exsretion, and prevents hepatic metabolism to potentially toxic metabolites (Beauaboin et al., J. Clin. Invest.
(1975) 56:1431-1~41).
As mentiorled above, conjugating groups are bonded to C21 via any suitable linkage, e~q. amide or ester~
Conjugation is carried out using conventional techniques.
As an example) taurine bonded to C21 via an amide 1 nkage is shown below (the presence of a cation, e.
K or Na, is indicated in the parentheses):
C-N-CH2-CH2-S03 (K or Na ) 21 ~1 The properties of the steroid are also affected by the nature of the substituents at C3~ C6 and Cl60 Generally9 OAc groups at ~hese positions tend to aid solubility; howaver, OAc groups are also quite labile, and tend to decrease stability and shelf-life.
The fusidlc acid or cephalosporin P1P5 derivatives can be made by ~ppropria~ely modifying commercially available fu~idic acid or cephalo~porin Pl~P5. Such techni~ues are known in the art.
The drugs which are admixed with a st~roid carrier preferably have a molecular weight of between ~bout 100 daltons and about 300,000 daltons~ The drug may be either water soluble or lipid soluble, and may be peptide, e.~7 a peptide hormone such as insulin or a peptide hormone precursor ~uch as proinsulin. Water soluble dru~s, ~ some peptides and vi~amins, can also be transported across mucosal membranes by any of the steroids of the invention, including ~hose whose unconjugated deriva~ives have relatively low k' values (between about 7 and about 15)~ E'or hydrophobic, lipid-soluble drugs, e.~. the lipid-soluble vitamins, the unconjugated derivative of the steroid should have a higher k' value, preferably above about 20~
Drugs for which the method of administration of the invention is par~icularly important are peptides.
Suitable pepti~es include but are not limited to insulin, proinsulin, glucagon, parathyroid hormone and an~agonists of it, calcitonin, vasopressin, renin, prolactin, growth hormone, thyroid s~imula~ing hormone~ corticotropin, follicle stimulating hormone, luteinizing hormone, chorionic gonadotropin~ atrial peptides (a natriuretic factor), interferon, tissue plasminogen ac~ivator, gammaglobulin, ~actor VIII~ and chemical modifications of these peptides~
The invention can al~o be used to administer hormone releasing hormones, ~ growth hormone relea~ing hormone, corticotropin releasing factor~ lu~einizing hormone releasing hormone, growth hormone release ...~ . . _ r inhibiting hormone ~somatostatin) and thyrotropin releas~ng hormone.
Other suitable drugs include the physiologically active enzymes: transferases, hydrola6es, isomerases, proteases, ligases, and oxidoreductases such as esterases, phosphata3es, glycosidases and peptidases; enzyme inhibitors such as leupeptinp chymostatin and pepstatin;
and growth factors such as tumor angiogenesis factor, epidexmal growth factor, nerve growth factor and insulin-like growth factors~ Other ~uitable drugs are those normally absorbed to a limited extent across the gastrointes~inal mucosa after oral administration; e.q.
antihistamines (~ diphenhydramine and chlorpheniramine), and drugs affecting the cardiovascular (e.q., antihypertensives), renal, hepatic and immune systems (including vaccines). Additionally, sympathomimetic drugs, such as the catecholamines (e.q.
epinephrine~ and non-catecholamines (e.q. phenylephrine and pseudoephedrine) ~ay be administered according to the method of the present invention.
Drugs such as anti-infectiv~ agents, including antibacterial, antiviral and antifungal agents may also be administered according to the method of the present invention. For example, antibiotics such as the aminoglycosides (~ g~, streptomycin~ gentamicin, kanamycin, etc.) are generally not adequately absorbed after oral administration, and may therefore be advantageously admini~tered by the method o~ the invention, Many other drugs may also be adminis~ered according to the inventiont ~ the many drugs currently used to treat arthritis such ~s narcotic pain relievers.
An~i-inflammatory agents (e g. indomethacin, dexamethasone and triamcinolone), anti-tumor agents (~ 5-fluorouracil ~2~ 3~
and methotrexa~e) and tranquilizer~ such as diazepam may also be administered according to khe invention.
Other suitable drugs are the water lnsoluble, fat-soluble hydrophobic drugs, ~ ~ s'ceroids æuch as progesterone, ~strogen~ ~including con~raceptives suc:h as ethinyl estradiol~ and androgen~ and ~heir analogs, and the fat-soluble YitaminS~ ~ vitamins A~ D, E and K, and their analogs, qlhe ~urf ace across which transpor~ occurs may be any mucosal ~urface such as the nasopharynx, conjunctiva~
oropharynx, ear canal~ rectal, in~estinal (enteral)~
15 respiratory tract, en~ometrial, cervical vaginal, urethra, urinary bladder or, in ~ome circumstances, a skin surface ~uch as the axilla, the gluteal cleft, ympanic membrane, between the toes, and the groin. Additionally, transport of the drug according to the method of the present invention may enhance penetration into the skin for increased l~cal effects7 The ratio of drug and steroid present in a therapeutic composition will vary depending on a number of factors, including khe k' and CMC of the steroid, the dosage of the drug to be adminis~ered, and the chemical characteristics, e.q. hydrophobicity, of the drug~
Generally, the steroid is provided in an aqueous physiological buffer solu~ion which i3 ~hen mixed with the drugO The 601ution generally contain~ about n. 1% to about 2.5~, W/v9 steroid in a physiologically acceptable carrier, ~ sodium phosph~te buffered NaCl; pH 5-8, having a NaCl concentration of about 0.05 M to about 006 M.
The concentration of ~he drug in the ~olution will of course vary widely, depending on the nature of the drug, and on the extent to which absorption is facilitated by the steroid. In some cases, administration according to the invention will enable ~he delivery of a higher dosage of the drug where needed than if the conventional mode of administration i~ used; in other cases, a much smaller do~age can be used becau~e of efficient administration to a site. For instance~ the amount of drug potentially can be decreased to one ~housandth the amount or increased to ten times the amount of the drug normally used with conventional administration methods.
The therap2utic composition may con~ain, in addition to steroid and drug~ any other desired non-toxic, pharmaceutically acceptable substance~, ~ a preservative such a phenol or cresol or stabilizing agents.
The dosage given a~ any one time will depend on a number of factors including, in addition to those mentioned above, the frequency of administration.
The compositi.ons of the present inventi4n may be administered to human and animal body surfaces in a variety of forms, including bu not limited to~ sprays, 2~ drops, ~uppositorie~, douches, salves, ointments, and creamsO Some composi~ion~ may be advantageously applied in long term release dosage forms such as slow rel ase, continuous xelease and intermittent release dosage forms~
These long term release dosage forms include but are not limited to polymers, microcapsules~ microspheres, osmotic diffusion devices and membrane release devices.
~X_ The following exam21es are intended to illust~ate the invention, without actlng as a limitation upon its scope.
Examples 1-14 demonstrate the effec~iveness of using various u~idic acid derivatives (Leo Pharmaceutical~, Ballerup, Denmark~ and cephalosporin ~s adjuvants for the delivery of insulin, glucagon, human chorionic gonado'cropin (hCG), proinsuli~, corticotropin releasing-f~ctor (CRF) and epinephrine across nasal mucosal membranes or conjunctival membrane~ in humans or sheep. A~says of insulin~ glucagon, and hCG across nasal 0 mucosal membranes and conjunctlval membranes were accomplished by highly specific radioimmuno2ssay (R~A).
(Protocol~ for RIA of insulin followed the procedures given in ~GammaCoat ~125I~ Insulin Radioimmunoassay Kit,~ Cat. No. CA 532, Clinical Assays Division of Travenol Laboratories, Inc., Cambridge; MA and for glucagon, the procedures given in ~Protocol for the Radioimmunoassay of Glucagon [ I], Cat. No. 520, Cambridge Medical Diagnostics, ~iddle Billerica, MA) In the case of proin~ulin, an insulin immunoassay with signiicant cross~reactivity for proinsulin was adapted to e~timate the amounts of proin~ulin absorbad. (The protocol is given in ~Insulin [125I] Radioimmunoassay,~
Corning Medical and Scientific, Medfield, MAo~ The values obtained for ins~lin were ad~usted to correlate with known cross-reactivity (i.~., 36%) of proinsulin in $he assay.
The "Ga~maDab [ I] ~-HCG ~adioimmunoassay Rit,~
Clinical Assays Cat. No. 589, Clinical Assays Division of Travenol Laboratories, Inc., CambridgeO MA was used ~o evaluate hCG levels in serum.
INTRANASAL ADMINISTRATION OF INSULIN TO HUMANS
The final concentration of insulin varied for each ~ubject since they were of different weights.
Sodium ~auro-24,25-dihydrofusida~e was dissolved in 0.15 M NaCl, pH 7~4 to form a 5~ solution, w/v~
Commercially ~vailable porcine regular insulin ~U-500) (Eli Lilly & Co~, Xndianapolis, IN) was mixed in a ~otal volume of 2.0 mQ wlth 0.15 M NaCl, p~ 7.~ and the 5~
~olution of sodium tauro-24,25-dihydrofusidate to give final concentrations of 216 U/mQ insuli~ and 1% (w/v) ~odium tauro-24,25-dihydrofusidate~ A normal human subject (subjec~ 40) wa~ administered at time 0, by nasal spray, two 75 microliter aliquots, 50 that the dosage of in~ulin administered to the subject was 0.5 Units/kg body weight, For subjects 92 and 93, sodium tauro-24,25-dihydrofusidate was dissolved in 0.15 M NaCl, 0.05 M
sodium phosphate bu~fert pH 7~ to form a 2% solution, w/v. Insulin was mixed in a total volume of 7.0 m~ with ~he 0.15 M NaCl, 0.05 M sodium phosphate buffer and the 2%
solution of ~odium tauro-24,25-dihydrofusidate to give final concentrations of 220 Units/mQ for subject 92 and 233 Units/mQ for sub]ect 93~
As shown in Table I, below, five minutes after nasal administra~ion, subject 4~'s serum insulin level had increased more than twenty-fold~ demonstrating that the insulin had been rapidly and effectively absorbed across the nasal ~ucosa. After ten minutes serum insulin levels for subjects 92 and 93 had increased more than ten-fold, indicating rapid absorption across the nasal mucosa.
Furthermore, as is ~hown in Table I~ each subjects' blood glucose was lowered significantly after twenty minutes, and was reduced more than fifty percent after thirty minutes for subjects 40 and 92.
