EP1526855A2

EP1526855A2 - Pharmaceutical compositions for the treatment of urinary incontinence

Info

Publication number: EP1526855A2
Application number: EP03756527A
Authority: EP
Inventors: Caroline Rougaignon; Michel Lanquetin
Original assignee: R & D Pharma - Sam
Current assignee: R & D Pharma - Sam
Priority date: 2002-08-07
Filing date: 2003-08-06
Publication date: 2005-05-04
Also published as: WO2004014360A2; FR2843303A1; US20060100182A1; AU2003283153A1; AU2003283153A8; FR2843303B1; WO2004014360A3

Abstract

The invention relates to the field of therapeutic chemistry and, in particular, the field of pharmaceutical technology. More specifically, the invention relates to novel pharmaceutical compositions for the local treatment of urinary incontinence using a musculotropic and cholinergic substance which may or may not be associated with a poorly-absorbed oestrogen agent. The invention is characterised in that the musculotropic and cholinergic substance is oxybutynin or one of the salts thereof and in that the poorly-absorbed oestrogen agent is selected from estriol, 16-epiestriol or estradiol in free, esterified and/or etherified form. The invention is further characterised in that the composition is administered in one of the suitable forms thereof either vaginally or rectally for women and rectally for men, the form administered to men being devoid of oestrogen. The invention also relates to the vaginal or rectal use of said pharmaceutical compositions.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF URINARY INCONTINENCE

The present invention relates to the field of therapeutic chemistry and in particular to the field of pharmacotechnology.

In particular, it has new dosage forms intended for the treatment of urinary incontinence, in particular of urgency and instability in women.

It relates specifically to new pharmaceutical compositions intended for the treatment of urinary incontinence containing a cholinergic and musculotropic substance, associated or not with a moderate estrogenic agent, little resorbed locally, characterized in that the cholinergic substance is oxybutynin, the slightly absorbed estrogen agent is an estrogen derivative chosen from estriol, 16-epiestriol, estradiol and their esterified and / or etherified derivatives and in that the administration takes place in one of the forms suitable for the route vaginal or rectal.

In a combination of two active ingredients of very different chemical nature, the problem always arises of being able to achieve a balanced release of the active ingredients, by reducing the speed of absorption of one of the active ingredients and / or by adapting the diffusion. from the most rapidly diffusible active ingredient to that of the active ingredient mons diffusible.

However, this technical principle is difficult to put into practice and it is observed, especially generally, that in a mixture of active principles, one of the active principles is absorbed more quickly than the other or that the active principle is not very absorbed adversely affects the absorption of the other active ingredient.

This is why the problem of the simultaneous absorption of several active ingredients is often a difficult problem to solve.

The problem of the treatment of urinary incontinence by administration of oxybutynin resides in the fact that it is an active ingredient very quickly absorbed by digestive way, and that its absorption is irregular and requires the addition of another active principle, in particular one of those which slow resorption.

We know that urinary incontinence affects around 20% of adults, and mainly women, and has a significant psychosocial impact, since it is a condition that affects all activities of daily life . It particularly affects women.

There are two types of urinary incontinence in women:

1. Stress incontinence, characterized by involuntary urinary leakage, occurring, regardless of bladder filling, during exercise, and ceasing with it. It is due to a malfunction of the bladder sphincter.

2. Urge incontinence manifested by urinary leakage preceded or accompanied by urge. It is the translation of a detrusor instability (smooth muscle of the bladder), which contracts in an anarchic and uncontrollable manner, during the filling phase of the bladder.

The prevalence of incontinence increases with age and, after fifty, it is common to observe mixed incontinence combining the two types described above.

After menopause, the cessation of estrogen secretion by the ovary, which is ultimately responsible for vulvovaginal atrophy, also affects the lining of the urethra and the bladder trigone, which are rich in estrogen receptors . This results in a decrease in the thickness of the mucosa and changes in the chorion which reduce the flexibility of the urethra and worsen urinary disorders.

Treatment of incontinence involves administering a smooth muscle relaxant, such as oxybutynin which acts directly on the site distal to the cholinergic receptor. The usual dose in drug therapy is repeated doses of oxybutynin two to four times a day. This type of administration is difficult to carry out because the administration requires compliance with the therapeutic regimen and it is unfavorable from the point of view of costs. In addition, oxybutynin is adversely affected by light and needs protection from air. These properties do not help the formulation of a drug in a form of administration thanks to which one can administer the oxybutynin which resorbs it at a controlled and known rate, per unit of time, to produce the intended therapy.

