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WO1997017992A1 - Formulation amelioree pour l'administration de composes steroidiens - Google Patents

Formulation amelioree pour l'administration de composes steroidiens Download PDF

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Publication number
WO1997017992A1
WO1997017992A1 PCT/US1996/018189 US9618189W WO9717992A1 WO 1997017992 A1 WO1997017992 A1 WO 1997017992A1 US 9618189 W US9618189 W US 9618189W WO 9717992 A1 WO9717992 A1 WO 9717992A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
composition
steroids
dhea
steroid
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.)
Ceased
Application number
PCT/US1996/018189
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English (en)
Inventor
Joseph Rubinfeld
Julius A. Vida
H. Leon Bradlow
Elliott L. Fineman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astex Pharmaceuticals Inc
Original Assignee
Supergen Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/744,979 external-priority patent/US5824668A/en
Application filed by Supergen Inc filed Critical Supergen Inc
Priority to CA002237023A priority Critical patent/CA2237023C/fr
Priority to EP96942747A priority patent/EP0866722A1/fr
Priority to AU11587/97A priority patent/AU718232B2/en
Priority to JP51903597A priority patent/JP2002507960A/ja
Priority to HU9902286A priority patent/HUP9902286A3/hu
Publication of WO1997017992A1 publication Critical patent/WO1997017992A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to improved formulations for the administration of certain steroid and steroid related compounds, which renders them more effective and which also facilitates parenteral administration of these compounds
  • Steroid compounds are powerful drug substances generally well known in biology, medicine and pharmaceutical sciences These compounds effect a number of important physiological functions in mammals and in human beings in particular
  • Formulations have been proposed in the past to improve the availability of water-insoluble compounds in dosage forms that may be administered parenterally, either intravenously, intra peritoneally, intrathecally or intramuscularly Of these routes, the first three are the most desirable since the highest concentration of the compound is achieved in the shortest time
  • Liposomes small envelopes of fat-like compounds containing an aqueous chamber or chambers within, have been proposed for the parenteral administration of a number of water- insoluble compounds
  • the water insoluble compound is dissolved in the fat-like compound comprising the envelope of the liposome Liposomes, however, have the disadvantage of being preferentially removed from the circulation and retained in the liver and spleen Therefore, unless it is proposed to target the water-insoluble therapeutic compound to these organs, liposomes are not desirable Liposomes also have a number of other disadvantages, including instability when stored for long and short periods of time Change in the size of the liposome on storage is also a major problem
  • Shimazu et al 4,352,793 discloses that a formulation wherein bencyclane fumarate an anti- convulsive compound and ⁇ -cyclodextrin or ⁇ -cyclodextrin yields a complex in which the bencyclane fumarate is an inclusion compound
  • These complexes when formulated as a liquid suitable for oral administration were claimed to be less irritating in an isotonic buffered pH 7 solution when administered as drops to the eyes of rabbits, as compared to bencyclane fumarate drops at the same drug concentration Shimazu et al , also discloses that similar complexes dissolved in rabbit blood in vitro yielded reduced hemolysis as compared to equal concentrations of bencyclane fumarate alone mixed with rabbit blood
  • Ueka a et al , 4,565,807 discloses complexes of -, ⁇ - and ⁇ - cyclodextrin , piprofen and a pharmaceutically acceptable base
  • Piprofen is an analgesic and anti-inflammatory compound which is bitter and can cause irritation to the gastrointestinal tract
  • the complexes disclosed in the patent have improved less bitter taste and are less gastrointestinal irritating than the un-complexed compound piprofen
  • No preparations suitable for intravenous injection were disclosed
