KR101847484B1 - A pharmaceutical composition comprising solifenacin, or pharmaceutically acceptable salt thereof as an active ingredient for prevention and treatment of premature ejaculation - Google Patents

Abstract

The present invention relates to a composition for preventing and treating premature ejaculation comprising solifenacin as an active ingredient. Specifically, it was confirmed that patients suffering from premature ejaculation were delayed by administering Vesicare, containing solifenacin as a main ingredient to be used as a treatment for irritable bladder symptoms, to patients suffering from premature ejaculation and overactive bladder symptoms together, and thus the solifenacin may be useful as a pharmaceutical composition or food composition for preventing and treating the premature ejaculation.

Description

[0001] The present invention relates to a pharmaceutical composition for prevention and treatment of premature ejaculation comprising solifenacin or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutical composition for preventing and treating premature ejaculation comprising solifenacin or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a pharmaceutical composition for the prevention and treatment of premature ejaculation comprising solifenacin or a pharmaceutically acceptable salt thereof as an active ingredient.

Premature ejaculation is a lexical meaning that 'ejaculation' occurs abnormally too quickly when having sex. Or such a disease. In other words, premature ejaculation refers to a condition that occurs continuously or recurrently with minimal stimulation before the patient inserts, inserts, immediately after insertion, or before the patient (or partner) asks for an ejaculation.

The causes of these diseases are known to occur mostly as mental factors, have a genetic tendency, and can be caused by abnormalities of the peripheral nervous system and the nervous system of the central nervous system. In addition, premature ejaculation is generally caused by depression of central nervous system depression due to fatigue of the nervous system, hypersensitivity of the urethra or glans receptor due to genital diseases, endocrine and psychological causes, low levels of serotonin neurotransmission, .

This is one of the male sexual dysfunctions. According to global statistics, about one-third of the adult male population is the most common sexual dysfunction that adult men in modern society are suffering from, including premature ejaculation. And lethargy caused by loss of self-confidence are emerging as social problems.

The diagnostic criteria of the most commonly used premature ejaculation in the world are the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision). According to this definition, premature ejaculation is defined as persistent, repetitive minimal sexual stimulation immediately before, immediately after, or before ejaculation, and personal, relative psychological state, drug, and interpersonal state should be considered in premature ejaculation diagnosis Respectively. According to this definition, although objective time, which is an objective criterion, is not defined, it is generally used to compare the diagnosis and treatment efficacy of premature ejaculation using intravaginal ejaculatory latency time (IELT) , And IELT cut-off points, which can be diagnosed as premature ejaculation in most clinical trials, in 2 minutes.

The treatment of premature ejaculation is divided into psychotherapy and pharmacotherapy. Psychotherapy is a method of overcoming problems by long-term sexual training through dialogue and co-operation between doctors, patients and ladies, but also because of the hassle of long-term treatment, high cost of treatment and external stress, It is reported that the success rate is only about 50%, because patients are avoided because of difficulties in maintaining or failing or relapse.

Therefore, drug - based therapies are more effective and more frequently used than psychotherapy. Most of the drugs used for the treatment of premature ejaculation are products that are licensed (or notified) by the Pharmaceutical Affairs Law or those that are prescribed or taken out of the scope (efficacy, effect, usage, (2) a selective serotonin reuptake inhibitor (SSRI), which is an off-label, antidepressant such as an antidepressant that inhibits the stimulation of the sexual central nerve, a topical anesthetic agent that slows the sensation by slowing the sensation of the peripheral nerve, Topical anesthetic, tramadol, and phosphodiesterase type 5 inhibi (PDE5).

