WO2007125074A1

WO2007125074A1 - Use of alverine for the prevention and/or treatment of male and female sexual dysfunctions

Info

Publication number: WO2007125074A1
Application number: PCT/EP2007/054094
Authority: WO
Inventors: Mark Crawford; Frédéric Revah
Original assignee: Cerep
Priority date: 2006-04-28
Filing date: 2007-04-26
Publication date: 2007-11-08
Also published as: FR2900337A1

Abstract

The present invention relates to the preparation of a pharmaceutical composition comprising Alverine, its metabolites, salts or esters designed to prevent or treat sexual dysfunctions in men and women, in particular hypoactive sexual desire disorders. The present invention relates in particular to the preparation of a pharmaceutical composition designed to prevent or treat the disorders of the physiological and/or anatomical responses to sexual stimulation in humans.

Description

Use of Alverine for the prevention and/or treatment of male and female sexual dysfunctions

The present invention relates to the utilization of a drug for the prevention and/or treatment of sexual dysfunctions in men and women, and particularly hypoactive sexual desire disorder (or hypoactive sexual desire disease). This invention relates in particular to the use of a drug designed to improve the syndrome known as Hypoactive Sexual Desire

Disease (HSDD).

Such a drug contains the active ingredient Alverine, or its metabolites, salts or esters. BACKGROUND OF THE INVENTION

In men and women, the desire for, and pleasure derived from, sexual contact may be altered temporarily, and sometimes chronically, without identifiable organic cause. The most frequent disturbances observed include absence of sexual thoughts, absence of sexual desire even after stimulation, difficulty to reach an orgasm, limited sexual pleasure and/or decrease or absence of natural vaginal lubrication. These disturbances often lead to a lack of interest in sexual activities. These disturbances are called in the present application "sexual dysfunctions". According to some estimates, the frequency of temporary or chronic sexual dysfunctions in women would be similar to that of erectile dysfunctions in men (see for instance Laumann E. O., JAMA 281; 537-544, 1999). In particular, one of the known types of male and female sexual dysfunctions is the

Hypoactive Sexual Desire Disease (or Hypoactive Sexual Desire Disorder) or HSDD, which is defined as a lack of sexual desire, leading to a feeling of personal distress. It is the most frequently reported sexual disorder by women (see Laumann E.O., J.A.M.A. 281; 537-544, 1999). HSDD can be at the origin of a feeling of malaise, concern or frustration and have negative consequences on the relationship between a woman and her partner. According to a recent study, it is estimated that one woman out of three following surgical menopause, suffers from a decrease in sexual desire and almost half of these women develop the related feeling of personal distress (Leiblum S, Koochaki P, Rodenberg C, Rosen R. Prevalence of low sexual desire and sexual activity levels amongst populations of menopausal women, NAMS Oral presentation 2002). This disorder, despite presenting several clinical signs similar to depression, is distinct and unrelated to underlying causes of depression.

Psychotherapy is currently the primary treatment option to attempt to control and reduce HSDD, with generally unsatisfactory results. Today, the only known pharmaceutical treatment for HSDD is testosterone supplementation. The disadvantages of testosterone are well known. The first risk is increased incidence of cancer. In some cases, testosterone can also lead to an increase in the number of red blood cells, with an increased risk of thrombosis due to the increased viscosity of the blood. Finally, in men, testosterone administration reduces the levels of LH and FSH, leading to a decrease in the sperm production.

It is therefore desirable to have treatments capable of reducing the severity and/or the duration of this disorder, or to prevent its development, and to restore in affected individuals their ability to have satisfactory sexual relationships.

In addition, the preferred route of administration for a medication designed to treat sexual dysfunctions is the oral route, and the drug itself must be as well tolerated as possible and have as few contraindications as possible.

BRIEF DISCLOSURE OF THE INVENTION The present invention is based on the unexpected finding of the properties of

Alverine to reduce the signs of sexual dysfunctions and in particular of HSDD.

The advantage of Alverine is that it is a drug which has been on the market for more than 50 years and which shows a very low level of toxicity and side effects compared to most drugs. The present invention relates to the new therapeutic use of Alverine or its metabolites, esters and salts for the preparation of pharmaceutical compositions for the prevention and/or treatment of male and female sexual dysfunctions.

The present invention relates to a method for the prevention and/or treatment of male and female sexual dysfunctions in humans, particularly HSDD, comprising administering Alverine or its metabolites, esters and salts.

The invention also concerns a method to increase sexual desire and/or to increase sexual activity and/or to increase sexual performances and/or to increase the intensity of sexual pleasure and/or to increase sexual satisfaction, by administration of a pharmaceutical composition containing Alverine or its metabolites, salts and esters, in humans not suffering from sexual dysfunctions.

DETAILED DISCLOSURE OF THE INVENTION

Alverine means N-Ethyl-3,3'-diphenyldipropylamine:

CH₂CH₂CN₃ CH₅CH₃N

Alverine metabolites include in particular, but not only, the mono or poly- hydroxylated derivatives on the phenyl rings and the mono or poly-carboxylation of the aliphatic chains. Three of the main metabolites following incubation of Alverine with human liver microsomes are: Metabolite 1:

Metabolite 2:

Metabolite 3:

Pharmaceutically acceptable salts are defined as salts combined with Alverine which can be obtained by chemical reaction of Alverine with a mineral or organic acid, using a known chemical method. Amongst acids which can be used for this purpose, one can list the sulphuric, chlorhydric, bromhydric; phosphoric, 4-toluene-sulfonic, methane- sulfonic, cyclohexyl sulfamic, axalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic, glutamic, N-acetyl aspartic, N-acetyl glutamic, ascorbic, malic, benzoic, nicotinic and acetic acids. Alverine citrate and tartrate have been widely used for pharmaceutical preparations in other indications.

