JP2003518502A - Pharmaceutical composition containing pectin effective for suppressing male reproductive toxicity - Google Patents

Abstract

  (57) [Summary] The present invention relates to a pharmaceutical composition containing pectin which is effective for suppressing male reproductive toxicity. The pharmaceutical composition is usually orally administered in a therapeutically effective amount of 1 μg to 1000 mg of pectin per 1 kg of body weight of a subject, and male spermatozoa induced by environmental hormones including dioxin, hypospermia, It can be used as a prophylactic or therapeutic agent for prostate atrophy and male infertility.

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to a pectin-containing pharmaceutical composition for suppressing or preventing male reproductive toxicity.

BACKGROUND ART Recently, an endocrine-disordering substance called an endocrine system, which has been recently announced in the United States, Europe, Japan and the like and has been attracting attention, interferes with the function of the endocrine system and is invaded into the body to cause hormones. It is a chemical substance that acts similar to. As substances that induce endocrine disorders, various industrial chemicals, pesticides such as insecticides and herbicides, organic heavy metals, dioxins in incinerators, hormonal analogues such as phytoestrogens, Examples thereof include synthetic estrogens used as medicines such as DES (diethylstilbestrol) and other foods and food additives. Of these, the most noticeable substances are:
There are dioxins.

Dioxin is a kind of organic chemical compound in which two oxygen atoms are chemically bonded to two benzene rings, and usually dioxin chloride in which hydrogen in the benzene ring is replaced with chlorine. There are dozens of species depending on the number and position of this chlorine. The most toxic and stable of these dioxins are
2,3,7,8-TCDD (tetrachlorodibenzo-, substituted with 4 chlorines)
p-dioxin). This dioxin is generated during the incineration process of household waste and the softening process of gasoline, and is easily released to the environment, which is even more dangerous (see:
S. Alex. Villalobos, Michael J Andeerson, and Peter kelley, 1996. "Dioxi
nlike Properties of a Trichloroethylene Combustion-Generated Aerosol, "E
nvironmental Health Perspectives, 104. p.734-743).

Dioxins are mainly absorbed through the digestive tract, skin, respiratory organs, etc., and the degree of absorption depends on species, solvent, dioxin homologues and isomers. It depends on the substance type, dose and age. The absorbed dioxins are characterized in that they are mainly accumulated in the liver and adipose tissue and are hardly excreted from the body.

The toxicity of dioxin has been clarified in animal experiments, and it has been reported that dioxin causes skin diseases, liver toxicity, carcinogenicity, malformation, etc. even in a very small amount. In addition, recently, the toxicity of dioxin has been confirmed from the results of human experiments. Typical examples are imbalance of hormone secretion, decreased fertility and malformation of reproductive organs, growth inhibition, cancer induction, and inhibition of immune function. In particular, based on these experiments, well-known examples of male fertility loss include decreased sperm count, decreased sperm, decreased testosterone concentration, decreased sperm motility, and altered sperm count. increase,
These include genital malformations, prostate disease, and other reproductive-related tissue abnormalities.

[0006] Although research on toxicity of environmental hormones has been actively conducted, research on preventive agents and therapeutic agents for toxicity of environmental hormones has not been sufficiently conducted. At present, green tea extract (including epicatechin and epigallocatechin as active ingredients), ginseng extract, etc. are known to have an effect of suppressing the reduction of fertility due to dioxin. In an experiment in which ginseng was administered to guinea pigs, it was confirmed that the decrease in the weight of the testes, the size of the seminiferous tubules, the destruction of the germinal epithelium, the deformation of germ cells, etc., were significantly suppressed by the administration of TCDD. (Reference: W.Kim, S.Hwang, H.Song, and S.Ki
m, "Panax Ginseng Protect the Testis against 2,3,7,8-Tetrachlorodibenzo-
p-dioxin Induced Testicular Damage in Guinea Pigs, "BJU International 19
99: 83: 842-849).

