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WO1996036339A2 - Utilisation de composes de dihydrotestosterone pour traiter une dysfonction sexuelle chez l'homme - Google Patents

Utilisation de composes de dihydrotestosterone pour traiter une dysfonction sexuelle chez l'homme Download PDF

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Publication number
WO1996036339A2
WO1996036339A2 PCT/US1996/006078 US9606078W WO9636339A2 WO 1996036339 A2 WO1996036339 A2 WO 1996036339A2 US 9606078 W US9606078 W US 9606078W WO 9636339 A2 WO9636339 A2 WO 9636339A2
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WO
WIPO (PCT)
Prior art keywords
dihydrotestosterone
dht
sexual dysfunction
subject
compound
Prior art date
Application number
PCT/US1996/006078
Other languages
English (en)
Other versions
WO1996036339A3 (fr
Inventor
Christo S. Mantzoros
Original Assignee
Beth Israel Hospital
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
Application filed by Beth Israel Hospital filed Critical Beth Israel Hospital
Priority to EP96913887A priority Critical patent/EP0827405A2/fr
Priority to AU56714/96A priority patent/AU5671496A/en
Publication of WO1996036339A2 publication Critical patent/WO1996036339A2/fr
Publication of WO1996036339A3 publication Critical patent/WO1996036339A3/fr

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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

