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Combinations of vasoactive agents and their use in the treatment of sexual dysfunctions

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Publication number
CA2532825A1
CA2532825A1 CA 2532825 CA2532825A CA2532825A1 CA 2532825 A1 CA2532825 A1 CA 2532825A1 CA 2532825 CA2532825 CA 2532825 CA 2532825 A CA2532825 A CA 2532825A CA 2532825 A1 CA2532825 A1 CA 2532825A1
Authority
CA
Grant status
Application
Patent type
Prior art keywords
icarin
extracts
sexual
purified
visnadine
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.)
Granted
Application number
CA 2532825
Other languages
French (fr)
Other versions
CA2532825C (en )
Inventor
Ezio Bombardelli
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.)
Indena SpA
Original Assignee
Indena S.P.A.
Ezio Bombardelli
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

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/39Convolvulaceae (Morning-glory family), e.g. bindweed
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/53Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender

Abstract

This invention relates to combinations of vasoactive substances which are useful in the treatment of sexual dysfunctions associated with poor local blood supply and/or insufficient lubrication. The active compounds are selected from a: - esculoside or visnadine; - forskolin or extracts containing it, or alternatively, purified lipophilic extracts of plants of the genus Ipomea; - esters of ximenynic acid; - optionally, at least one compound selected from a icarin or derivatives or extracts thereof which contain it, amentoflavone, and Gingko biloba dimeric flavones. The combination of these vasoactive substances is incorporated in gels and lotions designed to be applied to the genital organs. These formulations are useful in inducing erection of the male and female sex organs and enhancing orgasm and sexual performance. The formulations are particularly useful in the treatment of female sexual dysfunctions.

Description

COMDiNATIONS OF VASOAC 11 VE AOENTS AND 1 HEIR U SE 1N
THE TREATMENT OF SEXUAL DYSFUNCTIONS
This invention relates to combinations of vasoactive substances which are useful in the treatment of sexual dysfunctions associated with poor local blood supply andfor insufficient lubrication.
Loss of erectile capacity in men is an event which adversely affects the physical, emotional and social sphere of the sufferer. When this sexual dysfunction arises, men come to expect yet another "failure" whenever they have sexual intercourse, thus generating a particular state of mind which is both cause and effect of a problem that was originally only physical.
As sexuality is an important means of communication between a couple, deterioration of erectile potency leads to a build-up of emotional tension between the two partners and a consequent deterioration in their relationship.
Loss or absence of erectile capacity and lubrication to various extents also constitutes a serious problem in women, with adverse consequences on the couple's relationship. A variety of mediators and receptors are involved in the tumescence of the male and female genital organs. Acetylcholine (Ach), for example, is the best-known parasympathetic neurotransmitter. ItZ vitt~~, it causes relax~.tion of smooth muscle striations pre~riously contracted by noradrcnaline, and contraction of smooth muscle cell isolates. This suggests that the main action of Ach is to contract the smooth muscles and determine the release of a substance which causes cavernous relaxation. In addition to Ach, the parasympathetic nerves also release other neurotransmitters, including nitric oxide (NO), VIP and CGI~P (calcitonin gene-related peptide).
Nitric oxide (NO) is synthesised from L-Arginine through the action of the en~,ynae l~TOs (nitric oxide synthetase). The two sources of NO in the penis CONFIRMATION COPY