In view of the presentation of the above therapeutic problem, the Scientists use the medical distribution and pharmaceutical distribution techniques to which the present invention belongs and agree that there is an urgent need for a form of administration that can deliver the valuable drug oxybutynin, at a controlled dose, to patients in clinical need of incontinence treatment. There is also an urgent need to have an original form of administration and to be able to have the means of implementing a mode of therapeutic treatment allowing the delivery of oxybutynin at a controlled speed without this drug manifesting bothersome side effects.

Oxybutynin is the active ingredient in DITROPAN®. It is chemically 4- (diethylarnino) -2-butynyl -cyclohexyl oc-hydroxyphenyl acetate hydrochloride.

The molecule has an asymmetric carbon atom. The compound and its desethylated metabolite have already been split into (R) - and (S) -oxybutynin or into (R) - or (S) -desethyloxybutynin (Sepracor EP914113). S-oxybutynin has also been used in the treatment of urinary incontinence.

It goes without saying that in the absence of oxybutynin hydrochloride, another therapeutically acceptable salt of oxybutynin can be used with the same efficiency, chosen in particular from the group consisting of acetate, bitartrate, citrate, edetate , edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, hydrobromide, iodhydrate, lactate, malate, maleate, mandelate, mesylate, methylnitrate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate, salicylate, stearate, succinate, tannate and tartrate. The only factors involved are the choice of solubility or absorption rate factors.

The international patent application WO 95/23593 constitutes the closest prior art. This document proposes a treatment for urinary incontinence in women, and in particular in menopausal women, by an association containing a substrate for oxide. nitric - Synthase (NOSS) or a nitric oxide donor (NOD) and a progestogen, an estrogen and or a partial estrogen agonist.

The substrate for nitric oxide synthase is arginine. The nitric oxide donor is sodium nitroprusside.

NOD is administered orally or transdermally.

The estrogen used in this combination is preferably an estradiol ester such as estradiol valerate or estradiol benzoate, conjugated equine estrogens, 17β-estradiol or even estrone or estriol.

Also patent US 6,262,115 (Alza Corp.) describes a method of treating incontinence which consists in administering orally a dose of oxybutynin presented in a sustained release form.

Indeed, oxybutynin, a musculotropic drug widely used for the treatment of urinary incontinence, has drawbacks which reside in the fact that it is a drug rapidly metabolized in the body to its more toxic desethylated derivative. and having largely lost musculotropic activity (Hughes, Xenobiotica (1992) 7 859-869). Therefore, to maintain effective blood levels for a long time, it is necessary to achieve a two-tablet system whose active ingredient is oxybutynin, a first tablet ensures a release of oxybutynin for a short period of time. (for example less than 6 hours) and a second tablet releases oxybutynin for an extended period, for example from 18 to 24 hours (see US patent 6,148,359).

However, oxybutynin has bothersome side effects of the cholinergic type, such as dry mouth, difficulty in accommodating, constipation, tachycardia, dizziness, worsening of psychiatric disorders (Jonville AP et al. Therapy 1992, 47 389-392) . Increasing the doses of oxybutynin is therefore not an easy problem to solve.

The object of this patent application is to develop a long-acting galenic preparation, administered vaginally or rectally, of an active principle: oxybutynin, associated or not with an estrogenic derivative such as example estriol. Administering oxybutinyne vaginally or rectally has two advantages:

1. It allows absorption of the active ingredient in the very vicinity of the target organ, the bladder muscle.

2. It avoids the effect of first hepatic passage, compulsory after an oral intake, it consequently reduces the amount of active principle destroyed by the liver and it therefore reduces the necessary therapeutic doses.

Administration by the vaginal and rectal routes thus makes it possible to use lower doses by increasing the local effect of the product, while reducing its cholinergic side effects due to its action on organs other than the bladder.

The objective is also to develop a galenical formulation ensuring a prolonged release as regular as possible of the active principle with systemic action during nycthememer, so as to compensate for the short half-life of oxybutynin and to avoid the need for taken repeatedly during the day.

