WO2017164707A1 - Pharmaceutical composition and dietary supplement for preventing or treating overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction caused by benign prostatic hyperplasia - Google Patents

Abstract

The present invention contains Cornus officinalis fruit, Angelica gigas, Lycium chinense, deer antler, red ginseng and Cinnamomum cassia Presl extracts and a blocker selectively acting on an alpha-1A adrenergic receptor, thereby exhibiting excellent medicinal effects on an overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction caused by benign prostatic hyperplasia. Particularly, the present invention relates to a pharmaceutical composition and a dietary supplement for preventing or treating an overactive bladder, which is a complication of benign prostatic hyperplasia, the composition being capable of exhibiting excellent medicinal effects even on an overactive bladder of which the main cause is not resolved even when bladder outlet obstruction disappears because of benign prostatic hyperplasia surgical therapy or administration of an alpha-blocker and the like.

Description

Pharmaceutical composition and health functional food for the prevention or treatment of overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction caused by enlarged prostate

The present invention relates to a pharmaceutical composition and a dietary supplement for the prevention or treatment of overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction due to an enlarged prostate.

Representative disease of urination disorder is prostate hyperplasia. Prostatic hyperplasia is found in 40-70% of elderly people in their 60's, and the main conditions are hyperproliferation and hyperplasia of prostate epithelial and interstitial tissues. Factors that control prostate cell proliferation and death include endocrine factors, growth factors, interstitial and epithelial cell interactions, neuroendocrine and neurotransmitters, cell cycle and death control agents, Inflammation is mentioned.

When the prostate enlarges, it blocks the urethra, which leads to a blockage of the bladder outlet where urine cannot be discharged.This causes urinary excretion and also prevents the urine from holding the urine well such as urinary tract and urinary tract. Irritable bladder symptoms may occur. In addition, if the bladder outlet occlusion persists for a long time, the contractile force of the detrusor muscle is inadequate, resulting in an increase in residual urine volume and urinary tract, and as a result, complications such as urinary tract infection, bladder stones, and kidney failure.

An overactive bladder (OAB) is a condition with urinary urinary symptoms that causes sudden urinary irrelevance regardless of the will, with or without urinary incontinence. The prevalence of overactive bladder was 45% in patients with enlarged prostate, 55% of patients with lower urinary tract symptom showed pure bladder outlet obstruction, and there was a strong correlation between bladder outlet obstruction and irritable bladder. As this worsened, the rate of overactive bladder increased. In addition, patients with prostatic hyperplasia have urinary symptoms due to bladder outlet obstruction and storage symptoms due to exacerbation of bladder outlet obstruction (particularly irritable bladder symptoms), which increases with age and increases with detrusor muscle overactivity. It is known that over 60 years of age, more than one-third of the elderly population are irritable bladder. Most of these patients control urination by reducing fluid intake, but this also reduces external activity.

Lower urinary tract symptoms (LUTs) refer to urinary storage and excretion symptoms and are caused by urination disorders such as enlarged prostate, overactive bladder, and neurogenic disorders. Prostatic hypertrophy suffers from two types of problems as the disease progresses because urinary excretion is difficult due to a blocked bladder outlet. In the early stage, increased pressure in the bladder causes overactivity of the bladder muscles, causing the bladder to become sensitive, resulting in storage symptoms such as frequent urination, night urination, urinary urgency, urinary incontinence, and urination pain. Second, if the bladder outlet obstruction is long, the bladder muscles become thick and the bladder does not contract and thus the urine in the bladder cannot be completely discharged, which may result in residual urine or obstructive urination symptoms such as weakness, delayed urination and urinary retention. . If this condition persists, eventually the bladder will be unable to function, and urinary tract may come when normal urine discharge is rarely achieved.

The bladder is primarily a parasympathetic stimulus that activates the muscarinic receptors in the bladder and contracts them. The sympathetic nerve relaxes the bladder through the β receptor in the bladder body and also through the purine receptors rather than the sympathetic and parasympathetic nerves. In addition, the sympathetic nerve causes contraction through the a1 receptor in the bladder neck and prostate urethra, and the external urethral sphincter located in the mesothelial urethra may control the contraction relaxation by the body nerve.

