KR20050076057A - Female sexual enhancer containing ginsenosides as an effective component - Google Patents

Abstract

The present invention relates to a female sexual function improving agent containing ginsenoside as a ginseng extract as an active ingredient, and more particularly, to improve female sexual function by concentration-dependent relaxation of vaginal smooth muscle by containing ginsenosides. Improve.

The present invention also relates to a vaginal smooth muscle relaxant composition containing ginsenosides as an active ingredient.

Description

Female sexual enhancer containing ginsenosides as an effective component

The present invention relates to a female sexual function improving agent containing ginsenosides (ginsenosides) as an active ingredient, and more particularly, female sexual function improving agent according to the present invention concentration-dependently relax vaginal smooth muscle by containing ginsenosides. Improve sexual function.

The present invention also relates to a vaginal smooth muscle relaxant composition containing ginsenosides as an active ingredient.

In women, sexual excitement is caused by an increase in vaginal lubrication due to an increase in vaginal blood flow and smooth muscle relaxation (Levin RJ. The mechanism of human female sexual arousal. Annu Rev Sex Res 1992; 3: 1-48, Park K, Goldstein I , Andry C, Siroky MB, Krane RJ, Azadzoi KM, Vasculogenic female sexual dysfunction: the hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency.IntJ Impot Res 1997; 9: 27-37, and Goldstein I. Female sexual arousal disorder: new insights.Int J Impot Res, 2000; 12 (Suppl): S152-7). Neurotransmitters involved in vaginal smooth muscle relaxation include Vasoactive Intestinal Peptide (VIP), Neuropeptide Y (NPY), and Calcitonin gene-related peptide (CGRP). There is increasing interest in nitric oxide (NO) (Goldstein I. Female sexual arousal disorder: new insights. Int J Impot Res, 2000; 12 (Suppl): S152-7).

Female sexual dysfunction increases with age and increases after high risk factors of vascular diseases such as diabetes, arteriosclerosis, and hypertension or after menopause (Sadeghi-Nejad H, Mreland R, Traish A, Azadzoi KM, Nehra A, Rabea AA, et al. Impotence is a couple's disease: studies in female sexual dysfunction.J Urol 1996; 155: 677A). In the treatment of female sexual dysfunction, vascular agents such as male hormones and sildenafil (viagra), which is a treatment for erectile dysfunction, have recently been tried. There is still much debate about the effects and side effects (Park K. Diagnosis and treatment of female sexual). dysfunction.Korean J Androl, 1999; 17: 93-97).

Ginseng has been used as a therapeutic agent for various diseases in Korea and other countries for a long time, and its safety has been proved. Recently, clinical research has been actively conducted in basic research and various diseases. Ginseng pharmacological action is effective in improving diabetes, hypertension, hyperlipidemia, and is known to help sexual dysfunction by improving peripheral circulation.

Recently, studies on ginseng have been reported as a therapeutic drug for sexual dysfunction in men (Choi HK, Seong DH. Clinical efficacy of Korean red ginseng for erectile dysfunction.Korean J Ginseng Sci 1995; 19: 17-21, Choi HK) , Seong DH.Rha KH.Clinical efficacy of Korean red ginseng for erectile dysfunction.Int J Impot Res 1995; 7: 57-61, Jung HC, Yu JW, Park JM, Shin HS, Moon KH, Kim WJ, et al. Effect of ginseng on penile erection: a combined in virto and in vivo study.Kor J Androl 2001; 19: 57-61, and Kim SW, Paick JS.Clinical efficacy of Korean red ginseng on vasculogenic impotent patients.Kor J Androl 1999; 17: 23-28). Ahn et al. (Ahn TY, Park HS, Kim KS, Park T. Effect of ginseng on relaxation of penile corpus cavernosal smooth muscle in rabbit.J Urol 1996; 155 (Suppl): 618A Reported that ginseng enhances endothelial dependent acetylcholine-induced relaxation of corpus cavernosum smooth muscle.

Animal studies on the effects of each fraction of ginseng on sexual function are mostly conducted using male rabbits or rats. Choi et al. (Choi YD, Xin ZC, Choi HK. Effect of Korean red ginseng on The rabbit corpus cavernosal smooth muscle.Int J Impot Res 1998; 10: 37-43) is involved in nitric oxide in the mechanism by which Korean ginseng relaxes the corpus cavernosum smooth muscle. Choi (Choi YD, Rha KH, In vitro and in vivo experimental effect of Korean red ginseng on erection, J Urol 1999; 162: 1508-11) Compared with the increase in the relaxation and erection of the corpus cavernosum.

