WO2000009134A1 - Use of misoprostol or/and misoprostol acid for preparing drug in order to cure sexual dysfunction in women - Google Patents

Use of misoprostol or/and misoprostol acid for preparing drug in order to cure sexual dysfunction in women Download PDF

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Publication number
WO2000009134A1
WO2000009134A1 PCT/GR1999/000030 GR9900030W WO0009134A1 WO 2000009134 A1 WO2000009134 A1 WO 2000009134A1 GR 9900030 W GR9900030 W GR 9900030W WO 0009134 A1 WO0009134 A1 WO 0009134A1
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misoprostol
acid
women
sexual dysfunction
drug
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French (fr)
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Petros Karouzakis
Panagiotis Kanakaris
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Priority to US09/762,602 priority Critical patent/US6897239B1/en
Priority to JP2000564637A priority patent/JP2002522500A/en
Priority to DE69927985T priority patent/DE69927985T2/en
Priority to AT99936893T priority patent/ATE307590T1/en
Priority to AU51862/99A priority patent/AU5186299A/en
Priority to EP99936893A priority patent/EP1107762B9/en
Publication of WO2000009134A1 publication Critical patent/WO2000009134A1/en
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the invention relates to the use of an already known pharmaceutical substance, misoprostol as well as its first metabolite, misoprostol acid, for preparation of a drug for external use which is destined to cure sexual dysfunction in women
  • the present method aims at the removal of the disadvantages of the above methods with the use of a simple method, that consists of the local application of a vasoactive substance, known as misoprostol, to the clitoris or/and to the vagina, in order to cure sexual dysfunction in women due to vascular, hormonal, phychogenic or other cause.
  • a simple method that consists of the local application of a vasoactive substance, known as misoprostol, to the clitoris or/and to the vagina, in order to cure sexual dysfunction in women due to vascular, hormonal, phychogenic or other cause.
  • Misoprostol is the general name of a synthetic prostaglandin belonging to the Ei series (PGE i analogs). Synthesis:P.W.Collins,R.Pappo,Belgian patent 827.127, American patent 3.965.143 (The Merck Index,ed. Merck & Co. Inc,l l th edition.1989,p.6128).
  • Misoprostol -compared to other vasodilatory drugs e.g.nitroglycerin, Prostaglandin Ei etc.
  • vasodilatory drugs e.g.nitroglycerin, Prostaglandin Ei etc.
  • misoprostol cause a strong local vasodilation and as a result increase of the blood flow when it is used externally to the clitoris or/and to the vagina.
  • the local vasodilation is caused tumescence of the clitoris, intence bleeding of the vagina and feeling of sexual desire.
  • women with anorgasmia of various causes promote after masturbation or sexual intercourse, the coming of orgasm.
  • misoprostol misoprostol acid
  • misoprostol acid misoprostol acid
  • the two pharmaceutical molecules reinforce the absorption of other vasoactive substances (e.g.alprostadil) resulting in the occurrence of synergic action.
  • Misoprostol can be dissolved in water and its compatibility with excipients provides the opportunity of production of a variety of simple pharmacotechnical forms for external use, which are at the same time very well tolerated by the skin and the mucosa. From the above mentioned description it appears that the most serious advantage of the method is the manner of administration of the drug (external in combination with the lack of undesirable action in the suggested doses or/and the proposed pharmacotechnical forms) the relatively low cost and especially the most satisfactory result together with corresponding methods.
  • a complexforming means as 1 ,6% w/v a-cyclodextrine and substances suitable for the formation of a gel e.g.hy droxypropyl methylcellulose "3000" 2% w/v,propylene glycol 10% v/v and Water to 100 ml.
  • the gel contains 3-9 mg of active substance per ml.
  • Method of application ⁇ .1 (or more,depending on responce) are applied to the clitoris or/and to the vagina.
  • aqueous solution of misoprostol containing 0,3-0,9% w/v for clitoral or/and vaginal application can also contain propylene glycol or glycerol in the corresponding proportions (e.g.10%) to increase the viscosity of the solution.
  • Vanishing Cream to 100 g (Although for the requirements of this example as Vanishing Cream we used Bepanthene (R Cream of Roche.we have various creams o/w which are available in commerce or are described in National Pharmacopoeies and can be used for the same purpose).
  • Vaginal ovules of suitable dimensions weight about 300-900 mg, containing 0,04- 0,20% w/w misoprostol for vaginal use.
  • misoprostol e.g.Urea,Acid Citric.
  • misoprostol >1000 meg to the clitoris or to the vagina
  • shudder.feeling of hard ship,excitement and diarrhea The presence of a-cycodextrine reduces the undesirable effects and allows the application once only of higher doses without notable effect on the timing of its action but with positive effect on the intensity result and with prolonging of its duration.
  • misoprostol is an extremely hydrophile molecule compared with other prostaglandins of Ei series (e.g. with alprostadil which can be dissolved in alcohol but her solubility in water is only 8000 mcg/100 ml at 35°C).