  • Lipari 4,383,992 discloses topical and ophthalmic solutions comprising a number of different steroid-related compounds including corticosteroids, androgens, anabolic steroids, estrogens, and progestagens complexed with ⁇ cyclodextrin None of the cyclodextrin compounds disclosed by Lipari are substituted or amorphous cyclodextrins In addition, none or the steroid related compounds disclosed by Lipari are 5 ⁇ steroids
  • the Bodor references attribute the precipitation and organ deposition problems associated with parenteral administration of lipophilic drugs to the effects of organic solvents used to solubilized the drug in the parenteral vehicle
  • the Bodor references additionally state that drugs which are particularly useful in the parenteral composition and methods disclosed therein are those which are relatively insoluble in water but whose water solubility can be substantially improved by formulation with 20 to 50% ofthe selected cyclodextrin, e.g , HPCD, in water
  • the selected cyclodextrin e.g , HPCD
  • U S Patent 5,006,517 to Bradlow, et al discloses that Prader-Willi Syndrome a congenital disease caused by a chromosomal defect may be treated by administering etiocholanolone or etiocholanolondione to individuals suffering from the syndrome resulting in either weight loss or a decrease in the rate of weight gain in the treated individuals
  • the compounds While several ofthe 5 ⁇ steroids are known to be active in control of obesity and associated diabetic and/or hyper cortical syndrome, the compounds are effective for treatment of these conditions when they are administered orally By the oral route, the absorption of the 5 ⁇ steroids is only 5 to 15% as measured by blood levels using various assays Thus a large portion of the administered drug is never absorbed into the blood stream and the greatest part ofthe drug that is administered is eliminated in the feces
  • 5 ⁇ steroids do not appear to exert any of their anti-obesity, anti-diabetic or anti-hypercortical activities when administered intramuscularly (im). Furthermore the im route of administration engenders pyrogenic reactions with some of the 5 ⁇ steroids as described above in Kappas et al. Thus, it would be desirable to have a formulation that would allow parenteral administration of the 5 ⁇ steroids, preferably by the intravenous (iv) route and which would preserve the anti-obesity, anti-diabetic and anti-hypercortical activities of these compounds.
  • a further long-felt need in the administration of these 5 ⁇ steroid drugs is to obtain a high serum concentration of the drug without resorting to the intramuscular (im) route of administration which causes local irritation and, at least in the case of ⁇ -ET pyrogenic reaction and notable patient discomfort
  • im intramuscular
  • the steroid dehydroepiandrosterone (3- ⁇ -hydroxy-androst-5-en-17-one, DHEA) and its sulfate derivatives are major steroid adrenal secretory products in humans DHEA is metabolized to testosterone (17- ⁇ -hydroxy-androst-4-en-3-one) and estradiol (estra-1, 3,5 ( 10)-triene-3, 17-diol), two major sex hormones in humans.
  • DHEA DHEA
  • ⁇ ET is a major metabolite of DHEA, and in normal individuals, is excreted in the urine in amounts of about 3-5 mg per day, whereas ⁇ ET is a minor metabolite in man
  • DHEA has been shown to be effective in controlling diabetes and obesity in rats and mice by Coleman, however in human usage for a number of different inflammatory conditions including the treatment ol ' Lupus Erythematosus, DHEA has demonstrated a number of undesirable side effects In particular, in female patients, who are the most frequent sufferers of lupus erythematosus, DHEA causes severe acne and may also cause masculinizing effects, particularly hirsutism, the production of facial and body hair
  • One of the advantages that may be obtained through the present invention is to reduce the amount of DHEA administered to a patient when administered in an iv formulation
  • the administration of DHEA by the iv route is advantageous in itself in that the circulating concentrations ofthe drug can be precisely monitored
  • the amount of DHEA absorbed through the alimentary tract and reaching the blood stream may vary substantially depending upon the amount if food and liquid the subject has consumed
