Composition for preventing, ameliorating or treating benign prostatic hyperplasia comprising alpiniae oxyphyllae fructus extract

Abstract

The present invention relates to a pharmaceutical composition, a food composition and a feed composition for preventing, ameliorating or treating benign prostatic hyperplasia, each composition comprising an Alpiniae oxyphyllae Fructus extract, and a method for treating benign prostatic hyperplasia by using the pharmaceutical composition. The pharmaceutical composition, the food composition, and the feed composition exhibit the effect of inhibiting prostatic hypertrophy caused by male hormone imbalance, can reduce lower urinary tract symptoms caused by prostatic hypertrophy by inhibiting prostatic proliferation, and can be developed, through non-clinical and clinical studies, as pharmaceuticals that are effective in preventing and treating benign prostatic hyperplasia, health functional foods and health foods that are beneficial to prostate health, and the like.

Description

A composition for the prevention, improvement, or treatment of benign prostatic hyperplasia containing *Ikji* extract

[0001] The present invention provides a composition for the prevention, improvement, or treatment of benign prostatic hyperplasia comprising an extract of *Alpiniae Oxyphyllae Fructus*.

[0002] Benign prostatic hyperplasia (BPH) is a condition in which the prostate gland enlarges due to the abnormal proliferation of normal cells within the prostate. It is a representative disease of old age that frequently occurs in men aged 60 to 70 and older. The abnormally enlarged prostate compresses the nearby urethra, which can lead to urinary dysfunction such as lower urinary tract symptoms, as well as lower abdominal tension and sexual dysfunction. The incidence of BPH has been rapidly increasing recently due to the rise in the elderly population. Although it is not a life-threatening disease, it is emerging as a major issue in modern aging society because it lowers the quality of life in old age.

[0003] Although the exact cause of benign prostatic hyperplasia (BPH) has not been clearly identified, given that it frequently occurs in elderly individuals with reduced endocrine function, it is closely related to changes in male hormones associated with aging. Additionally, cell death occurs less than the growth of the prostate, which can result in the prostate becoming larger.

[0004] Treatment for benign prostatic hyperplasia primarily involves drug therapy, mainly using alpha-adrenergic receptor antagonists (α-adrenergic receptor antagonists) that rapidly relieve symptoms by relaxing the muscles around the prostatic urethra, and 5α-reductase inhibitors that reduce the size of the prostate by regulating the production of dihydrotestosterone, either alone or in combination.

[0005] However, these drugs can cause side effects such as dizziness, lethargy, headaches, decreased libido, and erectile dysfunction, and saw palmetto, a representative health supplement for improving benign prostatic hyperplasia, has also been reported to be ineffective. Therefore, there is a need to develop new substances using natural products with minimal side effects that can prevent, improve, or treat benign prostatic hyperplasia.

[0006] The object of the present invention is to provide a composition for the prevention, improvement, or treatment of benign prostatic hyperplasia comprising an extract of *Alpiniae Oxyphyllae Fructus*.

[0007] To achieve the above objective, the present invention provides a pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0008] In addition, the present invention provides a health functional food composition for the prevention or improvement of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0009] In addition, the present invention provides a feed composition for the prevention or improvement of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0010] The present invention relates to a pharmaceutical composition, food composition, and feed composition for the prevention, improvement, or treatment of benign prostatic hyperplasia comprising an extract of *Alpiniae Oxyphyllae Fructus*, and a method for treating benign prostatic hyperplasia using said pharmaceutical composition. It exhibits an effect of inhibiting prostate enlargement induced by male hormone imbalance and can reduce lower urinary tract symptoms caused by prostate enlargement by inhibiting prostate proliferation. Furthermore, through non-clinical and clinical studies, it can be developed into a pharmaceutical product effective for the prevention and treatment of benign prostatic hyperplasia, a health functional food that helps with prostate health, and a health food.

[0011] Figure 1 is a schematic diagram showing the process of animal model experiments performed in Examples 2 and 3 below.

[0012] Figure 2 shows the results of analyzing the effects of Alpinia oxyphylla fruit or seed extracts on prostate weight and prostate index. Fina; finasteride (1 mg / kg / day), AOF; Alpinia oxyphylla fruit extract (300 mg / kg / day), AOS; Alpinia oxyphylla seed extract (200 mg / kg / day).

