WO2000048570A1

WO2000048570A1 - Pharmaceutical composition for balanic transmucosal administration of alfuzosin

Info

Publication number: WO2000048570A1
Application number: PCT/FR2000/000358
Authority: WO
Inventors: Anne Charlier; Alain Cuine; Alain Dufour
Original assignee: Sanofi-Synthelabo
Priority date: 1999-02-16
Filing date: 2000-02-14
Publication date: 2000-08-24
Also published as: FR2789586A1; AU2676600A

Abstract

The invention concerns a pharmaceutical composition for balanic transmucosal administration, characterised in that it comprises an active principle consisting in alfuzosin, in free form or one of its salts, and an exclusively hydrophile or partly hydrophile absorption promoter

Description

PHARMACEUTICAL COMPOSITION FOR BALANIC TRANSMUCOSAL ADMINISTRATION OF ALFUZOSINE

The subject of the present invention is a pharmaceutical composition for balanic transmucosal administration, comprising as active ingredient N- [3- [(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide ( or alfuzosin), in free form or in a salt, as well as the use of this pharmaceutical composition in therapy.

For the purposes of the present invention, the term "alfuzosin" means N- [3 - [(4-amino- 6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furanecarboxamide, in free form or in form of a salt with a pharmaceutically acceptable acid. Among the pharmaceutically acceptable acids which can form a salt with alfuzosin, mention may be made, for example, of hydrochloric, ascorbic, maleic, succinic, tartaric, citric and hydroxymaleic acids. Alfuzosin hydrochlorides are the preferred salts in the context of the present invention.

Alfuzosin, some of its salts, as well as their preparation processes, are described in patent FR2466462. Alfuzosin, and in particular its hydrochloride, are currently marketed in the form of tablets for the treatment of benign prostatic hyperplasia.

The present invention relates to a balanic transmucosal pharmaceutical composition, intended for the treatment of erectile dysfunctions, formulated so as to allow the absorption of alfuzosin through the balanic mucosa.

Another object of the present invention is to allow rapid absorption of alfuzosin at the application site with a level of alfuzosin sufficient to achieve the desired therapeutic effect.

In the context of the present invention, the quantities, unless otherwise indicated, are expressed in% by weight of the total composition.

More specifically, the invention consists of a pharmaceutical composition characterized in that it comprises an active principle consisting of alfuzosin, as well as at least one specific absorption promoter, said composition being formulated to allow balanic transmucosal administration. The term absorption promoter is understood to mean a pharmaceutically acceptable compound which makes it possible to improve the passage of the principle through a mucosa and more particularly the balanic mucosa. To this end, the absorption promoter can, in particular, modify the permeability or change the state of the surface of the mucosa in order to facilitate passage.

It has been discovered that specific absorption promoters, particularly suitable for a pharmaceutical composition according to the invention, are compounds having an exclusively hydrophilic or partially hydrophilic character. More specifically, we can cite:

- dioxolane or dioxane derivatives, more specifically derivatives 1, 3-dioxolanes (1, 3-dioxacyclopentanes) or 1, 3-dioxanes (1, 3-dioxacyclohexanes) such as 1, 3 dioxolane, methyl-1 , 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane, 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal), as well as the derivatives described in patent EP0268460 such as 2-n-pentyl-1, 3-dioxolane, 2-n-heptyl-1, 3-dioxolane, 2 -n-undecyl-1, 3-dioxolane, 2 (2 ', 6'-dimethyl-2'-heptaenyl) -1, 3-dioxane and 2-n-nonyl-1, 3-dioxolane. The derivatives 1, 3 dioxolane, methyl-1, 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane and the 2, 2-dimethyl-1, 3-dioxolane-4-methanol, more hydrophilic in character, are particularly preferred and more specifically 2,2-dimethyl-1,3-dioxolane-4-methanol (solketal);

- fatty acid monoglycerides, such as, for example, capric / caprylic acid monoglyceride; - fatty esters of glycerols and polyethylene glycol (PEG), by way of example, there may be mentioned glycerol and PEG-6 monooleate and glycerol and PEG-8 linoleate; - fatty esters of propylene glycol such as laurate or caprylate / caprate of propylene glycol

- terpenes such as t-anethole, carvacrol, carvone, 1-8 cineole, d-limonene, 1-menthol, menthone, terpinene and thymol or

- the constituents of essential oils such as carveol, nerolidol and linalool.

Under the present invention, the dioxolane or dioxane derivatives, as mentioned above and more particularly 2,2-dimethyl-1, 3-dioxolane-4-methanol (solketal) and 2-n-nonyl- 1, 3-dioxolane are particularly preferred.

