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EP0952833A1 - Application topique d'androgene par voie penienne pour le traitement de la dyserection - Google Patents

Application topique d'androgene par voie penienne pour le traitement de la dyserection

Info

Publication number
EP0952833A1
EP0952833A1 EP97923761A EP97923761A EP0952833A1 EP 0952833 A1 EP0952833 A1 EP 0952833A1 EP 97923761 A EP97923761 A EP 97923761A EP 97923761 A EP97923761 A EP 97923761A EP 0952833 A1 EP0952833 A1 EP 0952833A1
Authority
EP
European Patent Office
Prior art keywords
testosterone
oxymolonolone
topical
application
erectile dysfunction
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.)
Withdrawn
Application number
EP97923761A
Other languages
German (de)
English (en)
Inventor
Karl-Friedrich Klippel
Dirk-Michael Hiltl
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.)
Azupharma GmbH
Original Assignee
Azupharma GmbH
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 Azupharma GmbH filed Critical Azupharma GmbH
Publication of EP0952833A1 publication Critical patent/EP0952833A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/569—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 substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the invention relates to the use of androgen-containing topical preparations in the treatment of erectile dysfunction by topical penile, preferably glandular-sub-preputial or intraglandular-intraurethral application.
  • Erectile dysfunction led to a fundamental change in the perception of genesis and disease value Erectile dysfunction.
  • the erection is initiated and maintained by the relaxation of the smooth cavernous muscle cells. Compared to flaccidity, the arterial inflow is significantly increased at the beginning of tumescence. While in the flaccid, flaccid state, in which the majority of the arterial blood is directed past the cavernous sinusoids via a capillary system, the occlusion of these arteriovenous shunts and the arterial filling of the cavernous space lead to tumescence with functional rigidity. In parallel with the
  • vasoactive substances such as yohimbine, phenoxybenzamine, terbutaline, Bethanechol, levodopa, verapamil or theophylline was unsuccessful.
  • vasoactive substances such as yohimbine, phenoxybenzamine, terbutaline, Bethanechol, levodopa, verapamil or theophylline was unsuccessful.
  • an intracavernous injection of papaverine (Virag. Lancet, 2, 938, 1982), the ⁇ -receptor blocker phenoxybenzamine (Brindley. Br. J. Psychiatr. 143, 332. 1983) and a combination of Papaverin and the ⁇ -receptor blocker phentolamine (Stief, Urologe A, 25, 63, 1986) as successful.
  • the latter therapy method can be carried out independently by the patient and is also referred to as swelling body auto-injection therapy (SKAT).
  • a prerequisite for an individual assignment of the different treatment options for erectile dysfunction to the respective patient is the causal investigation of the erectile dysfunction.
  • grades such as double or duplex sonography of the penile arteries, the corpus cavernosum EMG or the cavernosometry and graphics.
  • testosterone has a promoting influence on the sensitivity of the neural excitation leads in the central nervous system which are important for the erection process. It is for them
  • Dendrite sprouting of the spinal nerves of the erectogenic axis and their synapses are of importance.
  • the role of testosterone in the peripheral erection process has not yet been fully clarified, but recent studies have shown that testosterone withdrawal leads to significantly reduced neuronal excitability and apoptosis (cell death) within the cavernous tissue.
  • a decrease in testosterone leads to a significant decrease in cavernous nitrogen oxide synthesis (NO synthesis).
  • NO is the main neurotransmitter of penile erection (Zvara et al., Int. J. Iirtpot. Res. 7, 209-219, 1995; Thompson, Science 267, 1456, 1995).
  • the topical application according to the invention is therefore a significant advance over the standard therapy for erectile dysfunction, namely erectile tissue auto-injection (SKAT), which due to its invasiveness per se with its specific application problems and possible complications negates and rejects many patients in the delicate situation of erotic being together becomes.
  • SKAT erectile tissue auto-injection
  • hypogonadism is generally uncommon in impotent men. However, it was surprisingly found that hypogonadism per se is associated with a significant reduction in quantity and
  • the intramuscular administration of testosterone preferably in In clinical use, the form of the enanthate or propionate ester is used exclusively for substitution in anorexic or highly testosterone-deprived patients.
  • the doses used are between 2.5 and 18 mg per day. It is disadvantageous and should therefore be noted that obstructive prostate symptoms can be exacerbated by additive systemic androgenization. These can possibly regress after stopping testosterone. However, it is particularly disadvantageous that with this therapeutic method, even without taking into account the hormonal circadian rhythm, unphysiologically high systemic hormone levels are achieved.
  • TTS peripheral transdermal application via testosterone patches
  • the object of the invention was therefore to develop a testosterone substitution option which is as simple as possible for the patient to use and has no side effects.
  • Ointment A placebo
  • B verum
