WO1997041865A1

WO1997041865A1 - Topical penile androgen application for treatment of erectile dysfunction

Info

Publication number: WO1997041865A1
Application number: PCT/DE1997/000863
Authority: WO
Inventors: Karl-Friedrich Klippel; Dirk-Michael Hiltl
Original assignee: Azupharma Gmbh
Priority date: 1996-05-02
Filing date: 1997-04-28
Publication date: 1997-11-13
Also published as: EP0952833A1

Abstract

This invention concerns the use of a topical preparation containing androgen for treating erectile dysfunction by topical, preferably, glandular-subpreputial or intraglandular-intraurethral application on the penis.

Description

Topical penile androgen application for the treatment of erectile dysfunction

description

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.

The prevalence of erectile dysfunction in Germany is estimated at approximately 5 million men. The loss of erectile potency essentially shakes the physical, mental and social self-image of the man, especially the young man. Patients with chronic erectile dysfunction are very unsettled in their entire behavior. Fears of failure and expectation play a co-determining and sustaining role in this phenomenon and potentiate the subjective experience of illness and insufficiency, so that secondary relevant ego disorders result.

Up until the early 1970s, medical literature found that erectile dysfunction was predominantly psychogenic. This view goes back to Freud's doctrine, who postulated erectile dysfunction as a result of early childhood development disorders.

As a result, over 90% of patients with erectile dysfunction were previously diagnosed with psychogenic causes. However, it was overlooked that somatic disorders lead to secondary psychological alterations.

The success of the couple-oriented sex therapy introduced by Masters and Johnson as well as the development of the first penile prosthesis and the associated treatment option for organically-related ones

Erectile dysfunction led to a fundamental change in the perception of genesis and disease value Erectile dysfunction.

Today it can be assumed that at least 70% of the cases are organic, i.e. are based on neurogenic, vascular or drug-induced disorders, although this magnitude is increasing due to increasingly improved diagnostics.

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

Increasing the arterial inflow and relaxation of the smooth cavernous muscles is accompanied by a considerable restriction of the venous outflow of the erectile tissue.

Based on these findings, all currently relevant pharmacological therapy approaches aim to directly influence this vascular event through the use of vasoactive substances.

Oral therapy for these organic dysfunctions with vasoactive substances such as yohimbine, phenoxybenzamine, terbutaline, Bethanechol, levodopa, verapamil or theophylline was unsuccessful. In addition to the use of prosthetic implants or revascularization operations, an intracavernous injection of papaverine (Virag. Lancet, 2, 938, 1982), the α-receptor blocker phenoxybenzamine (Brindley. Br. J. Psychiatr. 143, 332. 1983) and a combination of Papaverin and the α-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 disadvantage, however, turned out to be partially undesirable prolonged erection with the risk of priapism when using papaverine, undesirable painfulness when using phenoxybenzamine and a possible carcinogenicity of this compound, but also the risk for patients who do not tolerate transient hypotension or who at the same time receive anticoagulants (NIH Consensus Statement, 1992 ).

Recently, SKAT has achieved good results with PGE-L alone or in combination with CGRP.

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. Here are various specific andrological examinations of grades, such as double or duplex sonography of the penile arteries, the corpus cavernosum EMG or the cavernosometry and graphics.

Surprisingly, it has now been found that 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. Furthermore, 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).

In large groups of unselected patients with erectile dysfunction, 8.5% of the men found significantly lower testosterone levels. For this, a further, significant percentage can probably be calculated, at which the testosterone value found is borderline is lower than normal laboratory values, but this testosterone level may be too low for the individual patient to maintain androgen-associated functions.

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.

Oral administration of androgenic steroids (testosterone) has so far only been carried out in men with primary or secondary hypogonadism to replace low testosterone levels. The doses used here are between 80-250 mg per day. 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

Quality of the nocturnal penile erections, although this is not the same for erotically stimulated erections.

Although subnormally high levels of total testosterone can be achieved through oral therapy, most will

Cases at best only marginally improved libido and rarely improved frequency and quality of erectile episodes. In general, as well as in the context of the National Institutes of Health (NIH), Bethseda, Maryland 1992 consensus conference on impotence, the oral administration of androgenic steroids such as testosterone is described as disappointing and ineffective and the possible side effects of systemic testosterone administration ( high first pass effect), as indicated by hepatotoxicity. The NIH subsumes that oral androgens, as currently available, are not indicated.

