KR102299770B1 - Composition for treating for benign prostatic hyperplasia comprising melittin extract - Google Patents

Abstract

The present invention relates to a composition for preventing or treating benign prostatic hyperplasia. Specifically, a composition for preventing or treating benign prostatic hyperplasia including melittin may prevent or treat prostatic hyperplasia.

Description

Composition for the treatment of benign prostatic hyperplasia comprising melittin {COMPOSITION FOR TREATING FOR BENIGN PROSTATIC HYPERPLASIA COMPRISING MELITTIN EXTRACT}

The present invention relates to a composition for the treatment of benign prostatic hyperplasia comprising melittin.

With increasing interest in the improvement and improvement of the quality of life due to the aging of mankind, the demand for improvement of benign prostatic hyperplasia, one of the representative diseases of the elderly in men, is expanding.

Benign prostatic hyperplasia (BPH) is a lower urinary tract symptom that collectively refers to lower urinary tract voiding symptoms caused by an increase in the size of the prostate and damage to the urinary storage and excretion functions in the bladder. Symptoms include decreased urine output due to urethral obstruction, and various bladder irritation symptoms such as frequent urination, residual urination, and urgency (symptoms that cannot tolerate urination). Treatment includes drug therapy, non-invasive procedures, invasive surgery, and alternative therapies.

Histological changes of benign prostatic hyperplasia start at the age of 35 and are induced in 60% of men in their 60s and 90% of those in their 80s. reported to have been treated.

Testosterone is deeply involved in prostate growth, development, and pathology through androgen receptors in the prostate. BPH is governed by male hormones and plays an important role in BPH as dihydrotestosterone (DHT) is the most important male hormone in the prostate. Several subtypes of 5-alpha reductase have been known so far, and among them, 5-alpha reductase type 2 plays a major role in the prostate. Specifically, in patients deficient in 5-alpha reductase type 2, the prostate is very small and prostate enlargement does not appear.

Hospitals mainly prescribe selective alpha blockers (terazosin, doxazosin, tamsulosin) and 5-alpha reductase inhibitors (finasteride, dutasteride), but they have a fatal side effect of sexual dysfunction, so health functional foods (eg brand name) Saw Palmetto) is also sold.

Recently, a lot of pharmaceutical compositions for preventing and treating the existing prostatic hyperplasia have emerged.

For example, melittin is used in a pharmaceutical composition in Korean Patent Application Laid-Open No. 2016-0110410 (title of the invention: hybridosome, composition comprising same, preparation method thereof, and use thereof), and the treatment target is prostate cancer Bee venom containing melittin is described in Korean Patent Application Laid-Open No. 2010-0067301 (title of the invention: composition for the prevention and treatment of angiogenesis-related diseases, lung cancer or pain containing bee venom extract as an active ingredient) Although it has a therapeutic effect on prostate cancer, there was a description that it has a particularly therapeutic effect on lung cancer.

That is, Korean Patent Laid-Open Publication Nos. 2016-0110410 and 2010-0067301 were directed to prostate cancer rather than enlarged prostate.

In addition, it is generally known that Bongchim is effective for benign prostatic hyperplasia, so melittin alone was not used for the treatment of benign prostatic hyperplasia.

An object of the present invention is to provide a pharmaceutical composition for preventing or treating benign prostatic hyperplasia, which is commercialized or commercialized as a therapeutic agent or health food for prostate prevention and treatment.

In addition, the present invention is to provide a health functional food for the prevention or improvement of benign prostatic hyperplasia.

One embodiment of the present invention provides a composition for preventing or treating benign prostatic hyperplasia, containing melittin as an active ingredient.

Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating benign prostatic hyperplasia, containing the composition.

Another embodiment of the present invention provides a health functional food for preventing and improving prostatic hyperplasia, containing melittin as an active ingredient.

The pharmaceutical composition and health functional food for the prevention or treatment of benign prostatic hyperplasia of the present invention have an effect that can be commercialized or commercialized as a therapeutic agent or health food for prostate prevention and treatment.

1 shows the effect of melittin on prostatic hypertrophy in BPH-induced rat models.
Figure 2 shows the effect of melittin on prostate weight in BPH-induced rat models.
3 shows the effect of melittin on the prostate weight to body weight ratio (PW/BW) in BPH-induced rat models.

Hereinafter, some embodiments of the present invention will be described in detail with reference to exemplary drawings. In adding reference numerals to the components of each drawing, it should be noted that the same components are given the same reference numerals as much as possible even though they are indicated on different drawings. In addition, in describing the embodiments of the present invention, if it is determined that a detailed description of a related known configuration or function may obscure the gist of the present invention, the detailed description thereof will be omitted.