and clitoris are represented by the parasympathetic nerve endings and the endothelium, synthesised by different NOs enzymes: nNOs (neuronal NOs), which is present in the cytoplasm of the parasympathetic nerves, and eNOs (endothelial NOs), found in the endothelium of the blood vessels and trabecular tissue, which mainly seems to bond to the cell membranes.
Numerous experiments have demonstrated that stimulation of the parasympathetic nerves leads to the release of NO as a result of direct action by the nerve endings (reaction catalysed by nNOs) and indirect action resulting from the effect of Ach, released by the parasympathetic nerves, on the vascular endothelium, with stimulation of eNos. There is also evidence in support of a tonic release of NO by the endothelium and the involvement of partial oxygen pressure. In fact, periods when partial oxygen tension is low, as in conditions of flaccidity, are associated with reduced NOs activity.
Finally, various studies have confirmed the ability of other substances, whose physiological significance has not yet been established, to determine the release of NO by the endothelium. The clinical evidence that NO plays a part in the erection of the penis includes the observation that intracavernous injection of 1~T0-releasing substances can produce an erection in impotent ~nen as well as men with normal sexual potency.
The Ach released by the parasympathetic fibres bonds to muscarinic receptors present on the endothelial cell membranes and the smooth muscle cell membranes. In the endothelium, this bond promotes the activation of eNOs with subsequent release of NO and inhibition of noradrenaline (NA).
Inhibition of NA release is essential to the physiology of the erection. NA, released by the sympathetic nerve endings, bonds with cxl-adrenergic meir~brar~e receptors (in the cavernous tissue, type a receptors outnumber type ~i receptors by a ratio of 10:1), leading to an increase in the activity of phospholipase C (PLC), which converts phosphatidylinositol (PIP) into inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of calcium ions from the sarcoplasmic reticulum, and DAG stimulates the enzyme protein kinase C (PKC). This enzyme, by opening the L-type calcium channels and closing the potassium channels, increases the intracytoplasmic calcium concentration, leading to contraction of the smooth muscles.
The NO released by the parasympathetic nerve endings and the endothelium is a lipophilic molecule, and therefore able to cross the smooth muscle cell membrane.
Despite its short half life (approx. 5 seconds), after reaching the cytoplasm of the muscle cell it stimulates its receptor, the enzyme guanylate cyclase, to convert guanosine triphosphate (GTP) into the second active messenger, cyclic guanosine monophosphate (cGMP). The intracytoplasmic levels of cGMP are controlled by the extent of the nitrergic stimulus and the catabolism rate of the enzyme phosphodiesterase ~' (PDE). ~nce stimulated, cGIVIP activates the enzyme protein kinase G (PKG), which closes the L-type calcium channels and opens the potassium channels. ~Ih, lil~.e the prostanoids (PGE1), mainly acts via specific receptors on the surface of the smooth muscle cell, stimulating the enzyme adenylate cyclase (a membrane enzyme). This enzyme converts ATP
into cyclic AMP (cAMP), which in turn causes a reduction in the intracellular calcium concentration and relaxation of the smooth muscles.
It has now been discovered that by associating esculoside or visnadine, icarin and derivatives or extracts which contain it, amentoflavone, dimers of Cxi~cgk~ biloba, forskolin or purified extracts of C'~leus f~r~sholii, purified extracts of plants of the germs Ipo-rrEa and esters of ximenynic acid, which modify physiologically dulled or altered parameters, and exploiting the synergic interactions between the active constituents, the functionality of the genital organs can be restored very effectively.
This invention relates in particular to combinations of vasoactive substances useful in the treatment of sexual dysfunctions associated with poor local blood supply to the male and female sex organs.
The topical compositions according to the invention contain:
- esculoside or visnadine;
- forskolin or extracts containing it, or alternatively, purified lipophilic extracts of plants of the genus Ipomea;
- esters of ximenynic acid;
- optionally, at least one compound selected from a icarin or derivatives or extracts thereof which contain it, amentoflavone, and Caihgko biloba dimeric flavones.
Visnadine is a coumarin mainly found in the seeds of ~lmmi visa~aga, a plant traditionally used to treat anginoid disorders. The compound has recently been used in the pharmaceutical field as a coronary dilator. We have demonstrated on various occasions that this compound, when applied topically, has a strong vasokinetic action on the precapilla~-y arteries and arterioles, increasing the blood flow and tissue perfusion (EP 041 ~~06). The supply of arterial blood to the erectile tissues induces the start of the erection and maintains it for as long as the compound is present in the tissues.
Visnadine also has an anti-phosphodiesterase activity useful to maintain the cyclic nucleotides.
Esculoside, a coumarin glucoside present in many plants, such as A~sculus drippo~as~ayzu~rz, ~'y~axir~us ~o~rzmuy2is, etc., possesses a vasokinetic action and venotropic activity at both venous and arterial levels.
Icarin and its derivatives act on cGMP phosphodiesterase V. High levels of cGMP are required to maintain the erection in the male and female genital organs and therefore the performance necessary for sexual intercourse.