~23-._ ~
TABBE I
STUDY OF NASALLY ADMINISTERED INSULIN IN
SODIUM TAUR0~24,25-DI~YDROFUSIDATE TO ~UMANS
Blood Serum Insulin Time Glucose Insulin l~U/mQ
~ (mg/dQ) (~U/mQ) above basal) SUBJECT 40 -20 8909 5~6 1.1 -~0 88 ~5 115 110.5 82 100 95.5 90.5 54~5 62 57.5 31.5 ~ 17.5 ~0 3705 10 5.5 6.~ 1.9 72 B.8 4.3 7~ 85 5 gO 89 3.5 SUBJECT 92 -20 81 5.0 03 0 80 4.7 0 ~5 79~5 52 ~7,3 7~0~ 68 63.3 61~5 55 50.3 47 35 30.3 34.5 53.5 ~.4 1~7 67 3.2 71.5 2.8 0 SUBJECT 93 -20 91.5 7.2 1.8 O ~9 5.4 0 ~5 89.5 54 ~8.6 ~5 58 52.~
75~5 28~5 23~1 ~S 19.5 14.1 3~ 6505 7.2 108 ~0 75 4.7 0 8~1o5 9~4 4~t) 84.5 6.2 O.B
2~-_X~
Unconjugated ~odium fus~da~e was dis~olved in 0.15 M NaCl, pH 7.4 to form a 3% ~olution w/v.
Commercially avallable insulin (U-500) wa~ mixed in ~
total volume of 3 mQ with 0.15 M NaCl, pH 7.4 and the 3%
solution of 60dium fusidate to give final concentrations of 210 Units/mQ insulin and 1% (w~v) sodium fu~idate. A
normal human subject was administered the in~ulin preparation by na~al spray at time 0 as described in Exampl~ 1. The results obtained are ~hown in Tabl~ II
below. Twenty minutes after nasal adminis~ration the ~ubjectls ~erum insulin level had increased more than fifteen-foldO Additionally, a~ i~ shown in Table II, the ~ubject's blood glucose was reduced more than fifty percent after thirty minutes.
.. . . .. .. . . . . . _ .
TABLE II
STUDY OF NASALLY ADMINISTE~E~ INSULIN IN
UNCONJUGATED SODIUM FUSIDATE, pH 7.4 TO HUMANS
~5 Blood Serum Insulin T~me Gluco~e Insulin(~U/m~
~ L (mg/dQ ~ (~U~m~)above basal) SUBJECT 33 -20 75,5 3~7 -.8 0 79 4~5 0 ~5 16 11.5 77 60 55.5 75.5 59.5 85 B0.5 3~ 28 23.5 ~0 ~3.~ 10.5 6 56.5 7 2.5 68.5 4.5 _.. , ...... . . _ . __ ._ _ _ . . .
~X~
-~5-The insulin preparatlon was obtained by the same procedure as described in Example 2. ~owever, the pH of the solution was adju~ted to pM 7.95 and the final insulin concentration ~as 267 Unit~/m~. A normal human ~ubject was administered the insulin preparation by nasal spray at time 0 as described in Example l. As shown in ~able III
below the subject's eeru~ in~ulin level had increased more than thirty-~ive fold after fifteen minutes. Furthermore the patient's blood glucose was lowered ~ignificantly after thirty minutefi.
15 ~ e__ TABLE I I I
STUDY OF NASALLY ADMINISTERED INSULIN IN
UNCONJUGATED SODIUM FUSIDATE ~ pE~ 7 0 9 5 TO HUMANS
BloodSerumInsulin Time GlucoseInsu:i int~lU/mQ
(minutesl ~ U/m~)abo~re basal~
SUBJECT 3 5 - 2 0 1~, 7 O
0 80 1,7 ~5 ~5 43 0 3 ~ 6~ 58. 3 3~ 32. 3 ~0 64 20 1~. 3 ~ 10 8. 3 56 4.5 ~.8 73~,514 1203 84 7 5. 3 Sodium glyco-2~,25-dihydrousidate was di~solved in Q.15 M NaCl, p~ 7.6 to form a 3% 801ution W/V.
Commercially available porcine insulin (U-500) was mixed in a total volume of 3.9 mQ with 0.15 M NaCl, pH 7.S and the 3% solution of sodium glyco 24,25-dihydrofusidate to give final concentrations of 216 Units/mQ insulin and 1 (w/v) sodium glyco-24,25-dihydrofu~idate. Subject 40 wa~
adminis~ered ~he insulin preparation by nasal spray at time O as described ln Example 1. As shown in Table IV
below, five minutes after nasal administration~ subject 409S ~erum insulin had ~ncreased more than twenty-fold, indicating that the insulin had been rapidly and effectively absorbed through the nasal mucosa.
Furthermore, ~he ~ubject's blood glucose was lowered significantly after tw~nty minutes.
~~~
T~BLE IV
STUDY OF NASALLY ADMINISTERED INSULIN IN
SODIUM GLYCO-24,25-DIHYDROFUSIDATE TO HUMANS
~5 Blood Serum Insulin Time GlucoseInsulin (~U/m~
(minutes~ (m~dQ)~U/mQ) above basal) SUBJECT 40 -20 90 3.5 ,8 0 ~6.S 2.7 0 +5 66 63~3 81 58 55.3 38 35.3 23 20~3 51 6 3~3 6705 4.5 1 78.5 506 209 82~5 2.4 -.3 ~,,r~d ~
-~7-For subject 34, sodium 24~25-dihydrofusldate was dissolved in 0,15 M NaCl, pH 8.1 ~o form a 3% solution w/v. Commercially available porcine insulin tU-5003 was mixed in a total volume of 3 mQ with 0.15 M NaCl~ pH 8.1 and the 3% ~olution of sodium 24,25-dihydrofusidate to give final concentrations of 190 Units/m~ insulin and 1%
(w/v) ~odium 2~,25-dihydrofusidateO For ~ubject 35, the in~ulin preparation was made in the s~me manner as described above except that tha initial sodium 24, 25-dihydrofusidate concentration was 3.75% (w/v) and the final insulin concentration was 267 Units/mQ~ The two normal human subj~cts were administer~d the insulin preparat$on by na al ~pray at time 0 as described in Example 1. As shown in Table V below, fif~een minute~
after nasal administration su~ject 34's ~erum insulin level had increased thirty-fold and the subject's blood glucose was lowered significantly after thirty minutes.
Subject 35 showed a dramatic increase in ~erum insulin (6305-fold) after ten minutes, demonstrating that the insulin had been rapidly and effectively absorbed through the nasal ~ucosa. Additionally, ~he subjects' blood glucose was lowered mor~ than fifty percent after thirty minutes.
TABL~ V
STUDY OF NAS~LLY ADMI~ISTERED INSULIN
IN SODIUM 24,25-DI~YDROFUSIDATE TO HUMANS
BloodSerumInsulin Time Gluco~eIn~ulin(~U/mQ
(minutes) ~mg/dQ~(UU/mQ)above basal~
SU~JECT 34 -20 76 2.2 .3 76.5 1.9 0 ~5 9.6 7.7 7~ 36 34.1 38 36.1 65.5 28 26.1 49 9.~ 7.7 44.5 7 5.1 52.5 3 1.1 SUBJECT 35 -20 75.5 1.6 ~1 0 76.5206 0 ~5 94 9~.4 72 165 162.4 130 127.4
4~.5 g8 95.4 21.5 37 3~.4 29 8.4 5.8 44 ~.4 3.8 54.53~5 .9 ~ , .
~L~ 9~
~29-xample 6 Cephalo~porin Pl was dissolved in 0015 M NaGl, pH 7~6 to form a 5~ ~olution, w/v. Commercially aYailable insulln was mixed with 0.15 M NaCl, pH 7.6 and th~ 5%
solution of cephalo~porin Pl to give final concentrations of 220 Units/mQ insulin and 1~ (w/v) cephalosporin Plo A human ~ubject was administered, by nasal ~pray two 75 microliter aliquots ~33 Units) at time 0 80 that the dosage of insulin administered ~o the subject was ~.5 Units/kg body weightO
As shown ~n Table VI, the subject's blood glucose level decreased slightly. S2rum insulin levels are not yet availableO
~ . _ . _ _ . ... __ TABLE VI
STUDY OF NASALLY ADMINISTERED INSULIN
IN GEPHALOSPORIN Pl TO ~UMANS
Blood Time Glucose (minutes) (m~/dQ) ~7.5 ~5 92 90.5 86.5 76.5 82.5 ~8.5 _ _ . ,.,, ~", _ . _ , _ -3~-CONJUNCTIVAL ADMINISTRATIOM OF I~SULIN TO SEIEEP
_ _ __, _ __ _ _ _ __ Sodium tauro-24,25~dihydrofusidate was dissolved in 0.15 ~ NaCl, 0~05 M sodium phosphate bu~fer9 pH 7.6 ~o form a 2% ~olution~ w/v. Porcine insulln (U-500~ was mixed in a total volume of 1 m~ with 0.15 ~ NaCl, 0.05 M
sodium pho~phate buffer, pH 706 and the 2~ solution of sodium ~auro 24,25-dihydrofusida~e to give final concentrations of 97.5 Units/m~ in~ulin and 1~ (w/v~
80dium tauro-24,25-dihydrofusidate. Two sheep were administered 350 mg ketamine (a general anesthetic~
intravenously and 1.0 Unit/kg body weight of in~ulin to th~ conjunctival sac as drops at ~ime 0. As ~hown in Table VII below7 five minutes after conjunctival admini~tration, the serum insulin level of both sheep had increased greater than five fold. Unlike human subjects, ~O sheep do not respond to these increments in serum insulin levels with a decrease in blood glucose concentra~ions.
TABLE VII
STUDY OF CONJUNCTIVAL ADMINISTRATION OF INSULIN
IN SODIUM TAURO-24,25-DI~IY~ROFUSIDATE TO SHEEP
Serum Time Insulin lm~9~L (~U/m~
Sheep A -15 24
~L~ 9~
~29-xample 6 Cephalo~porin Pl was dissolved in 0015 M NaGl, pH 7~6 to form a 5~ ~olution, w/v. Commercially aYailable insulln was mixed with 0.15 M NaCl, pH 7.6 and th~ 5%
solution of cephalo~porin Pl to give final concentrations of 220 Units/mQ insulin and 1~ (w/v) cephalosporin Plo A human ~ubject was administered, by nasal ~pray two 75 microliter aliquots ~33 Units) at time 0 80 that the dosage of insulin administered ~o the subject was ~.5 Units/kg body weightO
As shown ~n Table VI, the subject's blood glucose level decreased slightly. S2rum insulin levels are not yet availableO
~ . _ . _ _ . ... __ TABLE VI
STUDY OF NASALLY ADMINISTERED INSULIN
IN GEPHALOSPORIN Pl TO ~UMANS
Blood Time Glucose (minutes) (m~/dQ) ~7.5 ~5 92 90.5 86.5 76.5 82.5 ~8.5 _ _ . ,.,, ~", _ . _ , _ -3~-CONJUNCTIVAL ADMINISTRATIOM OF I~SULIN TO SEIEEP
_ _ __, _ __ _ _ _ __ Sodium tauro-24,25~dihydrofusidate was dissolved in 0.15 ~ NaCl, 0~05 M sodium phosphate bu~fer9 pH 7.6 ~o form a 2% ~olution~ w/v. Porcine insulln (U-500~ was mixed in a total volume of 1 m~ with 0.15 ~ NaCl, 0.05 M
sodium pho~phate buffer, pH 706 and the 2~ solution of sodium ~auro 24,25-dihydrofusida~e to give final concentrations of 97.5 Units/m~ in~ulin and 1~ (w/v~
80dium tauro-24,25-dihydrofusidate. Two sheep were administered 350 mg ketamine (a general anesthetic~
intravenously and 1.0 Unit/kg body weight of in~ulin to th~ conjunctival sac as drops at ~ime 0. As ~hown in Table VII below7 five minutes after conjunctival admini~tration, the serum insulin level of both sheep had increased greater than five fold. Unlike human subjects, ~O sheep do not respond to these increments in serum insulin levels with a decrease in blood glucose concentra~ions.
