WO2003068314A1 - Administration pulmonaire de derives de testosterone 6-alpha-alkyle comme forme de therapie antiandrogene - Google Patents

Administration pulmonaire de derives de testosterone 6-alpha-alkyle comme forme de therapie antiandrogene Download PDF

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Publication number
WO2003068314A1
WO2003068314A1 PCT/NL2003/000111 NL0300111W WO03068314A1 WO 2003068314 A1 WO2003068314 A1 WO 2003068314A1 NL 0300111 W NL0300111 W NL 0300111W WO 03068314 A1 WO03068314 A1 WO 03068314A1
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alkyl
androgen
administration
treating
use according
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Herman Jan Tijmen Coelingh Bennink
René Frank VAN DER LINDEN
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Pantarhei Bioscience BV
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Pantarhei Bioscience BV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens

Definitions

  • the present invention relates to a method of treating hypogonadal males, more particularly to a method of treating or preventing androgen deficiency in male mammals.
  • the method according to the invention is characterised in that it employs pulmonary administration of 6 ⁇ -alkyl- and/or 7 ⁇ -alkyl-androgens to effectively suppress symptoms of androgen deficiency.
  • Another aspect of the invention is concerned with a pulmonary drug delivery composition based on biodegradable microparticles, said microparticles containing 6 ⁇ -alkyl and/or 7 ⁇ -alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs.
  • ADAM aging males
  • Adverse hepatic effects associated with prolonged use of these androgens include cholestasis, peliosis hepatis (blood-filled hepatic cysts), hepatocellular hyperplasia, hepatic adenomas, and hepatocellular carcinoma.
  • oral administration is rather unreliable in that the effective dosage is significantly influenced by the efficiency of intestinal uptake and/or metabolisation in the liver, both of which are largely dependent on an individual's physiology and even his/her diet.
  • androgen is usually applied in relatively high dosages in order to ensure that the minimum effective dosage is achieved in each individual.
  • high dosages have the disadvantage that they lead to relative overdosing in some individuals, which in turn is likely to produce pronounced side effects.
  • parenteral administration is a feasible alternative for oral administration.
  • this mode of administration has the disadvantage that it becomes quite burdensome in case of prolonged therapies.
  • Intramuscular or subcutaneous injection can be painful and self-administration of an injectable composition typically suffers from low user acceptance.
  • depot injections or implants are sometimes used to partly overcome this disadvantage.
  • both depot injections and implants suffer from the drawback that release of the active androgen is uneven, i.e. initially there is a much higher increase in serum androgen level than is required and indeed desirable.
  • Another disadvantage associated with (depot) injections resides in the fact that it is not possible to retrieve the injected drug from the body, e.g. in case an allergic reaction occurs or prostate cancer is diagnosed.
  • transdermal administration of testerone by means of patches.
  • the transdermal testosterone delivery systems provide adequate testosterone replacement for hypogonadal men.
  • An obvious inconvenience of these testosterone patches is the need to remove the old patch and to apply a new one each night. Skin irritation at the application site occurs frequently.
  • a study has shown that approximately 50% of men who participated in clinical trials reported transient, mild to moderate erythema at the application site during therapy, and burn-like blister reactions occurred in 12% of men during the clinical trials.
  • US 5,855,905 (Oettel et al.) describes a method of treating hypogonadism or hypophyseal disease in a man comprising administering a pharmaceutical preparation containing an androgen and an estrogen.
  • these preparations can be presentations for oral application such as tablets, capsules and lozenges, presentations for percutaneous application such as transdermal therapeutic systems (TTS) or gels, sprays or ointments, preparations for intranasal applications such as nasal sprays or nose drops, preparations for rectal application such as suppositories, and parenterals such as implants or compacts and ampules.
  • TTS transdermal therapeutic systems
  • parenterals such as implants or compacts and ampules.
  • a preparation containing 125 mg dihydrotestosterone(DHT) and 1 mg estradiol in the form of a spray is mentioned.
