HK1062142B - The use of n-acetyl-d-glucosamine in the manufacture of a medicament for treating urogenital tract infections - Google Patents

Description

Application of N-acetyl-D-glucosamine in preparation of medicine for treating urogenital tract infection

The invention relates to the use of N-acetyl-D-glucosamine in the manufacture of a medicament for the treatment of urogenital infections.

Urogenital infections are a common condition. The disease is difficult to cure, and the normal life is greatly influenced. At present, medicaments for treating urogenital infection at home and abroad are mainly broad-spectrum antibacterial medicaments and Chinese medicinal lotions. The abuse of broad-spectrum antibacterial drugs causes urogenital infection microorganisms to generate drug resistance, so that the dosage of antibiotics is larger and larger, but the treatment effect is poorer and poorer; another problem is that conventional antibiotic therapy is inherently poorly effective, as is the case with the treatment of condyloma acuminatum virus. On the other hand, the traditional Chinese medicine lotion is used for treating urogenital tract infection, and has the main problems of insignificant effect, inconvenient use and clothes pollution. Thus, there is a continuing need in the art for agents effective in the treatment of urogenital infections.

In the process of researching the 'biological wave' theory, the inventor establishes a bacteria wave growth model. Research has recognized that this fluctuation has its intrinsic regulatory mechanism: some chemical substances are involved in the regulation of biological fluctuation process to transform pathological periodic slow wave into normal physiological chaotic fast wave, and the substances are called wave promoting factors. Through separation, purification and identification, a factor N-acetyl-D-glucosamine is determined, and the wave-promoting effect of the factor N-acetyl-D-glucosamine is related to the lubrication and protection effect of the factor N-acetyl-D-glucosamine on cells. Many biochemical and physiological processes of the human body require the participation of wave-promoting factors, and when such wave-promoting factors are deficient in the body, natural regulation of wave processes at various levels of organs, cells, and molecules accompanying vital activities cannot be normally performed, and abnormal behaviors are exhibited in terms of defense against invasion and elimination of foreign pathogens.

N-acetyl-D-glucosamine is a chemical agent, and is used for treating diseases such as periodontitis (WO9102530A1), inflammatory bowel disease (WO9953929A1), corneal disease (JP10287570A2), prostatic hypertrophy (US05116615), lower gastrointestinal mucosal organic lesions (WO93/14765) and the like, as well as a tissue growth regulator (WO 8702244), beauty treatment (JP59013708A2), a shampoo preparation (JP2011505A2) and the like in the successive nineties of the twentieth century, and the application of the N-acetyl-D-glucosamine in preparing a medicament for treating urogenital infection is unavailable at present.

The present inventors have now found that N-acetyl-D-glucosamine is effective in the treatment of urogenital infections, which is very unexpected because many combinations of controlling microbial infections, combating local exudation, eliminating tissue inflammatory edema and pain, and promoting tissue repair are needed to cure urogenital infections, and physicians must prescribe a combination therapy with various drugs to patients, whereas a drug containing N-acetyl-D-glucosamine alone as an active ingredient has been found to be effective in the treatment of urogenital infections.

Based on the above findings, the present invention relates to the use of N-acetyl-D-glucosamine and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of urogenital infections.

In another aspect, the invention relates to a method of treating urogenital infections comprising administering to a patient in need thereof a therapeutically effective amount of N-acetyl-D-glucosamine or a pharmaceutically acceptable salt thereof. N-acetyl-D-glucosamine is a compound having the following structure:

N-acetyl-D-glucosamine is commercially available or can be prepared by known methods. For example, patent application WO97/31121 discloses a process for the enzymatic preparation of N-acetyl-D-glucosamine from chitin. Japanese patent application JP63273493 discloses a process for hydrolyzing chitin partially to N-acetyl-chitosan oligosaccharide and then treating with an enzyme to obtain N-acetyl-D-glucosamine.