Currently, the most commonly used drug for the treatment of enlarged prostate is alpha blocker. Among them, alpha blockers (tamsulosin, doxazosin, alfuzosin, etc.), which selectively act on the alpha-1A adrenergic receptor, relax the prostate smooth muscle, reduce the bladder neck obstruction, and cause obstructive urination symptoms (abnormal urination, delayed urination, incomplete urination, disconnected yoga) , Late urination drop, urine congestion). However, even if the bladder outlet obstruction is resolved, there are still cases of storage symptoms (frequent urination, night urination, urgent need, urgency, incontinence, urinary pain, etc.). Therefore, drugs such as anticholinergic agents (e.g., parasympathetic inhibitors such as tolterodine, solifenacin) and antipurinergic agents (propiverine HCl) are combined with tea blockers to alleviate these irritant storage symptoms. Administration.

Anticholinergic medications control urinary activity of the bladder during the fullness of the urination cycle, allowing urine to stand and increase bladder capacity. Clinically commonly used anticholinergic agents include Fesoterodine, Solifenacin, Tolterodine, Tropspium, Oxybutynin, and Propibrine. There is this. The important point to consider along with the therapeutic effect in the use of anticholinergic agents for the treatment of overactive bladder is the side effects of anticholinergic agents.

Adverse reactions that can occur with anticholinergic agents include gastrointestinal pain, gastritis, nausea, vomiting, blurred vision, urinary retention, voiding difficulty, dysuria, and urinary tract infections. tract infection, fatigue, sleepiness, sedation, insomnia, confusion, cognitive impairment, depression, headache, and palpitation ), Tachycardia, high blood pressure, orthostatic disturbance, and fall. In particular, anticholinergic drugs are contraindicated in cases of severe arrhythmia, angina glaucoma, obstructive diseases of the digestive system, and severe myasthenia gravis. In the case of irritable bladder symptoms that do not improve after prostate hypertrophy surgery, additional drug treatment is needed because the hyperactivity of the bladder remains intact even if the bladder outlet obstruction caused by prostatic hyperplasia is treated. Existing anticholinergic drugs are difficult to take in long-term patients due to side effects. Therefore, scientifically proven safe and effective from natural products that can replace anticholinergic drugs to resolve irritable bladder symptoms that persist in the treatment of prostatic hyperplasia. If you develop a long-term treatment or dietary supplement, it can be of great help to many prostatic hyperplasia patients with irritable bladder symptoms.

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction caused by an enlarged prostate.

An object of the present invention is to provide a dietary supplement for the prevention or improvement of overactive bladder caused by secondary bladder degeneration due to bladder outlet obstruction caused by an enlarged prostate.

1. A pharmaceutical composition for the prevention or treatment of overactive bladder, which is a complication of prostatic hyperplasia, comprising cornus fruit, Angelica, goji berry, antler, red ginseng and cinnamon extract and a blocker that selectively acts on alpha-1A adrenergic receptor.

2. The pharmaceutical composition for the prevention or treatment of overactive bladder according to the above 1, wherein the overactive bladder is caused by secondary bladder degeneration caused by bladder outlet obstruction.

3. The pharmaceutical composition for the prevention or treatment of overactive bladder according to the above 1, wherein the overactive bladder is not resolved even when the bladder outlet obstruction is lost.

4. In the above 1, 20-30 parts by weight of cornus fruit, Angelica 20-30 parts by weight, 20-30 parts by weight of wolfberry, 5-15 parts by weight of antler, 5-15 parts by weight of red ginseng and 2-8 parts by weight of cinnamon Pharmaceutical composition for the prevention or treatment of overactive bladder.

5. A dietary supplement for the prevention or improvement of an overactive bladder, a complication of prostatic hyperplasia, including maize, fruit, goji berry, antler, red ginseng and cinnamon extract, which are ingested upon administration of a blocker that selectively acts on the alpha-1A adrenergic receptor. .

6. In the above 5, the overactive bladder is a health functional food for the prevention or improvement of overactive bladder caused by secondary bladder degeneration caused by bladder outlet obstruction.