TABLE VII
STUDY OF CONJUNCTIVAL ADMINISTRATION OF INSULIN
IN SODIUM TAURO-24,25-DI~IY~ROFUSIDATE TO SHEEP
Serum Time Insulin lm~9~L (~U/m~
Sheep A -15 24
-5 30 0 2~5 ~5 ~200 ~200 >200 ~200 Sheep B 15 22 ~ -5 22 0 ~2 +5 ~200 >200 INTlRANASAL ADMIN~STRATION OF GLUCAGON TO SHEEP
_ Sodium tauro-24,25~dihydrofusidate was dissolved in 0.15 M NaCl, 0.5 M sodium phosphate, p~l 7.6. The dry powder of bovine glucagon (~li Lilly & CoO, Indian~polis~
Ind.~ was dissolved in the fusidate bu~fer to a final ~L~Z9~3 concentration of 1 mg/mQ, pH 7.6. A sheep was admlnistered 350 mg ketamine in~ravenously and 200 ~Q of the glucagon ~olution was adminis~ered as a ll~uid at time 0, by drops into each ~ide of the no~e of the sheep.
The dose of glucagon wa3 approximately 10 ~g/kg body weight~
Serum glucagon levels were determined as shown in Table VIII. Five minute~ after intranasal administration, the glucagon level had increased more than one hundred-twenty fold demonstrating that the glucagon had been rapidly and effectively absorbed ~hrough the nasal mucosa.
Glucagon was also administered to the nasal mucosa without adjuvant. However, no direct control studies were performed since glucagon is relatively insoluble at neutral pH. Instead, studies were performed as with the adjuvant, at pH 2.7. 4~0 ~g glucagon was dissolved in 0.002 N EICl to administer the same concentration of material as described above. 200 ~g of glucagon was administered to each side of the nose at time 0O Glucagon was absorbed across the nasal mucosa without adjuvant at p~ 2.7. However, the p~rcentage of increment was not as great without adjuvant as with adjuvant.
3~3 ~33-TABLE VI I I
STUDY OF NASALLY ADMINXSTERED GLUCA(;ON WITH OR
WITEIOUT SODIUM TAURO 24 25-DI~YDROFUSIDATE TO SHEEP
Time Glucagon (minutes~ ~pq/mQ) SHEEP 412~ -15 16 +5 3~00 Ç0 80 .105 SHEEP 412b -15 210 ~5 ~1900 3~ 6~0 4~ 580 ~0 800 -a Sodium tauro-24,25-dihydrofusidate (pH 7.6) b No sodium tauro-24,25-dihydrofusidate (highly acidic pH o~ 2.7 was necessary to dissolve glucagon at sufficient co~centration for administration) _ _ -3q-CONJUNCTIYAL ADMINISTRATION OF GLUCAGON IN SHEEP
~.
Sodium tauro-24j25-dihydrofusidate was dissolved in 0.15 M NaCl, 0.05 M ~odium phosphate, pM 7.6. Bovine glucagon was dissolved in the fusidate containing buffer to a final concentration of 1 mg/mQ, pH 7.6. A sheep wa~
administered 350 mg ketamine intravenously and a total of 400 ~g of the glucagon was administered to the conjunctivae in the pre~ence (pH 7.6) and absence (pH 2.7) of adjuvant at time 0 and 90, re~pectively. As described in Table IX below, ln the presence of the adjuvan~, glucagon was absorbed across the conjunctival mucosa.
Since glucagon i8 relatively insoluble at neu~ral pH, no direct controF studies were performed. However, in the absence of the adjuvant, glucagon was dissolved in 0.002 N
HCl, pH 2.7, a~ described in Example 8 above. The studies indicated that glucagon was not absorbed acros the conjunctival mucosa to a significant extent.
. ~
~5 3~
TABLE IX
STUDY OF CON~UNCTIVAL ADMINI5T~ATION
OF GLUCAGON WITH OR WIT~OUT SODIUM
5 ~ IDATE IN SHEEP
Time Glucayon ~L ~
Sheep 196a-15 250 ~5 3400 1~0~
~5 31 2~0 Sheep l9~b90 240 105 5~0 110 36~
~ 120 410 135 ~70 150 4~0 a ~odium tauro-24,25-dihydrofusidate (pH 7O6)5 b No ~odium tauro-24,25-dihydrofusidate (highly acldic pH of 2.7 was necessary to dissolve glucagon at su~ficient concentration for ~dministration) NASAL ADMINISTRATIO~ OF ~UMAN
CHORIONIC GONADOTROPIN IN S~EEP
Sodium tauro-24,25~dihydrofusida$e was dissolved in 0.15 M NaClt 0.05 M ~odium phosphate, pH 7.6. ~uman chorionic gonadotropin lhCG, a glycoprotein of MM 39,000) (Na~ional Pi~uitary Agency, Baltimore, MD) was dissolved 1~ at a concentration of 2 mgfmQ in 0.15 M NaCl and 0.5 M
~odium pho~phate. The hCG wa~ mixed with the fusidate c~ntaining buffer to a final concentration of 1%, pH 7.6.
350 mg of ketamine wa~ administered intravenously and one mg of hCG was administered at time O in the form of drops (250 ~Q in each no~tril) of a sheepO As shown in Table X
below, the data indicate that in the presPnce of adjuvant, significant blood levels of hCG did not appear in either animal until 20 to 30 minutes after administration.
-TABLE X
STUDY OF NASALLY ADMINISTERED HUMAN
CHORIONIC GONADOTROPIN IN SODIUM
, Tim hCG
(minute~) (mIU/mQi SHEEP 412 15 l.0 0 1.5 +5 2.5 4.3
_ Sodium tauro-24,25~dihydrofusidate was dissolved in 0.15 M NaCl, 0.5 M sodium phosphate, p~l 7.6. The dry powder of bovine glucagon (~li Lilly & CoO, Indian~polis~
Ind.~ was dissolved in the fusidate bu~fer to a final ~L~Z9~3 concentration of 1 mg/mQ, pH 7.6. A sheep was admlnistered 350 mg ketamine in~ravenously and 200 ~Q of the glucagon ~olution was adminis~ered as a ll~uid at time 0, by drops into each ~ide of the no~e of the sheep.
The dose of glucagon wa3 approximately 10 ~g/kg body weight~
Serum glucagon levels were determined as shown in Table VIII. Five minute~ after intranasal administration, the glucagon level had increased more than one hundred-twenty fold demonstrating that the glucagon had been rapidly and effectively absorbed ~hrough the nasal mucosa.
Glucagon was also administered to the nasal mucosa without adjuvant. However, no direct control studies were performed since glucagon is relatively insoluble at neutral pH. Instead, studies were performed as with the adjuvant, at pH 2.7. 4~0 ~g glucagon was dissolved in 0.002 N EICl to administer the same concentration of material as described above. 200 ~g of glucagon was administered to each side of the nose at time 0O Glucagon was absorbed across the nasal mucosa without adjuvant at p~ 2.7. However, the p~rcentage of increment was not as great without adjuvant as with adjuvant.
3~3 ~33-TABLE VI I I
STUDY OF NASALLY ADMINXSTERED GLUCA(;ON WITH OR
WITEIOUT SODIUM TAURO 24 25-DI~YDROFUSIDATE TO SHEEP
Time Glucagon (minutes~ ~pq/mQ) SHEEP 412~ -15 16 +5 3~00 Ç0 80 .105 SHEEP 412b -15 210 ~5 ~1900 3~ 6~0 4~ 580 ~0 800 -a Sodium tauro-24,25-dihydrofusidate (pH 7.6) b No sodium tauro-24,25-dihydrofusidate (highly acidic pH o~ 2.7 was necessary to dissolve glucagon at sufficient co~centration for administration) _ _ -3q-CONJUNCTIYAL ADMINISTRATION OF GLUCAGON IN SHEEP
~.
Sodium tauro-24j25-dihydrofusidate was dissolved in 0.15 M NaCl, 0.05 M ~odium phosphate, pM 7.6. Bovine glucagon was dissolved in the fusidate containing buffer to a final concentration of 1 mg/mQ, pH 7.6. A sheep wa~
administered 350 mg ketamine intravenously and a total of 400 ~g of the glucagon was administered to the conjunctivae in the pre~ence (pH 7.6) and absence (pH 2.7) of adjuvant at time 0 and 90, re~pectively. As described in Table IX below, ln the presence of the adjuvan~, glucagon was absorbed across the conjunctival mucosa.
Since glucagon i8 relatively insoluble at neu~ral pH, no direct controF studies were performed. However, in the absence of the adjuvant, glucagon was dissolved in 0.002 N
HCl, pH 2.7, a~ described in Example 8 above. The studies indicated that glucagon was not absorbed acros the conjunctival mucosa to a significant extent.
. ~
~5 3~
TABLE IX
STUDY OF CON~UNCTIVAL ADMINI5T~ATION
OF GLUCAGON WITH OR WIT~OUT SODIUM
5 ~ IDATE IN SHEEP
Time Glucayon ~L ~
Sheep 196a-15 250 ~5 3400 1~0~
~5 31 2~0 Sheep l9~b90 240 105 5~0 110 36~
~ 120 410 135 ~70 150 4~0 a ~odium tauro-24,25-dihydrofusidate (pH 7O6)5 b No ~odium tauro-24,25-dihydrofusidate (highly acldic pH of 2.7 was necessary to dissolve glucagon at su~ficient concentration for ~dministration) NASAL ADMINISTRATIO~ OF ~UMAN
CHORIONIC GONADOTROPIN IN S~EEP
Sodium tauro-24,25~dihydrofusida$e was dissolved in 0.15 M NaClt 0.05 M ~odium phosphate, pH 7.6. ~uman chorionic gonadotropin lhCG, a glycoprotein of MM 39,000) (Na~ional Pi~uitary Agency, Baltimore, MD) was dissolved 1~ at a concentration of 2 mgfmQ in 0.15 M NaCl and 0.5 M
~odium pho~phate. The hCG wa~ mixed with the fusidate c~ntaining buffer to a final concentration of 1%, pH 7.6.
