U.S. patent application number 10/563980 was filed with the patent office on 2006-08-31 for combinations of vasoactive agents and their use in the treatment of sexual dysfunctions.
Invention is credited to Ezio Bombardelli.
Application Number | 20060193927 10/563980 |
Document ID | / |
Family ID | 34044550 |
Filed Date | 2006-08-31 |
United States Patent
Application |
20060193927 |
Kind Code |
A1 |
Bombardelli; Ezio |
August 31, 2006 |
Combinations of vasoactive agents and their use in the treatment of
sexual dysfunctions
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.
Inventors: |
Bombardelli; Ezio;
(Groppello Cairoli, IT) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET
2ND FLOOR
ARLINGTON
VA
22202
US
|
Family ID: |
34044550 |
Appl. No.: |
10/563980 |
Filed: |
July 6, 2004 |
PCT Filed: |
July 6, 2004 |
PCT NO: |
PCT/EP04/07374 |
371 Date: |
February 27, 2006 |
Current U.S.
Class: |
424/725 |
Current CPC
Class: |
A61K 36/39 20130101;
A61K 36/16 20130101; A61P 15/00 20180101; A61P 15/10 20180101; A61K
36/39 20130101; A61K 31/352 20130101; A61K 36/16 20130101; A61K
31/352 20130101; A61K 36/53 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 36/53 20130101; A61P 43/00 20180101 |
Class at
Publication: |
424/725 |
International
Class: |
A61K 36/39 20060101
A61K036/39 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 11, 2003 |
IT |
MI2003A001428 |
Claims
1. Topical compositions containing: esculoside or visnadine;
forskolin or extracts containing it, or alternatively, purified lip
ophilic 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-amino
ethyl-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 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; for the preparation of
compositions for the topical treatment of sexual dysfunctions.
Description
[0001] 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.
[0002] 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.
[0003] 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. In vitro, it causes relaxation of smooth muscle
striations previously contracted by noradrenaline, 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 CGRP
(calcitonin gene-related peptide).
[0004] Nitric oxide (NO) is synthesised from L-Arginine through the
action of the enzyme NOs (nitric oxide synthetase). The two sources
of NO in the penis 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 NO-releasing substances can produce an erection in
impotent men as well as men with normal sexual potency.
[0005] 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 .alpha.1-adrenergic membrane
receptors (in the cavernous tissue, type .alpha. receptors
outnumber type .beta. 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.
[0006] 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.
[0007] 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 V (PDE). Once
stimulated, cGMP activates the enzyme protein kinase G (PKG), which
closes the L-type calcium channels and opens the potassium
channels. VIP, like 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.
[0008] It has now been discovered that by associating esculoside or
visnadine, icarin and derivatives or extracts which contain it,
amentoflavone, dimers of Gingko biloba, forskolin or purified
extracts of Coleus forskolii, purified extracts of plants of the
genus Ipomea 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.
[0009] 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.
[0010] The topical compositions according to the invention contain:
[0011] esculoside or visnadine; [0012] forskolin or extracts
containing it, or alternatively, purified lipophilic extracts of
plants of the genus Ipomea; [0013] esters of ximenynic acid; [0014]
optionally, at least one compound selected from a icarin or
derivatives or extracts thereof which contain it, amentoflavone,
and Gingko biloba dimeric flavones.
[0015] Visnadine is a coumarin mainly found in the seeds of Ammi
visnaga, 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 precapillary arteries and arterioles, increasing the
blood flow and tissue perfusion (EP 0418806). 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.
[0016] Esculoside, a coumarin glucoside present in many plants,
such as Aesculus hippocastanum, Fraxinus communis, etc., possesses
a vasokinetic action and venotropic activity at both venous and
arterial levels.
[0017] 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. Icarin derivatives include
7-hydroxyethyl-icarin or 7-aminoethyl-icarin,
7-hydroxyethyl-3-0-ramnosyl-icarin,
7-aminoethyl-7-desgluco-3-ramnosyl-icarin, 8-dihydro-icarin and its
glucosides in 7 and 3, and 7-hydroxyethyl-7-desgluco-icarin.
[0018] Amentoflavone is a biflavone present in modest amounts in
numerous plants, such as Gingko biloba, Brakeringea zanguebarica
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.
[0019] Forskolin, and the extracts which contain it, is a known
adenylate cyclase agonist. A purified extract of Coleus forskolii
is particularly preferred.
[0020] Extracts of plants of the genus Ipomea also possess a
significant activity on adenylate cyclase; the standardised
lipophilic extracts of Ipomea hederacea, Ipomea parassitica and
Ipomea batatas are particularly preferred.
[0021] The formulations according to the invention improve sexual
performance, especially in women. For example, a combination in gel
form containing 1% 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 formulations
according to the invention leads to a rapid erection which is
prolonged for as long as required to complete the act of sexual
intercourse.
[0022] The following examples illustrate the invention.
EXAMPLE 1
[0023] TABLE-US-00001 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 (Ultrez 10 - B F Goodrich) 1.00 g
Imidazolidinyl urea 0.30 g Xanthane gum (Keltrol TF - Kelco) 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 Perfume (Jenny - Dragoco)
0.01 g Water q.s. to 100 g
EXAMPLE 2
[0024] TABLE-US-00002 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 8.00 g Carbomer (Ultrez 10 - B F Goodrich) 1.00 g
Imidazolidinyl urea 0.30 g Xanthane gum (Keltrol TF - Kelco) 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 Perfume (Jenny - Dragoco)
0.01 g Water q.s. to 100 g
EXAMPLE 3
[0025] TABLE-US-00003 Visnadine 1.00 g
7-hydroxyethyl-7-desgluco-icarin 1.00 g Forskolin 0.20 g
Amentoflavone 0.20 g Ethyl ximeninate 2.00 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 8.00 g Carbomer (Ultrez 10 - B F Goodrich) 1.00 g
Imidazolidinyl urea 0.30 g Xanthane gum (Keltrol TF - Kelco) 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 Perfume (Jenny - Dragoco)
0.01 g Water q.s. to 100 g
EXAMPLE 4
[0026] TABLE-US-00004 Esculoside 1.00 g
7-Hydroxyethyl-7desgluco-icarin 1.00 g Ipomea hederacea lyophilic
standardized extract 0.20 g 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 8.00
g Carbomer (Ultrez 10 - B F Goodrich) 1.00 g Imidazolidinyl urea
0.30 g Xanthane gum (Keltrol TF - Kelco) 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 Perfume (Jenny - Dragoco) 0.01 g Water q.s.
to 100 g
* * * * *