  • the abso ⁇ tion of a drug from this area ofthe body may vary considerably if orally administered
  • iv administration may be particularly important for DHEA
  • Another object of the invention is to provide methods for treating a subject for a condition which responds to treatment with the 5 ⁇ steroids by administering to the subject an improved formulation ofthe 5 ⁇ steroids suitable for parenteral administration
  • these conditions may be obesity, diabetes syndrome, diabetes-associated hypercorticoidism or combinations thereof, anemic disorders including but not limited to aplastic anemia and anemia associated with renal failure or chemotherapy-induced or radiation-induced anemia or neutropenia, autoimmune or inflammatory disorders such as lupus erythematosus
  • Yet a still further object ofthe invention is to provide a method for treating a subject for a condition which responds to treatment with DHEA using a reduced amount of DHEA by administering to the subject at least one 5 ⁇ steroid and a reduced amount of DHEA in a formulation including an amorphous cyclodextrin wherein the formulation is suitable for parenteral administration Among these conditions are those listed above
  • Another object ofthe invention is to provide a method of treating a subject for a condition which responds to treatment with the 5 ⁇ steroids by administering to the subject an improved formulation ofthe 5 ⁇ steroids suitable for parenteral administration which is non- pyrogenic Among these conditions are those listed above
  • 5 ⁇ steroid is meant ⁇ ET, ⁇ ET, and ED
  • alkylated derivatives of these 5 ⁇ steroids are also included in this definition
  • 16- alkylated 5 ⁇ androstan-3-ol-17-one and 16-alkylated 5 ⁇ androstan-3, 7-diol-17-one which are disclosed in U S Patent 4,602,008, herein incorporated by reference, have been shown to be biologically effective as anti-diabetic, anti-obesity and erythropoietic agents in mammals
  • These compounds may be esterified at the 3 or 7 positions of the steroid ring structure by conventional means
  • 5- ⁇ -androstane -3, 17-diol or etiocholandiol herein after Ediol
  • ⁇ ET, ⁇ ET, Ediol and ED are all commercially available compounds (Research Plus Inc, POB 324 Bayonne, New Jersey 07002 USA)
  • diols ofthe 17 keto 5- ⁇ steroids are commercially available and may be used in the invention and may be esterified at the carbon at which the -OH moiety is attached
  • 5 ⁇ - androstan-3 ⁇ , 1 l ⁇ -diol-17-one, 5 ⁇ - androstan-3 ⁇ , 1 l ⁇ -diol-17-one, and 5 ⁇ - androstan-3 ⁇ , 1 l ⁇ -diol-17-one, 5 ⁇ -androstane-l l ⁇ -ol-3, 17-dione, 5 ⁇ -androstane -l l ⁇ -ol-3, 17-dione, 5 ⁇ -androstane -3 ⁇ , 16 ⁇ -diol-17-one are commercially available (Research Plus Inc, POB 324 Bayonne, New Jersey 07002 USA) and may be esterified at the 1 1 or 16 positions, as the case may be, by conventional means to produce the organic acid derivative of the 5 ⁇ steroids
  • cyclodextrin is meant ⁇ -, ⁇ -, or ⁇ - cyclodextrin Cyclodextrins are described in detail in Pitha et al , U S Patent 4,727,064 which is incorporated herein by reference Cyclodextrins are cyclic oligomers of glucose, these compounds form inclusion complexes with any drug whose molecule can fit into the lipophile-seeking cavities ofthe cyclodextrin molecule
  • cyclodextrin non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from ⁇ -, ⁇ -, or ⁇ - cyclodextrin
  • the amorphous cyclodextrin is prepared by non-selective additions, especially alkylation of the desired cyclodextrin species Reactions are carried out to yield mixtures containing a plurality of components thereby preventing crystallization of the cyclodextrin
  • various alkylated and hydroxyalkyl-cyclodextrins can be made and of course will vary, depending upon the starting species of cyclodextrin and the addition agent used
  • the amorphous cyclodextrins suitable for compositions according to the invention are hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -cyclodextrin, carboxyamidomethyl- ⁇ - cyclo
  • the cyclodextrin of the compositions according to the invention may be ⁇ -, ⁇ -, or ⁇ - cyclodextrin ⁇ -cyclodextrin contains six glucopyranose units, ⁇ -cyclodextrin contains seven glucopyranose units, and ⁇ -cyclodextrin contains eight glucopyranose units
  • the molecule is believed to form a truncated cone having a core opening of 4 7-5 3 A, 6 0-6 5
