KR20230116192A - Composition for Prevention or Treatment of Prostatic Desease Comprising Artemisia fukudo Makino Extract - Google Patents

Abstract

The present invention relates to a composition with excellent efficacy in preventing or treating/improving symptoms of prostate disease derived from natural products, which does not cause side effects or drug resistance of conventional therapeutic agents and has low toxicity and can be administered for a long period of time. It relates to a composition for preventing or treating/improving symptoms of a prostate disease selected from the group consisting of prostate cancer, prostatic hyperplasia and prostatitis, characterized in that it contains as an active ingredient.

Description

Composition for prevention or treatment of prostate disease containing an extract of Prostatic Desease {Composition for Prevention or Treatment of Prostatic Desease Comprising Artemisia fukudo Makino Extract}

The present invention relates to a composition with excellent efficacy in preventing or treating/improving symptoms of prostate disease derived from natural products that does not cause side effects or drug resistance of conventional therapeutic agents and has low toxicity and can be administered for a long period of time.

The prostate is an accessory gonadal gland composed of glandular tissue and fibromuscular tissue located below the bladder and surrounding the urethra. It produces and secretes semen and serves to block urinary tract infections. From birth to puberty, the size of the prostate does not change, but as the age increases after puberty, the size gradually increases due to the action of male hormones. The prostatic fluid produced in the prostate gland supplies nutrients to the sperm that have moved from the testis, and helps the sperm to move actively by maintaining a liquid state so that the ejaculated semen does not harden. Representative prostate-related diseases include prostatic hyperplasia, which mainly occurs after the age of 50, and prostatitis and prostate cancer, which mainly occur in the younger age group before the age of 40.

Benign prostatic hyperplasia (BPH) is a disease that causes various symptoms such as dysuria by compressing the urethra due to abnormal growth of the prostate around the urethra. In general, the size of the prostate in adults is about 20g, but when the prostate enlarges and grows to an abnormal size of 40-400g, it presses on the nearby urinary tract and causes urinary frequency of urinating more than 8 times a day, nocturia, and strong and sudden urge to urinate. If you have a urge to urinate while urinating, symptoms of bladder storage symptoms such as unbearable urgency, symptoms of bladder discharge disorders such as delayed urine in which urine comes out only when you urinate, interrupted urine in which urine flow is interrupted, and a phenomenon in which you have to apply force during urination appear. do. Although the cause of the disease has not yet been clearly identified, it is accepted that physical aging and changes in male hormones affect it. When testosterone is excessively present in the blood, a large amount of dihydrotestosterone (DHT) is synthesized by 5-alpha reductase present in prostate tissue. It binds to the androgen receptor and induces the growth of the cytoplasm of the epithelium and stroma.

According to the National Health Insurance Corporation's analysis of health insurance big data for the past six years (2012-2017), as of 2017, the number of people who received treatment for benign prostatic hyperplasia accounted for 5.1% of the total number of health insurance patients, which is one of the most common diseases among adult males. One. Prostatic hyperplasia is commonly said to be 50% in the 50s, 60% in the 60s, 70% in the 70s, and 80% in the 80s. It is also an increasing trend. According to the Health Insurance Review and Assessment Service, the number of patients in their 20s who visited the hospital for enlarged prostate increased by 61% from 1,822 in 2015 to 2,942 in 2019, and the number of patients in their 30s increased by 27% from 10,438 to 13,257, increasing the number of patients in their 50s to 12 % and 26% in their 60s.

Patients with prostatic hyperplasia do not require surgical treatment unless there is urinary tract obstruction or other complications, but about 50% of patients up to the age of 80 require treatment. Prostatic hyperplasia is not a fatal disease in itself, but it deteriorates the quality of life. In addition, if left untreated without proper treatment, it can cause various stones in the kidneys, cause urinary tract infection due to persistent residual urine in the bladder, and in severe cases, urinary tract sepsis, which can affect life support. In addition, in that some patients with BPH are related to prostate cancer, it has emerged as an important medical problem in the current society entering a super-aged society.

The treatment method for benign prostatic hyperplasia was performed mostly through surgery in the early days, but since the late 1980s, it has rapidly changed to a drug administration method. Alpha-adrenergic antagonists such as terazosin, doxazosin, and tamsulosin improve symptoms immediately after taking them, but they are drugs for symptom improvement rather than treatment. 5-α reductase inhibitors such as finasteride and dutasteride need to be taken for at least 6 months to see the response, and reduce libido and sexual function, and when administered to patients with high-grade prostate cancer There is a problem with increasing risk. As such, drugs used in the treatment of conventional prostate diseases exhibit many side effects and have limitations in their efficacy. Recently, various drugs extracted from natural products have been developed and used, but they have not yet been widely recognized. Therefore, it is necessary to develop a new therapeutic agent having excellent therapeutic effect without causing side effects or drug resistance.