Overactive bladder (OAB) Symptoms are very sensitive to the function of the bladder, which means that while the urine is being stored in the bladder, the bladder muscle shrinks irrespective of the doctor's intention, causing a sudden urge to urinate. According to the International Urinary Incontinence Association definition, an overactive bladder has no urinary tract infection and no other obvious illnesses, regardless of urge incontinence (urinary incontinence) or urinary urgency (urinary urgency: (Eg, symptoms that can not be tolerated in the dark) and frequent urination and nighttime urination (frequent urination at nighttime sleep time). In other words, it feels very sudden urination (feeling urine) that can not tolerate without special disease (more than 8 times a day), and it can be said that it frequently urinates even during sleep.

In other words, the symptom (urinary frequency) to urinate more than 8 times a day, symptoms that can not be tolerated if the urine is too hot (sudden urination), symptoms that can not be tolerated if the urine is too cold (urge incontinence) And frequent urination (nocturia) are common symptoms of irritable bladder.

These symptoms of irritable bladder syndrome, such as urgency, urinary frequency, and nighttime urination, are not life-threatening, but they can lead to depression, shame, sexual problems, sleep disturbances, and depression, It is estimated that between 50 million and 100 million people suffer from overactive bladder symptoms worldwide.

The causes of these IBD symptoms are not yet fully understood. However, the known causes are neurological diseases, local diseases of the urethra and bladder, bladder outlet obstruction, and aging and primary diseases.

 Drugs used in the treatment of overactive bladder symptoms include smooth muscle relaxants that inhibit smooth muscle activity in the bladder muscle, calcium channel antagonists that block calcium entry into the muscle cells that are necessary for muscle contraction, potassium that relaxes the smooth muscle by increasing potassium release from the smooth muscle Channel opener and the like.

The present inventors completed the present invention by confirming that Solifenacin (Patent Document 1, KR 10-2013-7032702), which is used as a therapeutic agent for overactive bladder symptoms, improves the symptoms of patients with premature ejaculation.

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KR 10-2013-7032702

It is an object of the present invention to provide a pharmaceutical composition for improving, preventing and treating premature ejaculation comprising solifenacin or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to accomplish the above object, the present invention provides a pharmaceutical composition for preventing and treating premature ejaculation comprising a compound selected from the following Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient:

[Chemical Formula 1]

.

.

The present invention also provides a composition for improving premature ejaculation comprising a compound selected from the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention relates to a method for preventing and treating premature ejaculation by administering solifenacin to patients suffering from both premature ejaculation and overactive bladder symptoms and confirming delayed ejaculation in patients suffering from premature ejaculation, It can be usefully used as a composition or a food composition.

Figure 1 compares IELT before and after 1 mg of 5 mg of Vesicare, a major component of solifenacin, in 15 patients with premature ejaculatory and overactive bladder symptoms to be. The pre-treatment IELT and the post-treatment IELT are p = 0.000 for the Paired t-test and p = 0.001 for the Student t-test.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing and treating premature ejaculation comprising a compound having the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

The present invention also provides a health functional food for improving premature ejaculation comprising the compound of Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

In a specific example of the present invention, the inventors of the present invention have found that administration of Bicycare, a principal component of solifenacin, which is used as a therapeutic agent for overactive bladder symptoms, to patients suffering from premature ejaculatory and overactive bladder symptoms, By confirming the delays in the patients, the solifenacin can be usefully used as a pharmaceutical or food composition for the prevention and treatment of premature ejaculation.

The present invention includes not only the compounds represented by the above formula (1), but also pharmaceutically acceptable salts thereof, possible solvates, hydrates, racemates or stereoisomers thereof, and mixtures thereof.

The present invention can be used in the form of a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Octaic acid, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinic acid, succinic acid, succinic acid, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluene sulfonate, chlorobenzene sulfoxide Sulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulphonate, naphthalene-1-sulphonate, , Naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be produced by a conventional method, for example, by dissolving the compound represented by the formula (1) in an excess amount of an acid aqueous solution, and adding the salt to a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile To precipitate it. It is also possible to prepare the same by heating the compound represented by the general formula (1) and an acid aqueous solution or alcohol, followed by evaporating the mixture or drying the precipitated salt by suction filtration.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

When the composition is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like which are usually used.