Amongst the hydroxy esters, the esters of carboxylic acid with 1-6 carbon atoms can be cited. Alverine is marketed as an antispasmodic agent specifically for symptomatic relief of pain due to irritable bowl and dysmenorrhoea. There are several publications demonstrating antispasmodic action in animal models (for example, see Bouvier, M; Grimaud, JC; Abysique, A; Chiarelli, P; Effects of alverine on the spontaneous electrical activity and nervous control of the proximal colon of the rabbit; Gastroenterol Clin Biol. 1992;16(4):334-8). However, there are published clinical trials suggesting that Alverine is no more effective than placebo in relieving pain associated with irritable bowel syndrome (Mitchell, S. A 1; Mee, A. S 2; Smith, GD; Palmer, K; Chapman, RW; Alverine citrate fails to relieve the symptoms of irritable bowel syndrome: results of a double-blind, randomized, placebo-controlled trial; Alimentary Pharmacology & Therapeutics. 16(6):1187-1195, June 2002).

The mode of action of Alverine remains unknown. The activity of Alverine as an agent useful to prevent of treat sexual dysfunctions has never been described, reported or suggested

Alverine, its metabolites, salts and esters can be administered in acceptable pharmaceutical compositions by several routes well known for this type of product.

Particularly, this invention relates to the utilization of Alverine and/or of its metabolites in a pharmaceutically acceptable composition to be administered by oral, sublingual, buccal, sub-cutaneous, transdermal, local, rectal, intranasal or injectable (in particular intra-peritoneal, intra-venous or intra-muscular) routes. Particularly, this invention relates to the utilization of Alverine and/or its metabolites, salts and esters for the preparation of a pharmaceutical composition which can be administered orally, particularly as tablets or capsules.

The active ingredients of the pharmaceutical compositions included in this invention may be in any form suitable for oral administration, including tablets, capsules and liquid preparations such as elixirs and syrups including various additional substances designed to modify the color, taste or stability of the preparation.

To realize the oral forms included in this invention, in particular capsules, the active ingredient can be mixed with various common substances such a starch, calcium carbonate, lactose, sucrose, dicalcium-phosphate to facilitate the encapsulation process. Magnesium stearate may be used in addition for its lubricating properties if necessary.

It may also in some instances be useful to realize slow-release or controlled-release formulations following known methods of preparation of such formulations. The present invention also relates to the utilization of Alverine and/or its metabolites, salts and esters, for the preparation of a pharmaceutical composition which can be administered via an injection.

The active ingredients of the injectable pharmaceutical preparations in this invention may be dissolved or mixed in a suspension in a pharmaceutically acceptable sterile liquid, such as sterile water, sterile organic solvent or a mixture of both for an intravenous preparation.

Other possible routes of administration include, but are not limited to, subcutaneous implants and other preparations to be administered by the buccal, sublingual, transdermal, topical, intranasal or rectal routes. Biodegradable and non-biodegradable systems may also be used.

According to a specific mode of realization, this invention relates to the utilization of Alverine, its metabolites, salts and esters for the preparation of a pharmaceutical composition to be administered through one of the above-mentioned routes at doses of 1 to 1000 mg of the active ingredient formulated as capsules or tablets or at doses of 0.1 to 500 mg of the active ingredient formulated as suppositories, ointments, creams, gels, aerosols, to be administered in human therapeutics in one or several daily doses for an adult of 60-70 kg of average weight.

According to a specific mode of realization, this invention relates to the utilization of Alverine, its metabolites, salts and esters for the preparation of a pharmaceutical composition designed to be administered to prevent or treat hypoactive sexual desire disorders.

According to another specific mode of realization, this invention relates to the non- therapeutic utilization of Alverine, its metabolites, salts and esters for the preparation of a pharmaceutical composition to be used to increase sexual desire and/or increase sexual activity and/or increase sexual performance and/or increase the intensity of sexual pleasure and/or increase the sexual intercourse satisfaction in humans not suffering from sexual dysfunctions.

Claims

1. Use Alverine, its metabolites, salts and esters for the preparation of pharmaceutical compositions for the prevention and/or treatment of male and female sexual dysfunctions.

2. The use of claim 1, wherein the pharmaceutical composition is administered by the oral route.

3. The use of one of claims 1 or 2, wherein the pharmaceutical composition contains 0.1 to 1000 mg of Alverine.

4. The use of one of claims 1 to 3, wherein the pharmaceutical composition is administered in one or several daily doses for an adult of 60-70 kg average weight.

Use as per claims 1 to 6 in which the sexual dysfunctions are hypoactive sexual desire disorders.

5. The use of one of claims 1 to 4, wherein sexual dysfunction is Hypoactive Sexual Desire Disease (HSDD).

6. A method to increase sexual desire and/or to increase sexual activity and/or to increase sexual performances and/or to increase the intensity of sexual pleasure and/or to increase sexual satisfaction, by administration of a pharmaceutical composition containing Alverine or its metabolites, salts and esters, in humans not suffering from sexual dysfunctions.