The object of the invention is therefore to provide a dosage form which guarantees the prolonged release of oxybutynin or one of its salts, so as to provide therapeutic cover for at least twelve hours. This is the advantage of vaginal or rectal administration.

Another object of the invention lies in the fact that one can associate with oxybutynin or with one of its salts an estrogen such as estriol, the trophic effects of which are added in a synergistic manner to those of oxybutynin, direct mediator of the musculature.

Furthermore, among the estrogenic derivatives, estriol is preferably used because it is a moderate estrogen, used in the treatment of local menopausal disorders, and the general distribution of which is of little importance when it is administered vaginally. . A - Association of two active ingredients:

The Applicant studied oxybutynin currently marketed and presented in the form of tablets dosed at 5 mg with a daily dosage in adults, from 2 to 4 tablets.

By the oral route, it is rapidly absorbed and, at the recommended doses, the measurement of plasma levels has revealed maximums of 8 to 18 ng / ml in a ^' max (T' max) time between 0.5 and 1.4 hours. Oxybutynin also undergoes an important effect of first hepatic passage and this results in a systemic bioavailability close to 6%.

It has also been found that estriol, a weak estrogen, known for its ability to locally improve urethral trophicity and to stimulate alpha-adrenergic receptors, responsible for the closure of the bladder neck, is likely to manifest its action on urinary incontinence with weak vaginal diffusion in the circulating systems.

The solution to the problem of bioavailability of the invention consisted in passing for the woman, either vaginally or rectally, and for the man rectally, oxybutynin, or a salt thereof, to obtain a prolonged systemic action, with circulating pharmacologically acceptable levels, and also to associate, possibly, in women, an estrogenic substance which locally stimulates the oc-adrenergic receptors responsible for the closure of the bladder neck, with a substance such as oxybutynin active by the oral route, therefore of systemic action; it is thus associated with an active ingredient known to improve a local trophicity and therefore it has a beneficial action on urinary incontinence. B - Choice of route of administration:

Depending on their mode of administration, as well as their pharmacological behavior, the active ingredients are directed towards the vaginal route for women. The rectal route, as far as it is intended for the man, does not contain an estrogenic agent.

For oxybutynin, this results in a decrease in its rapid metabolism due to the first hepatic passage and thus increases its bioavailability by seeking lower circulating rates than those encountered at T 'max. They are more constant over time. Vaginal or rectal absorption is one way to achieve these results.

As for the estrogen derivatives, given their low vaginal absorption and their essentially local pharmacological activity, the vaginal route is in this case the most suitable. C - General oxybutynin:

Today, oxybutynin, used in the treatment of urinary incontinence, is administered orally, the products marketed being tablets containing 5 mg immediate release.

This type of dosage, associated with the fact that the oxybutynin molecule has a short elimination half-life (2 hours), requires multiple daily doses (up to 4) to have an action throughout the day (DITROPAN® legal notices, Vidal dictionary 2001).

This results in discomfort inherent in the obligation to take these numerous daily doses, and these repetitions each time cause a significant plasma peak of the product (oxybutynin undergoing significant hepatic degradation by first pass effect), this having the consequence of d '' cause well known undesirable effects, which are very bothersome for patients (Vidal dictionary 2001 DITROPAN®). As a result, patients often discontinue treatment.

Currently, no sustained release form is available from the medical profession. However, a number of these forms are under study. They will undoubtedly soon be marketed.

These include DITROPAN® XL which reduces the number of incontinent episodes but which however does not prevent the appearance of undesirable effects (Gleason et al., Urology, 54 (3), 420-3, 1999 Sept.), which is explained by the systemic passage of the product equivalent to that of DITROPAN®.

Other routes of administration are being developed which will allow continuous diffusion of the product: for example the transdermal route (patent WO01 / 80796).

According to some authors, this route makes it possible to have an efficacy comparable to that of the oral route, but does not significantly eliminate the undesirable effects inherent in the systemic passage of oxybutynin which lead certain patients to abandon their treatment (Ho C, Issues Health. Technol., (24), 1-4, 2001 Oct). D - Oxybutinin by local (urogenital) route:

Vesical administration of oxybutynin via a catheter is used in some patients. This route of administration makes it possible to obtain a local action of the product, directly at the level of the bladder muscle and consequently makes it possible to reduce the intensity of the undesirable effects (Lethoranta K. Scand. J. Urol. Nephrol., 36, 18- 24,2002 / Ferrera P. et al., BJU Int., 87 (7), 674-8, 2001 May / Distasi SM et al., J. Urol., 165 (2), 491-8, 2001 Feb. ).