  • composition according to the invention may comprise a mixture of two or more of the ⁇ -, ⁇ -, c r ⁇ - cyclodextrins Usually, however the composition according to the invention will com jrise only one ofthe ⁇ -, ⁇ -, or ⁇ - cyclodextrins
  • the particular ⁇ -, ⁇ -, or ⁇ - cyclodextrir to be used with the particular 5 ⁇ steroid compound to form the compositions according to the invention may be selected based on the known size of the molecule of the 5 ⁇ steroid compound and the relative size of the cavity of the cyclodextrin compound Generally if the molecule of the 5 ⁇ steroid compound is relatively large, a cyclodextrin having a larger cavity is used to make the composition according to the invention Furthermore, if the 5 ⁇ steroid compound is administered with an excipient it may be desirable to use
  • the unmodified ⁇ -, ⁇ -, or ⁇ - cyclodextrins are less preferred in the compositions according to the invention because the unmodified forms tend to crystallize and are relatively less soluble in aqueous solutions More preferred for the compositions according to the invention are the ⁇ -, ⁇ -, and ⁇ - cyclodextrins that are chemically modified or substituted Chemical substitution at the 2,3 and 6 hydroxyl groups of the glucopyranose units of the cyclodextrin rings yields increases in solubility of the cyclodextrin compound
  • cyclodextrins in the compositions according to the invention are amorphous cyclodextrin compounds
  • amorphous cyclodextrin is meant non-crystalline mixtures of cyclodextrins wherein the mixture is prepared from ⁇ -, ⁇ -, or ⁇ - cyclodextrin
  • Suitable alkylation agents for this purpose include but are not limited to propylene oxide, glycidol, iodoacetamide, chloroacetate, and 2- diethylaminoethlychloride Reactions are carried out to yield mixtures containing a plurality of components thereby preventing crystallization of the cyclodextrin various alkylated cyclodextrins can be made and of course will vary, depending upon the starting species of cyclodextrin and the alkylating agent used
  • alkylated cyclodextrin having a larger cavity when the composition according to the invention also includes an excipient
  • the use of a particular ⁇ -, ⁇ -, or ⁇ - cyclodextrin with a particular 5 ⁇ steroid compound or 5 ⁇ steroid compound and excipient in the compositions according to the invention may of course be optimized based on the effectiveness in of maintaining the 5 ⁇ steroid or mixture there of with or without DHEA in solution
  • compositions of matter of the invention comprise an aqueous preparation of preferably substituted amorphous cyclodextrin and one or more 5 ⁇ steroids
  • the relative amounts of 5 ⁇ steroid compound and cyclodextrin will vary depending upon the relative amount of each o the 5 ⁇ steroid compounds and the effect o the cyclodextrin on the compound
  • the ratio of the weight of 5 ⁇ steroid compound to the weight of cyclodextrin compound will be in a range between 1 1 and 1 5000 Within this range, the circulating availability ofthe 5 ⁇ steroid will be significantly increased when the ratio of the weight of 5 ⁇ steroid to the weight of cyclodextrin compound is in a range between the concentration at which the 5 ⁇ steroid will not go into solution at the particular amorphous cyclodextrin concentration and 1 2000
  • ⁇ ET, ⁇ ET, ED, Ediol or DHEA each individually or in a mixture of two or more may be added to the cyclodextrin solution to form a complex of each compound individually or in a mixture of two or more of these compounds
  • the aqueous solution comprising the DHEA and /or 5 ⁇ steroid and amorphous cyclodextrin will be substantially free of pyrogenic contaminants
  • Amorphous hydroxypropyl- ⁇ -cyclodextrin maybe purchased from a number of vendors including Amaizo, Inc (Hammond Indiana, USA) under the tradename Encapsin
  • other forms of amo ⁇ hous cyclodextrin having different degrees of substitution or glucose residue number are available commercially
  • a method for the production of hydroxypropyl- ⁇ - cyclodextrin is disclosed in Pitha et d/ , U S Patent No 4, 727,064 which is incorporated herein by reference
  • a pre-weighed amount of hydroxypropyl- ⁇ -cyclodextrin compound, which is substantially pyrogen free is placed in a suitable depyrogenated sterile container.