350 mg of ketamine wa~ administered intravenously and one mg of hCG was administered at time O in the form of drops (250 ~Q in each no~tril) of a sheepO As shown in Table X
below, the data indicate that in the presPnce of adjuvant, significant blood levels of hCG did not appear in either animal until 20 to 30 minutes after administration.
-TABLE X
STUDY OF NASALLY ADMINISTERED HUMAN
CHORIONIC GONADOTROPIN IN SODIUM
, Tim hCG
(minute~) (mIU/mQi SHEEP 412 15 l.0 0 1.5 +5 2.5 4.3
6.4 l0.5 l~.0 . l9.0 2~.0 32.0 2~ 0 0 +5 0 39 4.1 ~5 1~.5 6~ 150 5 ~5 15.5 19.5 -3~-INTRANASAL ADMINISTRATION 0~ PROINSULIN I~ SHEEP
Example_ll Sodlum ~auro-24,25-dihydrofusidate was dissolved in 0.15 M NaCl, pH 7.6~ Commercially available proinsulin ~Eli Lilly ~ Co., Indlanapol~s, Ind.) was mixed with the sodium tauro-24,25-dihydro~usidate solut.ion or ln 0.15 M
NaClD pH 7.6 ~o give a final concentratisn of 6 mg/mQ of proinsulin and 1% ~w/v) æodium tauro-24, 25-dihydrofusidate. Sheep were adminis~cered by nasal drs~ps 1. 5 mg (250 llQ) of the solution into each nos~:ril at time 0. 5heep 25 was administered proinsulin without ad juvant a~ described above. As shown 1 n Table XI below, proinsulin was rapidly absorbed in the presence of adjuvantu However; in the absence of adjuvant the proinsulin was absorbed at a slower rate and to a much reduced extellt.
TA~LE X I
STUDY OF N~ALLY ADMINISTERED PROINSU~IN WITH OR
Time Proin~ulin (minutes~ U!m~ above baseline) 5EIEEP 4 0 8 a -15 Study 24 0 0 ~5 119 i5 60 53 1~0 53.
2~0 22 SHEEP 19 6b -15 0 Study 25 0 0 ~ o 2.
~6 120 o 180 o 240 2. 8 __ a Sodium tauro-24, 25-dihydrofusidate No sodium tauro-24, 25-dihydrofusidate CONJUNCTIV~L ADMINISTRATION OF PROINSULIN TO SHEEP
Example 12 Sodium ~auro-24,25-dihydrousidate was mixed with proinsulin as descr~bed in Example 11. Sheep were administered a total of approximately 2.1 mg of the proinsulin ~olution to the conjunctiva at time 0. As indi~ated in Table XII below, proinsulin was rapidly absorbed across the conjunctival mem~ranes in the presence of sodium tauro-24,25~dlhydrofusidate.
TABLE XII
STUDY OF CONJUNCTIV~L ADMINISTRATION OF PROINSULIN
IN SODIUM TAURO-24,25-DIHYDROFUSIDATE TO SHEEP _ Time Proinsulin (minutes)(~U~mQ above baseline) S~EEP 31 -15 0 O O
+5 117 b7 ~7 ~5 ~0 42 INTRANASAL ADMINISTRATION OF
CORTICOTROPIN ~ELEASING FACTOR
Sodium tauro-24,~5-dihydrofu~ida e was dissolYed in 0.15 M NaCl, pH 706 to form a 2~ 801ution, W/V-Corticotropin releasing-fac~or (CRF~ a hormone of ~W
49000) (~r~ George Chrousos, National Ins~itute of Health, Bethesda, ~D) was dissolved in 0.15 NaCl and mixed with the 2~ solution of ~odium tauro-24~25-dihydrofusidate.
CRF was also prepared without adjuvant. Two sheep were admini~tered 350 mg ketamine intravenously and a total of 460 ~g of CRF as a liquid, by drops into each side of the nose of the sheep at time 0. The dose of CRF was approximately 10 ~g/kg body weight. As shown in Table XIII, serum CRF levels were determined either with or without adjuvant. Five minutes after intranasal administration with adj1~vant, the CRF level had increased more than 200-fold. In contrast, without adjuvant the C~F
level increased only sligh~ly~ The da~a indic~te ~hat CRF
had been rapidly and effectively absorbed acro~s the nasal muco~.
~42-TABLE XIII
REEEASING-FACTOR WITH OR WITHOUT
TAURO-24,25-DIHYDROFUSIDATE IN SHEEP
Time CRF
(minutes~( ~ mQ) S~EEP lla 0 15-20 ~5 >200 ~200 >200 >200 >200 ~200 ~200 ~200 ~200 120 >200 125 1~7 13S 16~
165 1~8 180 12~
SHEEP 12b 0 16-20 ~5 33 ~8 120 ~4 a Sodium tauro-24,25-dihydrofusidate b No sodium tauro-24925-dihydrofusidate _ __ _.,.. ....... _ _ , _.
~.
Sodlum ~auro-24,25-dihydrofusidate was dissolved in 0.05 M sodium phosphate buffer, pH 7.6 to form a 3%
solutionO Commercially available epinephrine in solution (1:1000) (Elkins Sinn, ~ichmond, VA) was mixed with 0.1 mQ
of the 3% solution of ~odium tauro-24g25-dihydrsfusidate.
A sheep was administ~red 350 mg ketamine in~ravenously and 150 ~ of the epinephrlne solu~ion as drops to each nostril at time 0. The sheep was also adminis~ered epinephrine as described above without adjuvant at a later time~
Epinephrine levels were measured following extraction of plasma and running on HPLC with electrochemical detection.
As shown in Table XIV below, in ~he presence or adjuvant~ epinephrine was absorbed across the nasal mucosa to a greater extent than without adjuvant.
~4~
TABLE XIV
STUDY OF NASAL ADMINISTRATION OF EPINEPHRINE WITH OR
WITHOUT SODIUM TAURO-24,25-DIHYDROFUSIDATE IN SHEEP_ TimeEpinephrine ~mlnutes) ~ ~mQ) SHEEP 4l2a 0 33 ~5 86 l~ 134 SHEEP 4l2b 0 102 ~5 323 l90 a No sodium tauro-24,25-dihydrofusidate b Sodium tauro-24t25-dihydrousidate It is apparent that many modifications and variations of this invention as herein above set forth may be made without departing from the spirit and scope thereof. The specific embodiments described are given by way o example only and the invention is limited only by the terms of the appended claimsO
Example_ll Sodlum ~auro-24,25-dihydrofusidate was dissolved in 0.15 M NaCl, pH 7.6~ Commercially available proinsulin ~Eli Lilly ~ Co., Indlanapol~s, Ind.) was mixed with the sodium tauro-24,25-dihydro~usidate solut.ion or ln 0.15 M
NaClD pH 7.6 ~o give a final concentratisn of 6 mg/mQ of proinsulin and 1% ~w/v) æodium tauro-24, 25-dihydrofusidate. Sheep were adminis~cered by nasal drs~ps 1. 5 mg (250 llQ) of the solution into each nos~:ril at time 0. 5heep 25 was administered proinsulin without ad juvant a~ described above. As shown 1 n Table XI below, proinsulin was rapidly absorbed in the presence of adjuvantu However; in the absence of adjuvant the proinsulin was absorbed at a slower rate and to a much reduced extellt.
TA~LE X I
STUDY OF N~ALLY ADMINISTERED PROINSU~IN WITH OR
Time Proin~ulin (minutes~ U!m~ above baseline) 5EIEEP 4 0 8 a -15 Study 24 0 0 ~5 119 i5 60 53 1~0 53.
2~0 22 SHEEP 19 6b -15 0 Study 25 0 0 ~ o 2.
~6 120 o 180 o 240 2. 8 __ a Sodium tauro-24, 25-dihydrofusidate No sodium tauro-24, 25-dihydrofusidate CONJUNCTIV~L ADMINISTRATION OF PROINSULIN TO SHEEP
Example 12 Sodium ~auro-24,25-dihydrousidate was mixed with proinsulin as descr~bed in Example 11. Sheep were administered a total of approximately 2.1 mg of the proinsulin ~olution to the conjunctiva at time 0. As indi~ated in Table XII below, proinsulin was rapidly absorbed across the conjunctival mem~ranes in the presence of sodium tauro-24,25~dlhydrofusidate.
TABLE XII
STUDY OF CONJUNCTIV~L ADMINISTRATION OF PROINSULIN
IN SODIUM TAURO-24,25-DIHYDROFUSIDATE TO SHEEP _ Time Proinsulin (minutes)(~U~mQ above baseline) S~EEP 31 -15 0 O O
+5 117 b7 ~7 ~5 ~0 42 INTRANASAL ADMINISTRATION OF
CORTICOTROPIN ~ELEASING FACTOR
Sodium tauro-24,~5-dihydrofu~ida e was dissolYed in 0.15 M NaCl, pH 706 to form a 2~ 801ution, W/V-Corticotropin releasing-fac~or (CRF~ a hormone of ~W
49000) (~r~ George Chrousos, National Ins~itute of Health, Bethesda, ~D) was dissolved in 0.15 NaCl and mixed with the 2~ solution of ~odium tauro-24~25-dihydrofusidate.
CRF was also prepared without adjuvant. Two sheep were admini~tered 350 mg ketamine intravenously and a total of 460 ~g of CRF as a liquid, by drops into each side of the nose of the sheep at time 0. The dose of CRF was approximately 10 ~g/kg body weight. As shown in Table XIII, serum CRF levels were determined either with or without adjuvant. Five minutes after intranasal administration with adj1~vant, the CRF level had increased more than 200-fold. In contrast, without adjuvant the C~F
level increased only sligh~ly~ The da~a indic~te ~hat CRF
had been rapidly and effectively absorbed acro~s the nasal muco~.
~42-TABLE XIII
REEEASING-FACTOR WITH OR WITHOUT
TAURO-24,25-DIHYDROFUSIDATE IN SHEEP
Time CRF
(minutes~( ~ mQ) S~EEP lla 0 15-20 ~5 >200 ~200 >200 >200 >200 ~200 ~200 ~200 ~200 120 >200 125 1~7 13S 16~
165 1~8 180 12~
SHEEP 12b 0 16-20 ~5 33 ~8 120 ~4 a Sodium tauro-24,25-dihydrofusidate b No sodium tauro-24925-dihydrofusidate _ __ _.,.. ....... _ _ , _.
~.