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Use of misoprostol or land misoprostol acid for preparing of a pharmaceutical product in order to cure sexual dysfunction in women. The invention relates to using an already known pharmaceutical substance, misoprostol or/and its first metabolite (misoprostol acid) whose structural formulas are presented in Annex (I) (Figures 1 & 2), for preparing a drug of external use destined to cure sexual dysfunction in women. Misoprostol or/and misoprostol acid according to the described method are applied externally to the clitoris or/and to the vagina, are absorbed and cause topical vasodilation resulting in the feeling of sexual desire in women suffering from sexual dysfunction, due to vascular or other causes. Simultaneously misoprostol promotes the coming of orgasm.

Description

USE OF MISOPROSTOL OR/AND MISOPROSTOL ACID FOR PREPARING DRUG IN ORDER TO CURE SEXUAL DYSFUNCTION IN WOMEN.
The invention relates to the use of an already known pharmaceutical substance, misoprostol as well as its first metabolite, misoprostol acid, for preparation of a drug for external use which is destined to cure sexual dysfunction in women
The problem ot the temale sexual dysfunction even though it has been setted b\ the modern medicine decades ago, it hasn't been yet contronted with efficiency The extension ot the problem is not quite known (Scrip Reports, March 1098), but according to an older research (Frank et al.,1978) the percentage of women facing a kind ot dysfunction is going up to 63 %. In our days the sexual dvstunction of women is being confronted either with surgical restoratoin, when -rarelv- it has to do with anatomic problems, or with psychotherapy, that could be effective in cases where the causes are not functional, or even with the spesific treatment of substitution in cases where sexual inability has to do with hormonal disturbance rhese methods are being confronted with skeptikism. or because they are applying to a very small percentage ot women (e.g. women with anatomic problems), either because they are characterized by a low efficiency, m accordance -many times- to an adverse relation between benefit and πsk. The interest ot many searchers nowdays has been turned to the use ot vasoactive substances, m accordance with the methods used in the treatment of male impotence. But these methods even though they are successfully used in men (tor example intracavemosal injections), thev strike against the female genital system (inability of selfinjection into the corpora cavernosa of the clitoris), either the inefficiency of the methods that are for external use. The present method aims at the removal of the disadvantages of the above methods with the use of a simple method, that consists of the local application of a vasoactive substance, known as misoprostol, to the clitoris or/and to the vagina, in order to cure sexual dysfunction in women due to vascular, hormonal, phychogenic or other cause.
Misoprostol is the general name of a synthetic prostaglandin belonging to the Ei series (PGE i analogs). Synthesis:P.W.Collins,R.Pappo,Belgian patent 827.127, American patent 3.965.143 (The Merck Index,ed. Merck & Co. Inc,l lth edition.1989,p.6128).
Its chemical name is (l la,13E)-(±)-l l,16-Dihydroxy-16-methyl-9-oxoprost-13-en-l-oic acid methyl ester or (±)-(methyl)-(lR,2R,3R)-3-hydroxy-2-[(E)-(4RSι-4-hydroxy-4- methyl- 1 -octenyl]-5 -oxocyclopentaneheptanoate or (±)- 15 -deoxy-( 16RS)- 16-hydroxy- 16-methyl-PGEι methyl ester.lt is consisted of 4 stereoisomers in about equal proportions [(+)&(-) enantiomers of 16R- and 16S-forms].(The Merck Index, 1 ltn edition, 1989,p.6128).The empirical formula is C22H38O5. Its structural formula appears in page 8, Fig.l.