  • pulmonary administration offers several advantages over known methods of androgen administration, particularly oral and intramuscular administration. Firstly, pulmonary delivery is highly effective, i.e. a large fraction of the alkyl-androgen that is inhaled is indeed absorbed. Secondly, pulmonary administration is a very convenient and user-friendly method, as is demonstrated by the widespread use of pulmonary administration of several agents (i.e. anti-inflammatory, bronchodilatation) used in asthma therapy. Thirdly, pulmonary administration, unlike oral administration, has minimum impact on liver metabolism since only a minor fraction of the administered alkyl-androgen will pass through the liver.
  • agents i.e. anti-inflammatory, bronchodilatation
  • the present invention also facilitates the utilisation of androgens in the treatment or prevention of a variety of disorders and diseases such as: wasting syndrome, anti-retroviral drug induced lipodystrophia, lack of well- being or fatigue in HIV infected individuals; catabolic state; leydig cell dysfunction and germinal epithelial damage following cytotoxic chemotherapy; fatigue; reduction in hemoglobine or neutrophil count during or subsequent to cytotoxic chemotherapy or radiotherapy; benign gynaecological disorders; delayed puberty or in a method of weight maintenance.
  • disorders and diseases such as: wasting syndrome, anti-retroviral drug induced lipodystrophia, lack of well- being or fatigue in HIV infected individuals; catabolic state; leydig cell dysfunction and germinal epithelial damage following cytotoxic chemotherapy; fatigue; reduction in hemoglobine or neutrophil count during or subsequent to cytotoxic chemotherapy or radiotherapy; benign gynaecological disorders; delayed puberty or in a method of weight maintenance.
  • ⁇ -alkyl and 7 ⁇ -alkyl-androgens are relatively potent androgens which are metabolised in vivo into estrogen, but unlike testosterone and testosterone esters cannot be metabolised by 5 ⁇ -reductase into DHT. These properties make said alkyl-androgens particularly suitable for pulmonary administration to androgen deficient males.
  • the relatively low amount of alkyl-androgen that is required in androgen therapy or androgen supplementation makes it possible to employ relatively small pulmonary dosages, thereby eliminating the need for repeated administrations.
  • the partial in vivo metabolisation of the alkyl-androgen(s) into estrogen is advantageous in androgen deficient males because androgen deficiency is normally accompanied by estrogen deficiency.
  • Estrogens in males are known to have an important effect on bone (help to prevent osteoporosis resulting from estrogen deficiency), spermatogenesis, as well as on carbohydrate and lipid metabolism.
  • the fact that these alkyl-androgens are not metabolised into DHT is also beneficial because DHT has been associated with benign prostate hypertrophy and prostate cancer.
  • the present invention also offers the advantage that it provides a convenient way of administering alkyl-androgen. The only convenient method which has been practised on some scale for androgens, i.e. oral administration, is not effective for 6 ⁇ -alkyl or 7 ⁇ -alkyl- androgens, since said androgens are not bioavailable orally.
  • the present invention enables a method of treating androgen deficiency in male mammals that is both convenient and effective and that uses an androgen, i.e. a ⁇ -alkyl or 7 ⁇ -alkyl-androgen, that is particularly suited for such treatment.
  • an androgen i.e. a ⁇ -alkyl or 7 ⁇ -alkyl-androgen
  • the present invention is concerned with a method of treating or preventing androgen deficiency in male mammals, wherein the method comprises pulmonary administration of 6 ⁇ -alkyl and/or 7 ⁇ -alkyl-androgen to a male suffering from androgen deficiency in a therapeutically effective amount to reduce or prevent symptoms of androgen deficiency.
  • ⁇ -alkyl-androgen and 7 ⁇ -alkyl-androgen as used throughout this document encompass androgens comprising an alkyl-substituent on the 6a.- or 7 ⁇ -position as well as precursors thereof that are capable of liberating such an alkyl-androgen in vivo when used in accordance with the present invention.
  • the alkyl radical is a C 1 -C 4 alkyl. More preferably the alkyl radical is methyl or ethyl. Most preferably the alkyl radical is methyl.