Prostatitis is a disease in which the prostate is inflamed, and it is a disease so common that about 50% of adult men experience symptoms at least once during their lifetime. According to the statistics of the Health Insurance Review and Assessment Service, 260,000 people in 2016 and 270,000 people in 2019 are constantly increasing to the extent that they visit hospitals for prostatitis. Bacterial prostatitis caused by infection accounts for only 5-10% of prostatitis, and chronic non-bacterial prostatitis accounts for most of it. Bacterial prostatitis is most often caused by direct infection of bacteria through the urethra during urinary tract infections, and in addition, it can be caused by impaired excretion of prostatic fluid, urinary reflux into the prostate, and transmission of inflammation such as hemorrhoids or colitis. . Chronic nonbacterial prostatitis is considered to be caused by improper lifestyle habits such as excessive drinking, smoking, overwork, and stress, or continuous stimulation to the prostate, such as sitting for a long time or riding a bicycle.

Prostate cancer is the most common male cancer in Western countries and shows a high incidence, and its frequency is rapidly increasing in Korea as well. The treatment of prostate cancer differs depending on the stage of disease progression. In the case of local cancer, treatment is aimed at fundamental treatment, but in the case of metastatic cancer, systemic treatment is performed. For the treatment of localized prostate cancer, waiting therapy, radical prostatectomy, and radiation therapy can be selected in consideration of the patient's age, health status, sexual function status, tumor stage and differentiation, and patient preference. Metastatic prostate cancer can be treated with hormone therapy or chemotherapy.

Since prostatitis or prostate cancer as described above is also related to androgen, which is a male hormone, anti-androgen drugs that inhibit the expression of androgen receptors can treat and prevent diseases or relieve symptoms.

Artemisia fukudo Makino is a biennial plant belonging to the Asteraceae family and is a kind of salt plant that grows in groups in tidal flats on the seashore or in places submerged in seawater at high tide. Salt plants, unlike glycophytes, have salt tolerance in response to salt stress caused by high concentrations of salt. To do this, the salt is discharged out of the body through the salt line, and after the water evaporates, the salt remaining on the leaf surface is removed by blowing it off with the wind or melting it in the rain. In addition, organic substances having osmotic resistance, such as amino acids, sugars, and onium compounds, are accumulated in high concentrations in cells, and thus water can be absorbed even in a high-salinity environment. In the past, it was regarded as a 'weed on the beach', but recently, as the benefits of salt plants are known, it is emerging as a research theme in various industries. In particular, because these halophytes grow in various ways on the coast of Jeju, they are highly regarded for their potential as future marine resources. Anti-inflammatory activity and antimicrobial activity are known for Prosperm wormwood, but not much research has been done on other applications.

Registered Patent No. 10-1652073 Registered Patent No. 10-1733477 Registered Patent No. 10-1688018 Registered Patent No. 10-1141965

An object of the present invention is to provide a novel composition effective for preventing and treating/improving symptoms of prostate disease in order to solve the problems of the prior art as described above.

In addition, an object of the present invention is to provide a composition for preventing and treating/improving symptoms of prostate disease that is non-toxic and can be safely used without side effects or drug resistance.

Another object of the present invention is to provide a new way to utilize Sagebrush, a salt plant that is expected as a future marine resource.

The present invention for achieving the above object relates to a pharmaceutical composition for preventing or treating prostate diseases selected from the group consisting of prostate cancer, prostatic hyperplasia and prostatitis, characterized in that it contains an extract of Artemisia japonica as an active ingredient. Hereinafter, in describing the invention, if it is determined that a detailed description of a known technology related to the invention may unnecessarily obscure the subject matter of the invention, the detailed description will be omitted.

In the expression measurement of androgen receptor (AR), 5-alpha reductase, and prostate-specific antigen (PSA) using LNCaP cells, a prostate cancer cell line commonly used as an experimental model for prostate disease, the extract of Artemisia japonica was used to measure their expression at dose. It was shown to be effective in the prevention and treatment of prostate disease by inhibiting it dependently and effectively. In the present invention, the prostate disease is a disease affected by male hormones and may be prostate cancer, benign prostatic hyperplasia or prostatitis.