7. A pharmaceutical composition for the prophylaxis or treatment of overactive bladder caused by secondary bladder degeneration caused by bladder outlet obstruction, including cornus fruit, donkey, wolfberry, antler, red ginseng and cinnamon extract.

8. The pharmaceutical composition for the prevention or treatment of overactive bladder according to the above 7, wherein the overactive bladder is not resolved even when the bladder outlet obstruction is lost.

9. In the above 7, 20-20 parts by weight of cornus fruit, Angelica 20-30 parts by weight, 20-30 parts by weight of wolfberry, 5-15 parts by weight of antler, 5-15 parts by weight of red ginseng and 2-8 parts by weight of cinnamon Pharmaceutical composition for the prevention or treatment of overactive bladder.

The pharmaceutical composition of the present invention exhibits excellent efficacy against overactive bladder caused by secondary bladder degeneration by bladder outlet obstruction due to enlarged prostate. In particular, the main cause may be an excellent effect against irritable bladder that does not resolve even when the bladder outlet obstruction is lost by administration of prostatic hyperplasia or alpha blocker.

The dietary supplement of the present invention exhibits excellent functionality in irritable bladder symptoms caused by secondary bladder degeneration due to bladder outlet obstruction resulting from an enlarged prostate. In particular, the main cause may be excellent function even in irritable bladder that does not resolve even when the bladder outlet obstruction is lost by administering prostatic hyperplasia surgery or alpha blocker.

Figure 1 shows the results of the urethradynamic test after the treatment of the composition according to an embodiment of the present invention.

Figure 2 shows the results of histological examination after the treatment of the composition according to an embodiment of the present invention.

Figure 3 shows the results of measuring the concentration of inflammatory cytokines after the treatment of the composition according to an embodiment of the present invention.

Figure 4 shows the results of measurement of contraction-related protein expression of bladder smooth muscle after treatment of the composition according to an embodiment of the present invention.

Figure 5 shows the mRNA expression measurement results of musculin receptors related to bladder smooth muscle contraction after treatment of the composition according to an embodiment of the present invention.

Figure 6 shows the results of measurement of mRNA expression related to bladder smooth muscle contraction after treatment of the composition according to an embodiment of the present invention.

The present invention includes at least two extracts selected from the group consisting of cornus fruit, Angelica, goji berry, deer antler, red ginseng and cinnamon and blockers that selectively act on the alpha-1A adrenergic receptor, thereby preventing bladder outlet obstruction caused by enlarged prostate It shows good efficacy against overactive bladder caused by secondary bladder degeneration. In particular, the main cause for the prevention or treatment of overactive bladder, which is a complication of prostatic hyperplasia, which can show excellent efficacy against overactive bladder that does not resolve even when the bladder outlet obstruction is lost by administering prostatic hyperplasia or alpha blocker. A pharmaceutical composition and a nutraceutical.

Hereinafter, the present invention will be described in detail.

In this specification, prostatic hyperplasia is closely related to aging and male hormones, and in about 40 to 70% of men aged 60 years or older, prostate hypertrophy causes severe urinary tract symptoms and seriously affects the quality of life. have. A disease that occurs mainly in men over 50 years of age, who have urinary tracts that urinate more than eight times a day, night urination, and a strong, sudden urinary tract Symptoms of obstructive urination, such as irritant storage symptoms and delayed urine (a urine must be moisturized when urine is seen), slitting urine (breaking up of urine), and urinary excretion. Complains of common lower urinary tract symptoms.

In the present specification, the overactive bladder is a secondary change caused by an enlarged prostate, and when the prostate enlarges, it causes a blockage of the bladder outlet, which prevents urine from being discharged, and the pressure in the bladder increases, causing overactivity of the bladder muscle. Sensitivity bladder symptoms occur such as storage symptoms, such as urinary frequency, nighttime urination, urgency and urinary incontinence. An overactive bladder caused by secondary bladder degeneration caused by bladder outlet obstruction is referred to herein.

