WO2013111085A1

WO2013111085A1 - Pharmaceutical composition for the treatment of erectile dysfunction

Info

Publication number: WO2013111085A1
Application number: PCT/IB2013/050613
Authority: WO
Inventors: Raphaël SELLAM
Original assignee: Assistance Publique - Hopitaux De Paris
Priority date: 2012-01-24
Filing date: 2013-01-24
Publication date: 2013-08-01
Also published as: FR2985907A1; FR2985907B1

Abstract

The present invention concerns a pharmaceutical composition comprising, by way of active substances: - papaverine, or one of the pharmaceutically acceptable salts thereof, and - at least one calcium antagonist from the class of dihydropyridines, or a pharmaceutically acceptable salt thereof; and optionally - at least one nitrated derivative, or a pharmaceutically acceptable salt thereof; optionally in association with at least one pharmaceutically acceptable vehicle or excipient, in particular for the use thereof in the prevention or treatment of erectile dysfunction in a person.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ERECTILE DYSFUNCTIONS

Field of the invention

The present invention relates to a pharmaceutical composition useful for treating erectile dysfunction in an individual, in particular by intracavernous injection.

Technical background

Erectile dysfunction, commonly known as impotence, is considered to affect approximately 50% of men aged 40 to 70 years. Its treatment has recently been revolutionized by the arrival on the market of oral phophodiesterase type 5 inhibitors, such as sildenafil (Viagra®) and tadalafil (Cialis®). However, some individuals do not respond to these first-line oral treatments. In addition, the duration between the intake of phosphodiesterase type 5 inhibitors and the erectile response, of the order of the hour, is relatively long.

Given these drawbacks, it turns to second-line treatments, which involve, in particular, intra-cavernous injection of prostaglandin E _\ (PGE, alprostadil) (Montorsi et al (2003) 91 BJU International. 446- 454). This treatment, however, has several disadvantages. The use of alprostadil can lead to prolonged erections or priapism, and cause pain that may lead to discontinuation of treatment. In addition, some individuals respond poorly to Γ alprostadil.

However, at present, there is no real alternative to alprostadil. Thus, papaverine, which was routinely prescribed in the context of intracavernous injection before the arrival of Γ alprostadil on the market, presents a benefit-risk ratio that is more disadvantageous than the latter, both as regards the treatment. erectile dysfunction (Earle et al (1990) J Urol 143: 57-59) with respect to the risk of priapism and cavernous fibrosis (Montorsi et al (2003) BJU International 91: 446 -454). Various drug combinations involving papaverine, for example with phentolamine (Zentgraf et al., (1988) Urol 43: 65-68), have been tested to improve this ratio, but not enough, in the end , so that it is considered a real alternative to Γ alprostadil.

The object of the present invention is therefore to provide a pharmaceutical composition, in particular capable of being administered intracavernously, to overcome the disadvantages mentioned above. Description of the invention

Summary of the invention

The present invention stems from the unexpected finding by the inventor that the intracavernous injection of a combination of papaverine, nicardipine and trinitrin, was effective in treating erectile dysfunction, without being associated with the effects. usually caused by papaverine, namely prolonged erection and cavernous tissue fibrosis.

Thus, the present invention relates to a pharmaceutical composition comprising, as active substances:

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof; and or

at least one nitro derivative, or a pharmaceutically acceptable salt thereof;

optionally in combination with at least one pharmaceutically acceptable carrier or excipient, in particular for use in the prevention or treatment of erectile dysfunction in an individual.

The present invention also relates to a pharmaceutical composition comprising, as active substances:

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof; and eventually

at least one nitro derivative, or a pharmaceutically acceptable salt thereof;

optionally in combination with at least one pharmaceutically acceptable carrier or excipient,

for its use in the prevention or treatment of erectile dysfunction in an individual.

The present invention also relates to a method for preventing or treating erectile dysfunction in an individual, comprising administering, in particular intracavernously, to the individual a prophylactically or therapeutically effective amount:

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof; and or at least one nitro derivative, or a pharmaceutically acceptable salt thereof; and eventually

- prostaglandin

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one nitro derivative, or a pharmaceutically acceptable salt thereof; and eventually

- prostaglandin E _\ .

The present invention also relates to papaverine, or a pharmaceutically acceptable salt thereof, in combination with:

prostaglandin E);

for its use in the prevention or treatment of erectile dysfunction in an individual, particularly by intravenous administration.