Sodlum ~auro-24,25-dihydrofusidate was dissolved in 0.05 M sodium phosphate buffer, pH 7.6 to form a 3%
solutionO Commercially available epinephrine in solution (1:1000) (Elkins Sinn, ~ichmond, VA) was mixed with 0.1 mQ
of the 3% solution of ~odium tauro-24g25-dihydrsfusidate.
A sheep was administ~red 350 mg ketamine in~ravenously and 150 ~ of the epinephrlne solu~ion as drops to each nostril at time 0. The sheep was also adminis~ered epinephrine as described above without adjuvant at a later time~
Epinephrine levels were measured following extraction of plasma and running on HPLC with electrochemical detection.
As shown in Table XIV below, in ~he presence or adjuvant~ epinephrine was absorbed across the nasal mucosa to a greater extent than without adjuvant.
~4~
TABLE XIV
STUDY OF NASAL ADMINISTRATION OF EPINEPHRINE WITH OR
WITHOUT SODIUM TAURO-24,25-DIHYDROFUSIDATE IN SHEEP_ TimeEpinephrine ~mlnutes) ~ ~mQ) SHEEP 4l2a 0 33 ~5 86 l~ 134 SHEEP 4l2b 0 102 ~5 323 l90 a No sodium tauro-24,25-dihydrofusidate b Sodium tauro-24t25-dihydrousidate It is apparent that many modifications and variations of this invention as herein above set forth may be made without departing from the spirit and scope thereof. The specific embodiments described are given by way o example only and the invention is limited only by the terms of the appended claimsO
Claims (104)
1. A composition useful for the prevention or treat-ment of a human or animal disorder, other than a bacterial infection or bile disorder, or for the regulation of a human or animal physiological condition comprising, in admixture:
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-insoluble fat-soluble hydrophobic drug, a vacci-nating agent, a renal agent and a hepatic agent, other than an antibacterial agent, corticoster-oid or drug useful in the treatment of bile dis-orders specific for the particular disorder or condition; and b) as an adjuvant, a biocompatible, water-soluble, amphiphilic steroid other than a natural bile salt, capable of increasing drug permeability of a human or animal body surface across which the drug is to be administered, in an amount effect-ive to increase the permeability of said surface to said drug.
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-insoluble fat-soluble hydrophobic drug, a vacci-nating agent, a renal agent and a hepatic agent, other than an antibacterial agent, corticoster-oid or drug useful in the treatment of bile dis-orders specific for the particular disorder or condition; and b) as an adjuvant, a biocompatible, water-soluble, amphiphilic steroid other than a natural bile salt, capable of increasing drug permeability of a human or animal body surface across which the drug is to be administered, in an amount effect-ive to increase the permeability of said surface to said drug.
2. The composition of claim 1 wherein said amphi-philic steroid has the formula:
wherein a dashed line represents a single or a double bond;
D represents a group having a molecular weight be-low about 600 daltons which renders an effective amount of said steroid water-soluble within a range of about pH 2 to about pH 12;
E & G each represent OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents OAc or H; and Q, V & X each represent H or OH;
said steroid containing from two to three polar functions, exclusive of the function represented by D.
wherein a dashed line represents a single or a double bond;
D represents a group having a molecular weight be-low about 600 daltons which renders an effective amount of said steroid water-soluble within a range of about pH 2 to about pH 12;
E & G each represent OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents OAc or H; and Q, V & X each represent H or OH;
said steroid containing from two to three polar functions, exclusive of the function represented by D.
3. The composition of claim l wherein said amphi-philic steroid has the formula:
wherein a dashed line represents a single or a double bond;
D represents a group having a molecular weight be-low about 600 daltons which renders an effective amount of said steroid water-soluble within a range of about pH 2 to about pH 12;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
wherein a dashed line represents a single or a double bond;
D represents a group having a molecular weight be-low about 600 daltons which renders an effective amount of said steroid water-soluble within a range of about pH 2 to about pH 12;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
4. The composition of claim 2 wherein the steroid is in unconjugated form, with D being selected from the group consisting of O-Na+, O-K+, O-Rb+ and O-Cs+.
5. The composition of claim 2 wherein D is a coval-ently linked organic group which contains at least one car-bon atom.
6. The composition of claim 5 wherein the covalently linked organic group is an amino acid containing an ionic function which is dissociated within the range of about pH 2 to about pH 12.
7. The composition of claim 6 wherein the amino acid is selected from the group consisting of glycine, taurine, homoglycine and homotaurine.
8. The composition of claim 6 wherein the amino acid is selected from the group consisting of sulfobetaine and phosphobetaine.
9. The composition of claim 5 wherein the covalently linked organic group is a peptide of two to three amino acids, said peptide containing an ionic function which is dissociated within the range of about pH 2 to about pH 12.
10. The composition of claim 9 wherein the peptide is selected from the group consisting of diglycine and glutathi-one.
11. The composition of claim 9 wherein the peptide is selected from the group consisting of sarcosylcysteine, hy-droxyprolinetaurine and sarcosyltaurine.
12. The composition of claim 5 wherein the covalently linked organic group is a heteroalkyl group of about three or fewer carbon atoms, said group containing an ionic func-tion which is dissociated within the range of about pH 2 to about pH 12.
13. The composition of claim 5 wherein the covalently linked organic group is a uronic acid of about six or fewer carbon atoms, said uronic acid containing an ionic function which is dissociated within the range of about pH 2 to about pH 12.
14. The composition of claim 5 wherein the covalently linked organic group is a polyether containing between about six and about fourteen carbon atoms, inclusive, said poly-ether terminating in an ionic function which is dissociated within the range of about pH 2 to about pH 12.
15. The composition of claim 5 wherein the covalently linked organic group is a polyether containing between about sixteen and about twenty-four carbon atoms, inclusive.
16. The composition of claim 5 wherein the covalently linked organic group is a polyether containing between about sixteen and about twenty-four carbon atoms, inclusive, said polyether terminating in an ionic function which is dissoci-ated within the range of about pH 2 to about pH 12.
17. The composition of claim 5 wherein the covalently linked organic group is bonded to C21 of the steroid by an amide or an ester linkage.
18. The composition of claim 5 wherein the covalently linked organic group contains an ionic function, said ionic function being SO3- , SO4- or COO- .
19. The composition of claim 3 wherein the steroid is further characterized in that a) its unconjugated derivative is retained on a col-umn for a length of time sufficient to produce a k' factor value of at least about 4, said k' fac-tor value being obtained by subjecting a monomeric solution of 1 mg/ml of such unconjugated deriva-tive to high-performance (3,000 psi) liquid column chromatography using a 250 x 4.6 nm column having octadecylsilane-coated 5 µm silica particles as the stationary phase and a mobile phase, delivered at 1.0 ml/min., consisting of 75% methanol in wa-ter, v/v, buffered with 0.005M KH2PO4/H3PO4 to give an apparent pH value, as measured using a glass electrode, of pH 5.0, said k' factor value being defined by k'= , where t0 is the re-tention time in said column of the solvent front and tr is the retention time in said column of said unconjugated derivative as measured by ob-taining the elution profile of said steroid deriv-ative by absorbance at 210 nm;
b) the critical micellar temperature of an aqueous 1%
solution, w/v, of the steroid is below about 37°C
within the range of about pH 2 to about pH 12; and c) the critical micellar concentration of the steroid is less than about 8 mMolar in 0.15M NaCl at 37°C, as measured by surface tension.
b) the critical micellar temperature of an aqueous 1%
solution, w/v, of the steroid is below about 37°C
within the range of about pH 2 to about pH 12; and c) the critical micellar concentration of the steroid is less than about 8 mMolar in 0.15M NaCl at 37°C, as measured by surface tension.
20. The composition of claim 19 wherein the critical micellar temperature of the steroid is below about 20°C and the critical micellar concentration is less than about 4 mMo-lar.
21. A composition useful for the prevention or treat-ment of a human or animal disorder, other than a bacterial infection or bile disorder, or for the regulation of a human or animal physiological condition comprising, in admixture:
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-in-soluble fat-soluble hydrophobic drug, a vaccinat-ing agent, a renal agent and a hepatic agent, other than an antibacterial agent, corticosteroid or drug useful in the treatment of bile disorders, specific for the disorder or condition; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of fusidic acid or a derivative thereof, said fusidic acid or deriva-tive being capable of increasing drug permeability of a human or animal body surface across which the drug is to be administered, in an amount effective to increase the permeability of said surface to said drug.
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-in-soluble fat-soluble hydrophobic drug, a vaccinat-ing agent, a renal agent and a hepatic agent, other than an antibacterial agent, corticosteroid or drug useful in the treatment of bile disorders, specific for the disorder or condition; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of fusidic acid or a derivative thereof, said fusidic acid or deriva-tive being capable of increasing drug permeability of a human or animal body surface across which the drug is to be administered, in an amount effective to increase the permeability of said surface to said drug.
22. A composition useful for the prevention or treat-ment of a human or animal disorder or for the regulation of a human or animal physiological condition comprising, in ad-mixture:
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-insoluble fat-soluble hydrophobic drug, a vacci-nating agent, a renal agent and a hepatic agent, specific for the disorder or condition; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of cephalosporin P1, P2, P3, P4 or P5 or a derivative thereof, said cepha-losporin or derivative being capable of increasing drug permeability of a human or animal body sur-face across which the drug is to be administered, in an amount effective to increase the permeabil-ity of said surface to said drug.
a) as an active ingredient, a biologically-effective amount of a drug selected from the group consist-ing of a peptide, a glycoprotein, an antihista-mine, a sympathomimetic drug, an antiviral agent, an antifungal agent, an anti-arthritic agent, an anti-inflammatory agent, an antitumor agent, a tranquilizer, a cardiovascular agent, a water-insoluble fat-soluble hydrophobic drug, a vacci-nating agent, a renal agent and a hepatic agent, specific for the disorder or condition; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of cephalosporin P1, P2, P3, P4 or P5 or a derivative thereof, said cepha-losporin or derivative being capable of increasing drug permeability of a human or animal body sur-face across which the drug is to be administered, in an amount effective to increase the permeabil-ity of said surface to said drug.
23. The composition of claim 21 wherein the derivative of fusidic acid is 24,25-dihydrofusidic acid.
24. The composition of claim 21 wherein the derivative of fusidic acid is 17,20-24,25-tetrahydrofusidic acid.
25. The composition of claim 21 wherein the derivative of fusidic acid is 3-acetoxyl-fusidic acid.
26. The composition of claim 21, 23 or 24 wherein the fusidic acid or derivative thereof is conjugated at C21.
27. The composition of claim 25 wherein the fusidic acid or derivative thereof is conjugated at C21.
28. The composition of claim 22 wherein the cephalo-sporin or derivative is conjugated at C21.
29. The composition of claim 21 wherein the derivative of fusidic acid is tauro-24,25-dihydrofusidate.
30. The composition of claim 21 wherein the derivative of fusidic acid is tauro-16.alpha.-OH-17,20 24,25-tetrahydrofusi-date.
