RU2288735C2 - Agent, method for its preparing and method for prophylaxis and treatment of small pelvis organs inflammatory disease and rectum disease - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to the development of a novel vegetable-base agent that can be used in treatment of inflammatory diseases of small pelvis organs and diseases of rectum. Agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum comprises long turmeric (Curcuma longa L.) rhizome dried extract standardized by curcumin, anesthetic agent and pharmaceutically acceptable excipients. Agent is made as a suppository and comprises benzocaine as an anesthetic agent and vitepsol and cacao butter as a suppository base. Method for preparing agent used in prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves mixing long turmeric dried extract standardized by curcumin with anesthetic agent and a pharmaceutically acceptable excipient. Method for prophylaxis and treatment of diseases of small pelvis organs and diseases of rectum involves using the proposed agent.

EFFECT: improved preparing agent, valuable medicinal properties of agent.

9 cl, 3 ex

Description

The invention relates to the creation of a new herbal remedy in the form of rectal suppositories for the prevention and treatment of inflammatory diseases of the pelvic organs and diseases of the rectum.

A number of chemicals are known for the treatment of cracks, fistulas, and other diseases of the anus and rectum: laxatives - bisacodyl (RLS, M., 2002, p. 155), guttalax (p. 266), slabilin (p. 769); anticoagulants - hepatrombin (p. 236); antiseptics - etonium (p. 1020); local anesthetics - benzocaine, etc.

However, these drugs have a narrow spectrum of pharmacological action.

The objective of the present invention is to provide a therapeutic and prophylactic complex agent in the form of rectal suppositories for the treatment of inflammatory diseases of the pelvic organs (prostatitis, vesiculitis, adnexitis, metritis, salpingo-oophoritis), moderate and mild hemorrhoids, proctitis, proctosigmoiditis and paraproctitis, as well as cracks, fistulas and tumors of the rectum.

The problem is solved by a group of inventions, united by a single inventive concept.

An agent is proposed for the prevention and treatment of inflammatory diseases of the pelvic organs and diseases of the rectum, containing dry extract of rhizome of long turmeric (Curcuma longa L.), standardized for curcumin, anesthetic and pharmaceutically acceptable excipients.

The tool is made in the form of a suppository.

The agent as anesthetic contains benzocaine.

The product contains dry extract of rhizome rhizomes long, standardized on curcumin, benzocaine and a suppository base with a ratio of 1 suppository weighing 1 g:

dry extract of turmeric rhizome long 25-100 mg benzocaine 25 mg suppository base rest.

As a suppository base, vitepsol or cocoa butter is used.

A method for the preparation of a prophylaxis and treatment of inflammatory diseases of the pelvic organs and diseases of the rectum is proposed, which consists in mixing dry extract of turmeric rhizome long, standardized for curcumin, with an anesthetic and a pharmaceutically acceptable excipient.

Also, a method for the prevention and treatment of inflammatory diseases of the pelvic organs and diseases of the rectum, including the use of the above funds.

The tool is used for the prevention and treatment of diseases of the pelvic organs - prostatitis, vesiculitis, adnexitis, metritis, salpingo-oophoritis.

The tool is also used for the prevention and treatment of hemorrhoids, prostatitis, proctosigmoiditis, paraproctitis, fissures, fistulas, tumors of the rectum.

Turmeric is long, K. homemade - Curcuma longa L., C. domestica Val. - perennial herb of the ginger family (Zingiberaceae). The aerial part of it consists of several oblong, long-basal basal leaves up to 1 m long. The inflorescence is spike-shaped, about 30 cm tall, densely planted with green, lighter stipules at the top, in the sinuses of which flowers develop in the middle part of the peduncle. The flowers are tubular, with a three-lobed, slightly irregular limb, yellow, the lip is wide, yellow. The root system is complex: a tuberous, almost rounded rhizome up to 4 cm in diameter, yellowish-gray, with ring scars from the leaves, gives the aerial part from the apical kidney; several lateral buds develop into underground, relatively short (about 3-10 cm long and 0.5-1 cm in diameter) cylindrical shoots. Turmeric fruits are very rare.