The present inventors have mainly studied the effects of ginseng on sexual function and are limited to male foot function, and little effect is made on the female sexual function. Ginsenosides, known as the main ingredient, have been found to affect the relaxation of vaginal smooth muscle in rabbits and have completed the present invention.

Accordingly, it is an object of the present invention to provide a vaginal smooth muscle relaxant composition comprising ginsenoside as a ginseng extract as an active ingredient.

It is also an object of the present invention to provide a female sexual function improving agent for relaxing vaginal smooth muscle by containing ginsenoside of ginseng as an active ingredient.

Ginsenoside used in the present invention was provided by the Korea Tobacco Ginseng Corporation as saponin extracted by treating red ginseng with butanol.

Ginsenosides used in the present invention are Rb1 (18.26%), Rb2 (9.07%), Rc (9.65%), Rd (8.24%), Re (9.28%), Rf (3.48%), Rg1 (6.42%) , Rg2 (3.63%), Rg3 (4.7%), Ro (3.82%) and Ra (2.91%).

Ginsenoside used in the present invention has an effect of improving the sexual function of women by increasing the secretion of vaginal lubricating fluid by concentration-dependent relaxation of vaginal smooth muscle.

Therefore, the present invention relates to a female sexual function improving agent containing ginsenoside as an active ingredient.

In addition, the female sexual function improver according to the present invention may be prepared in a food form by combining with the ginsenoside can be added to the usual food additives.

In addition, the female sexual enhancer according to the present invention may be prepared in the form of a pharmaceutical composition comprising an effective amount of the ginsenoside, and may include one or more non-toxic, pharmaceutically acceptable carriers, adjuvants or diluents, or other active ingredients. It may include.

The pharmaceutical composition according to the present invention may be in the form of a solution, suspension, or emulsion in an oil or an aqueous medium, or in the form of a dry powder which is dissolved in sterile, pyrogen-free water before use, and may be formulated into an oral dosage form. have.

Female sexual enhancers of the present invention are known methods using pharmaceutically acceptable carriers and excipients, for example, tablets, troches, sugar-containing tablets, aqueous or oily suspensions, dispersible flours or particles, emulsions, soft Or formulated orally in the form of hard capsules, syrups, elixirs, which are contained in unit dosage forms and in multidose containers.

In oral formulations, tablets may be inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; Granulating agents such as corn, starch and alginic acid; Disintegrants; Binders such as starch, gelatin and acacia; The composition of the present invention is contained in admixture with excipients which can be used for the preparation of tablets such as lubricants such as magnesium stearate, stearic acid and talc. Tablets may be used uncoated or coated to inhibit absorption and degradation of the tablets in the gastrointestinal tract. For example, you may apply time inhibiting substances, such as glyceryl monostearate and glyceryl distearate. Hard capsule is a mixture of the composition of the present invention in an inert solid diluent such as calcium carbonate, calcium phosphate, kaolin, etc., soft capsule is a solvent such as polypropylene glycol (PE), polyethylene glycol (PEG), ethanol, etc. And the active ingredients in oil solvents such as peanut oil, liquid paraffin, olive oil.

The water-soluble suspending agent is a mixture of excipients and active ingredients suitable for the preparation of water-soluble suspending agents. Excipients include, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxy-propyl methyl cellulose, sodium alginate, polyvinyl-pi Suspending agents such as ralidone, gum tragacanth, gum acacia and the like; Compounds condensing fatty acids such as polyoxyethylene stearate and alkylene oxides; Compounds in which alkylene oxides are condensed with long fatty acids such as heptadecaethyleneoxycetanol; Compounds which condensate partial esters derived from anhydrous hexitol anhydride and fatty acids, such as polyoxyethylene sorbitol monooleate, with ethylene oxide; Wetting agents; Or dispersing agents. Water-soluble suspensions contain preservatives, colorants, spices, sweeteners and the like.

The oily suspension is a suspension of an active ingredient in a vegetable oil such as olive oil, sesami oil, or a mineral oil such as liquid paraffin. For example, a thickening agent such as beeswax, hardened paraffin, cetyl alcohol, etc. may be used. It contains. It also contains preservatives, colorants, spices, sweeteners and the like, which can be preserved by adding antioxidants such as vitamin C.

Dispersible powders and particles have an active ingredient in a state in which a dispersing agent, a wetting agent, a suspending agent, a preservative and the like are mixed together. Suitable dispersing, wetting or suspending agents can be mentioned by way of example already mentioned above. Additional excipients are, for example, sweeteners, spices, colorants and the like.