Blockers that selectively act on alpha-1A adrenergic receptors for hypersensitivity bladder, a complication of prostatic hyperplasia (alpha blockers, drugs that specifically block the action of α-receptors of adrenergic agents), androgen inhibitors, etc. Conventional methods of treating prostatic hyperplasia, such as hypertrophic surgery, have been used, but there is still a case where an overactive bladder is still maintained even when the bladder outlet obstruction is resolved.

On the other hand, if you take anti-choline drugs, which are an overactive bladder treatment to suppress this, dry mouth, constipation, blurred vision, drowsiness, cognitive impairment. Because of the side effects such as digestive disorders, most patients cannot take the drug or take it from the beginning, so new treatments are needed.

We take a combination of a blocker that selectively acts on the alpha-1A adrenergic receptor and extracts from cornus fruit, Angelica, goji berry, antler, red ginseng, and cinnamon, so that it is a complication of prostatic hyperplasia, moreover, prostatic hyperplasia or alpha blockers The present invention has been devised in view of the fact that it is possible to effectively suppress an overactive bladder that does not resolve even when the bladder outlet obstruction is lost by administering the back.

Pharmaceutical compositions for the prevention or treatment of overactive bladder induced by secondary bladder degeneration due to bladder outlet obstruction due to the enlarged prostate of the present invention are cornus fruit, Angelica, wolfberry, antler, red ginseng and cinnamon extract and alpha-1A adrenergic receptor It includes a blocker that selectively acts on.

The content ratio of the extract is not particularly limited, and for example, 20-30 parts by weight of cornus fruit, 20-30 parts by weight, Angelica 20-30 parts by weight, 5-15 parts by weight of deer antler, 5-15 parts by weight of red ginseng, cinnamon It may be included in 2 to 8 parts by weight.

Extracts of the respective medicinal herbs may be obtained by drying and extracting the respective medicinal herbs, concentrated and freeze-dried as necessary.

The extraction may be performed by hot water extraction with purified water, or a lower alcohol solvent of C1 to C4 or one or more hydrocarbon solvents selected from methyl acetate, ethyl acetate, benzene, n-hexane, diethyl ether and dichloromethane, It may be carried out at 100 ℃ for 1 hour to 6 hours, preferably 10 to 50% ethanol may be performed at 60 ℃ to 100 ℃ for 3 hours to 6 hours.

Alpha-1A Adrenoceptor Antagonists lower pressure and tension in the prostate urethra. Examples of commercially available alpha blockers that may be used include terazosin, doxazosin, tamsulosin, alfuzosin and the like.

The pharmaceutical compositions of the present invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral dosage forms, external preparations, suppositories, and sterile injectable solutions according to conventional methods.

Carriers, excipients and diluents that may be included in the composition containing the extract of the present invention 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 oil have. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used.

Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose in the compound. Mixed with 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 oil such as olive oil, injectable ester 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.

The amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, but may be 0.1 to 100 mg / kg, preferably 1 to 10 mg / kg once or several times daily. The dosage may also be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.

In addition, the present invention is derived from an enlarged prostate, comprising at least two extracts selected from the group consisting of Cornus fruit, Angelica, Wolfberry, Deer Antler, Red ginseng, and Cinnamon, ingested with a blocker that selectively acts on the alpha-1A adrenergic receptor. It provides a dietary supplement for the prevention or improvement of overactive bladder caused by secondary bladder degeneration due to one bladder outlet obstruction.

Each extract may be extracted by the above-described method, but may be included in the above content ratio, but is not limited thereto.

The dietary supplement of the present invention may be ingested with a blocker selectively acting on the alpha-1A adrenergic receptor, for example, may be ingested at the time of taking a blocker selectively acting on the alpha-1A adrenergic receptor. It may also be taken during the administration of a blocker that selectively acts on the 1A adrenergic receptor.

Ingestion during the period of taking a blocker that selectively acts on the alpha-1A adrenergic receptor alpha in consideration of the half-life of the blocker that selectively acts on the alpha-1A adrenergic receptor and the half-life of the active ingredient of the dietary supplement of the present invention If there is overlap between the time when the medicament of a blocker selectively acting on the -1A adrenergic receptor and the functional food functional function can be expressed, the timing and frequency of the dose are not limited.