5 Icarin derivatives include 7-hydroxyethyl-icarin or 7-aminoethyl-icarin, 7-hydroxyethyl-3-0-ramnosyl-icarin, 7-aminoethyl-7-desgluco-3-ramnosyl-icarin, ~-dihydro-icarin and its glucosides in 7 and 3, and 7-hydroxyethyl-7-desgluco-icarin.
Amentoflavone is a biflavone present in modest amounts in numerous plants, such as Gingko biloba, Brake~iugea zangueba~ica and Taxus sp. The addition of amentoflavone is particularly useful in some formulations, and is one of the subjects of this invention, because it acts as a very powerful inhibitor of phosphodiesterase and on the release of oxytocin, which is a known aphrodisiac at low doses.
Forskolin, and the extracts which contain it, is a known adenylate cyclase agonist. A purified extract of C'~leus f~r~sk~lii is particularly preferred.
Extracts of plants of the genus Ip~mea also possess a significant activity on adenylate cyclase~ the standardised lipophilic extracts of Ip~mea hedef°acea, Ip~f7zea paf°assitica and Ip~mea batatas are particularly preferred.
'The formulations according to the invention improve sexual performance, especially in women. For example, a combination in gel form containing 1~/o esculoside, 0.2~/~ forskolin and 1~/~ ethyl ximenynate was administered to a group of 10 female volunteers of child-bearing age. The efficacy test, in which the blood flow parameters in the external genital organs were instrumentally measured by a non-invasive method (Laser Doppler and optical probe videocapillaroscopy), demonstrated that the blood flow increased by up to 200°/~ of the basal value; as regards subjective sensations, the patients reported general well-being, and sexual excitement within half an hour. In men, application of the forimulations according to the invention leads to a rapid erection which is prolonged for as long as required to complete the act of sexual intercourse.
The following examples illustrate the invention.

Esculoside 1.00 g Ethyl ximeninate 2.00 g Coleus purified extract > 80% 0.20 g Polyethylene 400 10.00 g Ethoxydiglycol (Transcutol - Gattefosse)10.00 g Caprylic/Capric PEG-6 glycerides 10.00 g (Softigen 767 - Huls) Sorbitol 10.00 g Polysorbate 20 8.00 g Carbomer (LTltre~ 10 - EF Goodrich) 1.00 g Imida~olidinyl urea 0.30 g Xanthane gum (I~eltrol TF - I~elco) 0.30 g Methyl paraben 0.20 g I~isodium EFTA 0.10 g Hydroxytoluene butoxide 0.05 g 10~/~ sol. 5odlunl hydroxide 2.00 g Perfume (Jenny - Dragoco) 0.01 g Water q.s. to 100 g Visnadine 1.00 g Ethyl ximeninate 2.00 g Coleus purified extract > 80% 0.20 g polyethylene 400 10.00 g Ethoxydiglycol (Transcutol - Gattefosse)10.00 g Caprylic/Capric PEG-6 glycerides 10.00 g (Softigen 767 - Huls) Sorbitol 10.00 g Polysorbate 20 x.00 g Carbomer (Ultrez 10 - BF Goodrich) 1.00 g Imidazolidinyl urea 0.30 g Xanthane gum (I~eltrol TF - I~elco) 0.30 g Methyl paraben 0.20 g Disodium EDTA 0.10 g Hydroxytoluene butoxide 0.05 g 10% sol. sodium hydroxide 2.00 g Pelfu111e (Jenny - Dragoco) 0.01 g Water q.s. to 100 g EXAMPLE
Visnadine 1.00 g 7-hydroxyethyl-7-desgluco-icarin 1.00 g Forskolin 0.20 g Amentoflavone 0.20 g Ethyl ximeninate 2.00g Polyethylene 400 10.00 g Ethoxydiglycol (Transcutol - Gattefosse)10.00 g Caprylic/Capric PEG-6 glycerides 10.00 g (Softigen 767 - Huls) Sorbitol 10.00 g Polysorbate 20 x.00 g Carbomer (LTltrez 10 - BF Goodrich) 1.00 g Imidazolidinyl urea 0.30 g Xanthane gum (I~eltrol TF - I~elco) 0.30 g Methyl paraben 0.20 g L~isodium EFTA 0.10 g Hydr~~ytoluen a butoxide 0.05 g 10/~ sol. sodium hydroxide 2.00 g Perfume (Jenny - l~ragoco) 0.01 g Water q.s. to 100 g Esculoside 1.00 g 7-Hydroxyethyl-7desgluco-icarin 1.00 g Ipo~nea hede~acea lyophilic standardized0.20 g extract Gingko biloba dimeric flavones 0.20 g Ethyl ximeninate 1.00 g Polyethylene 400 10.00 g Ethoxydiglycol (Transcutol - Gattefosse)10.00 g Caprylic/Capric PEG-6 glycerides 10.00 g (Softigen 767 - Huls) Sorbitol 10.00 g Polysorbate 20 x.00 g Carbomer (LTltrez 10 - EF Goodrich) 1.00 g Imidazolidinyl urea 0.30 g Xanthane gum (Keltrol TF - I~elco) 0.30 g Methyl paraben 0.20 g I~isodium EFTA 0.10 g Hydr~~~ytoluen a butoxide 0.0~ g 10~/~ Sol. sodium hydroxide 2.00 g Perfume (Jenny - IW agoco) 0.01 g Water q.s. to 100 g