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.

In the further course of efforts to optimize testosterone substitution in hypogonadal and highly testosterone-deprived patients, peripheral transdermal application via testosterone patches (TTS) was developed, which are affixed to the back, abdomen, arms or legs overnight. The doses used are between 2.5 and 7.5 mg of active ingredient per day. These plasters are expressly not suitable for scrotal or penile application.

For these previously described therapeutic approaches (oral, im, TTS), the only systemically oriented testosterone substitution applies to pronounced hormone-deprived, hypogonadal or anorexic patients (Review: Montorsi, Drugs 50 (3), 465-479, 1995; Cunningham, JAMA, Vol. 261 , No. 17,

2525, 1989). The disadvantage here is that the extensive side effects and risk profile correlating with the exclusively systemic hormone flooding, among others. also due to the high first-pass effect and the associated hepatic stress (Dale, Impotence, Vol. 15, No. 1, 62, 1988).

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.

Experiments with other topical forms, again for exclusively systemic testosterone substitution, are described in the older literature, for example for an ointment, which is also used in testosterone-deprived hypogonadal patients Normalization of testosterone levels or in children with microphallus was used to stimulate penis growth (Findlay, J. Clin. Endocr. Metab. Vol. 68, No. 2, 369, 1989; Ben-Galim, Am J Dis Child, Vol. 134 , 296, 1980).

Surprisingly, it has now been found that suitable topical pharmaceutical testosterone preparations applied penilly, in particular glandular-subpraputially, are suitable for a therapeutically effective treatment of erectile dysfunction, and these findings are also given according to the invention for other application areas on the male genital organ, such as intraglandular-intraurethral or scrotal , be valid.

Even when using the first topical ointment formulation with testosterone propionate (on average approx.4.8 mg per day) with decidedly new, namely glandular-subpraputial or intraglandular-intraurethral application, in a double-blind therapeutic treatment against placebo control, an unexpectedly high effectiveness was shown in initially completely unselected patients with erectile dysfunction of variable origin. In addition to the high efficacy in 5 out of 14 patients tested, it was also noteworthy

Meaning that in the double-blind crossover none of the patients responded to placebo and no side effects were observed topically with verum (testosterone), as are observed with systemic administration of the hormone.

The following first clinical trials were carried out:

14 patients with chronic erectile dysfunction (duration at least 2 years) were offered the external application of an ointment containing testosterone as a form of treatment for the erectile dysfunction. In all patients, detailed diagnostics regarding the etiology of erectile

Dysfunction occurs. Each patient was cleared up in detail and this was documented in writing on the patient sheet.

Each patient applied a 0.5 to 1 cm long ointment strip to the glans penis and the distal shaft every day after showering and approx. 2 hours before traffic and then massaged them in. Ointment A (placebo) and B (verum) were used for about 14 days each. The patients were informed that there might be a placebo under the two ointments.

In the final evaluation, 5/14 patients showed a response to verum and none to placebo. The response patients did not differ very fundamentally from the non-responders in terms of etiology, but in two cases had a (partly borderline) subnormal Testosterone levels.

The patient characteristics for the responders to testosterone ointment are shown in Table I:

Table I

The abbreviations for atiology have the following meaning: A = arterial N = neurogenic vL = venous leak n = normal p = pathological DPVL = dorsal penile vein ligation

In view of the missing selection criteria and the extremely short application time, these first results can be seen as very promising

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.

There are three different topical areas on the male genitalia, both from the dermatological quality of the resorption area and the underlying structural parts of the anatomically distinguishable functional units, and from the vascular drainage situation after resorption after the active ingredient has been transferred from the extravascular space to the intravascular space. The distal portion (glandular-sub-preputial and intraglandular-intraurethral) of the shaft area and for the first time used with a testosterone ointment for application according to the invention and the scrotum clearly separated from it. While a stronger systemic flooding must also be expected in the case of scrotal application, this, according to the first findings here, clearly decreases distally. The first plasma level measurements after glandular-sub-preputial application after 30 or 60 minutes have meanwhile also shown a highly significant concentration of active substance intracavernously, but almost none

Change in peripheral systemic total testosterone. Because with Topika very different

Absorption ratios in distinguishable topical areas are often associated with changed effectiveness and tolerance, this point was also considered by the

Regulatory authorities national (Topic paper) as well as international (Locally acting products / EC / CPMP / Note for Guidance) are taken into account by requiring separate documents on kinetics, effectiveness and tolerability.