The extract of Prophet Artemisia of the present invention includes all forms in which useful components of Prophet Artemisia are concentrated. Most simply, the Argentine wormwood extract may be a dry substance or dry powder from which the water is removed from the Argentine wormwood. Alternatively, it can be prepared by extracting living things or dried products of Spiraea sagebrush using one or a mixture of two or more of C1-C4 lower alcohol and water as a solvent or applying a supercritical extraction method. Extraction may be performed by simply immersing in a solvent at room temperature, but extraction may be performed using ultrasonic waves or heating and stirring to increase extraction efficiency in a short time. It can also be extracted by crushing or grinding it into small pieces to make the extraction more efficient. The amount of solvent at the time of the extraction may be used in a volume ratio of 2 to 50 times the weight of the large mugwort. Since the extraction efficiency increases as the amount of the solvent increases, it is not a problem to use more than 50 times the solvent, but considering the efficiency and economics of the process, the amount of the solvent is preferably 50 times or less. In addition, in order to increase the extraction efficiency while using the same amount of solvent, it is recommended to increase the number of extractions.

The present invention also relates to a pharmaceutical composition for improving dysuria due to benign prostatic hyperplasia, characterized in that it contains an extract of Artemisia japonica as an active ingredient. The composition of the present invention has excellent 5-alpha reductase inhibitory effect, induces prostatic epithelium and prostatic cytoplasmic growth, and inhibits the synthesis of dihydrotestosterone, which thickens the prostate, thereby effectively reducing the size of the prostate and reducing pressure on the urethra. Because it alleviates, it can effectively improve urination disorders.

In order to use the pharmaceutical composition containing the extract of Artemisia japonica of the present invention as an active ingredient as a drug for treatment, it itself or a pharmaceutically acceptable carrier, excipient, It may be used in combination with a diluent or the like. The composition of the present invention can be formulated into a preparation for oral or parenteral administration and used as an agent for the treatment and prevention of prostate diseases. In addition, the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and when administered in combination with other therapeutic agents, it may be administered sequentially or simultaneously. The dosage of the active ingredient according to the present invention is the minimum amount without side effects in consideration of the route of administration, the form of the preparation, the absorption of the active ingredient in the sexual body, the age and weight of the patient, and the severity of the specific disease or pathological condition to be treated. It can be appropriately selected by those skilled in the art to obtain the maximum effect, and administration may be administered once a day or divided into several times. A typical dosage is 0.001 mg/kg·day to 10 g/kg·day.

In addition, the present invention provides a health functional food composition for preventing and improving symptoms of prostate disease, comprising an extract of Prodigal Artemisia as an active ingredient. The extract of Artemisia japonica may be added to the health functional food of the present invention in an amount of preferably 0.01 to 100% by weight. The health functional food of the present invention includes forms such as tablets, capsules, pills or liquids, and foods to which the composition of the present invention can be added include, for example, various foods, beverages, gum, tea, and vitamin complexes. , health functional foods, etc.

As described above, the artemisia extract of the present invention inhibits the expression of androgen receptor, 5-alpha reductase, and prostate-specific antigen, and thus can be effectively used for prevention and treatment/improvement of symptoms of prostate disease.

In addition, the composition of the present invention is made of natural materials and can be safely used without worrying about toxicity or side effects, and it provides a use that can be used as a pharmaceutical or health functional food composition with high added value, which was considered as a weed on the beach. can provide a new source of income for them.

Figure 1 is a Western blot result image showing that the artemisia extract inhibits the expression of AR, 5AR2 and PSA in LNCap cells.
Figure 2 is a graph showing that the Artemisia extract inhibits the expression of AR, 5AR2 and PSA in LNCap cells.

Hereinafter, the present invention will be described in more detail with reference to the attached examples. However, these embodiments are only examples for easily explaining the content and scope of the technical idea of the present invention, and thereby the technical scope of the present invention is not limited or changed. It will be obvious to those skilled in the art that various modifications and changes are possible within the scope of the technical spirit of the present invention based on these examples.

[Example]

Example 1: Preparation of Artemisia extract

Artemisia extract was used after receiving distribution (NP60200014) from the Marine Life Resources Bank. The method for preparing the extract is briefly as follows; The samples collected from Namyang-myeon, Goheung-gun, Jeollanam-do, South Korea, were washed with water, freeze-dried, and pulverized. 1 L of 70% EtOH was added to 100 g of the pulverized sample and ultrasonic extraction was performed for 7 hours. The extract was filtered with a filter paper to remove insoluble matter, and then the solvent was removed using a rotary vacuum concentrator. The solvent-free extract was dissolved in distilled water and lyophilized to obtain 11.37 g of the extract. The actual yield of the extract is 22.74. The extract was stored frozen and used.