  • depyrogenation is accomplished by exposing the objects to be depyrogenated to temperatures above 400°C for a period of time sufficient to fully incinerate any organic matter
  • the formulation will contain no more than 10 Bacterial Endotoxin Units per gram of amorphous cyclodextrin
  • substantially pyrogen free is meant that the hydroxypropyl- ⁇ -cyclodextrin contains less than 10 U S P bacterial endotoxin units per gram using the U S P method
  • the hydroxypropyl- ⁇ -cyclodextrin contains less than 10 U S P bacterial endotoxin units per gram using the U S P method
  • the hydroxypropyl- ⁇ -cyclodextrin contains less than 10 U S P bacterial endotoxin units per gram using the U S P method
  • sterile water for injection is added to the substantially pyrogen free amorphous cyclodextrin until the desired concentration of hydroxypropyl- ⁇ -cyclodextrin is in solution
  • a pre-weighed amount of the 5 ⁇ steroid is added with agitation and with additional standing if necessary until it dissolves
  • the solution is then filtered through a sterile 0 2 micron filter into a sterile holding vessel and is subsequently filled in sterile depyrogenated vials and is capped
  • a pharmaceutically acceptable preservative may be added to the solution of 5 ⁇ steroid and hydroxypropyl- ⁇ -cyclodextrin prior to filtration, filling and capping or alternatively, may be added sterilely after filtration
  • DHEA alone or together with one or more ofthe 5 ⁇ steroids may be used
  • the formulation including DHEA and ED or DHEA and ⁇ ET and ⁇ ET or DHEA, ED, ⁇ ET and ⁇ ET are desirable This is particularly desirable in relation to obesity control and inflammatory disease control
  • DHEA is metabolically transformed into the primary male and female sex steroid hormones, testosterone and estradiol respectively, and is ultimately metabolized to ⁇ ET and ⁇ ET
  • DHEA is metabolically transformed into the primary male and female sex steroid hormones, testosterone and estradiol respectively, and is ultimately metabolized to ⁇ ET and ⁇ ET
  • ⁇ ET and ⁇ ET By reducing the amount of DHEA to an amount which contributes in only a small way to the production of the sex steroids testosterone and estradiol, while at the same time maximizing the amount of ⁇ ET and ⁇ ET circulating in the blood from the initial dose administered to a subject, it is believed that enhancement ofthe desirable obesity control,
  • a 50% solution of hydroxypropyl- ⁇ -cyclodextrin was prepared as follows 5 grams of pyrogen free hydroxypropyl- ⁇ -cyclodextrin (sold under the trade name Encapsin, Amaizo,
  • Example V The same experiment as in Example V was performed except 80 g or 250mg ED was added to the stock solution In neither case did the ED completely dissolve
  • the optical density (OD) of the ET and ED dissolved in hydroxypropyl- ⁇ -cyclodextrin solutions was determined at 400 NM against a blank control containing water and set at an OD of 0.0
  • the dissolved solutions of ET and ED had OD readings of 0.12 whereas the hydroxypropyl- ⁇ -cyclodextrin solution containing 80mg of ED gave an OD of 1 2 at 499 NM
  • Example III the stock solution of hydroxypropyl- ⁇ -cyclodextrin is prepared as in Example III 15 mg of ⁇ ET, 15 mg ⁇ ET and 15 mg of ED will be added to 1 ml ofthe solution with agitation A clear aqueous solution containing 45 mg ofthe three 5 ⁇ steriods and no precipitate will be present after standing for 24 hours
  • Example III the stock solution of hydroxypropyl- ⁇ -cyclodextrin is prepared as in Example III 10 mg of ⁇ ET, 10 mg ⁇ ET, 1 mg of ED and 15 mg of DHEA will be added to 1 ml of the solution with agitation A clear aqueous solution containing 45 mg of the DHEA and the three 5 ⁇ steriods and no precipitate is present after standing for 24 hours
  • composition of mattei according to the invention may be supplied as a dry powder or as a solution If the composition of matter is to be injected into a subject it will be rendered sterile prior to injection Accordingly, the composition of matter according to the invention may be supplied as a sterile cake, plug or powder or as a sterile lyophilized preparation in a sterile vial suitable for the addition of a sterile diluent, or as a sterile liquid solution in a sterile container