Claims (9)

1. Topical compositions containing:
- esculoside or visnadine;
- forskolin or extracts containing it, or alternatively, purified lipophilic extracts of plants of the genus Ipomea;
- esters of ximenynic acid;
- optionally, at least one compound selected from icarin or derivatives or extracts thereof which contain it, amentoflavone, and Gingko biloba dimeric flavones.
2. Compositions as claimed in claim 1, wherein icarin derivatives comprise 7-hydroxyethyl-7-desgluco-icarin, 7-hydroxyethyl-icarin, 7-aminoethyl-icarin, 7-hydroxyethyl-3-0-rhamnosyl-icarin, 7-aminoethyl-3-rhamnosyl-icarin, 8-dihydro-icarin or its glycosides in 7 and 3.
3. Compositions as claimed in claim 1, wherein Gingko biloba dimeric flavones comprise amentoflavone.
4. Compositions as claimed in claim 1, wherein the ximenynic acid ester is the ethyl ester.
5. Compositions as claimed in claim 1 containing Visnadine, Coleus forskolii purified extract, ximenynic acid ethyl ester, lubricants and anti-irritant excipients.
6. Compositions as claimed in claim 1 containing esculoside, Coleus forskolii purified extract, ximenynic acid ethyl ester.
7. Compositions as claimed in claim 1 containing Visnadine, Forskolin e ethyl ximenynate.
8. Compositions as claimed in claim 1 wherein the purified extracts of Ipomea plants are selected from Ipomea hederacea, Ipomea parassitica, Ipomea batatas.
9. The use of a combination of:
- esculoside or visnadine;
- forskolin or extracts containing it, or alternatively, purified lipophilic extracts of plants of the genus Iponaea;
- esters of ximenynic acid;
- optionally, at least one compound selected from a icarin or derivatives or extracts thereof which contain it, amentoflavone, and Gingko biloba dimeric flavones;
for the preparation of compositions for the topical treatment of sexual dysfunctions.
CA 2532825 2003-07-11 2004-07-06 Combinations of vasoactive agents and their use in the treatment of sexual dysfunctions Active CA2532825C (en)

Priority Applications (3)

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ITMI20031428 2003-07-11
ITMI2003A001428 2003-07-11
PCT/EP2004/007374 WO2005004890A1 (en) 2003-07-11 2004-07-06 Combinations of vasoactive agents and their use in the treatment of sexual dysfunctions

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CA2532825C CA2532825C (en) 2013-12-10

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US (3) US20060193927A1 (en)
JP (1) JP4892342B2 (en)
KR (1) KR101146867B1 (en)
CN (1) CN1822848B (en)
CA (1) CA2532825C (en)
DE (2) DE602004023137D1 (en)
DK (2) DK1644014T3 (en)
EP (2) EP1644014B1 (en)
ES (2) ES2286658T3 (en)
RU (2) RU2356568C2 (en)
WO (1) WO2005004890A1 (en)