31. The composition of claim 21 wherein the derivative of fusidic acid is tauro-16.alpha.-OH-24,25-dihydrofusidate.
32. The composition of claim 21 wherein the derivative of fusidic acid is tauro-17,20-24,25-tetrahydrofusidate.
33. The composition of claim 21 wherein the derivative of fusidic acid is glyco-24,25-dihydrofusidate.
34. The composition of claim 21 wherein the derivative of fusidic acid is tauro-16-O-methyl-ether-24,25-dihydrofusi-date.
35. The composition of claim 21 wherein the derivative of fusidic acid is tauro-16-O-methyl-ether-17,20-24,25-tetra-hydrofusidate.
36. The composition of claim 1, 21 or 22 wherein said drug is a peptide.
37. The composition of claim 1, 21 or 22 wherein said drug is a peptide having a molecular weight between about 100 and about 300,000 daltons.
33. The composition of claim 1, 21 or 22 wherein said drug is a hormone or a precursor or inhibitor thereof.
39. The composition of claim 1, 21 or 22 wherein said drug is an enzyme or a precursor or an inhibitor thereof.
40. The composition of claim 1, 21 or 22 wherein said drug is a glycoprotein.
41. The composition of claim 1, 21 or 22 wherein said drug is selected from the group consisting of insulin, proin-sulin, glucagon, parathyroid hormone, parathyroid hormone an-tagonist, calcitonin, vasopressin, resin prolactin, growth hormone, thyroid stimulating hormone, corticotropin, cortico-tropin-releasing factor, follicle stimulating hormone, lu-teinizing hormone, chorionic gonadotropin, atrial peptides, interferon, tissue plasminogen activator, gammaglobulin, Fac-tor VIII, growth hormone-releasing hormone, luteinizing hor-mone-releasing hormone and somatostatin.
42. The composition of claim 1, 21 or 22 wherein said drug is an antihistamine.
43. The composition of claim 1, 21 or 22 wherein said drug is a sympathomimetic drug.
44. The composition of claim 1, 21 or 22 wherein said drug is an antiviral agent.
45. The composition of claim 1, 21 or 22 wherein said drug is an antifungal agent.
46. The composition of claim 1, 21 or 22 wherein said drug is an anti-arthritic agent.
47. The composition of claim 1, 21 or 22 wherein said drug is an anti-inflammatory agent.
48. The composition of claim 1, 21 or 22 wherein said drug is an antitumor agent.
49. The composition of claim 1, 21 or 22 wherein said drug is a tranquilizer.
The composition of claim 1, 21 or 22 wherein said drug is a cardiovascular agent.
51. The composition of claim 1, 21 or 22 wherein said drug is a water-insoluble fat-soluble hydrophobic drug.
52. The composition of claim 1, 21 or 22 wherein the drug is a water-insoluble fat-soluble hydrophobic drug sel-ected from the group consisting of progesterone, an estrogen, ethinyl estradiol, an androgen, an androgen analog, vitamin A, vitamin D, vitamin E and vitamin K.
53. The composition of claim 1, 21 or 22 wherein said drug is a vaccinating agent.
54. The composition of claim 1, 21 or 22 wherein said drug is selected from the group consisting of renal and hep-atic agents.
55. The composition of claim 1, 21 or 22 wherein the drug is insulin.
56. The composition of claim 1, 21 or 22 wherein the drug is glucagon.
57. The composition of claim 1, 21 or 22 wherein the drug is human chorionic gonadotropin.
58. The composition of claim 1, 21 or 22 wherein the drug is corticotropin-releasing factor.
59. The composition of claim 1, 21 or 22 wherein the drug is epinephrine.
60. A composition useful for the treatment of diabetes comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of insulin or precursor thereof; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of fusidic acid or a derivative thereof, said fusidic acid or deriva-tive being capable of increasing insulin permea-bility of a body surface across which the drug is to be administered, in an amount effective to in-crease the permeability of said surface to said drug.
a) as an active ingredient, a medically-effective am-ount of insulin or precursor thereof; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of fusidic acid or a derivative thereof, said fusidic acid or deriva-tive being capable of increasing insulin permea-bility of a body surface across which the drug is to be administered, in an amount effective to in-crease the permeability of said surface to said drug.
61. The composition of claim 60 wherein the derivative of fusidic acid is a salt of tauro-24,25-dihydrofusidate.
62. The composition of claim 60 wherein the adjuvant is a salt of fusidic acid.
63. The composition of claim 60 wherein the derivative of fusidic acid is glyco-24,25-dihydrofusidate.
64. The composition of claim 60 wherein the derivative of fusidic acid is a salt of 24,25-dihydrofusidate.
65. The composition of claim 61, 62 or 64 wherein the salt is a sodium salt.
66. A composition useful for the treatment of diabetes comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of insulin or precursor thereof; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of cephalosporin P1, P2, P3, P4 or P5 or a derivative thereof, said cepha-losporin or derivative being capable of increasing drug permeability of a human or animal body sur-face across which the drug is to be administered, in an amount effective to increase the permeability of said surface to said drug.
a) as an active ingredient, a medically-effective am-ount of insulin or precursor thereof; and b) as an adjuvant, an ionized or partially ionized, water-soluble alkali salt of cephalosporin P1, P2, P3, P4 or P5 or a derivative thereof, said cepha-losporin or derivative being capable of increasing drug permeability of a human or animal body sur-face across which the drug is to be administered, in an amount effective to increase the permeability of said surface to said drug.
67. A composition useful for regulating blood glucose and free fatty acid levels comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of glucagon; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
a) as an active ingredient, a medically-effective am-ount of glucagon; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
68. A composition useful for affecting human pregnancy comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of human chorionic gonadotropin; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
a) as an active ingredient, a medically-effective am-ount of human chorionic gonadotropin; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
69. A composition useful for regulating adrenocortico-tropin synthesis and release comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of corticotropin-releasing hormone; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
a) as an active ingredient, a medically-effective am-ount of corticotropin-releasing hormone; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
70. A composition useful for the treatment of disorders or regulation of physiological conditions responsive to sym-pathomimetic drugs comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of epinephrine; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
a) as an active ingredient, a medically-effective am-ount of epinephrine; and b) as an adjuvant, an effective amount of a salt of tauro-24,25-dihydrofusidate.
71. The composition of claim 67, 68 or 69 wherein the salt is a sodium salt.
72. The composition of claim 70 wherein the salt is a sodium salt.
73. A composition useful for the treatment of microbial infections comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a conjugate of an amphiphilic steroid having the formula:
wherein a dashed line represents a single or a double bond;
D is a covalently linked organic group which con-tains at least one carbon atom;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a conjugate of an amphiphilic steroid having the formula:
wherein a dashed line represents a single or a double bond;
D is a covalently linked organic group which con-tains at least one carbon atom;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
74. The composition of claim 73 wherein D, the coval-ently linked organic group, is an amino acid containing an ionic function which is dissociated within the range of about pH 2 to about pH 12.
75. A composition useful for the treatment of microbial infections comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a glycine conjugate of an amphiphilic steroid having the for-mula:
wherein a dashed line represents a single or a double bond;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a glycine conjugate of an amphiphilic steroid having the for-mula:
wherein a dashed line represents a single or a double bond;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
76. A composition useful for the treatment of microbial infections comprising, in admixture:
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a taurine conjugate of an amphiphilic steroid having the for-mula:
wherein a dashed line represents a single or a double bond;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
a) as an active ingredient, a medically-effective am-ount of an anti-infective agent; and b) as an adjuvant, an effective amount of a taurine conjugate of an amphiphilic steroid having the for-mula:
wherein a dashed line represents a single or a double bond;
E represents .beta.-OAc, .alpha.-OH, a lower alkyl group in .beta.-position or a lower heteroalkyl group in .beta.-posi-tion;
G represents .alpha.-OAc, OH, a lower alkyl group or a lower heteroalkyl group;
W represents .alpha.-OAc or H;
Q represents H or OH provided that, when W is .alpha.-OAc and Q is OH, Q is .beta.-equatorial;
V represents H or .alpha.-OH; and X represents H or .alpha.-OH;
said steroid containing from two to three OH groups.
77. The composition of claim 75 wherein the glycine conjugate has the formula:
wherein a dashed line represents a single or a double bond;
and R represents hydrogen or an acetyl group.
wherein a dashed line represents a single or a double bond;
and R represents hydrogen or an acetyl group.
78. The composition of claim 76 wherein the taurine conjugate has the formula:
wherein a dashed line represents a single or a double bond;
and R represents hydrogen or an acetyl group.
wherein a dashed line represents a single or a double bond;
and R represents hydrogen or an acetyl group.
79. The composition of claim 77 wherein the glycine conjugate is selected from the group consisting of glyco-fusidate, glyco-24,25-dihydrofusidate and glyco-17,20-24,25-tetrahydrofusidate.
80. The composition of claim 78 wherein the taurine conjugate is selected from the group consisting of tauro-fusidate, tauro-24,25-dihydrofusidate and tauro-17,20-24,25-tetrahydrofusidate.
81. The composition of claim 73, 74 or 75 wherein the anti-infective agent is selected from the group consisting of antibacterial agents, antiviral agents and antifungal ag-ents.
82. The composition of claim 76, 77 or 78 wherein the anti-infective agent is selected from the group consisting of antibacterial agents, antiviral agents and antifungal ag-ents.
83. The composition of claim 79 or 80 wherein the anti-infective agent is selected from the group consisting of anti-bacterial agents, antiviral agents and antifungal agents.
84. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 1 in a physiologically acceptable carrier.
85. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 21 in a physiologically acceptable carrier.
86. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 22 in a physiologically acceptable carrier.
87. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 60 in a physiologically acceptable carrier.
88. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 61 in a physiologically acceptable carrier.
89. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 62 in a physiologically acceptable carrier.
90. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 63 in a physiologically acceptable carrier.
91. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 64 in a physiologically acceptable carrier.
92. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 66 in a physiologically acceptable carrier.
93. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 67 in a physiologically acceptable carrier.
94. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 68 in a physiologically acceptable carrier.
95. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 69 in a physiologically acceptable carrier.
96. A pharmaceutical preparation suitable for use as a nasal spray or nose drops comprising a solution or suspension of the composition of claim 70 in a physiologically acceptable carrier.
97. The pharmaceutical preparation of claim 84, 85 or 86 wherein the physiologically acceptable carrier is a sodium phosphate buffer, a sodium phosphate buffered sodium chloride solution or a sodium chloride solution.
98. The pharmaceutical preparation of claim 87, 88 or 89 wherein the physiologically acceptable carrier is a sodium phosphate buffer, a sodium phosphate buffered sodium chloride solution or a sodium chloride solution.