As used herein, the term “derivative” refers to a compound obtained by substituting a part of the structure of a compound with another atom or group, and a product made by addition reaction or the like is also defined as belonging to the present invention.

As used herein, the term “prevention” refers to any action that suppresses or delays enlarged prostate by administering the composition of the present invention to a subject.

The term "treatment" as used in the present invention means any action of administering the composition of the present invention to an individual suspected of having an enlarged prostate so that the symptoms are improved or beneficial.

As used herein, the term “improvement” refers to any action that at least reduces a parameter associated with the condition being treated, for example, the severity of symptoms.

As used herein, the term “individual” refers to all animals including humans.

Hereinafter, a composition for preventing or treating benign prostatic hyperplasia containing melittin as an active ingredient according to an embodiment of the present invention will be described.

It was confirmed that the composition containing melittin as an active ingredient is effective in the actual prevention or treatment of benign prostatic hyperplasia.

As can be seen from the Examples to be described later, as in the Saw group administered with saw palmetto, a positive control drug, the size of the prostate in the Mel group administered with melittin was reduced compared to the BPH group, and the red light was reduced with the naked eye. (see Fig. 1).

A significant decrease in prostate weight was confirmed in the Saw group administered with saw palmetto, a positive control drug, and the Mel group administered with melittin compared to the BPH group (see FIG. 2).

In the Saw group and the Mel 0.1 and 0.2 groups, it was confirmed that the prostate weight-to-body weight ratio (PW/BW) was significantly decreased compared to the BPH group to 3.05, 2.90, and 2.45 in turn (see FIG. 3).

It has become possible to commercialize or commercialize a composition containing melittin as an active ingredient as a therapeutic agent or health food that has the effect of treating or alleviating an enlarged prostate without the side effects exhibited by an enlarged prostate treatment agent.

In another aspect, another embodiment of the present invention may provide a pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia, containing a composition for preventing or treating benign prostatic hyperplasia, containing melittin as an active ingredient.

In addition, the administration method of the pharmaceutical composition is not particularly limited, but may be an oral administration method.

In order to formulate the composition of the present invention into a dosage form for oral administration such as tablets or capsules, lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose (Cellulose) or gelatin ( gelatin) and the like; excipients such as dicalcium phosphate; disintegrating agents such as corn starch or sweet potato starch; and lubricating oils such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax. Furthermore, in the case of the capsule formulation, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be additionally contained.

A specific pharmaceutically effective amount of the composition for a specific animal may include the type and extent of the response to be achieved, the age, weight, general health condition, sex or diet of the subject, as well as the administration time of the composition, the route of administration and the composition of the composition. It may be determined in consideration of the secretion rate, the duration of treatment, and the like, and may vary depending on several factors, including components of drugs and other compositions used simultaneously or at the same time, and similar factors well known in the pharmaceutical field.

Specifically, the pharmaceutical composition according to this embodiment may be orally administered to an individual in an amount of 0.1 mg/kg to 1,000 mg/kg, specifically, to be orally administered in an amount of 0.1 mg/kg to 100 mg/kg. Can, for example, may be administered orally in a dose of 0.1 mg / kg or 50 mg / kg, it may exhibit an excellent treatment or prevention effect of benign prostatic hyperplasia in the corresponding range.

In addition, the pharmaceutical composition may further include a pharmaceutically acceptable carrier, and may be formulated with the carrier and provided as a food, drug, feed additive, drinking water additive, and the like. As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not inhibit the biological activity and properties of an administered compound without irritating the organism.

The type of carrier usable in the present invention is not particularly limited, and any carrier commonly used in the art and pharmaceutically acceptable may be used. Non-limiting examples of the carrier include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and the like. These may be used alone or in mixture of two or more.

In addition, if necessary, other conventional additives such as antioxidants, buffers and/or bacteriostats may be added and used, and diluents, dispersants, surfactants, binders and/or lubricants may be additionally added to aqueous solutions, suspensions, emulsions, etc. It can be formulated and used in the same dosage form for injection, pills, capsules, granules, or tablets.

The pharmaceutical composition may be formulated or used in combination with any one or more agents selected from bronchodilators, antihistamines, anti-inflammatory analgesics, anticancer agents, neuroprotective agents, and antibiotics.

The antibiotic is a carbapenem antibiotic, a cephalosporin antibiotic, a glycopeptide antibiotic, a penicillin antibiotic, a quinolone antibiotic, a serine protease antibiotic, and a polymic. It may be selected from the group consisting of polymyxin antibiotics, aminoglycoside antibiotics, bacteriostatic antibiotics, and combinations of the above antibiotics, but is not necessarily limited thereto.