Among the pharmaceutically acceptable salts of N-acetyl-D-glucosamine, mention may be made of those formed with pharmaceutically acceptable acids, for example those formed with inorganic acids, such as hydrochloride, hydrobromide, borate, phosphate, sulfate, bisulfate and biphosphate, and those formed with organic acids, such as citrate, benzoate, ascorbate, methylsulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate, methanesulfonate, toluenesulfonate, isethionate, α -ketoglutarate, α -glycerophosphate and glucose-1-phosphate.

The compound of formula (I) or its pharmaceutically acceptable salt is used as main active ingredient, and combined with various pharmaceutically acceptable excipients or/and carriers to prepare topical preparations in forms of aqua, emulsion, cream, lotion, ointment, suppository, etc., for treating genitourinary tract infection. The active substance is used in an amount of 0.1-10%, preferably 0.2-6% of the total formulation. The daily dosage of the drug is 10-10000mg, preferably 50-5000mg, more preferably 100 mg and 2000mg of N-acetyl-D glucosamine per person.

The compositions of the present invention in topical application form may be prepared as solutions, emulsions, suspensions, cohesive gels, creams, ointments and the like, for topical application or topical cleansing, by mixing the active ingredient with one or more pharmaceutical carriers and additives, such as solubilizing agents for water, polyethylene glycols, glycerin, petrolatum, xanthan gum, alcohols and the like, lubricants, binders, preservatives, stabilizers and ecological modifiers for use in conjunction with topical ecological characteristics, such as lactic acid and the like, according to techniques well known to those skilled in the art. A propellant may also be added to make an aerosol for topical spraying. Spray formulations are exemplified by: 1% of N-acetyl-D glucosamine, 3% of lactic acid and 0.3% of sodium benzoate

Without wishing to be bound by any theory, the inventors believe that the efficacy of the compounds of formula (I) of the present invention in the treatment of urogenital infections is achieved by modulating the cellular redistribution in the body. Cell redistribution refers to the continuous replacement of the positions of tissue cells or microbial cells of an organism and the replacement of the rhythmic coagulation-dissolution state of intracellular biomacromolecules. N-acetyl-D-glucosamine exerts its particular effects by regulating the redistribution of cells at different levels. The alternation of macroscopic cell positions exhibits fluctuating growth characteristics. The N-acetyl-D-glucosamine can prevent the microorganisms from being planted locally by regulating the normal growth of organism cells and microorganism cells. In terms of micro-ecological efficacy, the growth of normal flora is mainly supported, and a method for supplementing ecological flora is not adopted, so that the problem of adaptability of planting conditions existing in supplemented flora is solved. The product has the unique characteristic of controlling inflammation, injury, infection and exudation in the aspect of promoting the repair of skin mucosal tissues. Can be widely applied to controlling symptoms and treating fundamental problems.

The following test examples serve to demonstrate the wave-promoting properties, low toxicity, antimicrobial colonization activity and clinical observation of the treatment of urogenital infections of the compounds of formula (I) of the present invention.

A wave acceleration test of a compound of formula (I)

1. Experimental materials and methods:

1.1. sample preparation: the compound of formula (I) is pure product.

1.2. Experimental materials:

strain: proteus mirabilis and lactobacillus.

Culture medium: modified LB culture medium (composition: 1% tryptone, 0.5% yeast extract, 1% sodium chloride, 0.1% glucose, 0.002% TTC, pH7.2-7.4).

1.3. The experimental method comprises the following steps:

inoculating proteus mirabilis in the center of an LB plate, culturing at 37 ℃ for 9 hours, and beginning to generate concentric rings which continuously expand outwards and are spaced for 3 hours, wherein the concentric rings are used as a reference; as a result of adding the compound of the formula (I) to LB plates to a final concentration of 0.5% and inoculating Proteus mirabilis at 37 ℃ and culturing, not only concentric rings appeared at 3-hour intervals were formed, but also a lot of fine fluctuations were observed in each ring as compared with the control.