If necessary, the dietary supplement of the present invention may further include a blocker that selectively acts on the alpha-1A adrenergic receptor, which may be used as the above-mentioned commercially available alpha blocker, but is not limited thereto.

Health functional food of the present invention is a beverage containing the extract (including alcoholic beverages), fruits and processed foods thereof (e.g. canned fruit, canned food, jam, marmalade, etc.), fish, meat and processed foods thereof (e.g. Hams, sausage corn, etc.), breads and noodles (e.g. udon, soba noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juices, various drinks, cookies, syrups, dairy products (e.g. butter, cheese, etc.), edible vegetable oils, Margarine, vegetable protein, retort food, frozen food, various seasonings (eg, miso, soy sauce, sauce, etc.).

In addition, the health functional food of the present invention may be formulated into tablets, pills, powders, granules, powders, capsules, liquid formulations and the like. These may be formulated further comprising one or more of carriers, diluents, excipients and additives.

As additives that may be further included in the present invention, natural carbohydrates, flavors, nutrients, vitamins, minerals (electrolytes), flavors (synthetic flavors, natural flavors, etc.), colorants, fillers (cheese, chocolate, etc.), facts Acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, antioxidants, glycerin, alcohols, carbonating agents and flesh may be used.

Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As the flavoring agent, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used.

In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health functional food of the present invention may contain flesh for preparing natural fruit juice and vegetable beverage. These components can be used independently or in combination.

Specific examples of the carrier, excipient, diluent and additives include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium phosphate, calcium Silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate And at least one selected from the group consisting of mineral oils.

The content of the health functional food of the present invention as a functional ingredient in the above-described formulations can be appropriately adjusted according to the use form and purpose, user condition, type of symptom and severity, etc., based on the solid content weight, 0.001 to 99.9% by weight, preferably May be 0.01 to 50% by weight, but is not limited thereto.

The present invention also provides a pharmaceutical composition for the prevention or treatment of overactive bladder caused by secondary bladder degeneration caused by bladder outlet occlusion, including cornus fruit, Angelica, goji berry, antler, red ginseng and cinnamon extract.

As mentioned above, alpha blockers are used to reduce the pressure and tension of the prostate urethra and to relieve bladder exit obstruction, and are characterized by the use of bladder outlet obstruction with cornus fruit, donkey, wolfberry, antler, red ginseng and cinnamon extract without alpha blocker. It may be effective against overactive bladder caused by secondary bladder degeneration.

Cornus fruit, Angelica, Goji berry, Deer Antler, Red ginseng and Cinnamon extract may show efficacy against overactive bladder that does not resolve even with the loss of bladder outlet obstruction.

The extract may be included in a content ratio within the above range.

In another aspect, the present invention provides a health functional food for the prevention or improvement of overactive bladder caused by secondary bladder degeneration caused by bladder outlet obstruction, including cornus fruit, Angelica, goji berry, antler, red ginseng and cinnamon extract.

The content ratio of the overactive bladder, extract may be in the above range.

Hereinafter, the present invention will be described in detail with reference to Examples.

Production Example

Cornus Fructus, Angelica gigantis Radix, Lycii Fructus, Cervi parvum cornu, Red ginseng (Ginseng Radix Rubra) and Cinnaae (Cassiae cortkex), each dried 10 times 30% by weight. Ethanol was added and extracted for 3 hours or more. Each extract was filtered through a filter, concentrated in vacuo, and freeze-dried under reduced pressure, followed by 25 parts by weight of cornus fruit extract, 25 parts by weight of Angelica extract, 25 parts by weight of Gojiberry extract, 10 parts by weight of antler extract, 10 parts by weight of red ginseng extract and cinnamon. An extract complex was prepared, which was mixed at a ratio of 5 parts by weight of the extract.