Definitions

  • Impaired sexual function such as impotence and decreased libido, is relatively common in middle aged and elderly men. The percentages of these men that exhibit impaired sexual function is between 9% and 30%. Sexual dysfunction has been linked to low male hormone levels. For example, when normal men are made hypogonadic (experimental induction of low male hormone levels) they develop impaired sexual function.
  • testosterone regulates sexual behavior in humans, although this belief has never been confirmed experimentally.
  • Testosterone replacement treatment in the form of intramuscular injections, has been shown to restore sexual function. It has also been shown that subnormal libido and sexual function due to either induced or spontaneous hypogonadism improve with testosterone treatment. See Weinbauer et al. , Acta Endocrinol rCopenh) 122, 432-442 (1990), and Bragatell et al.. J. Clin. Endo. Metabol 78. 711-716 (1994). However, testosterone replacement therapy often has adverse side effects, including feminizing effects of estradiol, such as enlargement of the breasts (gynecomastia) and fluid retention.
  • Testosterone is converted in the human body to dihydrotestosterone (DHT) and estradiol. It remains unclear whether sexual behavior is regulated by testosterone itself or by one of its metabolites, such as DHT. Although normal levels of DHT cause no serious side effects, supraphysiological levels can cause benign prostatic hypertrophy and possibly other serious medical conditions. In particular, it has been shown that the threshold for prostate growth (initiation of prostatic hyperplasia) is approximately 1 nanogram of DHT per gram of prostatic tissue. Therefore, while physiological replacement therapy of DHT might have favorable effects, supraphysiological levels of DHT or testosterone replacement therapy to treat sexual dysfunction might result in significant health impairments.
  • DHT dihydrotestosterone
  • the present invention provides a method for treating sexual dysfunction of a subject by increasing bioactive dihydrotestosterone (DHT) plasma levels.
  • DHT bioactive dihydrotestosterone
  • the levels are increased from an undetectable, low abnormal, or even low normal level to within the normal range, without substantially exceeding the normal range (i.e., achieving supraphysiological concentrations of DHT).
  • the invention is based, at least in part, on the discovery that achieving physiological concentrations of dihydrotestosterone (while avoiding adverse side effects which can result from supraphysiological concentrations of DHT) is an effective means for treating sexual dysfunction in a subject.
  • Increase of plasma DHT to desired levels at which sexual function is restored can be achieved by administering to a subject exogenous DHT or a derivative thereof in a suitable form.
  • levels of DHT can be increased by inhibiting metabolic breakdown and excretion of endogenous DHT, or by increasing internal production of DHT.
  • the methods provided by the present invention can be prophylactic and/or therapeutic treatments of sexual dysfunction.
  • the methods provide the advantages of allowing a physician to recognize important determinants in the treatment of sexual dysfunction, and allowing the physician to adequately diagnose and treat the dysfunction.
  • the method of the present invention also can be advantageous over conventional procedures since it is easily adaptable to existing treatments and thus can be used in combination therapies.
  • the present invention provides a method for treating sexual dysfunction in a subject by increasing physiological concentrations of bioactive DHT to a serum level which corrects the dysfunction.
  • the present invention further pertains to compositions for treating sexual dysfunction in a subject.
  • Other aspects of the invention include packaged compounds that include instructions relating to use, dosage and regimen.
  • Figure 1 is a tabulation of the demographic lifestyle and endocrine correlates of the weekly number of orgasmic events of the subjects.
  • Figure 2 is a tabulation of an evaluation of dihydrotestosterone, androstenione and age as predictors of orgasmic events
  • the present invention pertains to a method of treating sexual dysfunction in a subject by achieving physiological concentrations of bioavailable dihydrotestosterone (DHT).
  • DHT dihydrotestosterone
  • the term "treating" sexual dysfunction is intended to include preventing, inhibiting, reducing, or delaying the progression and/or effects of the dysfunction.
  • sexual dysfunction is intended to include dysfunctions associated with the sexual activity and/ or sexual response of the subject.
  • sexual dysfunctions include erectile inadequacy, inhibited male orgasm, decreased libido or sexual drive, sexual arousal dysfunction, and impotence.
  • the sexual dysfunction can be a naturally occurring dysfunction, a trauma induced dysfunction, or a dysfunction that arises from the purposeful inducement of the dysfunction, such as by the administration of a selected compound to the subject.
  • Sexual dysfunction disorders can result in the inhibition in the sexual respons cycle which may occur at one or more sexual response phases, e.g., desire, arousal and performance, or their respective components.