The disadvantage of the bladder route is that this route of administration is only possible using an intra urethral catheter, which by definition limits the number of patients who can benefit from it.

Administration of the product to a neighboring cavity, the vagina, should be considered. It can be achieved by different forms:

1 - The vaginal ring

The vaginal ring is a device which is implanted in the vaginal cavity of the patient and which will release oxybutynin continuously for 28 days (patent WO 01/70154) (Schroder A. et al., Urology, 56 (6), 1063-7, 2000 Dec.).

The major drawback is the permanent presence of the ring and all that this implies in terms of discomfort, asepsis or local reaction.

2 - The vaginal or rectal ovum

To avoid this major disadvantage, the Applicant has developed a vaginal or rectal ovum of oxybutynin, or of a salt thereof, associated or not with an estgrogenic derivative, which is easily administrable and which is well tolerated, both locally systemically.

The interest of the association and the pharmaceutical form are explained in the following paragraphs.

The present invention therefore relates to the vaginal or rectal administration of an ovum containing oxybutynin, associated or not with an estrogen derived from estradiol. or estriol. Indeed, to agree all the hypotheses, the choice of an extended-release formulation seems to be the most suitable.

The vaginal or rectal routes of administration have so far been little used for this type of medication. Experience has already made it possible to achieve an effective form of an active ingredient salt. This formulation allows, thanks to a prolonged contact time with the mucosa, to obtain a more regular passage of oxybutynin in the circulating systems and a less metabolism, and, in the case of estriol, it is also directly absorbed at its site of action by the vaginal route.

The formulation according to the invention is composed of a combination of semi-synthetic glycerides with suitable melting points, having different lipophilic characters, characterized by their hydroxyl index, knowing that these are known to modify the profiles of release of certain active ingredients. Silica is added to it. Silica is used, for two very precise purposes: a) to maintain homogeneous the suspension of the active ingredient insoluble in fatty substances, b) to give the formulation a bio-adhesive character during the fusion of the fatty mass in the vagina or the rectal cavity, by hydrogen bonds between the proteins of the vaginal or rectal mucus and the acid groups of silicic acids.

The advantage of such a formulation resides in the fact of having, in the case of a combination, an active principle dissolved in the fatty phase (estriol) and another maintained in suspension (oxybutynin hydrochloride).

As a result of their respective chemical structures, in the case of an association, it is not expected to encounter any incompatibility between these two substances. The verification was carried out during form stability tests, under ICH conditions. Formulation study and evaluation methods:

These are carried out "in vitro" by comparative dissolution studies (high availability).

The formulations selected "in vitro" have been confirmed by "in vivo" studies, presented in the experimental part.

The search for final doses was carried out once the first kinetics of absorption of the active ingredients had been carried out.

The object of the invention is therefore defined by the production of a pharmaceutical form allowing administration which is best suited to the pathology of an incontinent patient, with attenuated side effects.

According to a preferred embodiment, the active ingredients are oxybutynin in base form, or salt, with a therapeutically compatible mineral or organic acid, in racemic or optically active form (epimers) and, in the case of a combination, an estrogenic active ingredient derived from estradiol or estriol, dissolved in a excipient or a fatty vehicle, suitable for vaginal administration and the other in suspension (oxybutynin hydrochloride).

Among the estradiol esters, mention may be made of acetates, butyrates, propionates, nicotinates, salicylates, cyclopentyl propionates, enanthates, hemisuccinate and cyclohexyl acetates. Among the estradiol ethers, mention will be made of the symmetrical di-ethers of the two alcohol or phenol functions, for example 3, 17 - dimethoxy-estradiol or of different ethers such as, for example, 3-propyloxy 17-methoxy estradiol or else mixed ether / ester structures such as 3-acetoxy, 17-methoxy estratriene or 3-propionoyloxy 17-methoxy estratriene.

Among the estriol derivatives, mention may be made of 3-methoxy 16, 17-dinicotinoyloxy estratriene or 3, 16-diacetoxy estra 1, 3, 5 (10) - triene 17 -one.