According to another aspect of the present invention, it is also possible to use a combination of at least two of the absorption promoters such as described above.

Some absorption promoters can, to be correctly formulated, be at least partially dissolved by one or more organic solvents, if necessary, in mixture with water. These organic solvents can also, in combination with absorption promoters, facilitate the transmucosal passage of the active principle. Among these solvents which can be used to dissolve the absorption promoters, mention may be made of ethanol, propanol, isopropanol, diethylene glycol monoethyl ether (transcutol®), glycofurol, glycerol, propylene glycol and polyethylene glycols. liquid state.

According to another advantageous aspect of the invention, the composition can contain a natural or synthetic prostaglandin. A prostaglandin is for example PGE1 or PGE2. Prostaglandin is preferably added in an amount of 10 μg to 25 mg / ml in the composition, preferably 50 μg to 10 mg / ml.

On the other hand, in order to facilitate the absorption of alfuzosin through the balanic mucosa, the pharmaceutical composition is in the form of a hydrophilic pharmaceutical composition. Such a hydrophilic pharmaceutical composition consists, for example, of a hydrophilic cream, a gel, an emulsion or microemulsion or a lotion. Advantageously, the pharmaceutical composition is in the form of a gel.

The term “gel” is intended to mean a semi-solid aqueous preparation comprising in particular gelling agents.

The gelling agents according to the invention are:

- cellulose derivatives in proportions of 1 to 20%, more particularly sodium carboxymethylcellulose, hydoxyethylcellulose (HEC) (for example Natrosol®) in proportions of 1 to 5%, hydroxypropylmethylcellulose (HPMC) (for example Metolose® grade

65SH-400 and 65SH-4000, or Methocel® E4M, F4M or 4KM) in proportions of 5 to 20% or hydroxypropylcellulose (HPC) (for example Klucel®) in proportions of 1 to 10%,

polyacrylic derivatives such as those sold under the Carbopol® brand or polyacrilamides such as Sepigel® 305, in proportions of 2 to 5%,

poloxamers (block copolymers of polyoxyethylene and polyoxypropylene), more specifically poloxamer 407 in proportions of 15 to 50%, and - natural gums such as xanthan gum, guar gum, locust bean gum in proportions of 1 to 10%.

The preparation can also include mineral thickening agents such as aluminum hydroxide gel or colloidal silica in proportions of 1 to 10%.

A pharmaceutical composition according to the invention can comprise from 1 to 50 mg / ml of active principle, preferably 5 to 25 mg / ml.

The content of absorption promoter in the composition of the invention can vary within wide limits, in particular as a function of the concentration of active principle and of the very nature of the absorption promoter used. It is thus possible to use an absorption promoter content of between 0.5 and 50% by weight of the composition. However, the promoter content is generally between 0.5 to 5% in the case of terpenes 2 to 50% in the case of other promoters.

The solvent content can vary depending, in particular, on the nature of the absorption promoter and on the fact that the solvent itself can facilitate the absorption of the active product. In fact, in addition to its role as solubilizing agent for the absorption promoter, the solvent can also be useful as a solubilizing agent for the active principle and / or as an excipient constituting said pharmaceutical composition. Based on these different parameters, the skilled person can determine the solvent content required.

In addition, a pharmaceutical composition according to the invention can comprise conventional excipients such as perfumes, essential oils, preservatives, soothing moisturizers, or colorings.

These compositions can be prepared according to conventional methods for a person skilled in the art. The methods are an integral part of the invention.

For example, the active principle can be mixed in solution in water and / or in a solvent necessary for the dissolution of the absorption promoter, as defined above, with this absorption promoter. Conventional excipients, as defined above, can be added to this solution. In the case of a gel, the gelling agent is preferably added last. The pharmaceutical compositions of the invention can be applied to the scrotum and the penis, but more particularly the application site concerns the balanic mucosa, either the glans or the balano-prepucial sulcus, preferably the glans. At the application site, the pharmaceutical composition is applied in an amount of 0.1 to 1 ml.

In order to simplify the application of the required dose, the pharmaceutical compositions according to the invention can be contained in a device for topical application.

Another object of the present invention is such a device comprising a pharmaceutical composition as described above. This device may in particular consist of a metering dispenser consisting of a reservoir provided with a system capable of releasing the pharmaceutical composition in a predetermined dose, such as a piston system. This dose can then be spread over the skin.

The use of a pharmaceutical composition according to the present invention for the preparation of a medicament intended for treating erectile dysfunctions is another object of the invention.