[0007] At present, there is no disclosure in any document or patent regarding the use of pectin to suppress the male reproductive toxicity induced by environmental hormones. However, U.S. Pat. Nos. 5,834,442 and 5,895,784 disclose a method of orally administering pH-modified citrus pectin to a subject to suppress early tumor metastasis. ing. Further, WO9710727 discloses a method of reducing the separation of serum with an aqueous vehicle containing pectin by using an enzyme. Further, WO9631239 discloses a drug consisting of a mixture of pectin and phospholipid, which is used for the prevention and treatment of diarrhea and gastric ulcer in mammals.

(Disclosure of the Invention) As a result of repeated studies, the present applicant has found that pectin has an effect of suppressing male reproductive toxicity due to environmental hormones such as dioxin. Pectin is abundantly contained in the primary cell wall and intermediate lamella of plants, and its main physiological functions are to connect and protect cell structures and affect water retention. Pectin consists of a partial methyl ester of the acid of a polysaccharide and its sodium, potassium, calcium, ammonium salts. The methyl ester group, which is closely related to the functionality of pectin, is easily hydrolyzed by alkali and has various functions depending on its degree. Generally, pectin is easily hydrated, has a strong hygroscopic property, and forms a hydrocolloid solution with water, and has a high viscosity in appearance.

Currently, pectin is applied to various industrial fields such as confectionery, food additives, dairy processed foods, and cosmetics, and what is particularly noteworthy is the application to the medical field. Pectin is recognized as one of high-efficiency preventive foods having various therapeutic capabilities.

[0010] The clarified efficacy includes, first, the efficacy of preventing poisoning by heavy metals or radioactive metals. As a result of research, pectin has excellent complexing ability with heavy metals such as lead, mercury, cadmium, molybdenum, and manganese, and radioactive metals such as cobalt, strontium, cesium, zirconium, and ruthenium. It was revealed that it has an excellent effect on the prevention of and the long-term metal accumulation process in the body.

[0011] Furthermore, the number of cholesterol in serum is lowered, the interlocking movement of the internal organs is promoted to eliminate constipation, and it is also effective for lowering blood glucose level, weight loss and treatment of gastrointestinal disease of diabetic patients. . The efficacy of such pectin has been clarified by experiments, and is currently used for these indications, and studies of other potential applications are also underway.

Examples of pectin usable in the present invention include, but are not limited to, pectin extracted from citrus fruits, lemons, oranges, apples, and the like. Of these, it is preferable to use pectin extracted from citrus fruits. The general chemical formula of citrus pectin is as follows.

[0013]

[Chemical 1] GaLP-galactopyranose GaLUA-galacturonic acid L-Rhap-L-rhamnopyranose L-Araf-L-aravafuranose

The term “medical pectin” as used in the present application is a term that is distinguished from general lower pectins, and hereinafter, particularly, the degree of esterification (the organic acid group of pectin is methyl esterified) Pectin having a degree of treatment of 50 or less. However, the use of the present invention (that is, suppression of male reproductive toxicity) is not limited only by the medical pectin.

The pectin used in the present invention can be produced by the production method presented in Korean Patent Application No. 10-1999-45200 (filed on Oct. 19, 1999), which is a prior application of the present applicant. it can. That is, citrus fruits, apples, oranges, lemons and the like are dried, finely chopped, hydrolyzed and extracted, concentrated and dried with a membrane filter to produce pectin.
The method also includes a purification step in which the obtained pectin is treated with an alkali and an acid in this order, and water is removed with alcohol.

The present invention can achieve an excellent effect of suppressing male reproductive toxicity due to environmental hormones such as dioxins by using high-purity medical pectin produced by such a method. it can.

As used herein, the term “male reproductive toxicity” refers to decreased sperm count, decreased sperm, decreased testosterone concentration, decreased sperm motility, and increased deformed sperm count. It is a widespread manifestation of decreased male fertility, including genital malformations, prostate disease, and other reproductive-related tissue abnormalities.