The carbapenem-based antibiotic is Doripenem, the cephalosporin-based antibiotic is Ceftriaxone sodium, the glycopeptide-based antibiotic is Vancomycin hydrochloride, and the penicillin-based antibiotic is benzyl Potassium penicillin (Potassium benzylpenicillin), and the quinolone antibiotic is DW286(7-[3-(aminomethyl)-4-(methoxyimino)-3-methyltetrahydro-1H-1-pyrrolyl]-1-cyclopropyl-6-fluoro-4) -oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid hydrochloric acidsalt) or Ciprofloxacin hydrochloride hydrate, and the serine protease antibiotic is Drotrecogin alfa (activated) (activated)), the polymyxin antibiotic is colistin, the aminoglycoside antibiotic is tobramycin, and the bacteriostatic antibiotic is fusidic acid (fusidic acid), but is not necessarily limited thereto.

However, the compound-containing formulation according to the present invention is not limited to the above, and any formulation useful for the treatment or prevention of benign prostatic hyperplasia may be included.

In another aspect, another embodiment of the present invention provides a health functional food for preventing and improving prostatic hyperplasia, containing melittin as an active ingredient.

The composition according to an embodiment of the present invention can be manufactured and processed into health functional foods in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of preventing or improving BPH.

The health functional food includes, for example, various foods, beverages, gum, tea, vitamin complexes, health functional foods, and the like. In addition, it may be added to food or beverages for the purpose of preventing and treating benign prostatic hyperplasia, and there is no particular limitation on other ingredients added in addition to the cornus oil and bogolji. It may be contained as an additional ingredient. 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 polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (eg, 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 this embodiment includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and salts thereof, organic acids, protective colloidal 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 embodiment may contain natural fruit juice, fruit juice, and pulp for the production of fruit juice beverages and vegetable beverages. These components may be used independently or in combination. The proportion of these additives is not limited.

Hereinafter, the present invention will be described in more detail by describing Examples and Experimental Examples. However, the following examples and experimental examples are merely examples of the present invention, and the content of the present invention should not be construed as being limited thereto.

Example

1. 1. Experimental animals

6-week-old male Wistar rats (160±20 g) were purchased from Daejeon, Republic of Korea and tested.

Experimental animals were bred according to the guidelines for laboratory animals set by the Animal Experimental Ethics Committee of Sangji University. After giving an adaptation period for 1 week before the start of the experiment, feed and water were allowed to be freely ingested for 6 weeks during the experiment. has maintained Feed and water were provided ad libitum.

Experimental animals were randomly divided into 5 groups (n=10): a shark-operated group (control group); BPH induction group (BPH group); saw palmetto-treated group (Saw group); Melittin-treated group (Mel group) was divided into 0.1, 0.2 mg/kg.

Animals were castrated according to the previously reported paper, and after a recovery period of 1 week, testosterone (10 mg/kg) was injected subcutaneously to induce prostate enlargement. As a positive control group, saw palmetto was orally administered to the Saw group at the same time as prostate enlargement was induced, and melittin was administered intraperitoneally to the Mel group (see Table 1).

At the end of the 6-week experiment, the body weight was measured and all experimental animals were fasted for 12 hours. The next day, 0.5 ml of Zoletil (Virbac; Carros Cedex, France) was administered to anesthetize, and cardiac puncture was performed to draw blood from the heart. Collected blood was stored at -80°C until analysis. Prostate tissue was weighed after excision, washed with physiological saline, weighed, and stored at -80°C until testing.

experimental proup Operation Oral treatment Controls:
Sharm-operated group Orchiectomy - BPH group :
BPH model group After orchiectomy, injection of testosterone 10 mg/kg subcutaneously - Saw group :
saw palmetto-treated group After orchiectomy, injection of testosterone 10 mg/kg subcutaneously saw palmetto
100 mg/kg
(Oral) Mel 0.1 group :
Melittin-treated group After orchiectomy, injection of testosterone 10 mg/kg subcutaneously Mel
0.1 mg/kg
(Intraperitoneal) Mel 0.2 group :
Melittin-treated group After orchiectomy, injection of testosterone 10 mg/kg subcutaneously Mel
0.2 mg/kg
(Intraperitoneal)

2. Experimental method

2-1. experimental material

Testosterone propionate was purchased from Wako Chemicals (Chuo-Ku, Osaka, Japan), and melittin was obtained from Carbosynth Ltd. (Berkshire, UK). Saw palmetto used as a positive control material was 100% saw palmetto fruit extract purchased from Chong Kun Dang Health (Dangjin, Chungcheongnam-do, Korea). and other reagents were purchased from Sigma Aldrich (St. Louis, MO, USA).

