KR20070117299A - Pharmaceutical composition for the treatment and prevention of erectile dysfunction and male sexual function, including night view ethanol extract and a method of manufacturing the same - Google Patents

Abstract

A composition comprising the extract of Lespedeza cuneata is provided to relax Corpus cavernosum penis by increasing synthesis of nitrogen oxide and cGMP which have an important role in mechanism for controlling contraction and relaxation of smooth muscle of Corpus cavernosum penis without side effects, so that it is useful for treating or preventing male impotence. A composition for treating or preventing impotence and male disease comprises 0.02-50 wt.% of the extract of Lespedeza cuneata which is prepared by extracting Lespedeza cuneata with 35% ethanol, wherein the male disease is impotence, vitality insufficiency, premature ejaculation, involuntary emission of semen or seborrhea;. The composition is a pharmaceutical or health food composition having a drink formulation.

Description

Pharmaceutical composition comprising the extract of Lespsdeza cuneata for treating or preventing impotence}

1 is a diagram showing the concentration-dependent corpus cavernosum smooth muscle relaxation effect of night view ethanol extract.

Figure 2 is a diagram showing that the corpus cavernosum smooth muscle relaxation effect of night view ethanol extract is due to nitric oxide (nitric oxide) production.

Figure 3 is a diagram showing that the corpus cavernosum smooth muscle relaxation effect of night view ethanol extract via the NO / cGMP signaling system.

4 is a diagram showing that the night gate ethanol extract increases the cGMP concentration in the corpus cavernosum smooth muscle.

The present invention relates to a pharmaceutical composition for the treatment and prevention of male diseases, including erectile dysfunction, including night gate ethanol extract.

Penile erection is a reflex phenomena in which the neural system, the vascular system, the endocrine system and the corpus cavernosum smooth muscle act in combination to increase the blood supply into the corpus cavernosum due to the expansion of the penile artery and the corpus cavernosum cavity. Increased blood supply to the corpus cavernosum increases the amount and pressure of blood in the corpus cavernosum, resulting in penile erection. Since the cavernous white film has a limitation of elongation at the time of penile erection, when the subarachnoid vein is pressed by the expanded cavernous cavity, the outflow of penile cavernous blood decreases, thereby increasing the penile pressure and erection (expansion). The penis gained stiffness. Reportedly, erectile corpus cavernosum shows dilation of arteries, dilation of oriental vascular cavity, and compression of submucosal and evolving veins. On the other hand, in the cavernous corpus cavernosum, arteries and small arteries are twisted and constricted, and oriental vascular intensity is also contracted. In the pre-erectional state, endogenous smooth muscle tension caused by adrenergic secretion maintains the contractile state of the corpus cavernosum smooth muscle and allows only a minimal amount of blood to enter the oriental vasculature with high peripheral resistance. However, in the erectile state, the compliance of the oriental vascular cavity and the arterial system increases, so that resistance to blood inflow is reduced to a minimum, and as a result, a large amount of blood flow can be increased. Increasing compliance throughout the Oriental Vascular cavity can lead to a rapid increase in the length and diameter of the penis to the extent that the white membrane can expand when the blood is full. Meanwhile. The expansion of the oriental vascular cavity compresses the neighboring oriental vascular cavities, compressing the predetermined veins between the oriental vascular cavities, and compressing the venous total of the prescribed veins in the submucosa against the wall of the vasculature that has reached the limit of expansion. This results in a blockage effect and reduces blood outflow to a minimum. At this time, the cavernous pressure rises rapidly, causing the dilated penis to rise up causing an erect erection. The contraction of the penile artery and corpus cavernosum smooth muscle during this erection reduces blood inflow into the corpus cavernosum cavity, reducing swelling power, and increasing blood outflow into the vein, resulting in a decrease in the penis and stiffness during erection.

The most important involvement in penile erection is the relaxation and contractile action of the corpus cavernosum smooth muscle. Until now, the neurotransmitter involved in contractile action is norepinephrine and the neurotransmitter involved in the relaxation action is non-drenergic noncholinergic ( NANC: A nonadrenergic noncholinergic (NANC) substance that has recently been identified as one of these nitric oxides (NO).