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DE602006021192D1 (en) * 2005-03-12 2011-05-19 Unilever Nv Visnadine for the treatment of scalp itching
EP2011496A1 (en) * 2007-07-03 2009-01-07 Indena S.P.A. Combinations of vasoactive substances with estrogens and their use in the treatment of female sexual dysfunctions
US20090054497A1 (en) * 2007-08-21 2009-02-26 Nawaz Ahmad Methods for attaining enhanced sexual wellness using anhydrous compositions
US20090197892A1 (en) * 2007-08-21 2009-08-06 Nawaz Ahmad Anhydrous compositions useful for attaining enhanced sexual wellness
US20090054498A1 (en) * 2007-08-21 2009-02-26 Nawaz Ahmad Anhydrous Compositions Useful for Attaining Enhanced Sexual Wellness
CN101606928B (en) 2008-06-18 2011-12-07 河南大学 Use of a compound in the manufacture of ear Huashan Biflavones aspect hypolipidemic agents
WO2015099521A3 (en) 2013-12-24 2015-09-11 Biotropics Malaysia Bhd Fruit extracts and extract formulations of canarium odontophyllum as actives and related invention embodiments

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EP0304603B1 (en) 1987-07-27 1992-10-21 INDENA S.p.A. Polyunsaturated acids having vasokinetic action and pharmaceutical and cosmetic formulations containing them
EP0418806B1 (en) * 1989-09-21 1994-01-05 INDENA S.p.A. Pharmaceutical compositions havin activity on the cutaneous microcirculation
DE69022953T2 (en) * 1989-10-27 1996-03-14 Indena Spa Compositions for treating fat deposits.
DE69526882T2 (en) * 1994-07-12 2003-01-02 Indena Spa Esculosid containing preparations and their use in cosmetics and pharmacy
US5665335A (en) * 1994-07-19 1997-09-09 Indena S.A. Combinations of vasoactive substances with fatty acids to prevent hair loss
US6251436B1 (en) * 1995-09-29 2001-06-26 L.A.M. Pharmaceutical Corporation Drug preparations for treating sexual dysfunction
JPH09157136A (en) 1995-12-08 1997-06-17 Lion Corp Hair restorer/hair tonic
EP1027057A4 (en) * 1997-10-28 2003-01-02 Vivus Inc Treatment of female sexual dysfunction
CA2340206A1 (en) 1998-08-26 2000-03-09 Queen's University At Kingston Use of anti-pressor agents for vascular remodeling in genital dysfunction
US20020013280A1 (en) * 2000-06-16 2002-01-31 Zhongcheng Xin Pharmaceutical composition for preventing and treating sexual dysfunction and vasculargenic disease comprising icariin
DE60130007D1 (en) * 2000-06-27 2007-09-27 Qualilife Pharmaceuticals Inc Compositions and methods for treating female sexual response
DK1392335T3 (en) * 2001-06-05 2007-09-17 Indena Spa A pharmaceutical and / or cosmetic composition for the treatment of localized adiposities and cellulite

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Publication number Publication date Type
EP1644014A1 (en) 2006-04-12 application
US8092844B2 (en) 2012-01-10 grant
US8287926B2 (en) 2012-10-16 grant
RU2006100305A (en) 2006-06-10 application
ES2330795T3 (en) 2009-12-15 grant
ES2286658T3 (en) 2007-12-01 grant
DE602004023137D1 (en) 2009-10-22 grant
DK1797876T3 (en) 2009-12-21 grant
US20090269426A1 (en) 2009-10-29 application
RU2008148461A (en) 2010-06-20 application
WO2005004890A1 (en) 2005-01-20 application
CN1822848A (en) 2006-08-23 application
CA2532825C (en) 2013-12-10 grant
CN1822848B (en) 2010-05-26 grant
DE602004006271T2 (en) 2008-01-10 grant
EP1644014B1 (en) 2007-05-02 grant
KR101146867B1 (en) 2012-05-16 grant
JP4892342B2 (en) 2012-03-07 grant
JP2009513518A (en) 2009-04-02 application
EP1797876A1 (en) 2007-06-20 application
EP1797876B1 (en) 2009-09-09 grant
DK1644014T3 (en) 2007-09-10 grant
KR20060028746A (en) 2006-03-31 application
US20120009283A1 (en) 2012-01-12 application
RU2356568C2 (en) 2009-05-27 grant
US20060193927A1 (en) 2006-08-31 application
DE602004006271D1 (en) 2007-06-14 grant
RU2480229C2 (en) 2013-04-27 grant

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