RU2482847C2 - Pharmaceutical composition, containing sildenafil or alprostadil, minoxidil or euphyllin, testosteron or yohimbine and liposomes for local application - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutical compositions for local application. Claimed compositions include sildenafil, minoxidil, testosterone, or alprostadil, euphyllin, yohimbine, or sildenafil, minoxidil, yohimbine as active agents respectively. Claimed compositions also contain hydrogenated lecithins in combination with cholesterol, emulsifying agent, preservative and demineralised water in specified weight ratios.

EFFECT: group of inventions ensures fast penetration through skin and complex therapy of erectile dysfunction taking into account impact on psychogenic and endocrine factors.

3 cl, 4 tbl, 7 ex

Description

The present invention relates to medicine, namely to topical pharmaceutical compositions containing sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and liposomes containing hydrogenated lecithins in combination with cholesterol.

Recently, thanks to the achievements of medicine, a number of oral and injectable pharmaceuticals have appeared that can partially solve the problems of erectile dysfunction in men.

The known drug Viagra ™ (sildenafil citrate) -citrate 1 - [[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-α] pyrimidine-5- il) -4-ethoxyphenyl] sulfonyl] piperazine. Sildenafil citrate selectively inhibits the activity of the type 5 phosphodiesterase enzyme, which inactivates cyclic guanosine monophosphate, which is involved in the relaxation of the smooth muscles of the cavernous body and improves the blood supply to the penis. Sildenafil does not have a direct relaxing effect on the vessels of the corpora cavernosa, but enhances the vasodilating effect of nitric oxide released during sexual stimulation in relation to this tissue. The drug is prescribed orally in the form of tablets. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p.134.)

The known drug Levitra ™ (vardenafil) - 2- [2-ethoxy-5- (4-ethyl-piperazin-1-sulfonyl) phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f ] [1,2,4] triazine-4 single monohydrochloride trihydrate. Vardenafil, blocking the specific type 5 phosphodiesterase involved in cGMP cleavage, enhances the local action of endogenous nitric oxide in the cavernous bodies during sexual stimulation. This effect determines the ability of vardenafil to enhance the response to sexual stimulation. The drug is prescribed orally in the form of tablets.

Known drug Minoxidil - 2,4-diamino-6-piperidinopyrimidin-3-oxide, which has a peripheral vasodilator effect, which is associated with the opening of potassium channels, and produced in the form of tablets and solution for external use. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p.434.)

Alprostadil - synthetic prostaglandin E1 preparations are known: in injection form - Kaverdzhekt ™ and in the form of suppositories - Muse ™. Alprostadil causes contraction of smooth muscle organs and at the same time has a pronounced peripheral vasodilating effect (dilates arterioles and relaxes the sphincters of capillaries), increases blood flow in peripheral vessels, improves microcirculation, inhibits platelet aggregation, and increases the elasticity of red blood cells. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p.607.)

The well-known drug is Eufillin - theophylline (1,3-dimethylxanthine) with 1,2-ethylenediamine, which relaxes the smooth muscles of blood vessels. Inhibition of phosphodiesterase and the accumulation of cyclic 3 ", 5" -adenosine monophosphate in the tissues play a role in the mechanism of theophylline action. The accumulation in the cells of cyclic 3 ", 5" -adenosine monophosphate inhibits the connection of myosin with actin, which reduces the contractile activity of smooth muscles. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p. 420.)

From the Register of Medicinal Products of Russia. Radar Encyclopedia of drugs. - 16th edition, 2007, p. 101. It is known that aminophylline causes relaxation of the smooth muscles of the bronchi, blood vessels, gastrointestinal tract, and bile ducts. The mechanism of action of this drug is associated with its ability to inhibit phosphodiesterase and stabilize cAMP.

Known drug papaverine - lowering the tone and contractile activity of smooth muscles, thus exerting a vasodilating and antispasmodic effect. In some countries (USA, Canada, etc.), papaverine (Papaverine Intracavernosal) is used to stimulate an erection in men. A solution of papaverine hydrochloride (sometimes in combination with an α-blocker - phentolamine - is administered intracavernosally). The action is associated with relaxation of the smooth muscles of the trabeculae of the cavernous bodies and blood vessels of the penis, and increased arterial blood flow. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p. 147.)

Known drug Andriol ™ in the form of capsules containing testosterone undecanoate and used in connection with functional insufficiency of the male sex glands.