  • Pronounced symptoms of androgen deficiency are found particularly in chemically castrated and orchiectomised males. A significantly less dramatic form of androgen deficiency is observed in ageing males. Furthermore, androgen deficiency maybe caused by a disease or a disorder, e.g. AIDS or wasting (cachexia).
  • ADAM Androgen deficiency in ageing males
  • ADAM is diagnosed if a yes answer is obtained to questions 1, 7 or any three other questions.
  • androgen deficiency has been associated with loss of bone mass, along the lines of osteoporosis, ischaemic heart disease, obesity and reduced haemoglobin levels.
  • the present method is particularly effective when used to treat or prevent androgen deficiency in ageing males, and in particular when it is used to treat androgen deficiency in ageing males exhibiting symptoms of androgen deficiency. Since symptoms of ADAM usually do not become apparent until males have reached the age of about 45, the present method is particularly suitable for treating males at an age of least 45, preferably at an age of at least 50.
  • Another aspect of the invention relates to a method of treating or preventing wasting syndrome; a method of treating or preventing anti-retroviral drug induced lipodystrophia, lack of well-being or fatigue in HIV infected individuals; a method of treating or preventing catabolic state caused by a chronic illness, surgical intervention, oncological condition, trauma and/or malnutrition; a method of treating or preventing leydig cell dysfunction and germinal epithelial damage following cytotoxic chemotherapy; a method of treating or preventing fatigue or maintaining weight, a method of maintaining hemoglobine or neurrophil count during or subsequent to cytotoxic chemotherapy or radiotherapy; a method of treating or preventing benign gynaecological disorders; or a method of treating or preventing delayed puberty, wherein the method comprises pulmonary administration of an effective amount of an alkyl-androgen selected from the group consisting of ⁇ -alkyl-androgen, 7 ⁇ -alkyl- androgen and combinations thereof.
  • alkyl-androgens which may advantageously be employed in the present method include 7 ⁇ -methyl-19-nortestosterone, 7 ⁇ -methyl-14-dehydro-19-nortestosterone, 7 ⁇ - methyltestosterone, 7 ⁇ -methyl- 11 -hydroxytestosterone, 7a, 17-dimethyltestosterone, 7 ex, 17- dimethyl-11 -hydroxytestosterone, 7 ⁇ ,17-dimethyl-19-nortestosterone, 7 ⁇ ,17-dimethyl-l 1- hydroxy-19-nortestosterone, 6 ⁇ -methyltestosterone, 6 ⁇ -methyl-19-nortestosterone, 6o:- methyl-11 -hydroxytestosterone, 6a, 17-dimethyltestosterone, 6 ⁇ ,17-dimethyl-l 1- hydroxytestosterone, 6 ⁇ ,17-dimethyl-19-nortestosterone, 6 ⁇ ,17-dimethyl-l hydroxy-19- nortestosterone.
  • Particularly preferred for use in the present method are 7 ⁇ -alkyl-androgens, especially 7 ⁇ -methyl-androgens.
  • the alkyl androgen employed in the present method is 7 ⁇ -methyl-19-nortestosterone (MENT).
  • the pulmonary drug delivery composition is typically administered in an amount of 1-500 mg, preferably of 5-250 mg. These amounts maybe administered in a single metered dose or alternatively in a few doses that are administered within a short time interval, e.g. within 10 minutes, preferably within 5 minutes.
  • the present methods suitably employ continuous pulmonary administration of the alkyl-androgen during a period of at least 60 days, preferably of at least 150 days.
  • continuous means that the alkyl-androgen is administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention.
  • the administration regimen is deemed to be continuous if the longest interval between 2 subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times as long as the average interval.
  • the present invention also encompasses the pulmonary administration of a precursor of the present alkyl-androgens.
  • These precursors are preferably selected from the group of derivatives of the present alkyl-androgens, wherein the hydrogen atom of at least one hydroxyl-group has been substituted by an acyl radical of a hydrocarbon carboxylic, sulfonic or sulfamic acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranyl; or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue.