[0013] Figure 3 shows the results of analyzing the effects of Alpinia oxyphylla pericarp extract on prostate weight and prostate index. Fina; finasteride (1 mg / kg / day), AOP; Alpinia oxyphylla pericarp extract (100 mg / kg / day).

[0014] The present invention will be described in more detail below.

[0015]

[0016] The present invention provides a pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0017] The above-mentioned ripening material may consist of a fruit, fruit peel, or seed.

[0018] The above extract of Alpiniae Oxyphyllae Fructus can be extracted using various polar or non-polar solvents or organic solvents. In one embodiment, the extract can be extracted using one or more mixed organic solvents selected from the group consisting of hot water, lower alcohols having 1 to 4 carbon atoms, chloroform, dichloromethane, hexane, acetone, propylene glycol, ethyl acetate, butylene glycol, and ether.

[0019] The above extract of *Alpiniae Oxyphyllae Fructus* can inhibit prostate proliferation.

[0020] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, leavening agents, lubricants, lubricants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders, and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0021] Specifically, the carrier, excipient, and diluent may be lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc. These solid dosage forms may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the above composition. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, and syrups, and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents like water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. Witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used as the base for suppositories.

[0022] According to one embodiment of the present invention, the pharmaceutical composition may be administered to a subject in a conventional manner through an intravenous, intra-arterial, intra-abdominal, intramuscular, intra-arterial, intra-abdominal, intrasternal, transdermal, nasal, inhalation, local, rectal, oral, ocular, or intradermal route.

[0023] The dosage of the active ingredient according to the present invention may vary depending on the subject's condition and body weight, the type and severity of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by a person skilled in the art. The daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. The administration may be performed once a day or divided into several doses, and the scope of the present invention is not limited by this.

[0024]

[0025] In addition, the present invention provides a health functional food composition for the prevention or improvement of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0026] The above health functional food may contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0027] In addition, it may contain fruit pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. Furthermore, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, chewing gum, ice cream, soup, beverage, tea, functional water, drinkables, alcohol, and vitamin complexes.

[0028] In addition, the above-mentioned health functional food may further include food additives, and unless otherwise stipulated, suitability as a "food additive" shall be determined in accordance with the specifications and standards for the relevant item, based on the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety.

[0029] Examples of items listed in the above "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamon acid; natural additives such as persimmon dye, licorice extract, crystalline cellulose, kohlrabi dye, and guar gum; L-sodium glutamate preparations; alkaline agents added to noodles; preservative preparations; and mixed preparations such as tar dye preparations.

[0030] At this time, the content of the active ingredient added to the food during the process of manufacturing the health functional food can be appropriately increased or decreased as needed, and preferably, it can be added in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0031]

[0032] In addition, the present invention provides a feed composition for the prevention or improvement of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

[0033] The feed composition according to the present invention can be prepared from various forms of feed known in the art, and preferably may include concentrate feed, roughage, or special feed.

[0034] Concentrated feeds include seed grains such as wheat, oats, and corn; bran, which is a byproduct remaining after refining grains and includes rice bran, wheat bran, and barley bran; oilseed meal, which is a byproduct obtained from extracting oil from soybeans, rapeseed, sesame, flaxseed, and coconut; residues such as residual starch, which is the main component of starch residue remaining after removing starch from sweet potatoes and potatoes; fish meal, fish residue; fish soluble, which is a concentrated fresh liquid obtained from fish; meat meal; blood meal; feather meal; skim milk powder; dried whey, which is the residue obtained when making cheese from milk and casein from skim milk; yeast, Chlorella, and seaweed.

[0035] Forage includes fresh grass feeds such as wild grass, pasture grass, and green cuts; root vegetables such as feed turnips, feed beets, and a type of turnip called lutea bearger; silage, which is a stored feed made by filling a silo with fresh grass, green cut crops, and grains and fermenting them with lactic acid; hay made by cutting and drying wild grass and pasture grass; straw of livestock breeding crops; and leaves of legumes.

[0036] Special feeds include mineral feeds such as shells and rock salt, urea feeds such as urea or its derivatives such as diurea and isobutane, feed additives and dietary supplements, which are substances added in small amounts to compound feed to supplement components that are easily lacking when only natural feed ingredients are mixed or to improve the shelf life of the feed.

[0037] Meanwhile, the feed composition according to the present invention may include a feed additive or be a feed additive.