Compared with other prostaglandins of group E [ and especially alprostadil.misoprostol bears a methyl group (-CII3) on the carbon atom of position 16. According to a method which relates the biological action of various medicament molecules to its chemical structure it appears that due to this group we have a big penetration of misoprostol in the underlying tissues and a local vasodilation which cure sexual dysfunctions. Misoprostol is used today orally as antiulcer drug
(Physicians Desc Reference,PDR,ed.Medical Economics Data,Production Company at Montrale 48th edition, 1994,P .2197-2199).
In particular it is administered for the prevention of gastric ulcer to patients who take non-steroid antiinflammatory drugs.It is available in the countries of Europe and U.S.A. by Searle Company under the commercial name Cytotec®.In none country is the drug mentioned as suitable for male impotence nor are there any relevant reports on the international bibliography.On a contrary amongst the undesirable effects in oral therapy with misoprostol is male impotence (Physicians Desc Reference, ed.Medical Economics Data.Production Company at Montrale,48ln edition, 1994,p.2197-2199). Misoprostol -compared to other vasodilatory drugs (e.g.nitroglycerin, Prostaglandin Ei etc.)- cause a strong local vasodilation and as a result increase of the blood flow when it is used externally to the clitoris or/and to the vagina. Because of the local vasodilation is caused tumescence of the clitoris, intence bleeding of the vagina and feeling of sexual desire. Simultaneously, in women with anorgasmia of various causes, promote after masturbation or sexual intercourse, the coming of orgasm.
Equally strong topical vasodilation after external application is exerted by the hydrolysis product of misoprostol (misoprostol acid) which anyway constitutes the first misoprostol metabolite after its introduction in the organism (see page 8. Fig.2). Last because of the intense topical vasodilatory action of misoprostol and the corresponding free acid.the two pharmaceutical molecules reinforce the absorption of other vasoactive substances (e.g.alprostadil) resulting in the occurrence of synergic action.
Misoprostol can be dissolved in water and its compatibility with excipients provides the opportunity of production of a variety of simple pharmacotechnical forms for external use, which are at the same time very well tolerated by the skin and the mucosa. From the above mentioned description it appears that the most serious advantage of the method is the manner of administration of the drug (external in combination with the lack of undesirable action in the suggested doses or/and the proposed pharmacotechnical forms) the relatively low cost and especially the most satisfactory result together with corresponding methods.
Amongst the probable methods of application,most advantageous is a synthesis in the gel form of relatively low viscosity which contains
0,3-0,9 % w/v misoprostol in the methylform of methylester and/or free acid.a complexforming means. as 1 ,6% w/v a-cyclodextrine and substances suitable for the formation of a gel e.g.hy droxypropyl methylcellulose "3000" 2% w/v,propylene glycol 10% v/v and Water to 100 ml. The gel contains 3-9 mg of active substance per ml. Method of application^.1 (or more,depending on responce) are applied to the clitoris or/and to the vagina.
9 examples related to the pharmacotechnical forms and the ways of application of misorostol:
1)0.10 ml gel.relatively low viscosity containing 0,3-0,9% w/v misoprostol for applying to the clitoris or/and to the vagina. Synthesis:
1-1.Misoprostol 0.3-0,9 g Hydroxypropyl Methylcellulose "3000" 2 g Water purified to 100 ml l-2.Misoprostol 0,3-0,9 g
Sodium Carboxymethylcellulose 2 g
Propylene Glycol 25 ml Water purified to 100 ml 2)0,10 ml gel of relatively high viscosity,containing 0,30-0,90% w/v in misoprostol for vaginal application.
Synthesis:
2-1. Misoprostol 0,30-0.90 g Ilydroxypropyl Methylcellulose "3000" 4 g
Water purified to 1 (X) ml
2-2.Misoprostol 0,30-0,90 g