The present invention provides for a first purpose a pharmaceutical composition comprising pectin, preferably medical pectin. As a preferred embodiment of the present invention, there is provided a pharmaceutical composition containing pectin in an oral dosage form for suppressing male reproductive toxicity induced by environmental hormones. Thus, compositions containing pectin can be formulated in liquid solutions such as gels, solutions, suspensions, or in solid unit dosage forms such as compression purified or capsules. Methods for making both the solutions and solid unit dosage forms and excipients for making are well known in the art. Furthermore, dispersants, oiling agents, surfactants, flow regulators, preservatives, regulators, etc.
Within the scope of the invention they can be used together.

The Applicant has preferred that the pharmaceutical composition of the present invention is an oral dosage form, but nothing in this application should be construed as limiting its mode of administration. The present invention also contemplates combination therapy. That is, pectin can be co-administered with a component known to have a reproductive protection effect against environmental hormones (eg, ginseng extract, green tea extract, etc.). The pectin used in the composition of the present invention can be administered in any pharmaceutically acceptable carrier, preferably one that is non-toxic and compatible with the particular mode of administration,
It can be formulated for administration by methods known in the pharmaceutical art.

[0020] Pectin can be formulated in various other forms such as food products such as dietary supplements, additives, etc., in addition to the above-mentioned drug form formulation.

The oral dosage form is formulated so as to contain pectin in an amount sufficient to exert a suppressive effect on male reproductive toxicity induced by environmental hormones such as dioxin when administered to a subject. It should be. Therefore, the pharmaceutical composition of the present invention has an oral dose of 1 μg / kg body weight.
It can contain ~ 1000 mg of pectin. The therapeutically effective amount of pectin varies depending on the subject's age, sex, condition, diet characteristics, etc., and the optimal dose is
An appropriate amount is determined according to the intention of those skilled in the art. Here, the "therapeutically effective amount" means an amount effective for obtaining a predetermined result according to the present invention without excessive physiological adverse effects and side effects. Predetermined results are generally clinically observable reductions in accessory gonadal weight reduction, sperm motility reduction, sperm count reduction, and the like. In addition, the pectin can be administered in a single dosage form or a divided multiple dosage form.

BEST MODE FOR CARRYING OUT THE INVENTION The applicant carried out the following experiment in order to examine the effect of pectin on dioxin-induced reduction in male fertility. The following examples are for illustrative purposes, and the present invention is not limited thereto.

Example 1 Materials and Methods (1) Experimental Animal Five 4-week-old male SD rats (Sprague-Dawley rats) were treated as one group, and three groups were adapted to the laboratory environment for 5 weeks. It was used for the experiment at the age (110 to 120 g). (2) Experimental substance 2,3,7,8-tetrachlorodibenzo-p-dioxin (T
CDD) (NIH, USA) is dissolved in acetone and then diluted with corn oil,
It was intraperitoneally administered once at a concentration of 15 μg / kg. Pectin was dissolved in sterile distilled water and orally administered at 50 mg / kg daily. (3) Experimental group The experimental group was a group (A group) to which pectin was administered one week before the administration of TCDD,
It was composed of a group to which only TCDD was administered (group B) and a group to which only physiological saline was administered (control group). Figure 1 details these groups.

Analytical method and results (1) Weight of prostate and seminal vesicles Analytical method After separating the rat prostate and seminal vesicles, the bound adipose tissue was removed and the weight was measured. Results Prostate and seminal vesicle weights were divided by rat weight for comparison. The results for 10 rats in each group are as follows.

[0025]

[Table 1]

This is shown in detail in FIGS. 2 and 3. The proportion of prostate and seminal vesicles to body weight was significantly reduced in the group administered with TCDD compared with the control group, whereas it was confirmed that the seminal vesicles were recovered by 31.2% when pectin was administered. However, the prostate was unchanged.