The liquid culture result shows that the compound of the formula (I) can promote the growth of lactobacillus.

2. Experimental results and evaluation:

the experiment adopts a biological wave motion model to research the wave acceleration effect of the compound shown in the formula (I), and the result shows that the compound shown in the formula (I) can not only enable bacterial cells to show normal biological wave characteristics, but also enable the wave to show a finer wave motion mode, and shows that the compound shown in the formula (I) has the effect of promoting the biological wave motion, and the wave acceleration effect can participate in the repair and redistribution of skin cells.

Secondly, the toxicological test of the compound of formula (I) comprises:

1. acute toxicity test: including oral, intravenous and maximum-limit dosing tests;

ames test;

3. micronucleus test of mouse bone marrow cells;

4. a rat sperm teratogenicity test;

5. mouse testicular chromosomal aberration test;

6. chronic lethal trial;

7. subchronic toxicity (90 day feeding) test;

8. traditional teratogenesis tests;

the test result shows that: the acute toxicity test dose of the compound shown in the formula (I) exceeds 2g/kg, is 300 times of the injection dose of a human, and acute toxic reaction does not occur; in a long-term toxicity test, the highest dose reaches 1g/kg, and no toxic reaction is generated through four-week test observation; in a reproduction test, the compound shown in the formula (I) has no influence on the pregnancy, parturition, lactation and newborn mouse development of mice after three passages of feeding the mice with a conventional dose of 7mg/kg, and belongs to a nontoxic substance.

Third, test of antibacterial colonization

1. Anti-pseudomonas aeruginosa skin colonization test

2. Bacteriostasis test

The results of the two tests show that the compound of the formula (I) basically has no bactericidal and bacteriostatic effects, and pseudomonas aeruginosa can not be planted and grown through the effect of resisting planting, so that the aim of resisting infection is fulfilled.

Four clinical trials

1. 170 patients with various venereal diseases are selected, wherein 50 patients with gonorrhea, 50 patients with syphilis, 20 patients with condyloma acuminatum virus infection, 40 patients with trichomonas vaginalis infection, and 10 patients with candida albicans infection. The effect of the compound of formula (I) on the treatment of urogenital infections was determined by smear microscopy and isolation culture with a 2% N-acetyl-D-glucosamine spray applied topically to the infected area. The results show that the effective rate of N-acetyl-D-glucosamine on various urogenital tract infections is 79 percent, and the effective rate is shown in the following table:

observation of the therapeutic efficacy of N-acetyl-D-glucosamine formulations for the treatment of urogenital infections

Effective rate (%) inefficiency (%)

Gonorrhea infection 509010

Syphilis infection 506040

Condyloma acuminata virus infection 208020

Trichomonas vaginalis infection 407525

Candida albicans infection 109010

The invention opens up a new medical application of the N-acetyl-D-glucosamine which is different from the known application of the N-acetyl-D-glucosamine, expands the application range of the N-acetyl-D-glucosamine and improves the development value of the N-acetyl-D-glucosamine. The compound is used as an active substance to prepare external preparations in various preparation forms as urogenital infection prevention and treatment medicines, and has the advantages of convenient preparation and no toxic or side effect; because the medicine is a colorless, tasteless and non-irritant substance and has a new action way, the medicine not only has unique curative effect, but also avoids the defects of other products.

Claims (4)

1. Use of N-acetyl-D-glucosamine and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of urogenital infections.
2. 2. The use of claim 1, wherein the medicament is in the form of a topical formulation.
3. 3. Use according to claim 2, wherein the medicament is in the form of a lotion, aqueous, emulsion, cream, ointment, suppository.
4. 4. Use according to any one of claims 1 to 3, wherein the concentration of N-acetyl-D-glucosamine in the pharmaceutical formulation is between 0.1 and 10% by weight.