The well-known drug Yohimbine, available in the form of tablets, is methyl ester of 17α-hydroxyohymban - 16α-carboxylic acid, which is a selective competitive antagonist of α2-adrenoreceptors. Yohimbine activates adrenergic processes in the central nervous system, increases the heart rate, enhances motor activity, has a moderate stimulating effect on spinal cord reflexes, and stimulates sexual activity in case of neurogenic erection disorders. Yohimbine has the ability to improve erectile function due to increased blood flow to the hollow organs. (see the Register of Medicines of Russia. Radar Encyclopedia of Medicines. - 16th edition, 2007, p. 101, p. 365.)

The disadvantages of the above, in particular tablets, are their systemic effects on the human body, causing a number of serious side effects from the cardiovascular system, in particular myocardial ischemia, orthostatic hypotension, arterial hypertension, etc., the inconvenience of the use of injectable drugs. In addition, in therapy with such agents, only one link in the pathogenesis of erectile dysfunction is taken into account, in particular, the optimization of hemodynamic parameters.

A pharmaceutical composition is known for topical, in particular transdermal administration of active substances, in which at least one active substance (abstract, paragraph 28 of the formula) represented by sildenafil, alprostadil or minoxidil is present in the form included in liposomes and / or associated with liposomes ( p. 1, lines 25-29, 42-45). Liposomes contain phospholipids, including phosphatidylcholine, in combination with cholesterol (paragraphs 26, 27 of the formula; page 2, line 51), have good penetration through the skin (page 1, line 55).

The specified pharmaceutical composition provides a temporary depot of the active substance in the surrounding tissue from which the substance is continuously released, improves its bioavailability, and also provides a longer half-life compared to systemic use. Through the relaxing effect of this composition on smooth muscle cells, an enhanced blood supply to externally processed tissues, such as the genitals, is achieved, and as a result, increased sensitivity and susceptibility during sexual activity (p. 1, lines 31-36). (EA 011391 B1 (POLIMOUN SAYNTIFIK IMMUNBIOLOGICHE FORSHUNG GMBH (AT)) February 27, 2009. From IL Knunyants “Chemical encyclopedia in 5 volumes.” T.2, 1990, p. 588 it is known that the term “phosphatidylcholine” is synonymous with is "lecithin", that is, liposomes contain lecithins in combination with cholesterol.

The claimed invention differs from EA 011391 B1 in that it does not disclose a composition containing three active agents, nor does it disclose active agents such as testosterone and yohimbine, in addition, the liposomes used in EA 011391 were obtained using solutions of electrolytes: ammonium sulfate or buffer solutions, as well as glucose solution. Liposomes in the claimed inventions differ from EA 011391 B1 in that they are formed from hydrogenated lecithins in combination with cholesterol. The disadvantage of the agents listed above in EA 011391 is that psychogenic and endocrine etiological factors are not taken into account in such therapy of erectile dysfunction.

The possibility of sharing sildenafil and testosterone for the treatment of erectile dysfunction in men is known from R. SHABSIGH "Testosterone therapy in erectile disfunction" The aging male, 2004, pp.312-318 [online]. [Found on the Internet 04/17/2012]

URL: http: //www.hawaii.edu/hivandaids/Testosterone_Therapy_in_Erectile_Dysfunction.pdf.

A composition is known from EA 007151 B1 in which the active substance selected from the group of PDE 4 inhibitors is almost uniformly dispersed or dissolved in an excipient matrix containing one or more excipients selected from the group consisting of fatty alcohol, triglyceride, partial glyceride and fatty acid ester and while the composition is in the form of microspheres, the preferred PDE 4 inhibitors are roflumilast and pumafentrin in the form of rapidly disintegrating tablets, solutions or suspensions. The lecithins in EA 007151 B1 are proposed as other suitable excipients that may be present in solution or suspension as emulsifiers, but not as carriers of active substances. Also, the phrase “may be present” in relation to lecithins should be regarded as both the possible presence and absence of the composition, which allows attributing lecithins to minor components, the main function of which is to stabilize the emulsion or suspension, but not transfer active substances through the skin. In the claimed compositions, the active substances are included in liposomes based on phospholipids without the use of fatty alcohols, triglycerides, incomplete triglycerides and fatty acid esters, in contrast to the excipient matrix from EA 007151 B1, in addition, the complex effect of the combination of active substances with respect to erectile dysfunction is not claimed .

In medicine, liposomes are used as carriers of biologically active substances through the skin. The assortment of liposome drugs contains ointments, creams and gels for the treatment of various diseases.