Example 2: Efficacy evaluation of Artemisia in LNCaP cells

According to the following experiment, the effect of the extract on the expression of androgen receptor (AR), 5α-reductase (5AR, 5α-reductase) and prostate specific antigen (PSA), which are biomarkers related to prostate disease effect was confirmed.

LNCaP cells (ATCC, USA), a male hormone-dependent human prostate cancer cell line, were plated in a 6-well plate at a concentration of 5 × 10 ⁵ cell/well and supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptoprotein. It was cultured at 37°C for 15 hours in a medium containing mycin. The cultured cells were treated with 1 nM of testosterone (TP, Testosterone Propionate; TCI, Japan) and the extract (S26) at a concentration of 50, 100 or 200 μg/ml and cultured for an additional 72 hours and then harvested. As a negative control group, only 1 μM of testosterone was treated without treatment with the extract of artemisia japonica, and as a positive control group, 10 μM of finasteride (Fina, Finasteride), a representative prostatic hyperplasia treatment, was treated with 1 μM of testosterone instead of the extract of artemisia chinensis. The untreated group was referred to as the normal group (Control).

Cells harvested after culture are treated with RIPA buffer (50 mM Tris-HCl, pH 8.0, with 150 mM sodium chloride, 1% NP-40, 0.5% sodium deoxycholate, and 0.1% sodium dodecyl sulfate, with a protease inhibitor cocktail) and centrifuged at 12,000 rpm for 20 minutes to separate proteins. The separated protein was quantified by the Bicinchoninic acid (BCA) method.

30 μg of the quantified protein was processed on SDS-PEGE gel, electrophoresis was performed, and the protein was transferred to a PVDF membrane. Then, the PVDF membrane was reacted with 5% skim milk for about 1 hour to remove non-specific binding proteins on the surface, and the primary antibodies AR, 5AR2 (type 5α-reductase), PSA, and β-actin were added at 1:1000, respectively. , 1:1000, 1:5000 and reacted at 4 ℃ for one day. Then, the secondary antibody (Anti-goat; 1: 5000, Santacruz, CA, USA, Anti-Rabbit, 1:5000, Abfrontier, Seoul, Korea) was treated at room temperature for 1 hour, and AR, 5AR2 using ECL kit , the expression of PSA and PCNA proteins was confirmed.

Figure 1 is an electrophoresis image showing Western blotting results for the biomarker proteins, and Figure 2 is a graph showing the expression level of each protein in each experimental group. From Figures 1 and 2, the extract of Artemisia japonica inhibited the expression of AR, 5AR2 and PSA in a dose-dependent manner, and in particular, the expression inhibitory effect of 5α-reductase was excellent. The extract of Artemisia exhibited similar (PSA and AR) or significantly superior (5AR2) inhibitory efficacy to that of the control group, finasteride, even when treated at a concentration of 50 μg/ml.

Claims (7)

A pharmaceutical composition for preventing or treating prostate diseases selected from the group consisting of prostate cancer, benign prostatic hyperplasia and prostatitis, characterized in that it contains an extract of Artemisia japonica as an active ingredient.
The method of claim 1,
The pharmaceutical composition, characterized in that the dried artemisia extract is a dried product or dry powder of the artemisia.
The method of claim 1,
The pharmaceutical composition, characterized in that the extraction of the extract of artemisia japonica using one or a mixture of two or more selected from the group consisting of water and C1 ~ C4 lower alcohol as a solvent.
The method according to any one of claims 1 to 3,
The pharmaceutical composition, characterized in that the extract of Artemisia japonica inhibits the expression of androgen receptor, 5-alpha reductase or prostate-specific antigen protein.
The method according to any one of claims 1 to 3,
The pharmaceutical composition, characterized in that the extract of Artemisia japonica reduces the content of dihydrotestosterone in the blood.
A pharmaceutical composition for improving dysuria due to benign prostatic hyperplasia, characterized in that it contains an extract of Artemisia japonica as an active ingredient.
A health functional food composition for preventing or improving symptoms of prostate disease selected from the group consisting of prostate cancer, prostatic hyperplasia and prostatitis, characterized in that it contains an extract of Artemisia japonica as an active ingredient.