99. The pharmaceutical preparation of claim 90, 91 or 92 wherein the physiologically acceptable carrier is a sodium phosphate buffer, a sodium phosphate buffered sodium chloride solution or a sodium chloride solution.
100. The pharmaceutical preparation of claim 93, 94 or 95 wherein the physiologically acceptable carrier is a sodium phosphate buffer, a sodium phosphate buffered sodium chloride solution or a sodium chloride solution.
101. The pharmaceutical preparation of claim 96 wherein the physiologically acceptable carrier is a sodium phosphate buffer, a sodium phosphate buffered sodium chloride solution or a sodium chloride solution.
102. A pharmaceutical preparation suitable for use as eye drops comprising a solution or suspension of the composi-tion of claim 1, 21 or 22 in a physiologically acceptable car-rier.
103. A pharmaceutical preparation suitable for use as eye drops comprising a solution or suspension of the composi-tion of claim 61 or 67 in a physiologically acceptable carrier.
104. A pharmaceutical preparation in the form of a nasal spray or nose drops useful for the treatment of diabetes com-prising a solution or suspension in a physiologically buffered sodium chloride solution of an admixture of a medically-effec-tive amount of insulin as active ingredient and an effective amount of sodium tauro-24,25-dihydrofusidate as adjuvant.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/501,187 US4548922A (en) | 1983-06-06 | 1983-06-06 | Drug administration |
| US501,187 | 1983-06-06 | ||
| US06/614,115 US4746508A (en) | 1983-06-06 | 1984-05-25 | Drug administration |
| US614,115 | 1996-03-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1228298A true CA1228298A (en) | 1987-10-20 |
Family
ID=27053742
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000455465A Expired CA1228298A (en) | 1983-06-06 | 1984-05-30 | Compositions and methods for drug delivery involving amphiphilic steroids |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4746508A (en) |
| EP (1) | EP0128831B1 (en) |
| AU (2) | AU580262B2 (en) |
| CA (1) | CA1228298A (en) |
| DE (1) | DE3486028T2 (en) |
| DK (1) | DK164203C (en) |
| IL (1) | IL71967A (en) |
Families Citing this family (106)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5910304A (en) * | 1982-12-13 | 1999-06-08 | Texas A&M University System | Low-dose oral administration of interferons |
| US4959358A (en) * | 1983-06-06 | 1990-09-25 | Beth Israel Hospital Assn. | Drug administration |
| US4963367A (en) * | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
| NZ217821A (en) * | 1985-10-10 | 1989-07-27 | Biotech Australia Pty Ltd | Oral delivery system; complex of active agent and vitamin b12 or analogue thereof |
| US5045478A (en) * | 1986-03-03 | 1991-09-03 | Becton Dickinson And Company | Vesicles and use thereof in an assay |
| DK179286D0 (en) * | 1986-04-18 | 1986-04-18 | Nordisk Gentofte | INSULIN PREPARATION |
| GB8614189D0 (en) * | 1986-06-11 | 1986-07-16 | Leo Pharm Prod Ltd | Pharmaceutical composition |
| GB8618259D0 (en) * | 1986-07-25 | 1986-09-03 | Leo Pharm Prod Ltd | Pharmaceutical compositions |
| ATE76311T1 (en) | 1986-08-19 | 1992-06-15 | Genentech Inc | DEVICE AND DISPERSION FOR INTRAPULMONARY DELIVERY OF POLYPEPTIDE GROWTH SUBSTANCES AND CYTOKINES. |
| ZA878295B (en) * | 1986-11-06 | 1988-05-03 | Amarillo Cell Culture Co. Inc. | Treatment of immuno-resistant disease |
| CA1320905C (en) * | 1986-11-06 | 1993-08-03 | Joseph M. Cummins | Treatment of immuno-resistant disease |
| US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
| DE3707987A1 (en) * | 1987-03-12 | 1988-09-22 | Behringwerke Ag | INACTIVATION OF HUMAN IMMUNODEFICIENCY VIRUS (HIV) IN PROTEIN-CONTAINING SOLUTIONS BY PHENOLE |
| US5112804A (en) * | 1987-04-01 | 1992-05-12 | Temple University Of The Commonwealth System Of Higher Education | Pharmaceutical composition and method of intranasal administration |
| CA1335076C (en) * | 1987-04-01 | 1995-04-04 | Hanna R. Kowarski | Pharmaceutical composition and method for intranasal administration |
| US5807832A (en) * | 1987-06-09 | 1998-09-15 | Biotech Australia Pty Limited | Oral delivery of biologically active substances bound to vitamin B12 |
| JP2851627B2 (en) * | 1987-10-15 | 1999-01-27 | シンテックス（ユー・エス・エイ）インコーポレイテッド | Nasal administration of powdered polypeptides |
| FR2623715B1 (en) * | 1987-11-26 | 1990-12-21 | Lafon Labor | PEPTIDE STRUCTURES, IMMUNOGENS CONTAINING THEM AND THEIR APPLICATIONS IN FERTILITY CONTROL |
| US5017371A (en) * | 1988-01-06 | 1991-05-21 | Amarillo Cell Culture Company, Incorporated | Method for reducing side effects of cancer therapy |
| WO1989009225A1 (en) * | 1988-03-28 | 1989-10-05 | The Regents Of The University Of California | Nerve growth factor peptides |
| HU206367B (en) * | 1988-04-30 | 1992-10-28 | Sandoz Ag | Process for producing acid addition salts of steroid carboxylic acid-amidated taurine and glycine, as well as pharmaceutical compositions comprising such salts |
| US4937078A (en) * | 1988-08-26 | 1990-06-26 | Mezei Associates Limited | Liposomal local anesthetic and analgesic products |
| SE463851B (en) * | 1988-09-02 | 1991-02-04 | Amsu Ltd | COMPOSITION FOR TREATMENT OF ERECT DYSFUNCTION THROUGH URETRA |
| US5006343A (en) * | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
| US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
| US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
| WO1990009800A1 (en) * | 1989-02-21 | 1990-09-07 | Washington University | Modified forms of reproductive hormones |
| US5139023A (en) * | 1989-06-02 | 1992-08-18 | Theratech Inc. | Apparatus and method for noninvasive blood glucose monitoring |
| WO1990015568A2 (en) * | 1989-06-02 | 1990-12-27 | Stanley Theodore H | Apparatus and methods for noninvasive blood glucose monitoring |
| US6407061B1 (en) * | 1989-12-05 | 2002-06-18 | Chiron Corporation | Method for administering insulin-like growth factor to the brain |
| US5624898A (en) * | 1989-12-05 | 1997-04-29 | Ramsey Foundation | Method for administering neurologic agents to the brain |
| US5242391A (en) * | 1990-04-25 | 1993-09-07 | Alza Corporation | Urethral insert for treatment of erectile dysfunction |
| US5292730A (en) * | 1990-08-29 | 1994-03-08 | Humanetics Corporation | Modulation of immune system with Δ5-androstenes |
| US5585371A (en) * | 1990-08-29 | 1996-12-17 | Humanetics Corporation | Treatment of immune system with Δ5-androstenes |
| IE921050A1 (en) * | 1991-04-02 | 1992-10-07 | Biotech Australia Pty Ltd | Oral delivery systems for microparticles |
| EP0667783B1 (en) * | 1991-11-07 | 1999-04-21 | The University Of Southern California | Compositions and methods for preventing adhesion formation |
| GB2267435A (en) * | 1992-06-01 | 1993-12-08 | British Tech Group | Factor VIII |
| IT1255449B (en) * | 1992-06-30 | 1995-10-31 | Fabio Berlati | USE OF NOR- AND HOMO-DERIVATIVES OF BILE ACIDS AS DRUGS ABSORPTION PROMOTERS. |
| US5364838A (en) * | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
| RU2134693C1 (en) * | 1993-02-23 | 1999-08-20 | Зе Трастис оф Принстон Юниверсити | Methods of forming glycoside bonds, chemical composition, glycoside and glycoside library |
| US5639866A (en) * | 1993-02-23 | 1997-06-17 | Princeton University | Single-step formation of multiple glycosidic linkages |
| IS1796B (en) * | 1993-06-24 | 2001-12-31 | Ab Astra | Inhaled polypeptide formulation composition which also contains an enhancer compound |
| TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| US5506203C1 (en) * | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
| US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| US20010003739A1 (en) * | 1993-06-24 | 2001-06-14 | Astrazeneca Ab | Systemic administration of a therapeutic preparation |
| US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US5747445A (en) * | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| SE504074C2 (en) * | 1993-07-05 | 1996-11-04 | Pharmacia Ab | Protein preparation for subcutaneous, intramuscular or intradermal administration |
| US6737515B2 (en) | 1993-11-19 | 2004-05-18 | Washington University | Follicle stimulating hormone-glycosylation analogs |
| US6165976A (en) | 1994-06-23 | 2000-12-26 | Astra Aktiebolag | Therapeutic preparation for inhalation |
| CN1088580C (en) | 1994-12-22 | 2002-08-07 | 阿斯特拉公司 | Aerosol drug formulations |
| EP0806945B1 (en) * | 1994-12-22 | 2003-04-23 | AstraZeneca AB | Therapeutic preparation for inhalation containing parathyro d hormone, pth |
| US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
| US5861431A (en) * | 1995-06-07 | 1999-01-19 | Iotek, Inc. | Incontinence treatment |
| US5890489A (en) | 1996-04-23 | 1999-04-06 | Dermal Therapy (Barbados) Inc. | Method for non-invasive determination of glucose in body fluids |
| US5804218A (en) * | 1996-09-26 | 1998-09-08 | Brigham & Women's Hospital, Inc. | Methods and compositions for inhibiting enterohepatic cycling of bilirubin |
| US7135191B2 (en) * | 1997-09-04 | 2006-11-14 | Zsolt Istvan Hertelendy | Urogenital or anorectal transmucosal vaccine delivery system |
| US6110489A (en) * | 1998-05-01 | 2000-08-29 | Cutler; Neal R. | Use of quinolines and quinolones to treat male erectile dysfunction |
| US6132757A (en) * | 1998-05-01 | 2000-10-17 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
| US6426084B1 (en) * | 2000-06-19 | 2002-07-30 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
| US6194433B1 (en) | 1998-10-05 | 2001-02-27 | Neal R. Cutler | Sexual dysfunction in females |
| US6187790B1 (en) | 1999-03-04 | 2001-02-13 | Neal R. Cutler | Use of cilostazol for treatment of sexual dysfunction |