The solid semi-synthetic glycerides are chosen from Witepsol® WS or WH19 and Suppocire® NA 16, NA I 50. They are used as fatty masses for the production of ova.

The choice is determined by the level of the melting point (in general as close as possible to 37 ° C.), the nature of the viscosity near the melting point and their hydroxyl number.

Optimizing the release between fats, by varying the proportions of both, has shown that the most favorable fraction in terms of slow release of the active ingredient is a mixture in substantially equal proportions of Witepsol ® WH 19 and Suppocire® NAI 50.

Hydrophilic agents of the PEG 4000 to 6000 type can be added to the fatty masses in order to exert an influence on the melting points of the semi-synthetic glycerides and to modify the release profiles.

Among the suspending agents incorporated into the formulation, various qualities of silica will be noted, such as, for example, AEROSIL® 200, AEROSIL® R992, the products COR84 and 300 from the company Degussa which differ from one another by the lipophilic nature or hydrophilic of each.

The percentage of suspending agent may be between 0 and 10% but preferably between 1.5% and 5% depending on the desired release profile.

The formulation according to the invention also contains one or more gelling agents which improve the adhesion of the forms to the vaginal or rectal wall. The gelling agents according to the invention are derivatives of cellulose and in particular alkylated or hydroxyalkylated derivatives of cellulose. Hydroxypropyl celluloses (HPC), (hydroxypropyl) methyl celluloses (HPMC) and hydroxyethyl methyl cellulose are mentioned in this regard. They are present in amounts ranging from 5 to 20% of the formulation. HPMCs are preferably used, such as those of the SM4000 or 6J-60-90 SM4000 type, as well as those called 90 SH 100,000.

The hydrogels formed from these gelling agents are quite sensitive to shearing and require a very complicated industrial application. The preferred products are those marketed under the brand Métolose (Shin Etsu). Can also be used as gelling agent carbomers and more particularly Polycarbophil which forms a gel "in situ" with aqueous liquids from the vaginal or anal environment.

The dose of oxybutynin, or one of its salts, contained in the ova is between 1 and 25 mg and more particularly between 5 and 15 mg of Oxybutynin hydrochloride. In combination, the dose of moderate, poorly absorbed estrogen is between 0.01 and 5 mg. The dose of estriol or its esters or ethers is between 0, 1 mg and 2 mg. It is preferably between 0.2 mg and 1 mg per unit dose.

Another object of the invention is to produce a formulation whose administration by the rectal or vaginal route to the patient is easy.

Another object of the invention lies in the fact that it is thus possible to reduce the administrable doses of oxybutynin during a nycthemera.

Another object of the invention lies in the fact of developing a form of administration of a prolonged duration of action, the side effects of which linked to the presence of oxybutynin are significantly reduced and even eliminated. Pharmacokinetic results:

Study of pharmacokinetics with the compositions according to the invention in comparison with a specialized form of oxybutynin hydrochloride.

The clinical study was carried out in comparison between vaginal administration and oral administration. It was conducted cross-over on six randomized patients, with a period of seven-day wash-out between the two treatment periods. Each patient receives the two drug forms, dosed at 5 mg.

Results.

The attached Tables I and II collate the results of the blood levels of oxybutynin metabolite as a function of time.

The subjects referenced 2A, 3A and 6A are those which started with period 2.

Desethyloxybutynm blood levels are measured over a period of 36 hours. During the first eighteen hours, blood levels of desethyloxybutynm are noticeable after administration of the commercial form of oxybutynin.

On the other hand, by administration of ova according to the invention, the blood levels of desethyloxybutynme are very low and it is the blood levels of oxybutynin which are truly significant, as can be seen in Figures 1 and 2. They show the rapidity of absorption and metabolization of the commercial product while absorption with the ova according to the invention show a maximum peak in oxybutynin much more flattened and appreciably delayed, with resorption still perceptible after thirty-six hours, the maximum absorption of between six and eight hours, as can be seen in Figures 3 and 4 illustrating these results.

It can therefore be seen that, unlike the oral administration of oxybutynin, which gives rise to the N-desethylated metabolite, administration by vaginal route or rectally leads to high and prolonged blood levels of oxybutynin.