Water-in-oil emulsions are derived from vegetable oils such as olive oil or mineral oils such as liquid paraffin, and are derived from natural phospholipids such as soy bean lecithin, and esters of anhydrous hecitol or fatty acids such as sorbitan monooleate. The active ingredient is emulsified using compounds obtained by condensation of ethylene oxide with partial esters derived from anhydrous hexitol anhydride and fatty acids such as oxyoxysorbitol monooleate.

Syrups and elixirs are a mixture of active ingredients with sweeteners such as glycerol, propylene glycol, sorbitol and sucrose.

In the dosage form according to the present invention, the dose of ginsenoside as an active ingredient may vary depending on the patient's age, weight, general health condition, sex, meal, time of administration, rate of excretion, combination of drugs, degree of disease during treatment, and the like. And, although not particularly limited, preferably 1 to 50 mg per day may be used daily based on a person weighing 60 kg.

On the other hand, the amount of the compound of the present invention mixed with the carrier material to determine one dosage form depends on the mode of administration and the patient being treated.

Hereinafter, the present invention will be described in detail by test examples. However, the examples are only for illustrating the invention and the present invention is not limited by the following test examples.

In the test example of the present invention, 20 New Zealand white female rabbits (3.0 to 3.5 kg) were subjected to intravenous sacrifice of 50 mg / kg of pentobarbital (pentobarbital) in the rabbit's bilateral vein, and then distal 1 of the vagina. / 3 was removed, soaked in cold saline solution, the surrounding tissues were removed, and then dissected to make a vaginal smooth muscle section of size 3 × 3 × 10 mm.

General drugs used in the test examples of the present invention were purchased from Sigma Chemical Co. (St. Louis, MO) as phenylephrine hydrochloride, acetylcholine hydrochloride, and ginsenoside, a component of ginseng, is a Korean tobacco. Received from Ginseng Corporation.

The composition (mM / L) of the organ bath nutrient solution used in the test example of the present invention was NaCl 120, KCl 4.6, KH ₂ PO ₄ 1.17, NaHCO ₃ 23.8, CaCl ₂ 1.8, MgSO ₄ 1.2, glucose 10.

[Test Example 1] vaginal smooth muscle relaxation effect according to ginsenoside content

<How to measure tension>

Ligation of the vaginal smooth muscle section with the silk thread at both ends in the longitudinal direction, fixed at one end to the bottom of the test chamber, and tied at the other end to a thread, connected to an isometric force transducer (Fgrass FTO3), and the tension fluctuations were measured using a polygraph (Powerlab / 400). , Australia). The constant temperature water was circulated between the double walls of the experimental tank to maintain the temperature of the nutrient solution in the experimental tank at 37 ℃, and a mixture gas of 95% oxygen and 5% carbon dioxide was supplied. After vaginal smooth muscle sections were suspended in the test tank, 1gm of tension was equilibrated for 2 hours, and then 50mM KCl was administered 2-3 times, when the contraction reaction was constant. First, vaginal sections are shrunk with phenylephrine (5x10 ^-5 M), and then the relaxation reactions according to the dose of ginsenoside 100-500 µg / ml when the tension reaches equilibrium, N ^ω- After pretreatment with nitro-L-arginine methyl ester (L-NAME) for 20 minutes, the relaxation reaction of ginsenoside, 100 μg / ml of ginsenoside, 200 μg / ml was administered and 10 minutes after acetylcholine (ACh) 0.3 The relaxation response was evaluated by administering ˜10 μM.

<Calculation and Statistics Processing>

The relaxation degree of vaginal smooth muscle was expressed as a percentage by measuring the degree of contraction with phenylephrine from the first dropping point to the first stable point upon relaxation by full length stimulation. Unpaired t-test was used to compare responses, and statistical significance was at p <0.05.

<Result>

The vaginal smooth muscle section was shrunk with phenylephrine (5 ㅧ 10 ^-5 M) and treated with 100, 200, 300, 400 and 500 µg / ml of ginsenoside, a ginseng fraction, when the tension reached equilibrium. The relaxation degree of vaginal smooth muscle was measured, and the result is shown in FIG. As can be seen in Figure 1, when administered at different doses of ginsenosides vaginal smooth muscle showed a dose-dependent relaxation response, a relaxation rate of about 25% at a dose of 500㎍ / ㎖.