The well-known Essaven ™ gel, which includes: escin, "essential" phospholipids and heparin sodium salt, and used for phlebitis, thrombophlebitis and hemorrhoids. (Mashkovsky M.D. Medicines. - 15th ed., Revised., Rev. And add. - M.: New Wave, 2006. - p. 461-462.)

Pharmaceutical compositions containing sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and liposomes containing hydrogenated lecithins in combination with cholesterol are not described for topical application.

Thus, it is an object of the present invention to provide a topical pharmaceutical composition comprising sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and liposomes with rapid penetration through the skin, as well as the ability to induce sex drive (yohimbine, testosterone) , relax the smooth muscles of the corpora cavernosa (aminophylline) and improve the blood supply to the penis (sildenafil, alprostadil, minoxidil), i.e. provide complex therapy of erectile dysfunction.

The present invention provides a topical pharmaceutical composition comprising sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and pharmaceutically acceptable carriers or excipients, characterized in that it further includes liposomes containing hydrogenated lecithins in combination with cholesterol.

As a preferred embodiment of the claimed invention, a pharmaceutical composition is provided which has the following composition, wt.%:

sildenafil 0.01-5.0 minoxidil 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 testosterone 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41

As another of the preferred embodiments of the claimed invention, a pharmaceutical composition is provided, which has the following composition, wt.%:

alrolstadil 0.01-5.0 amyfillin 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 yohimbine 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41

As another of the preferred embodiments of the claimed invention, a pharmaceutical composition is provided, which has the following composition, wt.%:

sildenafil 0.01-5.0 minoxidil 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 yohimbine 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41

The technical result of the present invention is to obtain a pharmaceutical composition based on sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and liposomes with rapid penetration through the skin, as well as the ability to induce sex drive (testosterone, yohimbine), relax the smooth muscles of the cavernous body (eufilin) and improve blood supply to the penis (sildenafil, alprostadil, minoxidil).

Additional advantages are also ease of use and ease of dosing, as well as the fact that the claimed invention provides a comprehensive therapy for erectile dysfunction, taking into account the effects on the psychogenic and endocrine factors of the occurrence of erectile dysfunction.

The pharmaceutical composition of the present invention is usually prepared by conventional methods using solid or liquid pharmaceutically acceptable carriers or excipients selected from emulsifiers, dispersants, preservatives, flavorings, pH adjusters, polymer carriers and other excipients that are suitable for the preparation of compositions for topical use. The pharmaceutical composition of the present invention can be prepared in the form of a gel, cream, ointment and the like.

Rapid penetration through the skin is due to the binding of sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine to liposomes containing hydrogenated lecithins in combination with cholesterol.

From the foregoing, it is obvious for a specialist to obtain a pharmaceutical composition based on sildenafil or alprostadil, minoxidil or aminophylline, testosterone or yohimbine and liposomes, which has rapid penetration through the skin, as well as the ability to induce sex drive, relax the smooth muscles of the cavernous body and improve blood supply to the genitals.

In preferred embodiments, the compositions are oriented: in the first case, for the treatment of androgen deficiency complicated by erectile dysfunction, in the second - for the treatment of psychogenic erectile dysfunction, in the third - for the treatment of erectile dysfunction complicated by psychogenic factors and peripheral circulation disorders, the binding of active substances to liposomes provides their stability and duration of action, as well as penetration into the deep layers of tissues.

The present invention is illustrated by the following examples.

EXAMPLE 1

The pharmaceutical composition in the form of a cream based on sildenafil, minoxidil, testosterone and liposomes containing hydrogenated lecithins in combination with cholesterol, has the following composition:

sildenafil 5,0 minoxidil 5,0 liposomes containing hydrogenated lecithins in combination with cholesterol 20,0 testosterone 5,0 carbomer 10.0 preservative 1,0 demineralized water 64.0

The specified composition is prepared according to the following method. In demineralized water, when heated to 80 ° C, they mix: sildenafil, minoxidil, carbomer, then cool to 30 ° C and testosterone, liposomes containing hydrogenated lecithins in combination with cholesterol and a preservative are added. The resulting cream is homogenized and vacuum.

EXAMPLE 2

The pharmaceutical composition in the form of a cream based on alprostadil, aminophylline, yohimbine and liposomes containing hydrogenated lecithins in combination with cholesterol, has the following composition:

alrolstadil 0.01 amyfillin 0.01 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01 yohimbine 0.01 carbomer 0.5 preservative 0.05 demineralized water 99.41

The specified composition is prepared as in EXAMPLE 1, but alprostadil is used instead of sildenafil, aminophylline is used instead of minoxidil and yohimbine is used instead of testosterone.