Examples:

The following examples illustrate the invention. They do not limit it in any way. EXAMPLE I

Gynecological capsule for vaginal administration Unit formulation for one capsule Oxybutynin drop 5 mg

Estriol 1 mg

0.200 g petroleum jelly

Colloidal silica 0, 100 g

Sorbitol sesquioleate 0.05 g Perhydrosqualene qs.

Coating: Gelatin, glycerol, preservatives qsp one capsule weighing 1.85 g

EXAMPLE II Vaginal suppository

Unit formulation for a suppository

Oxybutynin 5 mg

Estriol 0.5 mg

Witepsol® H35 1.4 g

Witepsol® H37 1.6 g qs for a suppository weighing 3.0055 g

EXAMPLE III

Prolonged release vaginal suppository

Unit formulation

Estradiol 1.0 mg

Oxybutynin 7.5 mg

Witepsol® H 19 1.5 g

Witepsol® H35 1.2 g

Suppocire® BM 0.3 g

Precirol® 0.3 g

Vaginal suppositories with an average weight of 3.3085 g are thus prepared.

EXAMPLE IV

Compact bio-adhesive gel for gynecological use

Oxybutynin drop 5.00 mg

Estriol 1.00 mg

Polyethylene glycol 4000 1.00 g

Transcutol® 5.00 g

Polyvinyl carboxylic acid polymer 1,000 g Preservative 0.30 mg

Triethanolamine qs for pH 6.5 Purified water qs 100 g

This gel is divided into doses using a dosing pump fitted with a 4 g cannula EXAMPLE V

For a 2gr ovum (ovum 3)

Witepsol® H 19 0.965 g

Suppocire® NAI 50 0.965 g

Aérosil® 200 0.060 g

Oxybutynin drop 0.010 g

Estriol 1.5 mg

FP of the ovum 34.9 ° C Melting time 23 min Active PA released in 6 H = 30%

EXAMPLE VI

For a 2gr ovum (ovum 4)

Witepsol® H 19 0.995 g

Suppocire® 0.995 g

Oxybutynin drop 0.010 g

Estriol 0.005 g

FP of ovum 34.5 ° C Melting time 19 min PA. released in 6 hours = 75%

EXAMPLE VII

For a 2gr ovum (ovum 1)

Witepsol® H 19 0.960 g

PEG 6000 0.010 g

Aérosil® 300 0.060 g

Oxybutynin drop 0.010 g

Estriol 0.001 g

Suppocire® NAI 50 0.959 g

Mp 36 ° C

Melting time 38 min PA. released in 6 hours = 52% EXAMPLE VIII

For a 2gr ovum (ovum 2

Witepsol® H 19 0.960 g

PEG 4000 0.010 g

Aérosil® 200 0.060 g

Oxybutynin drop 0.010 g

Estradiol methyl ether 0.002 g

Suppocire® NAI 50 0.958 g

Mp 35 ° C

Melting time 30 min

PA. released in 6 hours = 60%

EXAMPLE IX

Soft capsule

Oxybutynin 10 mg

Peanut oil 100 mg

Polycarbopb.il 60 mg

Envelope

Gelatin, color

EXAMPLE X

For a 2gr ovum

Witepsol® H 19 0.950 g

Suppocire® NAI 15 0.950 g

Colloidal silica (Aérosil®200) 0.070 g

Polyvinyl carboxylic acid

(Carbopol 1382) 0.019 g

Estriol 0.001 g

Oxybutynin drop 0.010 g

EXAMPLE XI

For a 2gr ovum

Witepsol® S590 0.950 g Suppocire® NAI 50 0.950 g HPMC (Hydroxypropyl methyl cellulose). 0.078 g Oxybutynin drop 0.020 g

