WO2003068315A1 - Composition de medicament a administrer par voie pulmonaire contenant un progestogene et un androgene, destinee a etre utilisee dans une methode contraceptive masculine - Google Patents

Composition de medicament a administrer par voie pulmonaire contenant un progestogene et un androgene, destinee a etre utilisee dans une methode contraceptive masculine Download PDF

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Publication number
WO2003068315A1
WO2003068315A1 PCT/NL2003/000110 NL0300110W WO03068315A1 WO 2003068315 A1 WO2003068315 A1 WO 2003068315A1 NL 0300110 W NL0300110 W NL 0300110W WO 03068315 A1 WO03068315 A1 WO 03068315A1
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WO
WIPO (PCT)
Prior art keywords
pulmonary
delivery composition
drug delivery
androgen
composition according
Prior art date
Application number
PCT/NL2003/000110
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English (en)
Inventor
Herman Jan Tijmen Coelingh Bennink
René Frank VAN DER LINDEN
Original Assignee
Pantarhei Bioscience B.V.
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.)
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Publication date
Application filed by Pantarhei Bioscience B.V. filed Critical Pantarhei Bioscience B.V.
Priority to AU2003206433A priority Critical patent/AU2003206433A1/en
Publication of WO2003068315A1 publication Critical patent/WO2003068315A1/fr

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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
    • A61K9/007—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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives

Definitions

  • the present invention relates to drug delivery compositions for use in a method of male contraception as well as to such a contraceptive method.
  • the drag delivery compositions according to the invention contain a progestogen, an androgen and a pharmaceutically acceptable carrier.
  • Oral administration of DHEA in the context of a male contraceptive is not an option because the doses required to achieve the desired serum testosterone levels are extremely high and will inevitably lead to highly elevated estradiol levels.
  • a disadvantage of oral administration of all of the aforementioned androgens is associated with the fact that the androgen will exert a relatively strong effect on the liver and particular the liver metabolism.
  • the aforementioned 17c-alkylated derivatives of testosterone, for instance, are not recommended for clinical oral use because of their potential hepatoxicity (Bhasin et al. (1997) J. Clin. Endocr. Metab. 82:3-8).
  • 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 seram 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 drag from the body, e.g. in case an allergic reaction occurs or prostate cancer is diagnosed.
  • US 6,136,295 (Edwards et al.) relates to biocompatible particles for delivery of a therapeutic, prophylactic or diagnostic agent to the pulmonary system.
  • the synthesis of testosterone containing microparticles is described. No therapeutic or other applications of such testosterone containing microparticles are suggested in this US-patent.
  • the pulmonary administration offers several advantages over the aforementioned known methods of administration, particularly oral and intramuscular administration. Firstly, pulmonary delivery is highly effective, i.e. a large fraction of the androgen and progestogen that is inhaled will indeed be absorbed.
  • 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.
  • pulmonary administration unlike oral administration, has minimum impact on liver metabolism since only a minor fraction of the administered androgen and progestogen will pass through the liver.
  • one aspect of the present invention is concerned with a pulmonary drug delivery composition containing a progestogen, an androgen and a pharmaceutically acceptable carrier for administration to the lungs.
  • a progestogen encompass substances that are capable of triggering respectively an androgenic or progestogenic response in vivo, as well as precursors thereof that are capable of liberating the androgen or progestogen in vivo when used in accordance with the present invention, hi order for androgens or progestogens to trigger such a response they normally have to bind to their respective receptors, which receptors are found in various parts of the mammalian body.
  • a wide variety of androgens may suitably be employed in accordance with the present invention.
  • suitable androgens include: testosterone; testosterone esters such as testosterone undecanoate, testosterone propionate, testosterone phenylpropionate, testosterone isohexanoate, testosterone enantate, testosterone bucanate, testosterone decanoate, testosterone buciclate; methyltestosterone; 6 ⁇ -alkyl-androgens such as 6 ⁇ -methyltestosterone, 6c ⁇ methyl-l 9-nortestosterone, 6 ⁇ -methyl-l 1-hydroxytestosterone, 6a, 17- dimethyltestosterone, 6a 17-dimethyl- 11-hydroxytestosterone, 6c ⁇ l 7-dimethyl- 19- nortestosterone, 6c ⁇ 7-dimethyl- 11-hydroxy-l 9-nortestosterone; 7 ⁇ -alkyl-androgens such as 7 ⁇ -methyl- 19-nortestosterone (MENT), 7 ⁇ -methyl- 14-dehydro-
  • the present invention also encompasses the pulmonary administration of an androgen and/or progestogen precursor.
  • These precursors are preferably selected from the group of derivatives of the present androgens and progestogens, 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 androgen- or progestogen-molecule with substances that contain one or more carboxyl (M + " OOC-) groups, wherein M* represents a hydrogen or (akali)metal cation.
  • the androgen- and/or progestogen-precursors are derivatives of androgens or progestogens, 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.
  • alkyl-androgen and 7 ⁇ -alkyl-androgen encompass androgens comprising an alkyl-substituent on the 6a- or 7 ⁇ -position.
  • the alkyl radical is a C1 . -C 4 alkyl. More preferably the alkyl radical is methyl or ethyl. Most preferably the alkyl radical is methyl.
  • 6 ⁇ -alkyl and 7 ⁇ -alkyl-androgens are particularly 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, including males in whom endogenous androgen synthesis is suppressed by the administration of progestogen.
  • 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.
  • 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-l 9-nortestosterone (MENT).
  • testosterone is quickly metabolised in the liver and thus not suited for oral administration.
  • Pulmonary administration makes it possible to use testosterone in contraceptive protocols that require frequent (e.g. at least once daily) self-administration.
  • testosterone (and testosterone esters) is less potent than the aforementioned 6 ⁇ -alkyl- and 7 ⁇ -alkyl-androgens, testosterone is a preferred androgen since it occurs naturally in the human body, meaning that there is less concern about undesirable side-effects as a result of prolonged administration.
  • the progestogen used in the present method is selected from the group consisting of progesterone, desogestrel, etonogestrel, gestodene, dienogest, levonorgestrel, norgestimate, norethisterone, drospirenone, trimegestone, dydrogesterone, precursors of these progestogens and mixtures thereof.
  • the pulmonary drag delivery composition is typically administered in an amount of at least 0.1 mg, preferably of a least 0.5 mg, more preferably of at least 1 mg.
  • the maximum amount that is administered in accordance with the invention, not including any propellant contained in the drug delivery composition, is usually less than 50 mg, preferably less than 20 mg, more preferably less than 10 mg.
  • the aforementioned amounts may be 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.
  • pulmonary drug delivery systems it is possible to distinguish two different techniques, i.e. one which uses dry particulates and another that utilises liquid compositions.