In one embodiment of the present invention, the composition or preparation may be in the form of an oral preparation, an injection, a mucosal administration preparation, an oral mucosal administration preparation, a nasal administration preparation, an ophthalmic preparation, a vaginal administration preparation, an inhalant, , A transplant preparation, and a suppository, but is not limited thereto.

Solid formulations for oral administration include tablets, pills, powders, granules, capsules, troches and the like, which may contain one or more excipients such as one or more excipients such as, for example, , Starch, calcium carbonate, sucrose or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances and preservatives may be included. have.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. The base material of the suppository can be any one selected from witepsol, macrogol, tween 81, cacao paper, taurine paper, glycerol, gelatin and the like, But is not limited thereto.

The composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the dosage unit according to the present invention may contain, for example, 1, 2, 3 or 4 times, or 1/2, 1/3 or 1/4 times the individual dose. The individual dosages preferably contain amounts in which the active drug is administered in one go, which usually corresponds to the full, half, one-third or one-fourth of the daily dose. The effective dose of the composition of the present invention is 0.001 to 10,000 mg / kg, preferably 0.1 g to 5 g / kg, and can be administered 1 to 6 times a day. However, the dose may be varied depending on the administration route, severity of disease, sex, weight, age, etc., and therefore the dose is not limited to the scope of the present invention by any means.

The composition of the present invention may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The present invention also provides a food composition for prevention and improvement of premature ejaculation comprising a compound selected from the above-mentioned formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The composition of the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to conventional methods. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). In general, the amount of the compound in the health functional food may be 0.01 to 90 parts by weight based on the total weight of the food. However, when consumed for a long period of time for the purpose of health and hygiene or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

The functional beverage composition of the present invention is not particularly limited to the other components other than those containing the composition as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. As a flavor other than the above, a natural flavoring agent {tau martin, stevia extract (for example, rebaudioside A, glycyrrhizin etc.)} and synthetic flavorings (saccharin, aspartame, etc.) have. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention, but is not limited thereto.

In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.

These components may be used independently or in combination. Although the ratio of such additives is not so important, it is generally but not limited to be selected from the range of 0.1 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, the present invention will be described in detail by the following examples.

However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Human subject examination

The following experiments were conducted to confirm that Betic Care, a therapeutic drug used as a therapeutic agent for irritable bladder symptoms, is useful as a therapeutic agent for premature ejaculation.

<1-1> Subjects to be tested

Fifteen middle-aged men with concurrent hyperactivity bladder symptoms and premature ejaculation agreed with this test and were given 5 mg of Betic Care for 1 month.

<1-2> Prostate Symptom Score Questionnaire

The International Prostate Symptom Score (IPSS) is a test designed to objectively assess the lower urinary tract symptoms and the resulting discomfort associated with prostate health. IPSS has been translated into languages of the world and has been validated and used globally. In Korea, the validity and reliability of the test method have been proved and the representative test method used in Korean prostate health evaluation is shown in Table 1.

[Table 1]

<1-3> Irritable bladder  Symptom assessment

The degree of symptoms of overactive bladder is assessed by OABSS (Overactive Bladder Symptom Score) test. Table 2 shows the detailed items, and each item can evaluate the frequency of urinary frequency, nocturia, nasolabial dysfunction, urge incontinence, which are representative symptoms of overactive bladder.

[Table 2]

<1-4> Evaluation of premature ejaculation

The prevalence of premature ejaculation is assessed using the PEDT (Premature Ejaculation Diagnostic Tool) test. If the score is more than 11 points, it is judged as premature ejaculation.

[Table 3]

<1-5> Measurement of delayed vaginal discharge

The self-reported intravaginal ejaculatory latency time (IELT) was measured to determine if BetsyCare, a therapeutic agent for overactive bladder symptoms, was effective in treating premature ejaculation.