  • sexual dysfunction can involve both subjectiv parameters of sexual functioning, e.g., desire, arousal, and pleasure, as well as the objective parameters of sexual functioning, e.g., performance and orgasm.
  • sexual dysfunction can als involve fertility, such as decreased semen volume and quality (i.e., sperm counts, motility etc.).
  • either the subjective or objective set of parameters may be classified as being primary, e.g., with effective performance never having been experienced in any situation, or secondary, e.g., dysfunctions acquired after a period of normal functioning. Secondary parameters are often medication induced (e.g., chemotherapy, radiation etc.) or the result of other medical conditions.
  • Sexual dysfunction may also be characterized as generalized or limited to certain situations or with cetain partners.
  • the etiology of sexual dysfunction can also comprise psychological factors, interpersonal and situational causes, physical factors, and pharmacological agent side effects. Since sexual dysfunction can result from a variety of underlying causes, including those set forth above, the dihydrotestosterone compound of the present invention may be utilized alon or along with other treatment modalities.
  • subject is intended to include mammals having or being susceptible to sexual dysfunction. Examples of such subjects include humans, pigs, cows, horses, rats, mice, domestic animals, zoo animals, and rare or endangered species.
  • administering is intended to include all routes of administration including injection (subcutaneous, intramuscular, intravenous, parenterally, intraperitoneally intrathecal, etc.), oral, sublingual (e.g., cyclodextrin drug complexes), transdermal, and slow release microspheres.
  • injection subcutaneous, intramuscular, intravenous, parenterally, intraperitoneally intrathecal, etc.
  • oral sublingual
  • cyclodextrin drug complexes e.g., cyclodextrin drug complexes
  • transdermal e.g., transdermal, and slow release microspheres.
  • the injection can be bolus injections or can be continuous infusion.
  • the dihydrotestosterone compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function.
  • the agent can be encapsulated by a biocompatible and/or biodegradable microparticle, e.g., a polymeric matrix, to effectuate a time-controlled release of the bound agent.
  • a biocompatible and/or biodegradable microparticle e.g., a polymeric matrix
  • the dihydrotestosterone compound can be incorporated into a film or patch which is applied at regular intervals (e.g., daily), typically t the scrotal skin. This preparation permits maintenance of plasma concentrations of the agen within the normal range.
  • the compound may be formulated into a capsule (hard or soft) or tablet that is prepared by conventional techniques with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g., magnesium stearate, talc o silica), disintegrants (e.g., potato starch or sodium starch glycollate), or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g., magnesium stearate, talc o silica
  • disintegrants e.g.,
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional techniques with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), and non-aqueous vehicles (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid.
  • the dihydrotestosterone compound can be administered alone, or in conjunction with other suitable agents or with a pharmaceutically acceptable carrier, or both.
  • the dihydrotestosterone compound can be administered to the subject prior to the onset of the sexual dysfunction, during the dysfunction, or after the onset of the sexual dysfunction.
  • the dihydrotestosterone compound can also be administered as a prodrug which is converted to its active form in vivo.
  • pharmaceutically acceptable carrier is intended to include substances capable of being coadministered with the dihydrotestosterone compound, and which allows it to perform its intended function of treating sexual dysfunction.
  • examples of such carriers include solutions, solvents, dispersion media, delay agents, emulsions and the like.
  • the use of such media for pharmaceutically active substances are well known in the art. Any other conventional carrier suitable for use with the selective condition inhibitory agent also falls within the scope of the present invention.
  • the language "effective amount" of the dihydrotestosterone compound is that amount necessary or sufficient to treat sexual dysfunction in the subject.
  • the effective amount can vary depending on such factors as the type and severity of the sexual dysfunction being treated, the potency of the dihydrotestosterone compound, the residence time of the agent within the subject, the size and age of the subject, and the mode of application of the agent.
  • the type of dihydrotestosterone compound can affect what constitutes an effective amount.
  • DHT replacement therapy i.e., administration of an exogenous DHT compound
  • DHT levels can be monitored by currently available laboratory techniques, including laboratory determinations of blood level DHT.