수용체 봉쇄제, 콜린성 약물, nitric oxide(NO), peptides, prostaglandins, histamine, 칼슘통로 차단제, 칼륨통로 개방제, 혈관확장제 등이 알려져 있다.The process of penile erection control is controlled by the smooth muscle tension of the cavernous body, which is a nonadrenergic noncholinergic (NANC) neurotransmitter and a relaxing substance (EDRF: endothelium derived relaxing factor) secreted from endothelial cells of cavernous pores. Nitric oxide (NO) has recently been shown to play an important role in the relaxation of cavernous smooth muscle, the core of penile erection. Nitric oxide is already well known as a vascular smooth muscle relaxant and has been studied a lot. By the L-arginine as the substrate of nitric oxide produced by the vascular endothelium by nitric oxide synthase (nitric oxide synthase) is soluble guanylate the cyclization enzyme by (soluble guanylate cyclase) activating the ^{3, 5-cyclic monophosphate (cGMP} ) to increase the density, where the resulting cGMP is thereby suppressed in Ca ^{2 +} influx smooth muscle cells to relax the smooth muscle by decreasing the sensitivity to shrinkage factor of Ca ^{2 +.} As the physiological phenomenon of penile erection is revealed and the pharmacological actions and mechanisms of various drugs on cavernous smooth muscle are studied, efforts to use medicinal herbs having a relaxing effect on smooth muscle are used to treat erectile dysfunction. Adrenaline is currently a substance that relaxes spongy smooth muscle.

Receptor blockers, cholinergic drugs, nitric oxide (NO), peptides, prostaglandins, histamine, calcium channel blockers, potassium channel openers, and vasodilators are known.

In recent studies, herbal corpus cavernosum smooth muscle relaxation effect was measured and herbal drugs with smooth muscle relaxation effect were reported by inducing NO synthesis from cavernous smooth muscle tissue. Choi et al. (Choi YD, et al., J. Ginseng Res , 23 (1), pp13-20, 1999) reported the NO-dependent penile cavernous smooth muscle relaxation effect of red ginseng saponin.Ann et al. (Ann TY, et al., Korean J. Ginseng) Sci , 20 (3), pp339-343, 1996) also reported that ginseng showed NO-dependent penile cavernous smooth muscle relaxation effect in rabbit cavernous smooth muscle. In addition, Yoon et al. (Yoon SH, et al., J. of.Oriental.Chr. Dis, 4 (1), pp 210-222, 1998) also reported that the erectile dysfunction effect of honofah extract in experimental animal models. I have reported.

The corpus cavernosum smooth muscle relaxation effect induces the effect of increasing the swelling power and stiffness of the penis in erectile dysfunction. In addition, erectile dysfunction has been shown to improve male diseases such as rotosis, premature ejaculation and seborrhea.

In erectile dysfunction and male disease, half of those in their 40s and 70s and older men in their 40s and 70s show more than half of the subjects. In particular, the incidence of erectile dysfunction increases sharply after the 50s, and it is reported that 70-year-old men are three times more likely to have erectile dysfunction than 40-year-old men. Until recently, erectile dysfunction was mostly attributed to mental causes, but with the development of diagnostic technology, more than 50% of erectile dysfunction is caused by physical causes, and the rest is attributed to mental causes. However, most causes are not clearly distinguished, and more than 50% of physical causes are combined with mental causes.

Erectile dysfunction can lead to family discord as well as sexual life disorders in males as well as loss of self-confidence and depression, adversely affecting social life and problems with marital relationships. In addition, the recent trend of erectile dysfunction is a significant increase in physical factors rather than psychological factors, and prevention and treatment of erectile dysfunction are more important to improve the quality of life.

Sildenafil citrate (product name: viagra), a citrate drug, has been introduced as an erectile dysfunction treatment to date, but this product has excellent effects, but its effects are temporary, headache, hot flashes, indigestion, color vision In addition to side effects such as disorders, heart attack, stroke, arrhythmia and death have been reported in men taking Viagra. In particular, people who are taking organic nitrates, which are mainly used for cardiovascular diseases such as angina pectoris, heart failure, and high blood pressure, if they take Viagra, can cause severe heart attack and stroke due to sudden blood pressure drop.