- Prostaglandin Ei;

The present invention also relates to a product comprising:

papaverine, or a pharmaceutically acceptable salt thereof, and at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof; and or

- prostaglandin E _\ ;

as a combination product for simultaneous, separate or spread use over time in the prevention or treatment of erectile dysfunction in an individual.

The present invention also relates to a product comprising:

papaverine, or a pharmaceutically acceptable salt thereof, and

- Prostaglandin Ej;

In a preferred embodiment of the invention, the pharmaceutical composition according to the invention, the method according to the invention, the combination for its use according to the invention, or the product according to the invention comprises at least one a calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof, and at least one nitro derivative, or a pharmaceutically acceptable salt thereof.

Furthermore, in another preferred embodiment of the invention, the pharmaceutical composition according to the invention, the method according to the invention, the combination for its use according to the invention, or the product according to the invention comprises in besides prostaglandin Ei.

The present invention also relates to nicardipine, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of erectile dysfunction in an individual.

The present invention also relates to a method for preventing or treating erectile dysfunction in an individual, wherein the individual is administered a prophylactically or therapeutically effective amount of nicardipine or a pharmaceutically acceptable salt thereof.

The present invention also relates to at least one compound for the treatment of erectile dysfunction by the intracavernous route for its use in the treatment of erectile dysfunction in an individual, the compound for the treatment of erectile dysfunction by the intracavernous route being administered intracavernously using a pen injector.

The present invention also relates to a method for the prevention or treatment of erectile dysfunction in an individual in which the individual is administered intravenously and with the aid of a pen injector prophylactically or prophylactically. therapeutically effective at least one compound for the treatment of erectile dysfunction by the intracavernous route.

Erectile dysfunction

As used herein, the term "erectile dysfunction" is considered equivalent to the term "erectile dysfunction" or the term "impotence". Erectile dysfunction is generally defined as the inability to develop or maintain an erection consistent with sexual intercourse in at least 25% of all attempts. In this context, it will generally be considered that the prevention or treatment of erectile dysfunction according to the invention improves the erection of an individual so that less than 25% of his attempts at intercourse translate by failure. More specifically, it is considered that erectile dysfunction is prevented or treated according to the invention if the administration to the individual of the composition, combination, or product, according to the invention, or the application to the individual of the method according to the invention allows the individual to obtain an erection sufficient for sexual intercourse. The erectile dysfunction prevented or treated according to the invention may in particular be of psychological, neurological or vascular origin.

The individual according to the invention is a male mammal, preferably a man. In the case of a man, the individual according to the invention is preferably at least 40, 50, 60, 70, or 80 years old.

In addition, the individual may also have other diseases, or conditions, associated with erectile dysfunction, such as diabetes, paralysis, including paraplegia or quadriplegia, cancer, including prostate cancer or testicles. , multiple sclerosis, or having ablation of the prostate or testicles. However, it will be preferred that the individual according to the invention is not afflicted with Peyronie's disease.

Compound intended for the treatment of erectile dysfunction by the intracavernous route The compound intended for the treatment of erectile dysfunction by the intracavernous route according to the invention may be of any type making it possible to treat erectile dysfunction in the sense of the invention by administration by the intracavernous route. This compound is preferably selected from the group consisting of prostaglandin Ei, papaverine, a calcium antagonist, especially the class of dihydropyridines, a nitro derivative, and a pharmaceutically acceptable salt thereof. More preferably, the compound for the treatment of erectile dysfunction by the intracavernous route according to the invention is included in a pharmaceutical composition according to the invention.

papaveraceous

Papaverine, also called 1 - [(3,4-dimethoxyphenyl) methyl] -6,7-dimethoxy-isoquinoline, has the following formula:

Papaverine acts, in particular, as a nonspecific phosphodiesterase inhibitor.

The pharmaceutically acceptable salts of papaverine will be apparent to those skilled in the art. The preferred pharmaceutically acceptable papaverine salt according to the invention is papaverine hydrochloride.

In this respect, it is preferred that papaverine be present in the pharmaceutical composition according to the invention, or be administered or administered in the context of the method according to the invention, of the combination for its use according to the invention, or of the product. according to the invention, in the form of papaverine hydrochloride. In addition, it is preferred that the pharmaceutical composition according to the invention comprises papaverine hydrochloride at a dose of 10 mg to 100 mg, especially from 13 mg to 80 mg, or at a concentration of 40 mg / ml. Similarly, it is preferred that papaverine hydrochloride be administered or administered at a unit dose of 10 mg to 100 mg, in particular from 13 mg to 80 mg, in the context of the method according to the invention, of the combination of for its use according to the invention, or the product according to the invention. Calcium antagonists of the dihydropyridine class

"Calcium antagonists of the dihydropyridine class", also known as class II calcium antagonists, are well known to those skilled in the art. They are distinguished in particular antagonists of calcium class I, phenylalkylamine type, such as verapamil, or class III, benzothiazepine type, such as diltiazem.