  • the in vivo assays described below or an assay similar thereto can be used to determine an "effective amount" of the compound.
  • the ordinarily skilled artisan would select an appropriate amount of the compound for use in the aforementioned in vivo assays.
  • the regimen of administration also can affect what constitutes an effective amount.
  • the dihydrotestosterone can be administered to the subject prior to, simultaneously with, or after the onset of the sexual dysfunction. Further, several divided dosages, staggered dosages, as well as a time-controlled release of the agent in selected dosages, can be administered daily or sequentially, or the dose can be continuously infused depending upon the type of compound employed and the preferred mode of administration to the subject.
  • the dosages of the agent can be proportionally increased or decreased as indicated by the exigencies of the therapeutic situation.
  • dihydrotestosterone compound is intended to include dihydrotestosterone (DHT) and analogues of DHT which have been chemically modified to retard the rate of catabolism or to enhance the androgenic potency of DHT.
  • DHT dihydrotestosterone
  • analogues of DHT which have been chemically modified to retard the rate of catabolism or to enhance the androgenic potency of DHT.
  • These chemical modifications of DHT include esterification of the 17 ⁇ -hydroxyl group with any of several carboxylic acids to decrease the polarity of the molecule, making it more soluble in lipid vehicles used for injection and slowed release into the bloodstream. The longer the carbon chain in the ester, the more lipid soluble the steriod becomes and the more prolonged is the release of the steroid in vivo.
  • dihydrotestosterone esters include those derived from aliphatic carboxylic acids, derivatives and analogues of dihydrotestosterone, short chain esters of DHT (e.g., proprionate and cypionate) as well as long and branched chain esters, and esters of DHT (e.g., 3-alkyloxy form of DHT).
  • DHT short chain esters of DHT
  • esters of DHT e.g., 3-alkyloxy form of DHT
  • Other modifications of DHT which are encompassed by the invention also include alkylation at the 17 ⁇ position. Such alkylated derivatives are are slowly catabolized by the liver. The alkyl group is not removed metabolically. Therefore, the alkylated derivative mediates the action of the hormone within cells.
  • Preferred compounds of the invention include 5 ⁇ -dihydrotestosterone (5 ⁇ DHT), 5 ⁇ -dihydrotestosterone (5 ⁇ DHT), and esters, analogues and/or derivatives thereof, such as 5 ⁇ and 5 ⁇ reduced analogues, biocompatible derivatives, such as alkanoic acid derivatives, 17 alkylated (e.g., methylated) derivatives of 5 ⁇ and 5 ⁇ DHT, and 5 ⁇ and 5 ⁇ DHT esters that are hydrolyzable in vivo.
  • 5 ⁇ DHT 5 ⁇ -dihydrotestosterone
  • 5 ⁇ DHT 5 ⁇ -dihydrotestosterone
  • esters analogues and/or derivatives thereof, such as 5 ⁇ and 5 ⁇ reduced analogues
  • biocompatible derivatives such as alkanoic acid derivatives, 17 alkylated (e.g., methylated) derivatives of 5 ⁇ and 5 ⁇ DHT, and 5 ⁇ and 5 ⁇ DHT esters that are hydrolyzable in vivo.
  • esters examples include pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, undecenoic acid, palmitic acid and the branched chain and cyclic analogues of these acids.
  • the manufacture o these esters is set forth in U.S. Patent Nos. 4,098,802 and 4,220,599 of van der Vies, which are both herein incorporated by reference.
  • the present invention further pertains to packaged dihydrotestosterone compounds packaged with instructions for using the compound as a treatment for sexual dysfunction.
  • the instructions would provide selected information such as the appropriate dose of the compound or the appropriate regimen.
  • Another aspect of the present invention provides a method for treating sexual dysfunction in a subject, comprising increasing DHT concentrations in the subject to effectively treat the sexual dysfunction.
  • the invention aims at increasing bioactive dihydrotestosterone (DHT) plasma levels from an undetectable, low abnormal, or , even low normal level to within the normal range, without substantially exceeding the normal range (i.e., achieving supraphysiological concentrations of DHT).
  • DHT bioactive dihydrotestosterone
  • normal range means the range of DHT serum levels measured for individuals of a given population whose sexual function (e.g., sexual desire, sexual performance, and fertility) is normal. This range may vary depending on variables, such as age, demographics and lifestyle for any given population and can be determined as described below in the exemplification.
  • a normal range is the mean for a given population with a standard deviation of 0.6, preferably 0.4, and more preferably about 0.2.
  • the mean serum DHT level was 0.787 ng/ml and a standard deviation of 0.207.
  • low abnormal level of DHT means below the normal range of serum level DHT, as previously defined.
  • low normal level means above the lower limit of the normal range of serum level DHT, as previously defined, but not above the mean for the normal range.