  • compositions of matter according to the invention may by supplied as a powder comprising the active pharmaceutical 5 ⁇ steroid compound or compounds and amorphous cyclodextrin compound If the composition is to be administered parenterally, for example iv, the composition of matter will be rendered sterile prior to such administration Any of the several known means for rendering such pharmaceutical preparations sterile may be used so long as the active pharmaceutical compound is not inactivated and the complex with the amorphous cyclodextrin is not degraded If the active pharmaceutical compound is heat stable, the composition of matter according to the invention may be heat sterilized If the cytotoxic compound is not heat-stable but is not photo degraded the composition may be sterilized by exposure to ultraviolet light or by ionizing radiation Alternatively, the composition of matter if in a powder form may be gas sterilized using for example ethylene oxide gas In another alternative, the composition of matter according to the invention may be filter-sterilized using a 0 2 micron filter If the composition of matter is an aqueous liquid, it
  • compositions of matter according to the invention will be made by dissolving the cyclodextrin in water and adding the ⁇ steroid compound to the aqueous cyclodextrin solution Excipients, if any are desired. may be added with or subsequent to adding the 5 ⁇ steroid compound The resulting solution may be sterilized using any of the known methods appropriate to preserving the compound without significant degradation
  • the solution will be sterile filtered, although other means such as terminal heat sterilization or irradiation may be employed as is known in the art, provided that the cyclodextrin compound is not significantly degraded
  • the components may be sterilized by any of the known methods appropriate to preserving the compound prior to mixing in water and may be mixed using sterile equipment and technique
  • the solution may be lyophilized in sterile containers and capped Prior to use the lyophilized composition of matter may be reconstituted using sterile water for injection
  • compositions of matter according to the invention for parenteral administration will be non- pyrogenic Nonpyrogenic preparations according to the invention, when administered to a subject, does not cause a febrile (basal body temperature raising) reaction Although some bacterial endotoxin may be present, the amount is insufficient to elicit a febrile reaction In general, such non-pyrogenic compositions will contain less than 10 S P bacterial endotoxin units per gram of product
  • the formulation according to the invention may be supplied as a dry lyophilized powder as mentioned above or as a sterile non pyrogenic aqueous solution in a sterile container closure system such as a stoppered vial suitable for puncturing with a sterile syringe and needle
  • the formulation according to the invention may be supplied as a sterile non pyrogenic aqueous solution in a sterile syringe or syringe and needle
  • a sterile solution or powder it may also include a pharmaceutically acceptable preservative
  • the formulation according to the invention may also be included in other dosage forms in addition to those appropriate for parenteral administration
  • such other dosage forms will include one or more of the 5 ⁇ steroids with or without DHEA
  • Such dosage forms may be in the form of aqueous suspensions, elixirs, or syrups suitable for oral administration, or compounded as a cream or ointment in a pharmaceutically acceptable topical base allowing the 5 ⁇ steroid compounds with or without DHEA to be absorbed across the skin
  • the formulation according to the invention may be compounded in a lozenge or suppository suitable for trans mucosal absorption
  • the formulations according to the invention having been described herein may influence the ordinarily skilled artesian to make simila

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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Nanotechnology (AREA)
  • Obesity (AREA)
  • Biophysics (AREA)
  • Medical Informatics (AREA)
  • Inorganic Chemistry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Emergency Medicine (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne des formulations cyclodextriniques pour l'administration de 5 β stéroïdes dont α étiocholonolone, β étiocholonolone et étiocholandione. Elle porte également sur des formulations cyclodextriniques comprenant au moins un des 5 β stéroïdes et de la déshydroépiandostérone (DHEA). Lesdites formulations conviennent à l'administration parentérale, en particulier l'administration par voie intraveineuse et également au traitement d'un état qui répond au traitement aux 5 β stéroïdes seuls ou conjointement avec DHEA, en particulier lorsque l'on désire réduire la quantité de DHEA administrée. Ces états comprennent l'obésité, le syndrome diabétique, l'hypercorticoïdisme associé au diabète ou leur combinaison, des troubles anémiques dont, entre autres, l'anémie aplasique et la neutropénie ou l'anémie associée à une insuffisance rénale ou induite par une chimiothérapie ou les rayons, les troubles autoimmuns ou inflammatoires tels que le lupus érythémateux.