As a result, it was confirmed that when ViceCare was administered, the delay time of vaginal administration was increased compared with that before administration (Fig. 1).

Meanwhile, the compound represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. Hereinafter, some formulating methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient are exemplified, and the present invention is not limited thereto.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

<1-1> Preparation of powder

2 g of the compound of formula 1 according to the invention

Lactose 1 g

The above components are mixed and filled in airtight bags to prepare powders.

<1-2> Preparation of tablets

100 mg of the compound of Formula 1 according to the present invention

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets are prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-3 > Preparation of capsules

100 mg of the compound of Formula 1 according to the present invention

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, they are filled in gelatin capsules according to the conventional preparation method of capsules to prepare capsules.

&Lt; 1-4 >

1 g of the compound of formula 1 according to the invention

Lactose 1.5 g

Glycerin 1 g

0.5 g of xylitol

After mixing the above components, they are prepared so as to be 4 g per one ring according to a conventional method.

<1-5> Preparation of Injection

500 mg of the compound of formula 1 according to the present invention

Sterile sterilized water for injection

pH adjuster

(2 ml) per 1 ampoule according to the usual injection preparation method.

<1-6> Production of liquid agent

100 mg of the compound of formula (1)

10g per isomerization

Mannitol 5 g

Purified water quantity

Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and then purified water was added thereto. The whole was then adjusted to 100 ml with purified water, And sterilized to prepare a liquid.

Meanwhile, the compounds of the present invention are capable of producing health functional foods in various forms depending on the purpose. Examples of the preparation of a health functional food for the composition of the present invention are shown below.

&Lt; Formulation Example 2 > Production of dairy products

0.01 to 1.0 part by weight of the health functional food composition of the present invention is added to milk and various dairy products such as butter and ice cream are prepared using the milk.

&Lt; Formulation Example 3 >

Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer. The health functional food composition of the present invention was concentrated under reduced pressure in a vacuum concentrator to obtain a dry powder.

The grains, seeds, and dried powder of the compound of formula (1) according to the present invention were prepared in the following proportions.

Grain (34 parts by weight of brown rice, 19 parts by weight of yulmu, 20 parts by weight of barley)

Seeds (7 parts by weight of perilla, 8 parts by weight of black beans, 7 parts by weight of black sesame seeds)

A tetracycline derivative (2 parts by weight),

(1.5 parts by weight), and

Rhizome (1.5 parts by weight).

&Lt; Formulation Example 4 > Preparation of health functional food

100 mg of the compound of formula 1 according to the present invention

Vitamin mixture quantity

Vitamin A acetate 70 μg

Vitamin E 1.0 mg

Vitamin B1 0.13 mg

0.15 mg of vitamin B2

Vitamin B6 0.5 mg

Vitamin B12 0.2 μg

Vitamin C 10 mg

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 μg

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

Potassium monophosphate 15 mg

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

Calcium carbonate 100 mg

Magnesium chloride 24.8 mg

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a component suitable for a health functional food as a preferred embodiment, the compounding ratio may be arbitrarily changed, and the above components may be mixed , Granules may be prepared and used in the manufacture of health functional food compositions according to conventional methods.

 Formulation Example 5 Preparation of Health Functional Drink

100 mg of the compound of formula 1 according to the present invention

Citric acid 100 mg

Oligosaccharide 100 mg

Plum concentrate 2 mg

Taurine 100 mg

Purified water was added to the whole 500 mL

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated at 85 DEG C for about 1 hour with stirring, and the solution thus prepared was filtered to obtain a sterilized container. The resulting solution was sealed and sterilized, &Lt; / RTI &gt;

Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.

Claims (2)

A pharmaceutical composition for preventing and treating premature ejaculation comprising a compound having the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

.
A health functional food for improving premature ejaculation comprising a compound comprising the following formula (1), or a pharmaceutically acceptable salt thereof, as an active ingredient:
[Chemical Formula 1]

.

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