2-2. Dosage and dosage

Testosterone propionate was dissolved in corn oil: EtOH (9:1), and BPH was induced by subcutaneous injection once a day for 4 weeks at a concentration of 10 mg/kg in the BPH group, Saw group, and Mel group except for the control group.

Saw palmetto was dissolved in water and administered orally at 100 mg/kg once a day for 4 weeks, and melittin was dissolved in water and administered intraperitoneally at 0.1 and 0.2 mg/kg once a day.

2-3. statistical analysis

Data are presented as mean ± standard deviation (SD) of the experimental population. Statistical significance was determined using ANOVA and Dunnett's post hoc test, and a P value of 0.05 or less was considered statistically significant.

3. Experimental results

3-1. Effect of melittin on enlarged prostate

In the BPH group, which induced an enlarged prostate, compared to the control group, the prostate became enlarged and red blood vessels were confirmed.

On the other hand, as in the Saw group to which the positive control drug saw palmetto was administered, it was visually confirmed that the size of the prostate and the red light were reduced in the Mel group administered with melittin compared to the BPH group (see FIG. 1).

1 shows the effect of melittin on prostate hypertrophy in BPH-induced rat models. Representative pictures of the prostate in each group were provided.

3-2. Effect of melittin on prostate weight

In the case of the BPH group induced by prostate enlargement, it can be seen that the prostate weight increased significantly compared to the control group.

On the other hand, the Saw group administered with saw palmetto, a positive control drug, and the Mel group administered with melittin showed a significant decrease in prostate weight compared to the BPH group (see FIG. 2).

Figure 2 shows the effect of melittin on prostate weight in BPH-induced rat models. Changes in the total prostate weight of rats and the relative prostate weight ratio were estimated for the control group, HPH group, Saw group, and Mel group. As described above, data are expressed as mean ± standard deviation (SD) (n = 10) of the experimental population. ###P < 0.001 vs control group and ***P < 0.001 vs BPH group. Statistical significance between treated groups was determined using ANOVA and Dunnett's post hoc test.

3-3. melittin prostate per body weight weight ratio ( PW /BW) to impact

In the BPH group, the PW/BW ratio was 4.89, which was significantly increased compared to the control group.

However, in the Saw group and the Mel 0.1 and 0.2 groups, the prostate weight-to-body weight ratio (PW/BW) was significantly decreased compared to the BPH group to 3.05, 2.90, and 2.45, respectively (see FIG. 3 ).

3 shows the effect of melittin on the prostate weight to body weight ratio (PW/BW) in BPH-induced rat models. Prostate weight per body weight (PW/BW) ratio was estimated for the control group, HPH group, Saw group, and Mel group. As described above, data are expressed as mean ± standard deviation (SD) (n = 10) of the experimental population. ###P < 0.001 vs control group and ***P < 0.001 vs BPH group. Statistical significance between treated groups was determined using ANOVA and Dunnett's post hoc test.

The Mel group administered with melittin reduced prostate size, reduced red light, decreased prostate weight, and had a low prostate weight-to-weight ratio (PW/BW). It has been confirmed that the pharmaceutical composition for use can improve prostatic hyperplasia.

The above results indicate that a composition containing melittin as an active ingredient can be used as a composition for preventing or treating benign prostatic hyperplasia.

Although the embodiments have been described with reference to the drawings, the present invention is not limited thereto, and the above description is merely illustrative of the technical idea of the present invention, and those of ordinary skill in the art to which the present invention pertains. Various modifications and variations will be possible without departing from the essential characteristics of the invention. Accordingly, the embodiments disclosed in the present invention are not intended to limit the technical spirit of the present invention, but to explain, and the scope of the technical spirit of the present invention is not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all technical ideas within the scope equivalent thereto should be construed as being included in the scope of the present invention.

Claims (6)

delete delete A composition containing melittin as an active ingredient,
The composition is
With the melittin, lactose, saccharose (Saccharose), sorbitol (Sorbitol), mannitol (Mannitol), starch, amylopectin (Amylopectin), cellulose (Cellulose) or gelatin (Gelatin) at least one binder; excipients of dicalcium phosphate; a disintegrant of corn starch or sweet potato starch; It is formulated in a dosage form for oral administration, including a lubricant of at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax,
orally administered at 0.1 to 0.2 mg/kg,
A pharmaceutical composition for the prevention or treatment of benign prostatic hyperplasia, indicating a decrease in the weight of the prostate. delete delete delete

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