Long turmeric comes from East India and Vietnam.

Since time immemorial, it has been widely cultivated throughout tropical Asia.

Turmeric rhizomes are used for food and medical purposes. To speed up the ripening of the spices, the collected roots are boiled with boiling water before drying, destroying the cells with the coloring matter - curcumin. Curcumin, originally found in essential oil cells, evenly soaks the entire root during further fermentation. At the same time, the starch contained in the root is partially hydrolyzed and partially forms a colloid. When dried, the root impregnated with paste turns into a "stone" when it is dried, on the cut it shines like a horn, is very dense, drowns in water.

The most well-researched component of turmeric is curcumin (diferuloylmethane). Raw turmeric contains from 0.3 to 5.4% curcumin. Turmeric also contains 4-14% essential oil, including tumerone, atlantone, and zingiberone. These oils have medicinal properties and may be the primary active ingredient in turmeric under certain conditions. Turmeric also contains sugars (28% glucose, 12% arabinose), proteins and resins [Leung A. Encyclopedia of Common Natural Ingredients Used in Food, Drugs and Cosmetics. John Wiley & Sons, New York, NY 1980: 313-314, Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica 1991; 57: 1-7].

Curcumin is poorly absorbed by oral administration. It was found that it is much more active with parenteral administration than by mouth [Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica 1991; 57: 1-7]

Such a difference in action between enteral and parenteral administration may occur due to several factors. A study in animals showed that 40-75% of curcumin passes through the digestive system unchanged [Wahlstrom B., Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol 1978; 43: 86-92, Ravindranath V., Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicol 1980; 16: 259-265].

Most of what remains in the body is actively metabolized in the intestinal and liver mucosa [Shoba G., Joy D., Joseph T., et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356].

Only traces of curcumin were found in the blood after oral administration of a single, two-gram dose in humans and even larger doses in rats [Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica 1991; 57: 1-7, Shoba G., Joy D., Joseph T., et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356].

Oral absorption can be improved by concurrent administration of piperine (from black pepper). Piperine showed an increase in bioavailability of orally administered curcumin to 2% [Shoba G., Joy D., Joseph T., et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998; 64: 353-356.]. At the dosages used in this study, piperine increased the absorption, bioavailability and concentration of curcumin in serum in both rats and humans without side effects. Based on clinical experience, a typical recommended dose of curcumin is 400-600 mg three times a day.

Turmeric toxicity was found to be very low. No toxic reactions were detected with standard doses in either humans or animals. Neither mortality nor teratogenicity was detected when taking any dose of turmeric, its alcohol extracts or curcumin when studied in animals, including rats, mice, Guinea pigs and monkeys [Shankar TNB, Shantha NV, Ramesh NP, et al. Toxicity studies on turmeric (Curcuma longa): Acute toxicity studies in rats, guinea pigs, and monkeys. Indian J. Exp. Biol. 1980; 18: 86-92].

In an in vitro and in vivo study on animals, turmeric showed a hepatoprotective effect: however, there are no clinical trials in humans. Turmeric has been found to, like silymarin, protect the liver of animals from a variety of hepatotoxic substances, including carbon tetrachloride [Xiang ZX, He XQ, Zhou GF, et al. Protective effects of an ethanolic extract and essential oil of Curcuma kwangsinensis S. against experimental liver lesions in mice. Chung Kuo Chung Yao Tsa Chih 1989, 14: 303-305, 320. [Article in Chinese], Deshpande UR, Gadre SG, Raste AS, et al. Protective effect of turmeric (Curcuma longa L.) extract on carbon tetrachloride-induced liver damage in rats. Indian J. Exp. Biol. 1998; 36: 573-577], galactosamine [Kiso Y, Suzuki Y, Watanabe N, et al. Antihepatoxic principles of Curcuma longa rhizomes. Planta Med 1983, 49: 185-187], pentobarbitol, 1-chloro-2,4-dinitrobenzene, 7 4-hydroxy-nonenal [Piper JT, Singhal SS, Salameh MS, et al. Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver. Int J. Biochem. Cell Biol 1998; 30: 445-456] and acetaminophen (paracetamol) [Donatus IA, Sardjoko, Vermeulen NP. Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes. Biochem. Pharmacol 1990; 39: 1869-1875].