Preferably, the calcium antagonist of the dihydropyridine class according to the invention is selected from the group consisting of nicardipine, nifedipine, nitrendipine, amlodipine, felodipine, isradipine, lacidipine, lercanidipine and manidipine. In a particularly preferred manner, the calcium antagonist of the dihydropyridine class according to the invention is nicardipine.

The pharmaceutically acceptable salts of the calcium antagonist of the dihydropyridine class according to the invention will become clear to those skilled in the art. The salt of the calcium antagonist of the class of dihydropyridines according to the invention pharmaceutically acceptable preferred according to the invention is the hydrochloride salt.

In this respect, it is preferred that nicardipine be present in the pharmaceutical composition according to the invention, or be administered or administered in the context of the method according to the invention, of the combination for its use according to the invention, or of the product. according to the invention, in the form of nicardipine hydrochloride. In addition, it is preferred that the pharmaceutical composition according to the invention comprises nicardipine hydrochloride at a dose of 0.15 mg to 3 mg, in particular from 0.3 mg to 2 mg, or at a concentration of 1 mg / ml. . Similarly, it is preferred that nicardipine hydrochloride be administered, or administered, at a unit dose of 0.15 mg to 3 mg, particularly 0.3 mg to 2 mg, as part of the method according to US Pat. invention, the combination for its use according to the invention, or the product according to the invention.

Nitrate derivatives

The drug class of nitrates is well known to those skilled in the art. Nitrate derivatives act, in particular, as donors of nitric oxide (NO). Preferably, the nitrated derivative according to the invention is selected from the group consisting of trinitrin, isosorbide dinitrate, and isosorbide-5-mononitrate. In a particularly preferred manner, the nitro derivative according to the invention is trinitrin.

The pharmaceutically acceptable salts of the nitrated derivatives according to the invention will become clear to those skilled in the art.

It is preferred that the pharmaceutical composition according to the invention comprises trinitrin, at a dose of 0.05 mg to 1.5 mg, in particular from 0.15 mg to 1 mg, or at a dosage of concentration of 0.5 mg / ml. Similarly, it is preferred that trinitrin be administered or administered at a unit dose of 0.05 mg to 1.5 mg, in particular 0.15 mg to 1 mg, in the context of the method according to US Pat. invention, the combination for its use according to the invention, or the product according to the invention.

prostaglandin

Prostaglandin E _\ (PGEi) is also called alprostadil. When present, it is preferred that the prostaglandin Ei be included in the pharmaceutical composition according to the invention at a dose of 3 μg to 40 μg, or at a concentration of 20 μg / ml. Similarly, it is preferred that the prostaglandin Ei be administered or administered at a unit dose of 3 μg to 40 μg, in the context of the method according to the invention, of the combination for its use according to the invention, or of the product according to the invention.

Administration

Most preferably, the pharmaceutical composition according to the invention comprises:

papaverine hydrochloride at a dose of 13 mg to 80 mg or at a concentration of 40 mg / ml; and

nicardipine hydrochloride at a dose of 0.3 mg to 2 mg, or at a concentration of 1 mg / ml; and

trinitrin at a dose of 0.15 mg to 1 mg, or at a concentration of 0.5 mg / ml; and eventually :

prostaglandin _E1 at a dose of 3 μg at 40 μg, or at a concentration of 20 μg / ml;

optionally in combination with a pharmaceutically acceptable carrier or vehicle.

In the same way, the method according to the invention, the combination for its use according to the invention as well as the product according to the invention comprise the administration:

nicardipine hydrochloride at a unit dose of 0.3 mg to 2 mg; and

trinitrin at a unit dose of 0.15 mg to 1 mg; and eventually :

of prostaglandin Ej at a unit dose of 3 μg to 40 μg.

Preferably, the pharmaceutical composition according to the invention is administered, or administrable (that is to say, it is in a form suitable for administration), by the intracavernous route, in particular by an intracavernous injection, or by the intraurethral route, in particular by intraurethral injection. Likewise, the method according to the invention, the combination for its use according to the invention and the product according to the invention preferably make use of an administration, in particular by injection, by the intracavernous route or by the intravenous route. urethral.