Experimental Example

One. Detrusor Overactivity  Establishment of Associated Prostatic Hyperplasia Model Light abdomen  Route)

Experimental animals used 250-300 g of Sprague-Dawley male rats. The experimental animals were anesthetized by intramuscular injection of ketamine (40mg / kg) and xylazine (20mg / kg), followed by an incision in the lower abdomen at the supine position and exfoliation of the bladder neck and the urethra. The control group was sutured around the bladder neck and urethra without ureter ligation. The experimental group placed the polyethylene conduit in the same direction as the urethra and then properly bundled the polyethylene conduit with the urethra using a 3-0 suture in the bladder neck. The polyethylene conduit was then removed, the bladder and urethra were in place, and the abdominal incision was closed. All rats were controlled for 12 hours of day and night, and food and water were allowed to eat freely according to the prescribed protocol.

2. Urodynamic  inspection

Urethane (12 mg / kg) was anesthetized with experimental animals and the urethra entrance was confirmed in supine position. The polyethylene conduit was placed in the bladder through the urethra and then emptyed and fixed. The catheter was connected to the perfusion pump and the pressure transducer, and after passing through the ballast for about 10 minutes, the bladder internal pressure was zeroed to 0 mmHg. Bladder internal pressure was measured while physiological saline was injected into the bladder at a rate of 10 ml / hour. If urination contraction begins during urination pressure monitoring or saline leaks around the opening of the urethra, perfusion stops. Maximum urinary pressure, the number and intervals of non-drainage were measured in at least three repeated urination cycles.

3. Histological Examination

Bladder tissue samples were fixed with 4% paraformaldehyde for 1 day at 4 ° C. and inserted into paraffin. 7 μm thick slice sections were prepared for Masson's trichrome staining to observe bladder muscles.

The details of each group are as follows. All animal experiments were conducted according to the Research Ethics Guidelines of the Animal Experiment Ethics Committee of the Medical Center.

1) Normal: No treatment or treatment was given to Sprague-Dawley male rats that did not induce detrusor hyperactivity.

2) OAB: No drug treatment in prostatic hyperplasia rats with detrusor hyperactivity

3) Preparation Example (400mg / kg) administration group: The extract of Preparation Example was administered by diluting 1cc of distilled water using oral gavage twice a day for 2 weeks to 4 weeks after partial occlusion.

Experiment result

One) Urinary dynamics test  By enforcement Maximum urination pressure  Interval comparison

1, it can be seen that the cycle of the maximum urination pressure is more regular than the OAB group in the example administration group, and the difference between the maximum and the minimum is greater.

2) After the examination, the bladder was removed and biopsied; Bladder mucosa and Submucosa , Detrusor  Observe histological features

Referring to Figure 2, it can be seen that the bladder smooth muscle contraction is significantly reduced compared to the OAB group in the Example administration group.

3) Using ELISA on Collected Serum TNF of inflammatory cytokines such as -a, IL-6 and IL-8

After the experiment, blood was collected through puncture of the heart and centrifuged to separate serum. The separated serum was used for measuring the secretion amount of TNF-α, IL-6, IL-8 using the ELISA system. For the measurement of secretory cytokines, 50 μl of the biotinylated antibody was added to the plate coated with the antibody against the cytokine to be measured, and then 50 μl of the cell culture supernatant was left at room temperature for 2 hours, and then washed. Subsequently, 100 μl of streptavidine-HRP solution was added and left at room temperature for 30 minutes. Then, 100 μl of a 3,3'-5,5 'tetramethylbenzidine (TMB) substrate solution was added and reacted. Then, a stop solution was added and absorbance was measured at 450 nm. A standard curve was prepared to calculate the corresponding secretory cytokine concentrations.

Referring to Figure 3, it can be seen that the concentration of inflammatory cytokines in the treatment group was significantly reduced compared to the overactive bladder group.

4) Involved in smooth muscle contraction RhoA  Protein expression, RhoA / ROCK mRNA  (RhoA / ROCK pathway) expression and NOS comparison

RhoA protein expression or RhoA / ROCK mRNA (RhoA / ROCK pathway) expression: Rho kinase is activated by GTPase RhoA, and activated Rho kinase increases MLC phosphorylation by inhibiting MLC phosphatase without increasing intracellular Ca2 + concentration Causes smooth muscle contraction. RhoA monoclonal antibody was used for immunohistochemical staining to determine the expression level of RhoA protein in the control and experimental bladder.