  • Liquid aerosol compositions may be prepared by dissolving the progestogen and 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 the combination of progestogen and androgen.
  • each metered dose or 'puff of aerosol contains between 0.01 and 5 mg of the combination of progestogen and androgen.
  • the discharge volume of the aerosol system is typically between 5 and 250 ⁇ L.
  • Excluding propellant the discharged dosage is usually between 0.5 and 20 mg.
  • a pulmonary drag delivery 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.
  • biodegradable microparticles having a number weighted average diameter of 0.5 to 10 ⁇ m.
  • suitable biodegradable carrier materials examples include US 6,136,295, which is included herein by reference.
  • the microparticles are advantageously provided in the form of a capsule containing between 5 ⁇ g and 100 mg of the drug 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. Best results are obtained with pulmonary administration of androgen if the aforementioned microparticles contain relatively high concentrations of progestogen and/or androgen. Preferably, the microparticles contain between 1 and 50 wt.%, more preferably between 5 and 40% of the progestogen and/or the androgen.
  • the present drug delivery composition may comprise microparticles that contain the combination of the progestogen and the androgen
  • the composition comprises a blend of microparticles containing a progestogen and microparticles comprising an androgen.
  • the progestogen and androgen containing microparticles have essentially the same particle size distribution and tap density so as to avoid any demixing during bulk storage.
  • the pulmonary drug delivery composition contains between 0.1 and 30 wt.% of the progestogen, between 1 and 50 wt.% of the androgen and between 20 and 98.9 wt.% of the carrier.
  • the combination of the progestogen, the androgen and the carrier will constitute between 80 and 100 wt.% of the pulmonary drag delivery composition.
  • Another aspect of the invention relates to a pulmonary drug delivery system comprising pulmonary drug delivery device and a pulmonary drug delivery composition as defined herein before.
  • suitable devices for the pulmonary delivery of the present composition include aerosol drug delivery devices that are particularly suited for delivering liquid compositions as well as inhalers that are very suitable for delivering solid particulate systems, e.g. microparticles.
  • the aerosol drug delivery devices contain 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 pulmonary drug delivery composition.
  • the inhalers are advantageously provided with 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 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 drug delivery composition contained in the capsule.
  • Yet another aspect of the present invention relates to a contraceptive method in male mammals, wherein the method comprises the pulmonary administration of the pulmonary drug delivery composition, as described herein before, to a male mammal in an effective amount to reduce the male's fertility.
  • This reduction of the male's fertility is achieved in a particularly effective fashion by pulmonary administration of the present drug delivery composition in an effective amount to achieve azoospermia.
  • the present method suitably employs continuous pulmonary administration of the drag delivery composition during a period of at least 60 days, preferably of at least 150 days.
  • continuous means that the drug delivery composition is administered at relatively regular intervals, with no (therapeutically) significant interruptions.
  • 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.
  • a particularly preferred administration regimen comprises once daily pulmonary administration of the composition 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) that is observed in healthy young males. It is believed that by replicating the natural testosterone profile optimum substitution is achieved.
  • the present contraceptive method preferably comprises pulmonary administration of the androgen in an amount which is equivalent to a daily pulmonary dose of between 0.1 and 100 mg testosterone (e.g. daily pulmonary administration of between 0.01 and 10 mg MENT), more preferably of between 0.5-40 mg testosterone.
  • a daily pulmonary dose of between 0.1 and 100 mg testosterone (e.g. daily pulmonary administration of between 0.01 and 10 mg MENT), more preferably of between 0.5-40 mg testosterone.
  • the phrase "equivalent to a daily dosage" should not be interpreted restrictedly. For instance, the requirement that the administration is to provide the equivalent of a daily dosage of between 0.5 and 40 mg testosterone, encompasses a protocol wherein testosterone is administered once every 3 days, provided the dosage is between 0.3 and 300 mg, i.e. such that the average daily dose is between 0.1 and 100 mg testosterone.
  • the progestogen is advantageously administered pulmonary in an amount which is equivalent to a daily pulmonary dose of between 20 and 2000 ⁇ g etonogestrel, preferably of between 100 and 1000 ⁇ g etonogestrel.
  • the present method may suitable be used in mammals such as humans, pets and livestock. Due to the mode of administration, however, the present method is particularly suitable for use in human males.
  • Aerodynamically light testosterone containing microparticles are prepared according to the following procedure:
  • 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.
  • Pulmonary administration of testosterone and etonogestrel The microparticles obtained from the process described in example 1 are administered once daily to fertile males in the age of 20-40, between 5:00 and 10:00 a.m., in a pulmonary dose of about 40 mg (7.0 mg testosterone and 0.3 mg etonogestrel) during a period of 8 weeks.
  • Example 2 is repeated using the blend of microparticles obtained from example 3 and a pulmonary dosage of about 5 mg (0.8 mg gestodene and 0.1 mg MENT).
  • Propellant (1,1,1,2, tetrafluoroethane) 79.56 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.
  • the above aerosol formulation is administered to males in a daily amount of about lOO ⁇ L.

