EP1526855A2 - Pharmazeutische zusammensetzungen zur behandlung der harninkontinenz - Google Patents

Pharmazeutische zusammensetzungen zur behandlung der harninkontinenz

Info

Publication number
EP1526855A2
EP1526855A2 EP03756527A EP03756527A EP1526855A2 EP 1526855 A2 EP1526855 A2 EP 1526855A2 EP 03756527 A EP03756527 A EP 03756527A EP 03756527 A EP03756527 A EP 03756527A EP 1526855 A2 EP1526855 A2 EP 1526855A2
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical compositions
compositions according
oxybutynin
estriol
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP03756527A
Other languages
English (en)
French (fr)
Inventor
Caroline Rougaignon
Michel Lanquetin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
R & D Pharma - Sam
Original Assignee
R & D Pharma - Sam
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by R & D Pharma - Sam filed Critical R & D Pharma - Sam
Publication of EP1526855A2 publication Critical patent/EP1526855A2/de
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the present invention relates to the field of therapeutic chemistry and in particular to the field of pharmacotechnology.
  • 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.
  • 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.
  • Treatment of incontinence involves administering a smooth muscle relaxant, such as oxybutynin which acts directly on the site distal to the cholinergic receptor.
  • 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.
  • 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.
  • 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.
  • oxybutynin hydrochloride 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.
  • solubility or absorption rate factors The only factors involved are the choice of solubility or absorption rate factors.
  • 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.
  • 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, 17 ⁇ -estradiol or even estrone or estriol.
  • estradiol ester such as estradiol valerate or estradiol benzoate, conjugated equine estrogens, 17 ⁇ -estradiol or even estrone or estriol.
  • 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.
  • oxybutynin a musculotropic drug widely used for the treatment of urinary incontinence
  • drawbacks 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).
  • 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:
  • 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.
  • 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.
  • 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.
  • 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 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.
  • oxybutynin used in the treatment of urinary incontinence, is administered orally, the products marketed being tablets containing 5 mg immediate release.
  • DITROPAN® XL which reduces the number of incontinent episodes but which however does not prevent the appearance of undesirable effects
  • transdermal route (patent WO01 / 80796).
  • 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).
  • 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 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 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 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.
  • 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 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.
  • 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).
  • 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).
  • estradiol esters mention may be made of acetates, butyrates, propionates, nicotinates, salicylates, cyclopentyl propionates, enanthates, hemisuccinate and cyclohexyl acetates.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Gynecological capsule for vaginal administration Unit formulation for one capsule Oxybutynin drop 5 mg
  • Witepsol® H37 1.6 g qs for a suppository weighing 3.0055 g
  • Vaginal suppositories with an average weight of 3.3085 g are thus prepared.
  • This gel is divided into doses using a dosing pump fitted with a 4 g cannula EXAMPLE V
  • Colloidal silica (Aérosil®200) 0.070 g
  • Witepsol® H 19 1.4525 g to 1.4325 g
  • Aérosil® 200 0.0900 g to 0, 1200 g

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP03756527A 2002-08-07 2003-08-06 Pharmazeutische zusammensetzungen zur behandlung der harninkontinenz Ceased EP1526855A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0210058A FR2843303B1 (fr) 2002-08-07 2002-08-07 Nouvelles compositions pharmaceutiques destinees au traitement de l'incontinence urinaire
FR0210058 2002-08-07
PCT/FR2003/002471 WO2004014360A2 (fr) 2002-08-07 2003-08-06 Compositions pharmaceutiques destinees au traitement de l'incontinence urinaire

Publications (1)

Publication Number Publication Date
EP1526855A2 true EP1526855A2 (de) 2005-05-04

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ID=30470993

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03756527A Ceased EP1526855A2 (de) 2002-08-07 2003-08-06 Pharmazeutische zusammensetzungen zur behandlung der harninkontinenz

Country Status (5)

Country Link
US (1) US20060100182A1 (de)
EP (1) EP1526855A2 (de)
AU (1) AU2003283153A1 (de)
FR (1) FR2843303B1 (de)
WO (1) WO2004014360A2 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9173836B2 (en) 2003-01-02 2015-11-03 FemmeParma Holding Company, Inc. Pharmaceutical preparations for treatments of diseases and disorders of the breast
US20110003000A1 (en) * 2009-07-06 2011-01-06 Femmepharma Holding Company, Inc. Transvaginal Delivery of Drugs
GB201601855D0 (en) * 2016-02-02 2016-03-16 Inura Medical Ag Urethral devices for treatment of pathological urological conditions

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026564A2 (en) * 2001-09-27 2003-04-03 Pharmacia Ab Pharmaceutical compositions for the treatment of urinary disorders
WO2004043429A1 (en) * 2002-11-12 2004-05-27 Pharmacia & Upjohn Company Combination therapy for postmenopausal female sexual dysfunction comprising an androgen, and at least one agent selected from an estrogen and an anti-muscarinic
WO2004052440A1 (en) * 2002-12-11 2004-06-24 Coloplast A/S A urinary catheter device with a pharmaceutically active composition
WO2004073679A1 (en) * 2003-02-13 2004-09-02 Mulholland S Grant Reinforced urethral suppository
WO2004084879A1 (en) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. Methods for treating lower urinary tract disorders using smooth muscle modulators and alpha-2-delta subunit calcium channel modulators

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262115B1 (en) * 1995-05-22 2001-07-17 Alza Coporation Method for the management of incontinence
WO1998011888A1 (en) * 1996-09-19 1998-03-26 American Home Products Corporation Method of treating urinary incontinence
US6436428B1 (en) * 2000-03-21 2002-08-20 Enhance Pharmaceuticals, Inc. Device and method for treating urinary incontinence in females

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003026564A2 (en) * 2001-09-27 2003-04-03 Pharmacia Ab Pharmaceutical compositions for the treatment of urinary disorders
WO2004043429A1 (en) * 2002-11-12 2004-05-27 Pharmacia & Upjohn Company Combination therapy for postmenopausal female sexual dysfunction comprising an androgen, and at least one agent selected from an estrogen and an anti-muscarinic
WO2004052440A1 (en) * 2002-12-11 2004-06-24 Coloplast A/S A urinary catheter device with a pharmaceutically active composition
WO2004073679A1 (en) * 2003-02-13 2004-09-02 Mulholland S Grant Reinforced urethral suppository
WO2004084879A1 (en) * 2003-03-21 2004-10-07 Dynogen Pharmaceuticals, Inc. Methods for treating lower urinary tract disorders using smooth muscle modulators and alpha-2-delta subunit calcium channel modulators

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004014360A3 *

Also Published As

Publication number Publication date
AU2003283153A8 (en) 2004-02-25
WO2004014360A2 (fr) 2004-02-19
US20060100182A1 (en) 2006-05-11
FR2843303A1 (fr) 2004-02-13
FR2843303B1 (fr) 2006-01-21
AU2003283153A1 (en) 2004-02-25
WO2004014360A3 (fr) 2004-04-08

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