  • not substantially exceeding the normal range means serum DHT levels above the normal range, as previously defined, but not high enough to cause significant adverse effects, such as those associated with supraphysiological concentrations of DHT, including but not limited to benign prostatic hypertrophy.
  • serum level DHT is increased in a sexually dysfunctional patient by administering to the patient an effective amount of an exogenous dihydrotestosterone compound to treat the sexual dysfunction.
  • the DHT compound is administered in a controlled, sustained release manner, for example, by a transdermal therapeutic system (TTS) (e.g., a transdermal patch).
  • TTS transdermal therapeutic system
  • serum level DHT is increased in a sexually dysfunctional patient by inducing accumulation of endogenous DHT (i.e., DHT which is naturally produced within the patient).
  • endogenous DHT i.e., DHT which is naturally produced within the patient.
  • Accumulation of endogenous DHT can be induced in a number of different ways.
  • metabolism of endogenous DHT can b inhibited by, for example, inhibition of enzymes which convert DHT to other hormones. These enzymes include but are not limited to sulfatases, glucuronidases, and other hepatic enzymes responsible for metabolism of hormones. The activity of these enzymes can be reduced or abolished by, for example, chemical or biological means.
  • endogenous DHT can be induced by promotin production of endogenous DHT.
  • a patient can be administered an enzyme which causes conversion of DHT precursors, such as testosterone, to DHT.
  • DHT can be produced in vivo by causing its release from, or by preventing its binding to, certain androgen binding proteins with which DHT is normally associated with in vivo.
  • these androgen binding proteins include, for example, sex hormone binding globulin (SHBG).
  • DHT can be prevented from binding to such androgen binding proteins by administering an analogue of DHT which effectively competes with DHT for binding to the androgen binding protein.
  • the subjects were 100 male army recruits, 18-22 years old, who consented having a single blood sample drawn during their first day in the army. The subjects were healthy and were taking no medication.
  • Serum hormone levels were determined by commercially available RIA kits (Coat-a-Count, DPC, Los Angeles, CA for testosterone and dehydroepiandrosterone sulfate, Amersham Intl. UK for dihydrotestosterone, EIRRIA, Switzerland for estradiol and estrone. Buhlman Lab Ltd., Italy for delta-4-androstendione and Biodata Spa, Switzerland for Sex Hormone Binding Globulin).
  • the sensitivity of the assays was as follows: testosterone 4ng/dl, estrone 8 pg/ml, estradiol 6.2 ph/ml, delta-4- androstendione 0.02 ng/ml, dihydrotestosterone 5 ph/ml, dehydroepiandrosterone sulfate 21 ng/ml.
  • the coefficients of variation in the range of values measured were 5.2% for dihydrotestosterone, 4.5-5.5% for dehydroepiandrosterone sulfate, 5.8% for testosterone, 5- 8% for delta-4-androstendione, 5-6%> for estradiol and estrone, 2.8-6.9% for sex hormone binding globulin.
  • Table 1 of Figure 1 shows representative values of the demographic and lifestyle variables.
  • the mean weekly number of orgasmic events in this study was 3.9, the standard deviation 1.9, the median and the mode 3.5, the range was 0 to 11 and the first and third quintiles were 2.2 and 5.5 respectively.
  • Simple and multiple regression-deprived regression coefficients of the weekly number of orgasmic events regressed on these variables are also known in Table 1. Only age is a statistically significant predictor of the frequency o orgasmic events.
  • Table 1 also presents representative values of the endocrine variables as well as simple and multiple regression-deprived regression coefficients of weekly number of orgasmic events regressed on these hormones.
  • dihydrotestosterone is the active hormone for male sexual function as reflected in the frequency of orgasmic events.
  • An increase of dihydrotestosterone by two standard deviations (.4 ng/ml) is associated with an increase of the weekly number of orgasmic events by at least one, and conceivably more depending on the extend of biologically generated variation and consequent misclassification.
  • a difference of three years corresponds to an increase of the weekly number or orgasmic events by about two; this increase is likely to reflect socially conditioned enhancement of opportunities with increasing age.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention décrit une méthode de traitement d'une dysfonction sexuelle chez un patient, consistant à élever les taux de dihydrotestostérone (DHT) chez un patient pour traiter efficacement ladite dysfonction sexuelle. Les méthodes de l'invention peuvent être utilisées dans le cadre d'un traitement prophylactique et/ou thérapeutique des dysfonctions sexuelles.
PCT/US1996/006078 1995-05-15 1996-05-01 Utilisation de composes de dihydrotestosterone pour traiter une dysfonction sexuelle chez l'homme WO1996036339A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96913887A EP0827405A2 (fr) 1995-05-15 1996-05-01 Utilisation de composes de dihydrotestosterone pour traiter une dysfonction sexuelle chez l'homme
AU56714/96A AU5671496A (en) 1995-05-15 1996-05-01 Use of dihydrotestosterone compounds for treating male sexual dysfunction