In addition, ginseng extract or ginsenoside is known to play a major role as a mechanism to relax the corpus cavernosum smooth muscle (Kim HJ, Woo DS, Lee G, Kim JJ, The relaxation effects of ginseng saponin in rabbit corporal smooth muscle: is it a nitric oxide donor? Br J Urol 1998; 82: 744-8), Chen et al. (Chen X, Lee TJ, Gisenosides-induced nitric oxide-mediated relaxation of the rabbit corpus cavernosum.Br J Phamacol 1995; 115: 15 -8) suggested that NO plays a major role in the relaxation of penile cavernous smooth muscle by ginsenosides.

Test Example 2 Acetycholine-dependent Relaxation Effect of Ginsenosides

<How to measure cGMP in your organization>

After incubating at different concentrations of ginsenosides at 100-400 µg / ml for 7 minutes in the experimental bath, vaginal smooth muscle tissue was rapidly frozen in liquid nitrogen and homogenized in ice-cold 6% trichloracetic acid. The homogenized was centrifuged at 13,600 g for 15 minutes and then the cytosolic proteins were separated from the suspension by conventional methods. CGMP was measured by radioimmunotherapy in each sample, and the results are shown in FIG. 2. Vaginal smooth muscle sections that were not pre-treated with ginsenosides were used as controls.

<Result>

As can be seen in Figure 2, vaginal smooth muscle sections contracted by phenylephrine (5x10 ^-5 M) were treated in the control group that did not pretreat ginsenosides when pretreated with 100 and 200 µg / ml ginsenosides. There was a significant dose-dependent relaxation for acetylcholine (p <0.05). However, there was no significant difference in relaxation rate between the two doses of pretreated ginsenosides.

Test Example 3 Effect of NOS Blocker on Relaxation of Smooth Muscle

NOS blocker N ^ω - nitro -L- arginine methyl ester (L-NAME) 10 ^-4 for 20 minutes pretreatment of the test example 1 after the ginsenoside in the same manner as binary 100, 200, 300 and 400㎍ / ㎖ administration After the relaxation of the vaginal smooth muscle was measured, the results are shown in FIG. As can be seen from the results of Figure 3, when treated with ginsenosides after pre-treatment with NOS blockers, vaginal smooth muscle showed a dose-dependent relaxation response to ginsenosides, compared to the control group not pretreated with ginsenosides. The relaxation response was suppressed but was not statistically significant (p> 0.05).

Test Example 4 Effect of Ginsenosides on Vaginal cGMP in Vaginal Tissues

To determine the effect of ginsenosides on vaginal cGMP in vaginal tissues, the amount of cGMP in vaginal tissues was measured in the same manner as in Test Example 3 after administration of ginsenosides at 100, 200, 300 and 400 µg / ml. The results are shown in FIG. 4.

Referring to FIG. 4, when ginsenosides were administered up to 100-300 μg / ml, no significant change was observed, but it was statistically increased to 400 p / 0.045 at a dose of 400 μg / ml.

Therefore, ginsenoside, an active fraction of ginseng, relaxes vaginal smooth muscle and the NO-cGMP pathway is partially involved as a relaxation mechanism.

As described above, ginsenoside, the active ingredient of ginseng used as an active ingredient in the present invention, relaxed the vaginal smooth muscle of rabbits in a concentration-dependent manner. In addition, it was found that NO-cGMPrP is involved in the relaxation mechanism by increasing the amount of cGMP in the vaginal tissue. Therefore, in the present invention, by using ginsenoside as an active ingredient, it was possible to prepare a female sexual function improving agent and vaginal smooth muscle relaxant composition which promotes secretion of vaginal lubricating fluid through concentration-dependent relaxation of vaginal smooth muscle.

1 is a graph showing the relaxation effect of vaginal smooth muscle according to the ginsenoside dose.

2 is a graph showing the acetylcholine-dependent relaxation effect of ginsenosides.

Figure 3 is a graph showing the effect of ginsenosides on the relaxation of smooth muscle after treatment with NOS blocker.

Figure 4 is a graph showing the effect of ginsenosides on vaginal cGMP in vaginal tissue.

Claims (4)

Female sexual function improver containing ginsenoside, a ginseng extract, as an active ingredient. The method of claim 1, wherein the ginsenoside is Rb1 (18.26%), Rb2 (9.07%), Rc (9.65%), Rd (8.24%), Re (9.28%), Rf (3.48%), Rg1 (6.42) %), Rg2 (3.63%), Rg3 (4.7%), Ro (3.82%) and Ra (2.91%). The female sexual function improving agent according to claim 1, wherein the ginsenoside improves female sexual function by relaxing vaginal smooth muscle and increasing the secretion of vaginal lubricating fluid. Vaginal smooth muscle relaxant composition comprising ginsenoside ginseng extract as an active ingredient.