| US6132753A (en) * | 1998-05-01 | 2000-10-17 | Neal R. Cutler | Treatment of sexual dysfunction in certain patient groups |
| US20030166525A1 (en) * | 1998-07-23 | 2003-09-04 | Hoffmann James Arthur | FSH Formulation |
| US7273618B2 (en) * | 1998-12-09 | 2007-09-25 | Chiron Corporation | Method for administering agents to the central nervous system |
| JP2003501404A (en) | 1999-06-04 | 2003-01-14 | デルルックス ファーマシューティカル コーポレイション | Preparation comprising dehydrated particles of drug and method of preparing same |
| US6303135B1 (en) | 1999-07-08 | 2001-10-16 | Neal R. Cutler | Use of quinolines and quinolones to treat male erectile dysfunction |
| AU783208B2 (en) * | 1999-12-09 | 2005-10-06 | Novartis Vaccines And Diagnostics, Inc. | Method for administering a cytokine to the central nervous system and the lymphatic system |
| WO2002070537A2 (en) * | 2001-03-08 | 2002-09-12 | Leo Pharma A/S | Fusidic acid derivatives |
| US7041677B2 (en) * | 2002-03-01 | 2006-05-09 | R.T. Alamo Ventures I, Llc | Use of monochloroflosequinan in the treatment of sexual dysfunction |
| AU2003225277A1 (en) * | 2002-05-02 | 2003-11-17 | Robert Harris | Lipid removal from the body |
| US20040057983A1 (en) | 2002-09-25 | 2004-03-25 | David Schmidt | Biomolecular wearable apparatus |
| US8999372B2 (en) * | 2002-11-14 | 2015-04-07 | Cure Pharmaceutical Corporation | Methods for modulating dissolution, bioavailability, bioequivalence and drug delivery profile of thin film drug delivery systems, controlled-release thin film dosage formats, and methods for their manufacture and use |
| US20040131662A1 (en) | 2003-11-12 | 2004-07-08 | Davidson Robert S. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
| US20040191302A1 (en) | 2003-03-28 | 2004-09-30 | Davidson Robert S. | Method and apparatus for minimizing heat, moisture, and shear damage to medicants and other compositions during incorporation of same with edible films |
| US9561182B2 (en) * | 2003-08-22 | 2017-02-07 | Cure Pharmaceutical Corporation | Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals |
| AU2004226666B9 (en) * | 2003-04-02 | 2010-04-08 | Ares Trading S.A. | Liquid pharmaceutical formulations of FSH and LH together with a non-ionic surfactant |
| JP4871124B2 (en) * | 2003-06-20 | 2012-02-08 | アレス トレーディング ソシエテ アノニム | Freeze-dried FSH / LH formulation |
| US20070059346A1 (en) * | 2003-07-01 | 2007-03-15 | Todd Maibach | Film comprising therapeutic agents |
| US20060024725A1 (en) | 2004-07-30 | 2006-02-02 | Robert Hussa | Oncofetal fibronectin as a marker for pregnancy-related indications |
| US7523762B2 (en) * | 2006-03-22 | 2009-04-28 | Honeywell International Inc. | Modulating gas valves and systems |
| EP2124883A2 (en) * | 2006-12-12 | 2009-12-02 | Amylin Pharmaceuticals, Inc. | Pharmaceutical formulations and methods for making the same |
| WO2008098195A2 (en) * | 2007-02-09 | 2008-08-14 | Todd Maibach | Film comprising nitroglycerin |
| US20090004254A1 (en) * | 2007-06-19 | 2009-01-01 | Todd Maibach | Film comprising active drugs |
| US8602961B2 (en) | 2008-05-15 | 2013-12-10 | Lifewave Products Llc | Apparatus and method of stimulating elevation of glutathione levels in a subject |
| WO2010065342A1 (en) | 2008-11-25 | 2010-06-10 | Temple University | Angiocidin inhibition of tumor cell growth |
| PT2381923T (en) | 2008-12-22 | 2018-11-13 | Serenity Pharmaceuticals Llc | Intranasal desmopressin administration |
| US20100286762A1 (en) * | 2009-03-18 | 2010-11-11 | Musc Foundation For Research Development | Compositions and Methods for Ameliorating Clinical Electrical Disturbances |
| KR20120042836A (en) | 2009-06-12 | 2012-05-03 | 아다지오 파마슈티컬즈 엘티디 | Sublingual apomorphine |
| KR101792696B1 (en) | 2009-06-18 | 2017-11-02 | 알레간 인코포레이티드 | Safe desmopressin administration |
| KR101890317B1 (en) | 2010-12-16 | 2018-08-22 | 선오비온 파마슈티컬스 인코포레이티드 | Sublingual Films |
| US9789071B2 (en) | 2012-06-27 | 2017-10-17 | G2B Pharma, Inc. | Intranasal formulation of epinephrine for the treatment of anaphylaxis |
| US9459201B2 (en) | 2014-09-29 | 2016-10-04 | Zyomed Corp. | Systems and methods for noninvasive blood glucose and other analyte detection and measurement using collision computing |
| US9925233B2 (en) | 2015-01-30 | 2018-03-27 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| US9744209B2 (en) | 2015-01-30 | 2017-08-29 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| US9750785B2 (en) | 2015-01-30 | 2017-09-05 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| US9937223B2 (en) | 2015-01-30 | 2018-04-10 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| US9687526B2 (en) | 2015-01-30 | 2017-06-27 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| US9375478B1 (en) | 2015-01-30 | 2016-06-28 | Par Pharmaceutical, Inc. | Vasopressin formulations for use in treatment of hypotension |
| CA3019769C (en) | 2015-04-21 | 2021-10-12 | Sunovion Pharmaceuticals Inc. | Methods of treating parkinson's disease by administration of apomorphine to an oral mucosa |
| US9554738B1 (en) | 2016-03-30 | 2017-01-31 | Zyomed Corp. | Spectroscopic tomography systems and methods for noninvasive detection and measurement of analytes using collision computing |
| US10285998B1 (en) | 2018-04-04 | 2019-05-14 | The Menopause Method, Inc. | Composition and method to aid in hormone replacement therapy |
| WO2021078999A1 (en) | 2019-10-25 | 2021-04-29 | Newmark Biotech, Llc | Chewing gum or lozenge composition comprising cbd |
| US11617716B2 (en) | 2021-06-10 | 2023-04-04 | Belhaven BioPharma Inc. | Dry powder formulations of epinephrine and associated methods |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1447489A (en) * | 1972-10-06 | 1976-08-25 | Leo Pharm Prod Ltd | Fusidic acid conjugates |
| US4153689A (en) * | 1975-06-13 | 1979-05-08 | Takeda Chemical Industries, Ltd. | Stable insulin preparation for nasal administration |
| US4060606A (en) * | 1975-06-25 | 1977-11-29 | Leo Pharmaceutical Products Ltd. A/S | 16-Ethers of fusidic acid derivatives |
| GB1527605A (en) * | 1975-08-20 | 1978-10-04 | Takeda Chemical Industries Ltd | Insulin preparation for intranasal administration |
| IE44263B1 (en) * | 1975-12-03 | 1981-09-23 | Leo Pharm Prod Ltd | New fusidic acid derivatives |
| GB1581335A (en) * | 1976-07-05 | 1980-12-10 | Leo Pharm Prod Ltd | 16-s-acyl derivatives of fusidic acid |
| US4548922A (en) * | 1983-06-06 | 1985-10-22 | Beth Israel Hospital | Drug administration |
-
1984
- 1984-05-25 US US06/614,115 patent/US4746508A/en not_active Expired - Fee Related
- 1984-05-30 CA CA000455465A patent/CA1228298A/en not_active Expired
- 1984-05-30 IL IL71967A patent/IL71967A/en unknown
- 1984-06-04 DK DK277084A patent/DK164203C/en not_active IP Right Cessation
- 1984-06-04 AU AU29020/84A patent/AU580262B2/en not_active Ceased
- 1984-06-06 EP EP84401175A patent/EP0128831B1/en not_active Expired - Lifetime
- 1984-06-06 DE DE8484401175T patent/DE3486028T2/en not_active Expired - Fee Related
-
1989
- 1989-04-07 AU AU32561/89A patent/AU3256189A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| DK164203B (en) | 1992-05-25 |
| EP0128831A2 (en) | 1984-12-19 |
| EP0128831A3 (en) | 1986-12-30 |
| DK277084D0 (en) | 1984-06-04 |
| AU580262B2 (en) | 1989-01-12 |
| AU3256189A (en) | 1989-08-03 |
| DK277084A (en) | 1984-12-07 |
| AU2902084A (en) | 1984-12-13 |
| EP0128831B1 (en) | 1993-01-07 |
| DE3486028D1 (en) | 1993-02-18 |
| IL71967A (en) | 1989-09-10 |
| DK164203C (en) | 1992-10-19 |
| DE3486028T2 (en) | 1993-08-19 |
| US4746508A (en) | 1988-05-24 |
| IL71967A0 (en) | 1984-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1228298A (en) | Compositions and methods for drug delivery involving amphiphilic steroids | |
| US4959358A (en) | Drug administration | |
| US4548922A (en) | Drug administration | |
| CN1034105C (en) | Nasal formulations and process for preparation thereof | |
| KR100217258B1 (en) | Nasal composition | |
| EP1824488B1 (en) | Phycotoxins and uses thereof | |
| NO178564B (en) | Process for preparing a system for administering active drugs through mucosa | |
| JP2003522096A (en) | Transfer system and preparation method for mixed micellar drug | |
| WO1994003157A1 (en) | Pharmaceutical compositions for transmucosal delivery of peptides | |
| Tengamnuay et al. | Bile salt–fatty acid mixed micelles as nasal absorption promoters of peptides. II. In vivo nasal absorption of insulin in rats and effects of mixed micelles on the morphological integrity of the nasal mucosa | |
| WO2002009763A2 (en) | Transdermal drug delivery system | |
| WO2004000358A1 (en) | Transdermal drug delivery system | |
| EP0369437B1 (en) | Motilin preparation | |
| WO1996010991A1 (en) | Pharmaceutical composition containing derivatives of sex hormones | |
| EP1515706A2 (en) | A platform for transdermal formulations (ptf) | |
| Patki et al. | Progress made in non-invasive insulin delivery | |
| Hermens | Delivery of hormones: some new concepts | |
| AU609765B2 (en) | Method for inducing vaginal lubrication | |
| AU703691B2 (en) | Irritation relief using nonsteroidal anti-inflammatory compounds | |
| CN108635330B (en) | Long-acting sustained-release progesterone gel composition | |
| CN101057845B (en) | Bulleyaconitin A dry emulsion and its preparation method and application | |
| JPH0717520B2 (en) | Pharmaceutical composition for intranasal administration | |
| EP1061802B1 (en) | Topical carbamazepine formulations and methods of use | |
| Robertson et al. | Intravitreal injection of octreotide acetate | |
| Tengamnuay | Nasal absorption of selected amino acids and peptides in rats |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry | ||
| MKEX | Expiry |
Effective date: 20041020 |