Lespedeza cuneata G.Don is a perennial herbaceous outpost that is known to be effective in treating erectile dysfunction, lack of nourishment, premature ejaculation, oil well, and vulgaris. Even if you take 2-3 days, the effect is called because it has no side effects, it is called natural Viagra. According to <Traditional Chinese Medicine Metabolism>, the taste is very bitter and the characteristics are flat, and it is effective to relieve the liver, help the lung sound, remove the blood and swell the swelling. Treats dreams, urination, whitening, whitening, asthma, macular degeneration and acute mastitis. Pinitol, flavonid, phenolic compounds, tannin, and β-sisterol were identified as active ingredients, and quercetin, kaempferol, and vitexin were isolated from flavonoids.

However, no initiation or teaching has been made about the effect of the relaxation of the corpus cavernosum smooth muscle of night ethanol extract.

Accordingly, the present inventors completed the present invention by checking the excellent corpus cavernosum smooth muscle relaxation effect of night view ethanol extract, while searching for the effect of relaxation of the corpus cavernosum smooth muscle in 30 kinds of herbal medicines considered to be effective in treating erectile dysfunction.

An object of the present invention is nitric oxide (NO) which plays the most important role in regulating the contraction and relaxation of the corpus cavernosum penis smooth muscle, which plays the most important role in the hemodynamics of penile erection. The present invention provides a pharmaceutical composition for the treatment and prevention of erectile dysfunction and male disease, including a night gate ethanol extract that induces penile erection by relaxing the corpus cavernosum smooth muscle by increasing the synthesis of cGMP).

In order to achieve the above object, the present invention is a night view ( Lespedeza cuneata G. Don ) provides a pharmaceutical composition for the prevention and treatment of erectile dysfunction, containing an ethanol extract as an active ingredient

The night gate ethanol extract includes an extract obtained using an ethanol solvent.

Hereinafter, the present invention will be described in detail.

Night gate ethanol extract of the present invention can be obtained as follows.

In the present invention, the night gate was collected, dried and powdered with a crusher, and then extracted in a volume of 35% ethanol at a volume of about 2 to 10 times, preferably 3 to 5 times, the weight of the night gate sample at room temperature for one week. The extract was centrifuged at 2500 g 4 ° C for 20 minutes, and then Whatman NO. It filtered using 2 filter paper. The solution obtained after filtration may be concentrated under reduced pressure, and then freeze-dried to obtain a night gate ethanol extract powder.

The present invention provides a pharmaceutical composition for the prevention and treatment of erectile dysfunction, which contains the night portal ethanol extract obtained by the above-mentioned method as an active ingredient.

In addition, the night gate is a drug that has been used as a herbal medicine for a long time, the extracts of the present invention extracted therefrom also have no problems such as toxicity and side effects.

Night penetrating ethanol extract obtained by the above method was able to confirm a very excellent penile cavernous smooth muscle relaxation effect.

Pharmaceutical composition for preventing and treating erectile dysfunction of the present invention, the total weight of the composition comprises from 0.1 to 50% by weight of the extract.

Pharmaceutical compositions comprising the extract of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

The pharmaceutical dosage forms of the extracts of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

Pharmaceutical compositions comprising extracts according to the present invention are in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. Can be formulated and used. Carriers, excipients and diluents that may be included in the composition comprising the extract include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oils. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient in the extract, for example, starch is calcium carbonate, sucrose ( It is prepared by mixing sucrose or lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the extracts of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the extract of the present invention is preferably administered at 0.001 to 100mg / kg. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

The extract of the present invention can be administered to mammals such as mice, mice, livestock, humans, and the like by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

In addition, the present invention provides a health functional food comprising the night gate ethanol extract and a food supplement acceptable food supplement additive exhibiting an effect of preventing and improving erectile dysfunction. Examples of the food to which the extract can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods.

It may also be added to food or beverages for the purpose of preventing and improving cardiovascular disease. At this time, the amount of the extract in the food or beverage may be added in 0.01 to 15 quantitative% of the total food weight, the health beverage composition may be added in a ratio of 0.02 to 5g, preferably 0.3 to 1g based on 100ml.

The health functional beverage composition of the present invention is not particularly limited to other ingredients except for having the extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose; Disaccharides such as maltose, sucrose and the like; Polysaccharides such as conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. In addition to the above, natural flavors (tauumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavors (saccharin, aspartame, etc.) may be advantageously used as flavoring agents. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.