When performed by intracavernous injection, the administration according to the invention will preferably use a syringe capable of delivering a volume of 0.3 ml to 2 ml in one injection. In a particularly preferred manner, a syringe according to the invention is an injection pen, in particular of the insulin pen type.

Injection pens are well known to those skilled in the art; they are injection devices comprising a reservoir capable of containing several doses to be administered, the volume of each dose to be injected, in particular from 0.3 ml to 2 ml, being programmable before the injection, the injection of the dose to be injected at the programmed volume by pressing a push button. Examples of insulin pens include insulin pens, such as Novopen 3 and 4 (Novo), Humanpen (Lilly), Optipenprol and 2 (Aventis), or Flexpen (Novo Nordisk).

In the context of the invention, when the administration is carried out by the intraurethral route, the pharmaceutical composition according to the invention, the combination for its use according to the invention, the product according to the invention, papaverine, or a pharmaceutically acceptable salt thereof, the calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof, the nitro derivative, or a pharmaceutically acceptable salt thereof, and / or the prostaglandin Ei are in the form of a gel.

Moreover, as used herein, in the context of the method according to the invention, of the combination according to the invention or of the product according to the invention, papaverine and calcium channel blocker of the class of dihydropyridines and / or or the nitro derivative, as well as optionally the prostaglandin E ₁₅ can be administered together, within the same pharmaceutical composition, or separately, according to administration regimes and / or sites or routes of different administration. It is preferred, however, that the papaverine and dihydropyridine calcium channel blocker and / or the nitrate derivative, as well as possibly the prostaglandin E 1, be administered together, particularly by intracavernous injection.

The production of a pharmaceutical composition according to the invention may in particular be carried out by preparing a mixture of a volume of 2 ml comprising 80 mg of papaverine hydrochloride, 2 mg of nicardipine hydrochloride, 1 mg of trinitrin, and optionally 40 μg of prostaglandin E1, in a liquid solution adapted to intracavernous injection, such as water, in particular water for injection (ppi), which may comprise in particular salt (NaCl), preferably at the concentration of 9 g / 1.

As used herein, at least one pharmaceutically acceptable carrier or excipient may be present in the pharmaceutical composition according to the invention, or may accompany the administration of papaverine and calcium channel blocker of the dihydropyridine class and / or nitro derivative, as well as optionally prostaglandin Ei, in the context of the method according to the invention, the combination for use according to the invention or the product according to the invention.

Pharmaceutically acceptable vehicles or excipients according to the invention, that is to say vehicles or excipients whose administration to an individual is not accompanied by significant deleterious effects, are well known to those skilled in the art.

Examples

Example 1

A first mixture according to the invention is prepared by adding 2 mg of nicardipine hydrochloride in powder form and 1 mg of trinitrin in powder form to the content of two 1 ml ampoules each comprising 40 mg of papaverine hydrochloride in saline ppi water (NaCl). This mixture is placed in a syringe of the insulin pen type which makes it possible to accurately inject unit volumes starting from 0.1 ml (corresponding to the volume for injecting 10 international units (IU) of insulin, which is usually in solution of 100 IU / ml in this type of pen).

Example 2

A second mixture according to the invention is prepared as for the first mixture of Example 1 but additionally adding 40 μg of prostaglandin E _\ . As in Example 1, this mixture is placed in a syringe of the insulin pen type.

Example 3

Patients with erectile dysfunction in whom oral phophodiesterase type 5 (IPDE5) inhibitors, such as sildenafil, tadalafil and vardenafil, are effective, can not use them because of their financial resources limited.

These patients can benefit from treatment with unit injections of 0.10 to 0.20 mL, corresponding to 10 to 20 international units (IU), using an insulin pen-type syringe filled by the first one. solution described in Example 1.

The estimated cost of this treatment is 3 to 6 times lower than that using

(PDE5 inhibitors).

Example 4

Patients with erectile dysfunction usually well controlled by prostaglandin syringes E _\ of Edex or Caverject type and administering is by this means 5, 10, 15 or 20 micrograms of prostaglandin may advantageously receive injections performed with a syringe insulin pen type with a unit volume of 0.1 to 0.8 ml, corresponding to 10 to 80 IU, of the second mixture described in Example 2, which provide similar efficacy with less prostaglandin Ei.