EXAMPLE 3

The pharmaceutical composition in the form of a cream based on terbinafine and liposomes containing hydrogenated lecithins in combination with cholesterol, has the following composition:

sildenafil 1,0 minoxidil 2.0 liposomes 2.0 yohimbine 1,0 carbomer 1,0 preservative 0.05 demineralized water 92.95

The composition is prepared as in EXAMPLE 1, but yohimbine is used instead of testosterone.

EXAMPLE 4

The study of the pharmaceutical composition with sildenafil and liposomes containing hydrogenated lecithins in combination with cholesterol, the ability to quickly penetrate the skin

To this end, the ability to rapidly penetrate into the skin of a composition of the present invention based on sildenafil and a control composition containing sildenafil without liposomes containing hydrogenated lecithins in combination with cholesterol was compared. The tests were carried out on rabbits. These compositions were applied to the inner surface of the rabbit's ear. Absorption was determined by the amount of sildenafil remaining on the rabbit skin 10 minutes after application of the compositions, and expressed as a percentage of the initial amount of sildenafil in the composition.

Results of the study: control composition - 50% of the remaining sildenafil; the composition of the present invention is 10% of the remaining sildenafil.

Thus, the pharmaceutical composition according to this invention has the ability to quickly penetrate the skin, providing a more rapid manifestation of the therapeutic effect exerted by the active substances of the composition.

EXAMPLE 5

The study of the pharmaceutical composition with sildenafil, minoxidil, testosterone and liposomes for the ability to quickly penetrate the skin

To this end, the ability to rapidly penetrate into the skin of a composition of the present invention based on sildenafil, minoxidil, testosterone and a control composition containing sildenafil, minoxidil and testosterone without liposomes containing hydrogenated lecithins in combination with cholesterol was compared. The tests were carried out on rabbits. These compositions were applied to the inner surface of the rabbit's ear. Absorption was determined by the amount of sildenafil, minoxidil and testosterone remaining on the rabbit skin 10 minutes after application of the compositions, and was expressed as a percentage of the initial amount of sildenafil, minoxidil, testosterone in the composition.

Results of the study: control composition - 50% of the remaining sildenafil, 60% of the remaining minoxidil and 20% of the remaining testosterone; the composition of the present invention is 10% of the remaining sildenafil, 10% of the remaining minoxidil, 1% of the remaining testosterone.

EXAMPLE 6

The study of the pharmaceutical composition with alprostadil, aminophylline, yohimbine and liposomes containing hydrogenated lecithins in combination with cholesterol, for the ability to quickly penetrate the skin

To this end, the ability to rapidly penetrate into the skin of a composition of the present invention based on alprostadil, aminophylline, yohimbine and a control composition containing alprostadil, aminophylline and yohimbine without liposomes containing hydrogenated lecithins in combination with cholesterol was compared. The tests were carried out on rabbits. These compositions were applied to the inner surface of the rabbit's ear. Absorption was determined by the amount of alprostadil, aminophylline, yohimbine remaining on the rabbit skin 10 minutes after application of the compositions, and was expressed as a percentage of the initial amount of alprostadil, aminophylline, yohimbine in the composition.

Research results: control composition - 50% of the remaining alprostadil; 60% of the remaining aminophylline and 20% of the remaining yohimbine, the composition of the present invention is 10% of the remaining alprostadil, 10% of the remaining aminophylline, 10% of the remaining yohimbine.

Thus, the pharmaceutical composition according to this invention has the ability to quickly penetrate the skin, providing a more rapid manifestation of the therapeutic effect exerted by the active substances of the composition.

EXAMPLE 7

The study of the pharmaceutical composition on the ability to influence the psychogenic and endocrine factors of erectile dysfunction

To assess the effectiveness of the pharmaceutical composition with respect to the effect on the psychogenic and endocrine factors of erectile dysfunction, a comparative study of the compositions of EXAMPLES 1 and 3 was carried out. 40 patients participated in the study. All patients complained of erectile dysfunction, difficulties in achieving and maintaining an erection, weakening sensations. The subjects were combined in 2 groups: the 1st at the age of 30 to 50 years (n = 20) received the composition from EXAMPLE 1, the 2nd group - from 51 to 70 years (n = 20) received the composition from EXAMPLE 3. All For patients, the compositions were applied to the surface of the penis 1 hour before sexual intercourse 1 time per day, the duration of use was 2 months. Evaluation of the effectiveness of the composition was carried out according to the MKF scale.