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.

Examples of the application forms according to the invention are the following preparations, which, however, are not to be regarded as limiting (amounts in each case in g):

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.

Example 2 - Cream / Emulsion

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.

Example 2 - Gel

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

Testosterone propionate (1.00), plastic fiber (99.00) In sum:

100.00

Example 5 - ointment / paste testosterone propionate (1.00), propylene glycol (10.00),

Polyoxyethylene stearate (10.00), glycerol monostearate (5.00), sorbitan monostearate (2.00), paraffin oil viscous (25.00), white petroleum jelly (30.00), ger. Water (17.00). In sum: 100.00

Example 6 - ointment / paste testosterone propionate (1.25), cetylstearyl alcohol (0.50),

Wool wax alcohols (6.00), white petroleum jelly (92.25). In sum: 100.00

Example 7 - Pen

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

Example 8 - Spray

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

Example 9 - Suspension

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.

The esterification of the 17-beta-hydroxyl group improves the

Fat solubility of testosterone and delays its release. For example, in clinical application

Testosterone enanthate, 250 mg intramuscularly every 2-3 weeks, for

Substitution in anorexic or testosterone-privates

Patients. Testosterone propionate, on the other hand, 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, lontanyl, fluoxymesterone, mestanolone, mibolerone, norethandrolone, normethandone, oxymolonolonolone, oxymolonolonolone, oxymolonolone, oxymolonolonolone, oxymonolonolone, oxymolonolone, oxymonolone, oxymolonolone, oxymonolone, oxymonolone, oxymonolone, oxymolonolone, oxymonolone, oxymonolone, oxymonolonolone, oxymonolone, oxymonolonolone, oxymonolonolone like, stolone, like , Tiomesterone, nandrolone decanoate, Clost ebol acetate or metenolone enanthate.

The use of 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. In the favorable case, 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.

Claims

1. Use of androgens or their pharmacologically acceptable and suitable derivatives or metabolites and salts for the manufacture of medicaments for topical scrotal or penile, in particular glandular-subpraputial or intraglandular-intraurethral application for the treatment of erectile dysfunction in humans and mammals.

2. Use of testosterone or its pharmacologically contractual and suitable derivatives or metabolites and salts according to / 3 claim 1.

3. Use of testosterone, testosterone acetate, testosterone caproat, testosterone cipionate, testosterone cyclohexane carboxylate, testosterone decanoate, testosterone enantate, testosterone hexahydrobenzyl carbonate, testosterone isobutyrate, testosterone isocaproate, testosterone ketolaurate, testosterone (testosterone) (testosterone), testosterone (4-methylpentone) 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, l7-hydroxy-ether 17-methyl-2-oxaandrostan-3-one, dehydroepiandrosterone sulfate, mesterolone, boldenone, danazol, desogestrel, dimethisterone, epiandrosterone, androsterone, lontanyl, fluoxymesterone, mestanolone, mibolerone, norethandrolone, normethandone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolonone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonolone, oxymolonone, oxymolone Tiomesterone, Nandrolone Decanoate, Clostebolaceta t or Metenolonenantat gema _/ 3 claim. 1

4. Use of testosterone propionate according to / 3 claim 1.

5. Use of compounds for the preparation of medicaments according to / 3 of claims 1 to 4 containing 0.005 to 300 mg of active compound per dose unit.

6. Use of compounds for the production of Medicaments according to / 3 of claims 1 to 4 containing 0.1 to 250 mg of active compound per dose unit.

7. Use of compounds for the manufacture of medicaments according to / 3 of claims 1 to 4 containing 1 to 10 mg of active compound per dose unit.

8. Use of testosterone propionate for the production of medicaments containing 2 mg per dose unit.

9. Topical pharmaceutical preparation with a delayed release rate of an androgenic compound for glandular-subpraputiale or intraglandular-intraurethral application.

10. Topical pharmaceutical preparation containing a derivative with a depot effect of an androgenic compound for glandular-sub-preputial or intraglandular-intraurethral application.