PCT/US1996/018189 1995-11-13 1996-11-12 Formulation amelioree pour l'administration de composes steroidiens Ceased WO1997017992A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002237023A CA2237023C (fr) 1995-11-13 1996-11-12 Formulation amelioree pour l'administration de composes steroidiens
EP96942747A EP0866722A1 (fr) 1995-11-13 1996-11-12 Formulation amelioree pour l'administration de composes steroidiens
AU11587/97A AU718232B2 (en) 1995-11-13 1996-11-12 Improved formulation for administration of steroid compounds
JP51903597A JP2002507960A (ja) 1995-11-13 1996-11-12 ステロイド化合物投与のための改良された製剤
HU9902286A HUP9902286A3 (en) 1996-11-12 1996-11-12 Improved formulation for administration of steroid compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US655795P 1995-11-13 1995-11-13
US06/006,557 1995-11-13
US08/744,979 US5824668A (en) 1996-11-07 1996-11-07 Formulation for administration of steroid compounds
US08/774,979 1996-11-07

Publications (1)

Publication Number Publication Date
WO1997017992A1 true WO1997017992A1 (fr) 1997-05-22

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PCT/US1996/018189 Ceased WO1997017992A1 (fr) 1995-11-13 1996-11-12 Formulation amelioree pour l'administration de composes steroidiens

Country Status (7)

Country Link
EP (1) EP0866722A1 (fr)
JP (1) JP2002507960A (fr)
CN (1) CN1201397A (fr)
AU (1) AU718232B2 (fr)
CA (1) CA2237023C (fr)
IL (1) IL124001A (fr)
WO (1) WO1997017992A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037109A3 (fr) * 1998-12-18 2000-09-14 Euphar Group Srl Clathrates de dehydroepiandrosterone et compositions pharmaceutiques correspondantes
WO2001030802A3 (fr) * 1999-10-25 2002-02-14 Hollis Eden Pharmaceuticals Traitements therapeutiques pour des deficiences en cellules sanguines
FR2847475A1 (fr) * 2002-11-25 2004-05-28 Oreal COMPOSITION COSMETIQUE OU PHARMACEUTIQUE ASSOCIANT UN AGENT MODULATEUR DE L'EXPRESSION DE L'OXYSTEROL 7alpha-HYDROXYLASE ET UN SUBSTRAT BIOLOGIQUE DE LADITE ENZYME
US9161985B2 (en) 2010-09-21 2015-10-20 Guangzhou Cellprotek Pharmaceutical Ltd. 5α-androstane (alkyl)-3β, 5, 6β-triol injection and preparation method therefor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103330946B (zh) * 2013-05-29 2015-03-25 广州市赛普特医药科技有限公司 5α-雄甾-3β,5,6β-三醇注射剂其制备方法
CN105078954A (zh) * 2015-08-20 2015-11-25 南京华宽信息咨询中心 一种治疗急性肾衰药物及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4507289A (en) * 1983-12-28 1985-03-26 Progenics, Inc. Treatment of diabetes and other symptoms of hypercorticoidism using a synergistic combination of etiocholanolones and estrogen
EP0149220A2 (fr) * 1983-12-28 1985-07-24 The Jackson Laboratory Etiocholananes pour le traitement de l'obésité, du diabète et d'autres symptômes d'hypercorticoidisme
EP0261891A2 (fr) * 1986-09-22 1988-03-30 Progenics, Inc. Compositions pharmaceutiques contenant de l'étiochiolandione
EP0477107A1 (fr) * 1990-09-21 1992-03-25 Laboratoires BESINS ISCOVESCO Société anonyme dite : Stéroides inclus dans des cyclodextrines
WO1992004888A1 (fr) * 1990-09-20 1992-04-02 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Preparation de complexes lipophiles : hydroxypropylcyclodextrinesselon un procede utilisant des agents de cosolubilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4507289A (en) * 1983-12-28 1985-03-26 Progenics, Inc. Treatment of diabetes and other symptoms of hypercorticoidism using a synergistic combination of etiocholanolones and estrogen