  • the invention therefore relates to the use of androgens, namely testosterone or other androgenically active substances, and their active and pharmacologically tolerable metabolites or derivatives (for example 17-beta esters or salts), or of derivatives of its metabolites or of metabolites of the derivatives, as well as all other chemical Physicochemically or biologically-naturally derived descendants of testosterone and other androgenically active substances for the production of topical drugs for penile application, distally, medially, proximally or scrotal, preferably glandularly-sub-preputially or intraglandularly-intraurethrally in topical dosage form for the treatment of erectile dysfunctions in mammals, preferred in humans.
  • androgens namely testosterone or other androgenically active substances, and their active and pharmacologically tolerable metabolites or derivatives (for example 17-beta esters or salts), or of derivatives of its metabolites or of metabolites of the derivatives,
  • the application to the penis is therefore primarily distal, secondary medial and proximal and, in special cases, also scrotal.
  • the preferred area of application is the glans penis and the prepuce (glandular-subpreputial and intraglandular-intraurethral).
  • All topical galenic formulations suitable for transdermal use can be used, such as, for. B. ointments, creams, emulsions, foams, pastes, gels, lubricating gels, sprays, solutions, lotions, massage oils, plasters, adhesive films, films,
  • Retard liposomes pens, topical powders or suspensions, biodegradable elastomers or gums.
  • the active substance can also be incorporated directly into a carrier material or microencapsulated or in the form of liposomes.
  • Example 1 Cream / Emulsion testosterone propionate (0.85), emulsifying cetyl stearyl alcohol (16.00), medium chain triglycerides (10,00), sorbic acid (0.10), potassium sorbate (0.10), propylene glycol (4.00) , Perfume oil (0.02), citric acid (0.01), ger. Water (68.92). In sum: 100.00.
  • Testosterone propionate (1.00), Arlatone 9835 (5.00), Dimeticon AKF 350 (0.30), cetylstearyl alcohol (1.50), thin paraffin oil (5.00), white petroleum jelly (9.00), propylene glycol (15 , 00), Ger. Water (63.20). In sum: 100.00.
  • Testosterone propionate (0.80), polyacrylic acid (1.00), propylene glycol (500), oleyl oleate (2.00), glycerol (15.00), triethanolamine (0.22), Ger. Water (75.98). In sum: 100,000.
  • Example 3 Gel testosterone propionate (0.85), poly (O-2-hydroxypropyl) 0-methyl cellulose (2.50), propylene glycol (30.00), Ger. Water (66.65). In sum: 100.00
  • Example 4 Ointment / Paste
  • Example 5 - ointment / paste testosterone propionate (1.00), propylene glycol (10.00),
  • Example 6 ointment / paste testosterone propionate (1.25), cetylstearyl alcohol (0.50),
  • Testosterone propionate (0.85), disorbed LCR (3.00), hydroxypropyl cellulose (2, -00), propylene glycol (45.00), PEG 300 (15.00), dipropylene glycol (10.00), Ger. Water (24 , 15). In sum: 100.00
  • Testosterone propionate (1.00), propylene glycol (25.00), glycerol (10.00), pHB methyl ester (0.10), pHB propyl ester (0.06), ger. Water (63.84). In sum: 100.00
  • Testosterone propionate (0.85), medium chain triglycerides (15.00), oleyl oleate (20.00), isopropyl myristate (5.00), paraffin oil viscous (59.15). In sum: 100.00
  • the preferred inventive testosterone formulation for topical application consists in the use of an emulsifier or an ointment.
  • the topical formulations used according to the invention contain, in addition to the customary auxiliaries, carriers and additives, an effective dose of an androgen, preferably testosterone or active metabolites or derivatives (eg 17-beta-esters) of testosterone or derivatives of its metabolites or of other androgenic substances (eg anabolic steroids) and their metabolites, salts, esters and other derivatives.
  • an androgen preferably testosterone or active metabolites or derivatives (eg 17-beta-esters) of testosterone or derivatives of its metabolites or of other androgenic substances (eg anabolic steroids) and their metabolites, salts, esters and other derivatives.
  • Testosterone enanthate 250 mg intramuscularly every 2-3 weeks, for
  • Testosterone propionate requires a 2-day injection cycle. It is therefore particularly preferred to use an ester which has a certain depot effect due to delayed metabolization to the effective compound.
  • Preferred androgens are testosterone, testosterone acetate, testosterone caproat, testosterone cipionate, testosterone cyclohexane carboxylate, testosterone decanoate, testosterone enantate, testosterone hexahydrobenzyl carbonate, testosterone isobutyrate, testosterone isocaproate, testosterone ketolaurate, testosterone (4) Testosterone phenylacetate, testosterone pivalate, testosterone propionate, testosterone undecanoate, testosterone valerate, testosterone-17-chloral hemiacetal, methyltestosterone, methandrostenolone, 19-hydroxytestosterone, 17-methyltestosterone, 17-alpha-methyltestosterone-3-cyclopentyl-enol ether, 17 -17- methyl-2-oxaandrostan-3-one, dehydroepiandrosterone sulfate, mesterolone, boldenone, danazol, desogestrel, dimethisterone, epiandrosterone, androsterone,
  • testosterone propionate is particularly preferred.
  • the dose of androgenic substance (here e.g. testosterone propionate) is pharmaceutically determined by the absorption size and the derivative used (e.g.
  • Testosterone ester and medically determined by effectiveness.
  • the longer-term topical is sufficient Administration of traces of the active substance from ( ⁇ 0.1 mg) to achieve a restoration of cavernous function, in the event that very high local concentrations were required and topical administration, as expected, predominantly to intracavernous drug pooling with a greatly reduced systemic Flooding leads, especially initially, to concentrations that are in the range of the oral range (> 250 mg).
  • a dose unit of the topical preparation therefore contains 0.005 to 300 mg per dose unit, preferably 0.1 to 250 mg, particularly preferably 1 to 10 mg.
  • the very particularly preferred topical contains 2 mg testosterone propionate per dose unit, e.g. 1 cm ointment strand.