In addition to the above, the extract of the present invention may be used in various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, flavoring agents such as coloring and neutralizing agents (cheese, chocolate, etc.), pectic acid and salts thereof, organic acids, protection Sex colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages and the like. In addition, the extracts of the present invention may contain flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but is usually selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the extract of the present invention.

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

However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Experimental Examples.

Example 1 Preparation of Night Gate Ethanol Extract

600 g of the night gate, collected in September 2005, in Imsil-gun, Jeonbuk, Korea, was dried and extracted for one week in ethanol 35% at room temperature. The extract was centrifuged at 2500 g 4 ° C for 20 minutes, and then Whatman NO. It filtered using 2 filter paper. The solution obtained after filtration was concentrated under reduced pressure, and freeze-dried to obtain 31.01 g of ethanol extract powder of night view, and refrigerated at 4 ° C. was used for the experiment.

Experimental Example 1.Reagents and Experimental Preparation

1-1. reagent

Acetylcholine chloride (ACh), phenylephrine HCl, N ^G -nitroarginine methyl ester (L-NAME), 1H- [1,2,4] -oxadiazole- [4,3-α] -quinoxalin-1-one (ODQ), 3-isobutyl-1-methylxanthine (IBMX) and the like were purchased from Sigma Chemical Co (St. Louis, USA) and used. ACh, phenylephrine, and L-NAME reagents were used by dissolving in tertiary distilled water. IBMX reagents were used in experiments by dissolving in dimethyl sulfoxide (DMSO), and had no effect on the cavernous smooth muscle.

1-2. Isolation of Cavernous Smooth Muscle

Anesthetized with sodium pentobarbital (30 mg / kg IV) through bilateral venous veins of healthy rabbits and sacrificed by cardiac bleeding, the penile tissues branched below the pubis and removed and removed. Place the penile tissue in 4 ° C Krebs buffer and carefully remove the corpus cavernosum, so as not to damage the corpus cavernosum smooth muscle endothelial cells, and then remove a corpus cavernosal tissue strip of 2 x 2 x 6 mm size. 4 made per rabbit. Krebs buffer is NaCl 118.3mM, KCl 4.7mM, MgSO ₄ 0.6mM, KH ₂ PO ₄ 1.2mM, CaCl ₂ 2.5mM, NaHCO ₃ 25.0 mM, Ca EDTA 0.026 mM, Glucose 11.1 mM composition.

Experimental Example 2. Measurement of relaxation effect of penile cavernous smooth muscle and night mechanism of ethanol extract

The corpus cavernosum smooth muscle tissue section in Experimental Example 1-2 95% O ₂ - of which 37 ° C, pH 7.4 saturated with 5% CO ₂ gas was fixed in the Krebs buffer solution, isometric tension a force-displacement transducer (Grass Measurement was performed using a physiological recorder (Grass Model 7E, Grass Instrument, MA, USA) equipped with FT 03, Grass Instrument, MA, USA. First, after shrinking with 1 × 10 ^-6 M phenylephrine, 10 minutes later, 1 × 10 ^-6 M acetylcholine (ACh) was used to measure stability of penile cavernous smooth muscle endothelial cells, and then washed three times with Krebs buffer solution. The experiment was performed. The measurement of the vasorelaxant effect of nightgate ethanol extract on various drugs was first pretreated for 20 min, contracted with phenylephrine, and then the concentration-dependent relaxation of the nightgate ethanol extract was observed.

As a result of measuring the relaxation effect of the corpus cavernosum smooth muscle relaxation of the night-gate ethanol extract, the smooth muscle contracted by phenylephrine was concentration-dependently relaxed and the smooth muscle relaxation rate at the final concentration of 1 × 10 ^-4 g / ml was very high as compared to phenylephrine contraction Smooth muscle relaxation effect was shown (see FIG. 1).

To investigate whether the corpus cavernosum smooth muscle relaxation effect of night view ethanol extract is related to the endothelial cell relaxation effect in relation to nitric oxide (NO) system, pretreatment with 1 × 10 ^-6 M L-NAME, a nonspecific nitric oxide inhibitor, As a result of measuring the smooth muscle relaxation effect of the extract, it was found that the cavernous smooth muscle relaxation effect is completely suppressed (see Fig. 2).