(2) Sperm Motility Analysis Method 3 ml of HB preheated to 37.5 ° C. immediately after cutting the caudal epididymis on the right side
Put it in a 35 mm Petri dish containing SS (Hank's balanced salt solution),
A few wounds were made with a surgical knife (No. 15) avoiding blood vessels. The Petri dish was covered with a cover, gently shaken, and then pipetted a few times, and then one or two drops were dropped on a slide glass heated to 37.5 ° C. All 200 spermatozoa were observed under an optical microscope at a magnification of 100, and the percentage (%) of motile sperm was calculated. Results The proportion of motile spermatozoa among the 200 spermatozoa observed was as follows.

[0028]

[Table 2]

This is shown in detail in FIG. The administration of TCDD significantly reduced the sperm motility as compared to the control group, whereas the administration of pectin increased the motility by 40.5%, confirming the excellent protective effect.

(3) Sperm Count Analysis Method After peeling off the right testicle, weigh it, put it in a conical tube, and sterilized distilled water 2
0 ml was added. This was homogenized and then sonicated for 5 minutes. 2 ml of this was taken, 8 ml of sterilized distilled water was added, and the mixture was diluted 5-fold and then transferred to a hemocytometer. Then, it was counted with an optical microscope at a magnification of 400 times. The calculation formula is as follows. Sperm count x square coefficient x hemacytometer factor x dilution factor / testicle weight = sperm count x 1 x 104 x (20 x 5) / testicle weight result

[0031]

[Table 3]

This is shown in detail in FIG. The sperm count significantly decreased by the administration of TCDD was 21.
It increased by 3%, and an excellent protective effect was recognized.

TCDD is known as the most potent environmental hormone among dioxins, and also in this experiment, when administered to immature rats, a marked decrease in sperm count,
Decreased sperm motility and decreased weight of seminal vesicles and prostate were observed. On the other hand, pectin suppresses the function of TCDD as an environmental hormone,
Sperm count, sperm motility, seminal vesicles and prostate weight were restored. Therefore, it was confirmed that pectin has a protective effect against a decrease in male fertility due to environmental hormones such as dioxin.

As shown in the above Examples, pectin has no inhibitory or preventive effect on dioxin poisoning in reducing the weight of seminal vesicles and prostate, reducing sperm motility, and reducing sperm count. it is obvious. Therefore, pectin can be used as a preventive agent or therapeutic agent for the reduction of male fertility induced by environmental hormones such as dioxin.

[Brief description of drawings]

[Figure 1]   FIG. 1 is a graph showing the experimental group.

FIG. 2 is a graph showing the protective effect of pectin against male reproductive toxicity induced by TCDD by the weight of accessory gonads.

FIG. 3 is a graph showing the protective effect of pectin on male reproductive toxicity induced by TCDD by the weight of seminal vesicles.

FIG. 4 is a graph showing the protective effect of pectin on male reproductive toxicity induced by TCDD in sperm motility.

FIG. 5 is a graph showing the protective effect of pectin on male reproductive toxicity induced by TCDD in terms of sperm count.

─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Lee, Bon Woo             Republic of Korea, Kyungui 412-210, Koya             Nsi, Dokyang, Todan Dong, 90             -5, Yuil Apartment # 104 F term (reference) 4C086 AA01 AA02 EA25 MA01 MA04                       NA14 ZA81 ZC03

Claims (6)

[Claims] 1. A pharmaceutical composition for suppressing reproductive toxicity in a male, which comprises a therapeutically effective amount of pectin. 2. The pharmaceutical composition according to claim 1, wherein the therapeutically effective amount of the pectin is 1 μg to 1000 mg / kg body weight of the subject. 3. The pharmaceutical composition according to claim 1, which is orally administered. 4. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier. 5. The male reproductive toxicity includes decreased sperm count, decreased semen, decreased testosterone concentration, decreased sperm motility, increased deformed sperm count, genital malformation, prostate disease, and The pharmaceutical composition according to claim 1, further comprising a tissue abnormality associated with reproduction. 6. The pharmaceutical composition according to claim 1, further comprising another active ingredient having a male reproductive protection effect.