Example 5

Patients with erectile dysfunction who require high doses of prostaglandin (40 μg) to be treated may, instead of giving two injections of 20 μg prostaglandin Ei (maximum unit dose Edex and Caverject systems), make a single injection of 1.5 ml to 2 ml of the second mixture described in Example 2.

Example 6

Patients suffering from erectile dysfunction in whom the administration of prostaglandin Ei is painful, which may lead to the discontinuation of treatment, may advantageously use the first mixture of Example 1, which does not include prostaglandin Ei, or the second mixture of Example 2, which provides treatment efficacy similar to that of prostaglandin alone but with lesser amounts.

Example 7

Patients suffering from erectile dysfunction and refractory to treatment with prostaglandin Ei at 40 μg, maximum acceptable dose, can inject 2 ml of the second mixture described in Example 2.

This last injection may also represent a therapeutic test because the inefficiency of the administration of this mixture must lead to the establishment of a penile prosthesis.

In conclusion, the use of the mixtures according to the invention, in particular in conjunction with syringes of the insulin syringe type, makes it possible to treat the entire range of patients suffering from erectile dysfunction.

Claims

A pharmaceutical composition comprising, as active substances:

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one nitro derivative, or a pharmaceutically acceptable salt thereof;

A pharmaceutical composition for use according to claim 1, comprising both at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof, and at least one nitro derivative, or a pharmaceutically acceptable salt of it.

A pharmaceutical composition for use according to claim 1 or 2, wherein the calcium antagonist of the dihydropyridine class is selected from the group consisting of nicardipine, nifedipine, nitrendipine, amlodipine, felodipine, isradipine, lacidipine, lercanidipine and manidipine.

4. Pharmaceutical composition for use according to one of claims 1 to 3, wherein the calcium antagonist of the dihydropyridine class is nicardipine.

A pharmaceutical composition for use according to any one of claims 1 to 4, wherein the nitro derivative is selected from the group consisting of trinitrin, isosorbide dinitrate, and isosorbide-5-mononitrate.

Pharmaceutical composition for use according to one of claims 1 to 5, wherein the nitro derivative is trinitrin.

Pharmaceutical composition for use according to one of claims 1 to 6, comprising papaverine hydrochloride at a dose of 10 mg to 100 mg.

8. Pharmaceutical composition for its use according to one of claims 1 to 7, comprising nicardipine hydrochloride at a dose of 0.15 mg to 3 mg.

A pharmaceutical composition for use according to any one of claims 1 to 8, comprising trinitrin at a dose of 0.05 mg to 1.5 mg.

10. Pharmaceutical composition for its use according to one of claims 1 to 9, further comprising prostaglandin E _\ .

Pharmaceutical composition for use according to one of claims 1 to 10, in a form suitable for administration by the intracavernous or intraurethral route.

12. Pharmaceutical composition comprising, as active substances:

papaverine, or a pharmaceutically acceptable salt thereof, and

at least one calcium antagonist of the dihydropyridine class, or a pharmaceutically acceptable salt thereof; and

at least one nitro derivative, or a pharmaceutically acceptable salt thereof;

optionally in combination with at least one pharmaceutically acceptable carrier or excipient.

The pharmaceutical composition according to claim 12, wherein the calcium antagonist of the dihydropyridine class is selected from the group consisting of nicardipine, nifedipine, nitrendipine, amlodipine, felodipine, isradipine, lacidipine, lercanidipine and manidipine.

The pharmaceutical composition of claim 12 or 13 wherein the calcium antagonist of the dihydropyridine class is nicardipine.

15. Pharmaceutical composition according to one of claims 12 to 14, wherein the nitro derivative is selected from the group consisting of trinitrin, isosorbide dinitrate, and isosorbide 5 -mononitrate.

16. A pharmaceutical composition for use according to one of claims 12 to 15, wherein the nitro derivative is trinitrin.

17. Pharmaceutical composition according to one of claims 12 to 16, comprising papaverine hydrochloride at a dose of 10 mg to 100 mg.

18. Pharmaceutical composition according to one of claims 12 to 17, comprising nicardipine hydrochloride at a dose of 0.15 mg to 3 mg.

19. Pharmaceutical composition according to one of claims 12 to 18, comprising trinitrin at a dose of 0.05 mg to 1.5 mg.

20. Pharmaceutical composition according to one of claims 12 to 19, further comprising prostaglandin Έ.

21. Pharmaceutical composition according to one of claims 12 to 20, in a form suitable for administration by the intracavernous or intraurethral route.