  • Typical examples of precursors which can suitably be used in accordance with the invention are esters that can be obtained by reacting the hydroxyl group present in the alkyl-androgen-molecule with substances that contain one or more carboxyl (M 4 OOC-) groups, wherein M + represents a hydrogen or (akali)metal cation.
  • the alkyl-androgen- precursors are derivatives of a 6 ⁇ -alkyl or 7 ⁇ -alkyl-androgen, wherein the hydrogen atom of the hydroxyl group has been substituted by -CO-R, wherein R is a hydrocarbon radical comprising from 1-25 carbon atoms.
  • R is hydrogen, or an alkyl, alkenyl or aryl radical comprising from 1-20 carbon atoms.
  • a particularly preferred administration regimen comprises once daily pulmonary administration of alkyl-androgen in the morning, preferably between 5:00 a.m. and 10:00 a.m. This regimen offers the advantage that it mimics the natural plasma serum testosterone profile (circadian rhythm) as observed in non-androgen deficient males. By replicating the natural testosterone profile, the symptoms of androgen deficiency are most effectively treated.
  • the present invention also encompasses the pulmonary administration of alkyl- androgen in combination with one or more other active principles.
  • An example of an active principle that may suitably be co-administered in accordance with the present method is aromatase inhibitor (e.g. aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, YM 511, TZA-2237, CGS 16949 A, MEN 11066).
  • aromatase inhibitor e.g. aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, YM 511, TZA-2237, CGS 16949 A, MEN 11066.
  • Liquid aerosol compositions may be prepared by dissolving the alkyl-androgen in a suitable solvent (e.g. ethanol), combining it with a suitable propellant (e.g. a hydrofluoroalkane) and filling it into an aerosol container provided with a metering valve.
  • a suitable solvent e.g. ethanol
  • a suitable propellant e.g. a hydrofluoroalkane
  • a dispersing agent such as oleic acid, sorbitan trioleate, dioctyl sodium or calcium sulphoscuccinate may be incorporated.
  • the liquid aerosol composition will comprise between 0.1 and 5 wt.% of alkyl-androgen.
  • each metered dose or 'puff of aerosol contains between 0.01 and 5 mg alkyl-androgen.
  • the discharge volume of the aerosol system is typically between 5 and 250 ⁇ L.
  • alkyl-androgens may display limited stability in solvents that can be used for pulmonary administration, it is preferred to use a pulmonary alkyl-androgen containing composition in the form of dry particulates, in particular in the form of biodegradable microparticles having a number weighted average diameter of 0.5 to 10 ⁇ m, which microparticles contain alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs.
  • Examples of procedures for the preparation of aerodynamically light microparticles that may advantageously be employed in accordance with the present invention may be found in US 6,136,295, which is included herein by reference.
  • the alkyl-androgen content of the microparticles is between 1 and 50 wt.%, more preferably between 5 and 40%.
  • alkyl-androgen and carrier will normally constitute at least 50 wt.%, preferably at least 75 wt.% of the microparticles.
  • microparticles are advantageously provided in the form of a capsule containing between 5 ⁇ ,g and 100 mg of the drag delivery composition as described in this document.
  • the invention also encompasses a unit comprising two or more discrete capsules, such as a disk comprising a plurality of capsules from which the contents may be released for pulmonary administration in a sequential fashion.
  • the present method preferably comprises pulmonary administration of 6 ⁇ -alkyl- and/or 7 ⁇ -alkyl-androgen in an average daily amount of at least 0.01 mg, more preferably of a least 0.1 mg.
  • the daily administered amount of alkyl-androgen will not exceed 20 mg.
  • the administered average daily amount does not exceed 10 mg.
  • alkyl-androgen is preferably administered in an average daily amount of 0.5-10 mg, more preferably in an average daily amount of 1-8 mg.
  • alkyl-androgen is suitably administered in an average daily amount of 0.1-4 mg, more preferably in an average daily amount of 0.2-2 mg.