Frozen frozen bladder tissues were removed and attached to the slides and then reacted with non-immune horse serum for 30 minutes at room temperature to remove nonspecific staining reactions. Then, RhoA monoclonal antibody diluted 1: 200 was added for 24 hours at 4 ° C. After the reaction, immunostaining was performed using an avidin-biotin complex kit, followed by optical microscopy.

Western Blotting: Finely chopped tissue, RIPA buffer (25 mM Tris-HCl [pH 7.6], 150 mM NaCl, 1% NP-40, 1% sodium deoxycholate, 0.1% SDS, protease inhibitor cocktail) Place the tissue in 250 μl, crush the tissue using homogenize, put it on ice and leave it at 4 ℃ for 16 hours. After centrifugation at 13,000 rpm, 4 ℃ for 15 minutes, only the supernatant was transferred to a new tube and stored at -70 ℃ after quantification using Bradford protein assay. 8%, 15% SDS-polyacrylamide gel was prepared and electrophoresed at 100V for 1.5 hours using 50 ㎍ protein. After electrophoresis, transfer to PVDF membrane at 70V, 2 hours, blocked with 5% skim milk solution for 1 hour. After eNOS, nNOS, and beta-actin were reacted at 4 ° C. for 16 hours, they were washed three times with TBST solution for 10 minutes, and then anti-mouse IgG-HRP (1: 2,000, 1: 5,000 Invitrogen), anti-rabbit IgG-HRP ( 1: 2,000, Invitrogen) was reacted at room temperature for 1 hour, washed three times with TBST solution for 10 minutes, and reacted for 1 minute with ECL plus solution. .

4 to 6, it can be seen that shrinkage-related factors m2, eNOS increase in protein, mRNA levels, m3, RhoA, Rock-1, Rock-2 is reduced, the contraction is reduced compared to the OAB group.

Claims (9)

1. A pharmaceutical composition for the prophylaxis or treatment of overactive bladder, which is a complication of an enlarged prostate, comprising cornus fruit, Angelica, goji berry, antler, red ginseng and cinnamon extract and a blocker selectively acting on alpha-1A adrenergic receptor.
2. The pharmaceutical composition for preventing or treating an overactive bladder of claim 1, wherein the overactive bladder is caused by secondary bladder degeneration caused by bladder outlet obstruction.
3. The pharmaceutical composition for preventing or treating an overactive bladder according to claim 1, wherein the overactive bladder does not resolve even when the bladder outlet obstruction is lost.
4. The sensitizing composition of claim 1, comprising 20-30 parts by weight of cornus fruit, 20-30 parts by weight, Angelica 20-30 parts by weight, 5-15 parts by weight of antler, 5-15 parts by weight of red ginseng, and 2-8 parts by weight of cinnamon. Pharmaceutical composition for the prevention or treatment of the bladder.
5. A dietary supplement for the prevention or amelioration of an overactive bladder, which is a complication of an enlarged prostate, comprising maize, fruit, goji berry, antler, red ginseng and cinnamon extract, which are ingested upon administration of a blocker that selectively acts on the alpha-1A adrenergic receptor.
6. 6. The dietary supplement for preventing or improving overactive bladder of claim 5, wherein the overactive bladder is caused by secondary bladder degeneration caused by bladder outlet obstruction.
7. Pharmaceutical composition for the prevention or treatment of overactive bladder caused by secondary bladder degeneration caused by bladder outlet obstruction, including cornus fruit, Angelica, goji berry, antler, red ginseng and cinnamon extract.
8. The pharmaceutical composition for preventing or treating an overactive bladder according to claim 7, wherein the overactive bladder is not resolved even when the bladder outlet obstruction is lost.
9. The sensitizing composition of claim 7, comprising 20-30 parts by weight of cornus fruit, 20-30 parts by weight, Angelica 20-30 parts by weight, 5-15 parts by weight of antler, 5-15 parts by weight of red ginseng, and 2-8 parts by weight of cinnamon. Pharmaceutical composition for the prevention or treatment of the bladder.

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