Sodium Carboxymethylcellulose 4 g
Propylene Glycol 25 ml Water purified to 100 ml
3)0,10 ml of aqueous solution of misoprostol containing 0,3-0,9% w/v for clitoral or/and vaginal application.The solution can also contain propylene glycol or glycerol in the corresponding proportions (e.g.10%) to increase the viscosity of the solution.
4)0, 10 ml of ointment or emulsion o/w containing 0,3-0,9% w/w in misoprostol for clitoral or/and vaginal application,where misoprostol is found spread in the continuous
(aqueous) phase.
Synthesis:
4-1. Misoprostol 0.3-0.9 g
Vanishing Cream to 100 g (Although for the requirements of this example as Vanishing Cream we used Bepanthene(R Cream of Roche.we have various creams o/w which are available in commerce or are described in National Pharmacopoeies and can be used for the same purpose).
5) Vaginal ovules of suitable dimensions.weight about 300-900 mg, containing 0,04- 0,20% w/w misoprostol for vaginal use. Synthesis:
5- 1.Misoprostol 0,3-0,9 g
Glycerol 70 g
Gelatine 20 g Water purified to 100 g
6)0,10 ml gel (or more depending of response) according to the examples ( 1-1 ) and (2-1 ) which contains moreover 1,6% w/v a-cyclodextrine.
7)0,10 ml gel (or more depending of response) according to the example (6) which contains moreover 10 ml ethyl alcohol 96° and 0,5 mg/ml alprostadil. Notes: f )The incorporation of misoprostol in bases already mentioned took place in normal temperature (20-25 °C) and at a temperature not exceeding 40°C.
2)No significant changes in misoprostol activity was observed as a function of pH,we observent however an important reduction or/and neutralization of misoprostol action in the presence of Polysorbate "80". 3)The time of appearance of the result varies from 20-40 minutes.The timing of the appearance and the intensity of the result seems to be able been positively influenced by certain moisturising agents (e.g. Propylene Glycol.Glycerol) as well as by certain substances which reinforce by various mechanisms the transcutaneous absorption
(e.g.Urea,Acid Citric). 4)High once only doses of misoprostol (>1000 meg to the clitoris or to the vagina) cause certain systematic undesirable effects as shudder.feeling of hard ship,excitement and diarrhea.The presence of a-cycodextrine reduces the undesirable effects and allows the application once only of higher doses without notable effect on the timing of its action but with positive effect on the intensity result and with prolonging of its duration. 5)The doses which are mentioned in the examples are only indicative since the intensity of the result depends,apart from the nature and the grade of the sexual dysfunction on other factors as e.g.the degree of moisturising of the underlying tissue,the physiological situation of the skin or the mucosa etc.As had already been mentioned, misoprostol is an extremely hydrophile molecule compared with other prostaglandins of Ei series (e.g. with alprostadil which can be dissolved in alcohol but her solubility in water is only 8000 mcg/100 ml at 35°C). This consists an important advantage: a)Because no use of organic factors is required (e.g.ethyl alcohol) which usually irritate tissues and are thus unsuitable for application on the skin and especially the mucus, b) Because it allows the incorporation of active substances on a very small amount of excipient, suitable for application on surfaces of limited extent,as e.g.the clitoris. 6)Misoprostol hasn't been accused for carcinogenic or teratogenic effect but because of the described irritation of the smooth uterine fibbers (Physicians Desc Reference,PDR,ed.Medical Economics Data,Production Company at Montrale 48t'1 edition, 1994.P.2197-2199), misoprostol must not becoming in touch with the genital system of the women who are pregnant.
STRUCTURAL FORMS Fig. 1. isoprostol
Figure imgf000010_0001
(+) - R- form
Fig. 2. Misoprostol acid
Figure imgf000010_0002