  • the present method is particularly advantageous when used in human males.
  • Another aspect of the invention relates to a pulmonary drug delivery composition based on biodegradable microparticles having a number weighted average diameter between 0.5 and 10 ⁇ m, said microparticles containing between 1 and 50 wt.% of 6 ⁇ -alkyl and/or 7a- alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs.
  • the present drug delivery composition is suitably administered by means of an inhaler.
  • the present invention also comprises an inhaler containing the present pulmonary drag delivery composition.
  • An inhaler suitable for administering the present pulmonary drug delivery composition typically comprises a receptacle for receiving the drug delivery composition, which receptacle contains at least two apertures, a first aperture that is designed for releasing the contents of the receptacle into the mouth and another second aperture that is designed for allowing entry of atmospheric air at the same time as the contents are released from the receptacle.
  • the receptacle may furthermore contain protruding elements that are designed to puncture, cut or tear capsules that contain a pulmonary drug delivery composition after insertion into the receptacle.
  • the device is constructed in such a way that the user's action of closing the receptacle automatically results in the puncturing, cutting or tearing of the capsule, thereby releasing the drag delivery composition contained in the capsule.
  • a further aspect of the invention relates to a capsule containing between 5g and 100 mg of the drag delivery composition as described herein before.
  • the capsule is suitably designed in such a way that it can be easily be punctured, cut or torn when used in inhalers that are well-known in the pharmaceutical art.
  • an aerosol drug delivery system comprising an aerosol delivery device and a liquid pharmaceutical composition containing between 0.1 and 5 wt.% of 6 ⁇ -alkyl and/or 7 ⁇ -alkyl-androgen and a pharmaceutically acceptable liquid carrier for administration to the lungs.
  • the aerosol drug delivery device contains a nozzle for producing the aerosols.
  • the pressure required for releasing the composition through the nozzle may be provided by a pumping system or by a propellant that is contained within the device, especially as a component of the liquid pharmaceutical composition.
  • kits of parts that comprise an inhaler in combination with the drug delivery composition based on microparticles as defined above, or alternatively an aerosol delivery device in combination with the liquid pharmaceutical composition as described above.
  • the invention is further illustrated by means of the following examples.
  • Aerodynamically light MENT-containing microparticles are prepared according to the following procedure: 2.0 g poly(D,L-lactic-co-glycolic acid) with a molar ratio of 50:50 (PLGA 50:50, Resomer RG503, B.I. Chemicals, Montvale, N.J.) and 0.50 g MENT are completely dissolved in 100 mL dichloromethane at room temperature. The mixture is subsequently spray-dried through a 0.5 mm nozzle at a flow rate of 5 mL/min using a Buchi laboratory spray-drier (model 190, Buchi, Germany). The flow rate of compressed air is 700 nl. The inlet temperature is set to 30°C. and the outlet temperature to 25°C.
  • the aspirator is set to achieve a vacuum of -20 to -25 bar.
  • the yield is 51% and the mean particle size is approximately 5 ⁇ m. Larger particle size can be achieved by lowering the inlet compressed air flow rate, as well as by changing other variables.
  • the particles are aerodynamically light, as determined by a tap density less than or equal to 0.4 g/cm 3 . Porosity and surface roughness can be increased by varying the inlet and outlet temperatures, among other factors.
  • the formulation is filled into a metered dose inhaler vial equipped with a metering valve.
  • the vial is made of epoxy-phenolic lacquer coated aluminium (ex Cebal Printal U.K.
  • microparticles obtained from the process described in example 1 are administered once daily to ageing males in the age of 50-65, between 5:00 and 10:00 a.m., in a pulmonary dose of 2 mg (0.4 mg MENT) during a period of 8 weeks. It is found that the pulmonary administration of MENT assists in suppressing symptoms of testosterone deficiency.
  • Example 4
  • microparticles obtained from the process described in example 1 are administered in the same fashion as described in example 2 to males who are androgen deprived as a result of castration. This time the pulmonary dose is increased to 10 mg (2 mg MENT). Again it is found that the pulmonary administration of MENT helps to suppress symptoms of testosterone deficiency.