Estriol 0.002 g

EXAMPLE XII

For an egg of 2 gr

Witepsol® H 19 0.960 g

Suppocire® NAI 50 0.960 g

3-propyloxy 17-methoxy estradiol 0.002 g

Oxybutynin drop 0.015 g Polycarbophil as calcium salt (Goodrich) 0.063 g

EXAMPLE XIII

For a vaginal ovum of 3 gr

Witepsol® H 19 1.4525 g to 1.4325 g

Suppocire® NAI 50 1.4525 g to 1.4325 g

Aérosil® 200 0.0900 g to 0, 1200 g

Oxybutynin drop 0.0050 g to 0.0150 g

EXAMPLE XIV

For a rectal suppository of 2 gr

Witepsol® H 19 0.935 g

Suppocire® NAI 50 0.935 g

Aérosil® 200 0, 120 g

Oxybutynin drop 0.010 g For a suppository finished at about 2 g

TABLE I

1 = Subject 1 period 1 1A = Subject 1 period 2

Determination of desethyloxybutynme after administration of oxybutynint

TABLE II

1 = Subject 1 period 1 1A = Subject 1 period 2

Determination of oxybutynin in the blood after administration by vaginal route according to the invention or by oral route (Ditropan®)

Claims

R E V E N D I C A T I O N S

1 °) Pharmaceutical compositions intended for the treatment of urinary incontinence characterized in that they contain as active principle oxybutynin, in association or not with a moderate estrogen, in mixture with an excipient or an inert, non-toxic, pharmaceutically carrier vehicle acceptable, for vaginal or rectal use.

2) Pharmaceutical compositions according to claim 1, characterized in that the Oxybutynin is chosen from Oxybutynin base, its addition salts with a mineral or organic acid and the epimers thereof.

3 °) Pharmaceutical compositions according to claim 1, characterized in that the moderate estrogen is chosen from the group formed by Estriol, Estradiol and esters, ethers and mixed ethers of Estriol or Estradiol.

4) Pharmaceutical compositions according to claim 1, characterized in that they are formulated in the form of ovules, suppositories, vaginal capsules, rectal capsules or gels.

5) Pharmaceutical compositions according to one of the preceding claims, characterized in that they contain from 1 to 25 mg of Oxybutynin or its salts.

6 °) Pharmaceutical compositions according to claim 5, characterized in that they contain from 5 to 15 mg of Oxybutynin hydrochloride.

7 °) pharmaceutical compositions according to one of claims 1 to 6, characterized in that they contain a dose of moderately poorly absorbed estrogen ranging from 0.01 to 5 mg per unit dose.

8 °) Pharmaceutical compositions according to claim 7, characterized in that the moderate estrogen is estriol at a dose of 0.1 to 2 mg.

9 °) Pharmaceutical compositions according to claim 7 or claim 8, characterized in that the unit dose of estriol ranges from 0.2 mg to 1 mg.

10 °) Pharmaceutical compositions according to one of the preceding claims, characterized in that they additionally contain one or more suspending agents.

11 °) Pharmaceutical compositions according to claim 10, characterized in that the suspension agent (s) are derivatives of bioadhesive silicic acid and in particular colloidal silica sold under the brand Aérosil®.

12 °) Pharmaceutical compositions according to one of the preceding claims, characterized in that the excipient is a fatty phase formed from semi-synthetic glycerides.

13 °) Pharmaceutical compositions according to claim 11, characterized in that the semi-synthetic glycerides are those chosen from the products called Witepsol® and the products called Suppocire®.

14 °) Pharmaceutical compositions according to one of the preceding claims, characterized in that the formulations also contain one or more gelling agents.

15 °) Pharmaceutical compositions according to claim 14, characterized in that the gelling agent or agents are cellulose derivatives and in particular alkylated and / or hydroxyalkylated derivatives of cellulose.

16 °) Pharmaceutical compositions according to claim 14, in which the gelling agent is a carbomer.

17 °) Pharmaceutical compositions according to claim 16, in which the gelling agent is polycarbophil in acid form or in salified form.

18 °) Pharmaceutical compositions according to claim 16 or claim 17, wherein the gelling agent is polycarbophil in the form of calcium salt.

19 °) Pharmaceutical compositions according to one of the preceding claims, which cause a prolonged release of the active ingredients, spread over more than twenty-four hours, characterized in that the excipient is a fatty substance in which the oxybutynin chlororydrate is suspended.

20 °) Pharmaceutical compositions according to one of the preceding claims, making it possible to obtain Tmaxes in oxybutynin of between approximately two hours and approximately sixteen hours and preferably between six hours and twelve hours, characterized in that the excipient or the vehicle are chosen so that the release rate is as long as possible.

21 °) Pharmaceutical compositions according to one of the preceding claims, in which the excipient or the vehicle is chosen such that the administration of oxybutynin takes place once, or optionally twice, per twenty-four hours.