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  • Health & Medical Sciences (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pulmonology (AREA)
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Abstract

Un aspect de la présente invention concerne des compositions de médicaments à administrer par voie pulmonaire, destinées à être utilisées dans une méthode contraceptive masculine. Cet aspect de l'invention concerne plus précisément une composition de médicament contenant un progestogène, un androgène et un excipient de qualité pharmaceutique, destinée à être administrée par voie pulmonaire. Un autre aspect de l'invention concerne une méthode contraceptive destinée aux mammifères de sexe masculin, consistant à administrer une dose efficace de ladite composition à un mammifère de sexe masculin, par voie pulmonaire, pour réduire la fertilité du sujet. La méthode contraceptive de l'invention est hautement efficace, très appropriée et a peu d'effet sur le métabolisme hépatique.
PCT/NL2003/000110 2002-02-15 2003-02-14 Composition de medicament a administrer par voie pulmonaire contenant un progestogene et un androgene, destinee a etre utilisee dans une methode contraceptive masculine WO2003068315A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003206433A AU2003206433A1 (en) 2002-02-15 2003-02-14 A pulmonary drug delivery composition containing a progestogen and an androgen for use in a contraceptive method in males

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02075613 2002-02-15
EP02075613.6 2002-02-15

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WO2003068315A1 true WO2003068315A1 (fr) 2003-08-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071429A2 (fr) * 2006-12-12 2008-06-19 N.V. Organon Formulation contraceptive orale à pulvérisation
WO2009101182A1 (fr) * 2008-02-15 2009-08-20 N.V. Organon Utilisation d'étonogestrel pour une hyperplasie prostatique bénigne (bph)
WO2010094623A1 (fr) * 2009-02-18 2010-08-26 Bayer Schering Pharma Aktiengesellschaft Fo0rmulation comprenant de la drospirenone pour administration souscutanee ou intramusculaire
WO2010094624A1 (fr) * 2009-02-18 2010-08-26 Bayer Schering Pharma Aktiengesellschaft Particules comprenant de la drospirénone encapsulée dans un polymère
WO2011048613A3 (fr) * 2009-10-12 2012-01-12 Lyka Labs Limited Contraceptif d'urgence
EP3332778A4 (fr) * 2015-08-04 2019-04-17 Obshchestvo S Ogranichennoj Otvetstvennost'yu "Nauchno-Vnedrencheskij Centr Agrovetzashchita" Procédé pour réguler le comportement sexuel de mammifères mâles

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US3364236A (en) * 1962-12-14 1968-01-16 Merck & Co Inc 3-keto-delta4-unsaturated-6-formyl steroids and process for the production thereof
WO1998031346A1 (fr) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
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 (3)

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Publication number Priority date Publication date Assignee Title
US3364236A (en) * 1962-12-14 1968-01-16 Merck & Co Inc 3-keto-delta4-unsaturated-6-formyl steroids and process for the production thereof
WO1998031346A1 (fr) * 1997-01-16 1998-07-23 Massachusetts Institute Of Technology Preparation de particules pour inhalation
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 (3)

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Title
KUBBA A ET AL: "Contraception", LANCET, XX, XX, vol. 356, no. 9245, 2 December 2000 (2000-12-02), pages 1913 - 1919, XP004264270, ISSN: 0140-6736 *
MCLACHLAN ROBERT I ET AL: "Effects of testosterone plus medroxyprogesterone acetate on semen quality, reproductive hormones, and germ cell populations in normal young men.", JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 87, no. 2, February 2002 (2002-02-01), February, 2002, pages 546 - 556, XP001083865, ISSN: 0021-972X *
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 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008071429A2 (fr) * 2006-12-12 2008-06-19 N.V. Organon Formulation contraceptive orale à pulvérisation
WO2008071429A3 (fr) * 2006-12-12 2008-10-09 Organon Nv Formulation contraceptive orale à pulvérisation
WO2009101182A1 (fr) * 2008-02-15 2009-08-20 N.V. Organon Utilisation d'étonogestrel pour une hyperplasie prostatique bénigne (bph)
WO2010094623A1 (fr) * 2009-02-18 2010-08-26 Bayer Schering Pharma Aktiengesellschaft Fo0rmulation comprenant de la drospirenone pour administration souscutanee ou intramusculaire
WO2010094624A1 (fr) * 2009-02-18 2010-08-26 Bayer Schering Pharma Aktiengesellschaft Particules comprenant de la drospirénone encapsulée dans un polymère
US20120114757A1 (en) * 2009-02-18 2012-05-10 Bayer Pharma Aktiengesellschaft Particles comprising drospirenone encapsulated in a polymer
WO2011048613A3 (fr) * 2009-10-12 2012-01-12 Lyka Labs Limited Contraceptif d'urgence
EP3332778A4 (fr) * 2015-08-04 2019-04-17 Obshchestvo S Ogranichennoj Otvetstvennost'yu "Nauchno-Vnedrencheskij Centr Agrovetzashchita" Procédé pour réguler le comportement sexuel de mammifères mâles

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