EP0149220A2 (fr) * 1983-12-28 1985-07-24 The Jackson Laboratory Etiocholananes pour le traitement de l'obésité, du diabète et d'autres symptômes d'hypercorticoidisme
EP0261891A2 (fr) * 1986-09-22 1988-03-30 Progenics, Inc. Compositions pharmaceutiques contenant de l'étiochiolandione
WO1992004888A1 (fr) * 1990-09-20 1992-04-02 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce Preparation de complexes lipophiles : hydroxypropylcyclodextrinesselon un procede utilisant des agents de cosolubilisation
EP0477107A1 (fr) * 1990-09-21 1992-03-25 Laboratoires BESINS ISCOVESCO Société anonyme dite : Stéroides inclus dans des cyclodextrines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BREWSTER M E ET AL: "PREPARATION, CHARACTERIZAITON, AND ANESTHETIC PROPERTIES OF 2-HYDROXYPROPYL-B-CYCLODEXTRIN COMPLEXES OF PREGNANOLONE AND PREGNENOLONE IN RAT AND MOUSE", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 84, no. 10, 1 October 1995 (1995-10-01), pages 1154 - 1159, XP000529726 *
SHIMADA K. ET AL: "Studies on neurosteroids. I. retenetion behavior of derivatized 17-oxosteroids using high performance liquid chromatography", J. OF LIQUID CHROMATOGRAPHY, vol. 18, no. 4, 13 February 1995 (1995-02-13), NEW YORK, pages 713 - 723, XP000646352 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037109A3 (fr) * 1998-12-18 2000-09-14 Euphar Group Srl Clathrates de dehydroepiandrosterone et compositions pharmaceutiques correspondantes
JP2002532565A (ja) * 1998-12-18 2002-10-02 ユーファル グループ ソシエタ ア レスポンサビリタ リミタータ デヒドロエピアンドロステロンの包接化合物及び対応する薬学的組成物
EA003304B1 (ru) * 1998-12-18 2003-04-24 Эуфар Груп С.Р.Л. Клатраты дегидроэпиандростерона и соответствующие фармацевтические композиции
WO2001030802A3 (fr) * 1999-10-25 2002-02-14 Hollis Eden Pharmaceuticals Traitements therapeutiques pour des deficiences en cellules sanguines
JP2003512474A (ja) * 1999-10-25 2003-04-02 ホリス − イーデン ファーマスーティカルズ、 インコーポレイテッド 血液細胞欠乏症の治療処置
AU782736B2 (en) * 1999-10-25 2005-08-25 Harbor Biosciences, Inc. Therapeutic treatments for blood cell deficiencies
FR2847475A1 (fr) * 2002-11-25 2004-05-28 Oreal COMPOSITION COSMETIQUE OU PHARMACEUTIQUE ASSOCIANT UN AGENT MODULATEUR DE L'EXPRESSION DE L'OXYSTEROL 7alpha-HYDROXYLASE ET UN SUBSTRAT BIOLOGIQUE DE LADITE ENZYME
US9161985B2 (en) 2010-09-21 2015-10-20 Guangzhou Cellprotek Pharmaceutical Ltd. 5α-androstane (alkyl)-3β, 5, 6β-triol injection and preparation method therefor
US9265837B1 (en) 2010-09-21 2016-02-23 Guangzhou Cellprotek Pharmaceuticals Ltd. 5α-androstane-3β,5,6β-triol injection and preparation method therefor
EP2620153A4 (fr) * 2010-09-21 2016-07-13 Guangzhou Cellprotek Pharmaceutical Ltd Injection de 5 alpha-androstane-(alkyl)-3 beta,5,6 beta-triol et son procédé de préparation

Also Published As

Publication number Publication date
IL124001A (en) 2004-07-25
AU1158797A (en) 1997-06-05
EP0866722A1 (fr) 1998-09-30
CA2237023A1 (fr) 1997-05-22
AU718232B2 (en) 2000-04-13
JP2002507960A (ja) 2002-03-12
CA2237023C (fr) 2008-02-19
CN1201397A (zh) 1998-12-09

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