[0038] In the present invention, the term "feed additive" refers to a substance added to feed for the purpose of various effects, such as supplementing nutrients and preventing weight loss, improving the digestibility and utilization of fiber in the feed, improving milk quality, preventing reproductive disorders and improving conception rates, and preventing high-temperature stress during the summer. The feed additive of the present invention corresponds to an auxiliary feed under the Feed Management Act and may additionally include mineral preparations such as sodium bicarbonate (baking soda), bentonite, magnesium oxide, and complex minerals; mineral preparations that are trace minerals such as zinc, copper, cobalt, and selenium; vitamin preparations such as carotene, vitamin E, vitamins A, D, E, nicotinic acid, and vitamin B complex; protected amino acid preparations such as methionine and lysic acid; protected fatty acid preparations such as calcium salts of fatty acids; probiotics (lactic acid bacteria preparations); probiotics such as yeast cultures and mold fermentation products; and yeast preparations.

[0039] The feed composition according to the present invention is not particularly limited and can be applied to any individual intended for the purpose of fortifying high-functional fatty acids and raising livestock. The individual refers to animals, for example, non-primates (e.g., cattle, pigs, horses, cats, dogs, rats, and mice) and mammals including primates (e.g., monkeys, e.g., cynomolgous monkeys and chimpanzees). In another embodiment, the individual is a livestock animal (e.g., horses, cattle, pigs, etc.) or a pet animal (e.g., dogs or cats). Additionally, it is a fish, for example, flounder, sole, eel, freshwater eel, saltwater eel, rockfish, etc. In another embodiment, the individual is an insect, for example, a fly, a flower beetle, a scarab beetle, a mealworm, a cricket, a silkworm, a half-moon, a white silkworm, a grub, an earthworm, a leech, a centipede, a scorpion, a spider, etc. In a specific embodiment of the present invention, the preferred individual may be selected from the group consisting of beef cattle, dairy cows, pigs, chickens, ducks, goats, sheep, horses, goats, donkeys, cats, geese, pheasants, quails, ostriches, or mallards, and may preferably be beef cattle, but is not limited thereto.

[0040] The dosage of the feed composition according to the present invention may be influenced by a number of factors such as the species, size, weight, and age of the individual. In principle, a typical dosage may be in the range of 0.001 g to 1000 kg per individual per day. However, it is not limited thereto.

[0041] Hereinafter, to aid in understanding the present invention, examples and the like will be described in detail. However, the following examples and the like are merely illustrative of the content of the present invention and the scope of the present invention is not limited to the following examples and the like. The examples and the like of the present invention are provided to more completely explain the present invention to those with average knowledge in the art.

[0042]

[0043] [Example 1] Preparation of Ikji Extract

[0044] Dried *Alpiniae Oxyphyllae Fructus* was purchased from Kwangmyungdang Pharmaceutical Co., Ltd. (Ulsan, Korea) and used. The fruit, seeds, or pericarp of *Alpiniae Oxyphyllae* were reflux-cooled extracted using a heating mantle (MS-DM606, Misung Science & Instruments Co., Ltd., Gyeonggi-do, Korea) with 10 times the amount of purified water or 70% ethanol. For hot water extraction, extraction was performed at 100°C for 3 hours, and for 70% ethanol extraction, extraction was performed at 70°C for 3 hours. Afterward, the extracts were filtered through filter paper (Whatman™, Cytiva, USA), and the filtrate was concentrated under reduced pressure at 45°C using a rotary vacuum concentrator (N-1200A, EYELA, Tokyo, Japan). The concentrate was freeze-dried using a freeze dryer (FDU-1200, EYELA, Tokyo, Japan), and the yield of the extract is shown in Table 1.

[0045] Fruit hot water extract Fruit 70% ethanol extract Seed hot water extract Seed 70% ethanol extract Fruit peel hot water extract 15.2% 14.9% 13.7% 17.4% 19.1%

[0046]

[0047] [Example 2] Experimental animals

[0048] 10-week-old male Sprague-Dawley rats were supplied by Coatec Co., Ltd. (Gyeonggi-do, Korea) and acclimatized for one week before being used in the experiment. During the rearing period, the rearing space was maintained at a temperature of 23±1 ℃, humidity of 40-60%, and a 12-hour lighting cycle, and food and water were provided for free intake.