The results of the study are shown in tables 1 and 2.

Table 1 Dynamics of changes in the components of the copulative cycle Group of patients Age years Component of the copulative cycle mental erection ejaculatory neurohumoral Before treatment After treatment Before treatment After treatment Before treatment After treatment Before treatment After treatment 1st (n = 20) 30-50 5.5 ± 1.7 7.3 ± 2.4 4.2 ± 1.2 10.0 ± 2.5 7.3 ± 2.2 9.2 ± 1.8 7.0 ± 1.6 9.0 ± 2.1 2nd (n = 20) 51-70 3.5 ± 1.2 4.9 ± 1.1 2.7 ± 1.0 5.3 ± 1.4 5.2 ± 1.0 6.2 ± 1.7 3.7 ± 0.7 5.9 ± 1.0

table 2 Dynamics of integrating indicators Group of patients Age years Total points The state of copulative function in general Before treatment After treatment Before treatment After treatment 1st (n = 20) 30-50 24.0 ± 3.3 35.5 ± 4.4 4.7 ± 2.2 11.5 ± 1.7 2nd (n = 20) 51-70 15.1 ± 3.9 22.1 ± 4.3 3.3 ± 1.0 22.3 ± 1.2

To assess the effectiveness of the pharmaceutical composition in relation to the effect on the psychogenic and endocrine factors of erectile dysfunction, a comparative study of the compositions of EXAMPLE 2 was carried out in comparison with the drug Viagra (sildenafil) in 50 mg tablets. The study involved 40 patients. All patients complained of erectile dysfunction, difficulties in achieving and maintaining an erection, weakening sensations. The study was conducted on the age group from 30 to 50 years: the 1st (n = 20) received the composition from EXAMPLE 2, the 2nd group (n = 20) received Viagra (sildenafil) in 50 mg tablets. Patients from the 1st group were applied the composition to the surface of the penis 1 hour before sexual intercourse 1 time per day, patients from the 2nd group were prescribed 1 tablet 1 time per day 1 hour before sexual intercourse, the duration of use was 2 months. Evaluation of the effectiveness of the composition was carried out according to the MKF scale. The results of the study are shown in tables 3 and 4.

Table 3 Dynamics of changes in the components of the copulative cycle Group of patients Age years Component of the copulative cycle mental erection ejaculatory neurohumoral Before treatment After treatment Before treatment After treatment Before treatment After treatment Before treatment After treatment 1st (n = 20) 30-50 5.5 ± 1.7 8.3 ± 2.4 4.2 ± 1.2 10.0 ± 2.5 7.3 ± 2.2 9.2 ± 1.8 3.7 ± 1.6 9.0 ± 2.1 2nd (n = 20) 51-70 3.0 ± 1.2 3.2 ± 1.1 2.7 ± 1.0 7.3 ± 1.4 5.2 ± 1.0 6.2 ± 1.7 3.7 ± 0.7 4.9 ± 1.0

Table 4 Dynamics of integrating indicators Group of patients Age years Total points The state of copulative function in general Before treatment After treatment Before treatment After treatment 1st (n = 20) 30-50 20.7 ± 3.3 36.5 ± 4.4 4.2 ± 2.2 8.0 ± 1.7 2nd (n = 20) 30-50 14.6 ± 3.9 21, b ± 4.3 3.4 ± 1.0 6.2 ± 1.2

The data indicate the effect of the compositions of EXAMPLES 1, 2, 3 on all components of the copulative cycle, while when using only one sildenafil (Viagra), a significant effect was noted only on the erection component.

Thus, the compositions of the claimed invention affect the psychogenic and endocrine factors of erectile dysfunction.

Claims (3)

1. A pharmaceutical composition for topical application, having the following composition, wt.%:
sildenafil 0.01-5.0 minoxidil 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 testosterone 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41 2. A pharmaceutical composition for topical application, having the following composition, wt.%:
alprostadil 0.01-5.0 amyfillin 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 yohimbine 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41 3. A pharmaceutical composition for topical application, having the following composition, wt.%:
sildenafil 0.01-5.0 minoxidil 0.01-5.0 liposomes containing hydrogenated lecithins in combination with cholesterol 0.01-20.0 yohimbine 0.01-5.0 emulsifier 0.5-10.0 preservative 0.05-1.0 demineralized water 64.0-99.41