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US44072695A 1995-05-15 1995-05-15
US08/440,726 1995-05-15
US48747195A 1995-06-07 1995-06-07
US08/487,471 1995-06-07

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WO1996036339A2 true WO1996036339A2 (fr) 1996-11-21
WO1996036339A3 WO1996036339A3 (fr) 1997-02-13

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CA (1) CA2219082A1 (fr)
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Cited By (4)

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WO2005105104A1 (fr) * 2004-04-28 2005-11-10 Hunter-Fleming Limited Preparation steroidienne transdermique
WO2008054214A3 (fr) * 2006-11-03 2009-04-09 Emotional Brain Bv Utilisation de 3-alpha-androstanediol éventuellement combiné à un inhibiteur de la pde5, dans le traitement d'un dysfonctionnement sexuel
US8227453B2 (en) 2004-05-11 2012-07-24 Emotional Brain B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US9333203B2 (en) 2005-11-11 2016-05-10 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction

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Publication number Priority date Publication date Assignee Title
US6503894B1 (en) 2000-08-30 2003-01-07 Unimed Pharmaceuticals, Inc. Pharmaceutical composition and method for treating hypogonadism

Non-Patent Citations (3)

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Title
CLIN. ENDOCRINOL. METAB., vol. 11, no. 3, 1982, pages 599-623, XP000612869 J.M. DAVIDSON ET AL.: "Hormonal replacement and sexuality in men." *
ENDOCR. REV., vol. 8, no. 1, 1987, pages 1-28, XP000612870 A.D. MOORADIAN ET AL.: "Biological actions of androgens." *
J. CLIN. ENDOCRINOL. METAB., vol. 70, no. 3, 1990, pages 792-797, XP000612829 G.R. CUNNINGHAM ET AL.: "Testosterone replacement therapy and sleep-related erections in hypogonadal men." *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007534734A (ja) * 2004-04-28 2007-11-29 ハンター−フレミング・リミテッド 経皮ステロイド製剤
RU2371183C2 (ru) * 2004-04-28 2009-10-27 Хантер-Флеминг Лимитед Трансдермальные стероидные композиции
CN1997375B (zh) * 2004-04-28 2010-09-22 亨特-弗莱明有限公司 经皮类固醇制剂
AU2005237285B2 (en) * 2004-04-28 2010-10-14 Hunter-Fleming Limited Transdermal steroid formulation
JP4849478B2 (ja) * 2004-04-28 2012-01-11 ハンター−フレミング・リミテッド 経皮ステロイド製剤
WO2005105104A1 (fr) * 2004-04-28 2005-11-10 Hunter-Fleming Limited Preparation steroidienne transdermique
NO337073B1 (no) * 2004-04-28 2016-01-18 Hunter Fleming Ltd Adhesivt plaster for transdermal administrering av en steroidforbindelse, og en adhesiv sammensetning av forbindelsen.
US9192669B2 (en) 2004-05-11 2015-11-24 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US10441592B2 (en) 2004-05-11 2019-10-15 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US8227453B2 (en) 2004-05-11 2012-07-24 Emotional Brain B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US9700566B2 (en) 2004-05-11 2017-07-11 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US9333203B2 (en) 2005-11-11 2016-05-10 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US9737548B2 (en) 2005-11-11 2017-08-22 Eb Ip Lybrido B.V. Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US8669242B2 (en) 2006-11-03 2014-03-11 Emotional Brain B.V. Use of testosterone and a 5-HT1A agonist in the treatment of sexual dysfunction
US9211334B2 (en) 2006-11-03 2015-12-15 Eb Ip Lybridos B.V. Use of testosterone and a 5-HT1A agonist in the treatment of sexual dysfunction
US8653051B2 (en) 2006-11-03 2014-02-18 Emotional Brain B.V. Use of 3-alpha-androstanediol in combination with a PDE5 inhibitor, in the treatment of sexual dysfunction
US8648060B2 (en) 2006-11-03 2014-02-11 Emotional Brain B.V. Use of 3-alpha-androstanediol in combination with a 5-HT1a agonist, in the treatment of sexual dysfunction
US9597335B2 (en) 2006-11-03 2017-03-21 Eb Ip Lybridos B.V. Use of testosterone and a 5-HT1A agonist in the treatment of sexual dysfunction
US8575139B2 (en) 2006-11-03 2013-11-05 Emotional Brain B.V. Use of testosterone and a 5-HT1a agonist in the treatment of sexual dysfunction
US10314848B2 (en) 2006-11-03 2019-06-11 Eb Ip Lybridos B.V. Use of testosterone and a 5-HT1A agonist in the treatment of sexual dysfunction
WO2008054214A3 (fr) * 2006-11-03 2009-04-09 Emotional Brain Bv Utilisation de 3-alpha-androstanediol éventuellement combiné à un inhibiteur de la pde5, dans le traitement d'un dysfonctionnement sexuel

Also Published As

Publication number Publication date
WO1996036339A3 (fr) 1997-02-13
EP0827405A2 (fr) 1998-03-11
CA2219082A1 (fr) 1996-11-21
AU5671496A (en) 1996-11-29

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