[0049]

[0050] [Example 3] Induction of prostate enlargement and administration of extract

[0051] As shown in Figure 1, rats acclimated to the rearing space were randomly assigned to a sham, control group, finasteride-positive control group (finasteride 1 mg / kg / day), or a group administered with *Ikji* extract (100, 200, or 300 mg / kg / day), and castration was performed under isoflurane inhalation anesthesia. After incising the midline of the abdomen of the rats, both testes, epididymis, and epididymal fat were resected. After resection, the abdominal skin was sutured, and a recovery period of one week was observed. In the sham group, the abdominal skin was incised and sutured without any tissue resection. Prostatic hypertrophy was induced by dissolving testosterone propionate (Testosterone propionate, 3 mg / kg; TCI, Tokyo, Japan) in olive oil and administering it subcutaneously once daily for 14 days. The Sham group was administered olive oil by subcutaneous injection once daily for 14 days. Along with the induction of prostate enlargement, a mixture of *Ixeris chinensis* extract and finasteride (Organon, New Jersey, USA) dissolved in purified water was administered orally once daily for 14 days. The Sham group and the control group were administered purified water orally once daily for 14 days. The dosage was 1 mg / kg for subcutaneous administration and 10 mL / kg for oral administration.

[0052]

[0053] [Example 4] Analysis of effects on prostate weight and prostate index

[0054] To determine the effect of the extract on prostate weight and prostate index, after performing Example 3 above, the experimental animals were fasted overnight before sacrifice, and the fasting body weight was measured on the day of sacrifice. The prostate was excised under isoflurane inhalation anesthesia and its weight (mg) was measured, and the prostate index was calculated as prostate weight (mg) per 100 g of fasting body weight. The inhibition rate (%) of prostate weight and prostate index was calculated as (value of control group - value of treatment group) / (value of control group - value of sham group) × 100.

[0055] As a result, according to Figure 2, water and ethanol extracts of the fruit and seeds of the fruit significantly reduced prostate weight and prostate index, respectively, in a rat model of benign prostatic hyperplasia compared to the control group. Specifically, the prostate weight of the control group was 1460.2 ± 134.8 mg, while the prostate weight of the groups administered the water extract of the fruit and seeds was 1292.5 ± 54.1 mg and 1232.0 ± 52.1 mg, respectively, and the prostate weight of the groups administered the ethanol extract of the fruit and seeds was 1276.5 ± 97.8 mg and 1255.5 ± 97.6 mg, respectively. The prostate index was 417.6 ± 43.1 mg / 100 g body weight in the control group, 369.5 ± 16.6 and 348.1 ± 13.7 mg / 100 g body weight in the water extract group of the fruit and seeds, and 371.8 ± 20.3 and 354.4 ± 36.0 mg / 100 g body weight in the ethanol extract group of the fruit and seeds, respectively, showing that prostate weight and prostate index were significantly reduced in all extract groups compared to the control group.

[0056] In addition, according to Figure 3, the water extract of the fruit peel of the fruit significantly reduced prostate weight and prostate index, respectively, in a rat model of benign prostatic hyperplasia compared to the control group, specifically the reduction rates (%) of prostate weight and prostate index were 24.7% and 22.6%, respectively.

[0057] From the above results, it was confirmed that the Ikji extract exhibits the ability to inhibit prostate proliferation.

[0058]

[0059] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical spirit or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0060] The scope of the present invention is defined by the claims set forth below, and all modifications or variations derived from the meaning and scope of the claims and equivalent concepts thereof should be interpreted as being included within the scope of the present invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

2. A pharmaceutical composition according to claim 1, characterized in that it comprises the ripening fruit, fruit peel, or seed.

3. A pharmaceutical composition according to claim 1, wherein the extract of the *Ikji* is extracted using an extract of one or more mixed organic solvents selected from the group consisting of hot water, lower alcohols having 1 to 4 carbon atoms, chloroform, dichloromethane, hexane, acetone, propylene glycol, ethyl acetate, butylene glycol, and ether.

4. A pharmaceutical composition according to claim 1, wherein the extract of the ginseng inhibits prostate proliferation.

5. A health functional food composition for the prevention or improvement of benign prostatic hyperplasia containing an extract of *Alpiniae Oxyphyllae Fructus*.

6. A feed composition for the prevention or improvement of benign prostatic hyperplasia containing extract of *Alpiniae Oxyphyllae Fructus*.

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