Landscapes

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

Abstract

L'invention concerne l'utilisation de préparations topiques renfermant de l'androgène pour le traitement de la dysérection par application topique pénienne, de préférence par voie glandulaire-subpréputiale ou intraglandulaire-intra-urétrale.
EP97923761A 1996-05-02 1997-04-28 Application topique d'androgene par voie penienne pour le traitement de la dyserection Withdrawn EP0952833A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19617451 1996-05-02
DE19617451 1996-05-02
PCT/DE1997/000863 WO1997041865A1 (fr) 1996-05-02 1997-04-28 Application topique d'androgene par voie penienne pour le traitement de la dyserection

Publications (1)

Publication Number Publication Date
EP0952833A1 true EP0952833A1 (fr) 1999-11-03

Family

ID=7792998

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97923761A Withdrawn EP0952833A1 (fr) 1996-05-02 1997-04-28 Application topique d'androgene par voie penienne pour le traitement de la dyserection

Country Status (2)

Country Link
EP (1) EP0952833A1 (fr)
WO (1) WO1997041865A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
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
EP1347764B1 (fr) * 2000-12-22 2007-03-14 Dr. August Wolff GmbH & Co. KG Arzneimittel Gel a base d'alcool pour traiter l'hypogonadisme par voie trans-scrotale
US20040072810A1 (en) 2001-11-07 2004-04-15 Besins International Belgique Pharmaceutical composition in the form of a gel or a solution based on dihydrotestosterone, process for preparing it and uses thereof
PT1317921E (pt) * 2001-12-07 2009-11-06 Besins Mfg Belgium Composição farmacêutica sob a forma de gel ou de solução à base de di-hidrotestosterona, seu processo de preparação e suas utilizações
WO2005011705A1 (fr) * 2003-07-25 2005-02-10 Adams Kenneth W Activation de la fonction erectile
IL157535A0 (en) * 2003-08-21 2004-03-28 Topimed Ltd Preparations for the prevention of skin atrophy
GB2421183A (en) * 2004-12-17 2006-06-21 Stegram Pharmaceuticals Ltd Topical formulations for use in the treatment or prevention of skin cancers

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3148112A (en) * 1961-10-16 1964-09-08 Upjohn Co Steroid hormone compositions and method of employing same
EP0491076A1 (fr) * 1990-12-19 1992-06-24 Theratech, Inc. Augmentation de la pénétration avec un système à composants multiples contenant des pyrrolidones N-aliphatiques avec des alcools inférieurs
RU2036644C1 (ru) * 1994-01-05 1995-06-09 Олег Борисович Лоран Средство для нормализации половой потенции мужчин
JPH07328053A (ja) * 1994-06-03 1995-12-19 Tsuguto Kaieda 男性器ペニスの勃起力減退及び早漏性射精用薬剤塗布の避妊コンドーム及びその製造方法
US5840327A (en) * 1995-08-21 1998-11-24 Alza Corporation Transdermal drug delivery device having enhanced adhesion

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9741865A1 *

Also Published As

Publication number Publication date
WO1997041865A1 (fr) 1997-11-13

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