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Abstract

La présente invention concerne un procédé pour traiter les hommes souffrant d'hypogonadisme et un procédé pour le traitement ou la prévention de ce qui suit: cachexie, lipodystrophie induite par des médicaments anti-rétroviraux, perte de la sensation de bien-être ou fatigue chez les personnes atteintes par VIH, état catabolique, dysfonctionnement des cellules de Leydig et affection épithéliale germinale postérieure à une chimiothérapie cytotoxique, fatigue, baisse de l'hémoglobine ou de neutrophile pendant ou après une chimiothérapie cytotoxique ou une radiothérapie, troubles gynécologiques bénins ou puberté tardive; l'invention peut également s'utiliser dans la régulation du poids. L'invention concerne plus particulièrement un procédé de traitement qui comprend l'administration pulmonaire d'une quantité efficace d'un androgène 6?-alkylé et/ou 7?-alkylé. Dans un autre aspect, l'invention concerne une composition d'administration pulmonaire de médicaments, basées sur des microparticules biodégradables contant un androgène 6?-alkylé et/ou 7?-alkylé. En outre, elle concerne un système d'administration de médicaments par aérosol comprenant un dispositif d'administration par aérosol et une composition pharmaceutique liquide contenant un androgène 6?-alkylé et/ou 7?-alkylé.
PCT/NL2003/000111 2002-02-15 2003-02-14 Administration pulmonaire de derives de testosterone 6-alpha-alkyle comme forme de therapie antiandrogene Ceased WO2003068314A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003206434A AU2003206434A1 (en) 2002-02-15 2003-02-14 Pulmonary administration of 6-alpha-alkylated testosterone derivatives for androgen replacement therapy

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EP02075610.2 2002-02-15
EP02075610 2002-02-15

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809465A (en) * 1956-03-26 1959-02-25 British Drug Houses Ltd Improvements in or relating to 6-methyl steroid compounds
US3341557A (en) * 1961-06-05 1967-09-12 Upjohn Co 7-methyltestosterones
WO1998031346A1 (fr) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
US5855905A (en) * 1996-05-02 1999-01-05 Jenapharm Gmbh & Co. Kg Compound preparation for the treatment of hypogonadal men and men with hypophyseal diseases
WO1999013812A1 (fr) * 1997-09-17 1999-03-25 The Population Council, Inc. ADMINISTRATION TRANSDERMIQUE DE 7α-METHYL-19-NORTESTOSTERONE ('MENT')
WO2000066084A1 (fr) * 1999-05-04 2000-11-09 Aradigm Corporation Formulations d'aerosol et dispositifs destines a augmenter la libido chez la femme par l'administration aigue de testosterone

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB809465A (en) * 1956-03-26 1959-02-25 British Drug Houses Ltd Improvements in or relating to 6-methyl steroid compounds
US3341557A (en) * 1961-06-05 1967-09-12 Upjohn Co 7-methyltestosterones
US5855905A (en) * 1996-05-02 1999-01-05 Jenapharm Gmbh & Co. Kg Compound preparation for the treatment of hypogonadal men and men with hypophyseal diseases
WO1998031346A1 (fr) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
WO1999013812A1 (fr) * 1997-09-17 1999-03-25 The Population Council, Inc. ADMINISTRATION TRANSDERMIQUE DE 7α-METHYL-19-NORTESTOSTERONE ('MENT')
WO2000066084A1 (fr) * 1999-05-04 2000-11-09 Aradigm Corporation Formulations d'aerosol et dispositifs destines a augmenter la libido chez la femme par l'administration aigue de testosterone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUNDARAM KALYAN ET AL: "7alpha-Methyl-19-nortestosterone (MENT): The optimal androgen for male contraception and replacement therapy.", INTERNATIONAL JOURNAL OF ANDROLOGY, vol. 23, no. Supplement 2, 2000, pages 13 - 15, XP002201838, ISSN: 0105-6263 *

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