Claims

Claims l)The use of misoprostol or/and its first metabolite, misoprostol acid,for the production of a drug applied topically to the clitoris or/and to the vagina and is destined for the therapy of sexual dysfunction in women due to vascular or other causes. 2)The use of misoprostol and/or its metabolite (misoprostol acid) according to claim (1) either as racemic mixtures or in the form of one of the stereoisomers from which they consist: I (±)-R form & (±)-S form].
3)The use of misoprostol and misoprostol acid according to claims ( 1) and (2) in the form of various galenic preparations (solutions,ointments,endourethral sticks,systems of controlled transdermal absorption) which,according to the general principles of pharmacotechnics, facilitate the application and precise administration of the right doses for the achievement of the desired therapeutical or diagnostic aim as described in claim
(1).
4)The use of misoprostol and misoprostol acid according to claim (1),(2) and (3) in combination with other vasodilatory drugs as alprostadil for the appearance of synergistic action, as well as "passage accelerators" used normally in pharmaceutical technology aiming to increase absorption of drugs through the skin or the mucosa.
5)Use of misoprostol and misoprostol acid according to claim (1), (2) and (3) in combination with a-cyclodextrin or other substances which.according to the general methods used in pharmacotechny impedes or retards the appearance or undesired effects of the drug or prolong their pharmaceutical action.
PCT/GR1999/000030 1998-08-14 1999-08-13 Use of misoprostol or/and misoprostol acid for preparing drug in order to cure sexual dysfunction in women Ceased WO2000009134A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US09/762,602 US6897239B1 (en) 1998-08-14 1999-08-13 Use of misoprostol and/or metabolites of misoprostol for treating sexual dysfunction in women
JP2000564637A JP2002522500A (en) 1998-08-14 1999-08-13 Therapeutic agent for female sexual dysfunction containing misoprostol and / or misoprostolic acid
DE69927985T DE69927985T2 (en) 1998-08-14 1999-08-13 USE OF MISOPROSTOL OR / AND MISOPROSTOL TREATMENT FOR THE MANUFACTURE OF A MEDICAMENT FOR TREATING FEMALE SEXUAL DISORDER
AT99936893T ATE307590T1 (en) 1998-08-14 1999-08-13 USE OF MISOPROSTOL OR/AND MISOPROSTOL ACID IN THE PRODUCTION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF FEMALE SEXUAL DISORDER
AU51862/99A AU5186299A (en) 1998-08-14 1999-08-13 Use of misoprostol or/and misoprostol acid for preparing drug in order to cure sexual dysfunction in women
EP99936893A EP1107762B9 (en) 1998-08-14 1999-08-13 Use of misoprostol or/and misoprostol acid for preparing drug in order to cure sexual dysfunction in women

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR980100315 1998-08-14
GR98100315 1998-08-14

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EP (1) EP1107762B9 (en)
JP (1) JP2002522500A (en)
AT (1) ATE307590T1 (en)
AU (1) AU5186299A (en)
DE (1) DE69927985T2 (en)
ES (1) ES2249906T3 (en)
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WO (1) WO2000009134A1 (en)

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US6897239B1 (en) 2005-05-24
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DE69927985D1 (en) 2005-12-01
EP1107762B9 (en) 2006-08-16
EP1107762A1 (en) 2001-06-20
JP2002522500A (en) 2002-07-23
GR1003199B (en) 1999-09-01
ATE307590T1 (en) 2005-11-15
ES2249906T3 (en) 2006-04-01
DE69927985T2 (en) 2006-07-27

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