The following examples are intended to illustrate the present invention.

EXAMPLE 1 Gel for local application (in% by weight): Alfuzosin hydrochloride 4%

Solketal 10%

Miglyol 15%

Poloxamer 407 15%

Isopropanol 5% Water qs

Preparation: the active principle is dissolved in water, then the excipients are added, the gelling agent being introduced last. EXAMPLE 2 Emulsion / gel for local application (in% by weight):

Alfuzosin hydrochloride 1.5%

Propylene glycol 24% Capric / caprylic acid monoglyceride 24%

Carbopol 974 1%

Triethanolamine q.s. pH

Tween 80 2%

Water q.s

The preparation is identical to that of Example 1.

EXAMPLE 3 Gel for local application (in% by weight):

Alfuzosin hydrochloride 1.5% Propylene glycol 19%

Limonene 1%

Ethanol 10%

Carbopol 974 4.5%

Triethanolamine q.s. pH water q.s

The preparation is identical to that of Example 1.

EXAMPLE 4 Gel for local application (in% by weight Alfuzosin hydrochloride 4%

2-n-nonyl-1, 3 dioxolane 10%

Miglyol 15%

Poloxamer 407 15%

Isopropanol 5% Water qs EXAMPLE 5 Gel for local application (in% by weight):

Alfuzosin hydrochloride 4%

Solketal 10%

Miglyol 15%

Poloxamer 407 15%

Isopropanol 5%

PGE1 2%

Water qs

The preparation is identical to that of Example 1.

The gel can then be packaged in a rigid and opaque polypropylene tube, equipped with a dosing pump.

Transmucosal flow measurement

This determination was carried out on an “ex-vivo” model described by T.J. Franz (Current Problems in Dermatology, 7, 58-68, 1978) and by B. Neau et al. (Skin Pharmacol., 7, 121-129, 1994).

For example, absorption is monitored in Franz diffusion cells through the hairiess rat skin (normal or delaminated) and / or through a mucosa (great equine or possibly human). A dose of 5 to 10 mg / cm ² of the pharmaceutical composition can be applied to a defined surface which can range from 1 to 2 cm ² depending on the nature of the anatomical part. The survival liquid (phosphate buffer) is completely removed and analyzed at specified times.

Claims

claims

1. Pharmaceutical composition suitable for balanic transmucosal administration, characterized in that it comprises an active principle consisting of alfuzosin, in free form or one of its salts, as well as at least one specific absorption promoter having a exclusively hydrophilic or partially hydrophilic character.

2. Pharmaceutical composition according to claim 1, characterized in that the absorption promoter is chosen from the group consisting of:

- dioxolane or dioxane derivatives,

- fatty acid monoglycerides, - fatty esters of glycerols and of polyethylene glycol (PEG),

- terpenes and

- carveol, nerolidol or linalool.

3. Pharmaceutical composition according to one of claims 1 to 2, characterized in that the dioxolane or dioxane derivatives are chosen from methyl-

1, 3-dioxolane, 4-hydroxymethyl-1, 3-dioxolane, 4-methyl-dioxolane, 1, 3-dioxane, 2-methyl-1, 3-dioxane, 2,2-dimethyl-1 , 3-dioxolane-4-methanol, 2- n-pentyl-1, 3-dioxolane, 2-n-heptyl-1, 3-dioxolane, 2-n-undecyl-1, 3-dioxolane, 2- (2 \ 6'-dimethyl-2'-heptaenyl) -1, 3-dioxane and 2-n-nonyl-1, 3-dioxolane.

4. Pharmaceutical composition according to claim 3 characterized in that the dioxolane derivative is 2,2-dimethyl-1, 3-dioxolane-4-methanol.

5. Pharmaceutical composition according to claim 3 characterized in that the dioxolane derivative is 2-n-nonyl-1, 3-dioxolane.

6. Pharmaceutical composition according to one of claims 1 to 5 characterized in that it further comprises a natural or synthetic prostaglandin.

7. Pharmaceutical composition according to claim 6 characterized in that the prostaglandin is PGE1 or PGE2.

8. Pharmaceutical composition according to one of claims 1 to 4, characterized in that it is in the form of a gel, an emulsion or a micro emulsion.

9. Pharmaceutical composition according to one of claims 1 to 5, characterized in that the active principle consists of alfuzosin hydrochloride.

10. Device for topical application comprising a pharmaceutical composition according to one of claims 1 to 6.

11. Use of a pharmaceutical composition according to one of claims 1 to 6 for the preparation of a medicament intended for the treatment of erectile dysfunctions.