In order to investigate whether the corpus cavernosum smooth muscle relaxation effect of night view ethanol extract was related to cGMP, the relaxation effect of smooth muscle was measured after pretreatment of ODQ 1 × 10 ^-6 M, a cytoplasmic guanylate cyclase inhibitor. It can be seen that is completely blocked (see Figure 3).

To determine if the corpus cavernosum smooth muscle relaxation effect of night gate ethanol extract was related to cGMP production, the concentration of cGMP was measured after pretreatment of night gate ethanol extract on the corpus cavernosal tissue strip of rabbit. As a result, it was found that the cGMP concentration was increased in the night gate concentration-dependently compared to the control group (see FIG. 4).

Experimental Example 3. Statistical Processing

The significance of the experimental results was determined by the students t-test and one-way ANOVA test when p was less than 0.05, and the expression of the experimental value was mean ± SE.

Hereinafter, an example of the preparation of a pharmaceutical composition comprising the extract of the present invention will be described, but the present invention is not intended to be limited thereto but merely to be described in detail.

Formulation Example 1 Preparation of Powder

        Night Gate Extract Powder 20 mg

        Lactose 100 mg

        Talc 10 mg

The above ingredients are mixed and filled in an airtight cloth to prepare a powder.

Formulation Example 2. Preparation of Tablet

        Night Gate Extract Powder 10 mg

        Corn starch 100 mg

        Lactose 100 mg

        2 mg magnesium stearate

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

Formulation Example 3 Preparation of Capsule

        Night Gate Extract Powder 10 mg

        Crystalline Cellulose 3 mg

        Lactose 14.8 mg

        Magnesium Stearate 0.2 mg

According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.

Formulation Example 4. Preparation of Injection

        Night Gate Extract Powder 10 mg

        Mannitol 180 mg

        Sterile distilled water for injection 2974 mg

Na ₂ HPO ₄ , 12H ₂ O 26 mg

According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).

Formulation Example 5 Preparation of Liquid

        Night Gate Extract Powder 20 mg

        10 g of isomerized sugar

        5 g of mannitol

        Purified water

According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve it, and then lemon lemon is added in an appropriate amount. The above components are mixed, purified water is added to adjust the total amount to 100 ml, and then filled into a brown bottle and sterilized. Manufacture.

Formulation Example 6. Preparation of Healthy Beverages

        Night Gate Extract Powder 100 mg

        15 g of vitamin C

        100 g of vitamin E (powder)

        Iron lactate 19.75 g

        3.5 g of zinc oxide

        Nicotinamide 3.5 g

        0.2 g of vitamin A

0.25 g of vitamin B ₁

0.3 g of vitamin B ₂

        Water quantification

After mixing the above components according to the conventional healthy beverage production method, and stirred and heated at 85 ° C. for about 1 hour, the resulting solution is filtered and obtained in a sterile 2000 ml container, sealed sterilized and then refrigerated It is used to prepare a healthy beverage composition of the present invention.

Although the composition ratio is a composition that is relatively suitable for the preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

As described above, the night-gate ethanol extract of the present invention is the cGMP through the smooth muscle endothelial cell endothelial cell NO / cGMP signaling system known as the most important mechanism of the relaxation of the corpus cavernosum smooth muscle in the corpus cavernosum smooth muscle that plays a key role in penile erection Increasing the production, showing the relaxation effect of the corpus cavernosum smooth muscle, the composition containing the night gate ethanol extract can be usefully used as a pharmaceutical or health functional food for the treatment and prevention of erectile dysfunction male diseases.

Claims (6)

Night Gate ( Lespedeza cuneata G.Don) A pharmaceutical composition for the prevention and treatment of erectile dysfunction and male disease, containing an ethanol extract as an active ingredient. The pharmaceutical composition of claim 1, wherein the ethanol extract is an extract using 35% ethanol. The method of claim 1, wherein the erectile dysfunction and male diseases include sufficiency including premature dysfunction, premature ejaculation, oil well, vulgaris, seborrhea and the like. The pharmaceutical composition of claim 1, comprising 0.02-50 wt% of the night gate extract with respect to the total weight of the composition. A health functional food comprising the night gate ethanol extract of claim 1 and a food supplement acceptable food supplement additive which have an effect of preventing and improving erectile dysfunction and male disease. The health functional food of Claim 5 which is a health drink.

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