The hepatoprotective effect of turmeric is probably due to its powerful antioxidant effect. Turmeric contains several water- and fat-soluble antioxidant components, of which curcumin is considered the most active [Choiu JW, Wei HC, Chunk-Kuo. Preliminary study on the anti-oxidative components of some species grown in Taiwan. Nung Yeh Hua Hsuch Hui Chih 1983; 21: 97-103, Moken Y, Xianping D, Yaoshu T. Studies on the chemical constituents of common turmeric (Curcuma longa). Zhongcoayoa 1984; 15: 197-198]. The antioxidant properties of other turmeric substances are also significant. A heat-resistant protein was isolated from an aqueous extract of turmeric that turned out to be more effective against superoxides than curcumin and more effective in inhibiting oxidative DNA damage [Shalini VK, Srinivas L. Lipid peroxide induced DNA damage: Protection by turmeric (Curcuma longa). Mol. Cell. Biochem. 1987; 777: 3-10, Srinivas L, Shalini VK. DNA damage by smoke: Protection by turmeric and other inhibitors of ROS. Free Radical Biol Med 1991; 11: 277-283, Selvam R, Subramanian L, Gayathri R, et al. The anti-oxidant activity of turmeric (Curcuma longa). J. Ethnopharmacol. 1995; 47: 59-67].

When turmeric was added to the rat diet (one percent turmeric from the weight of food for 10 weeks), it was found that it significantly protects against iron-induced lipid peroxide formation. The activity of superoxide dismutase, catalase, and glutathione peroxidase was higher (about 19, 19, and 20%, respectively) in rat liver homogenates fed a diet containing turmeric compared to the control [Reddy AC, Lokesh BR. Effect of dietary turmeric (Curcuma longa) on iron-induced lipid peroxidation in the rat liver. Food Chem Toxicol 1994; 32: 279-283].

Compared to other known antioxidants, including butylate hydroxyanisole (butylated hydroxyanisole), butylate hydroxytoluene (butylated hydroxytoluene) and ellagic acid; turmeric extract and curcumin were more active in protecting against the action of aflatoxin B1 on rat liver [Soni KB, Lahiri M, Chackradeo P, et al. Protective effect of food additives on aflatoxin-induced mutagenicity and hepatocarcinogenicity. Cancer Lett, 1997; 115: 129-133].

It was also found that turmeric and curcumin completely repair aflatoxin-induced liver damage when ducklings are added to aflatoxin B1 (5 micrograms / day for 14 days). Fatty degeneration, necrosis and gallbladder hyperplasia caused by aflatoxin B1 were completely restored by curcumin [Soni KB, Rajan A, Kuttan R. Reversal of aflatoxin induced liver damage by turmeric and curcumin. Cancer Lett 1992; 66: 115-121].

In addition to its antioxidant effects, curcumin has also shown the ability to enhance the detoxification function of the liver by increasing the activity of glutathione S-transferase [Piper JT, Singhal SS, Salameh MS, et al. Mechanisms of anticarcinogenic properties of curcumin: the effect of curcumin on glutathione linked detoxification enzymes in rat liver. Int J. Biochem. Cell. Biol. 1998; 30: 445-456, Susan M, Rao MN. Induction of glutathione S-transferase activity by curcumin in mice. Arzneimittelforschung, 1992; 42: 962-964], an enzyme that binds glutathione with a large number of toxins, facilitating their removal from the body.

Essential oil and curcumin have shown potent anti-inflammatory effects [Chandra D, Gupta S. Anti-inflammatory and anti-arthritic activity of volatile oil of Curcuma longa (Haldi). Ind J Med Res 1972; 60: 138-142, Arora R, Basu N, Kapoor V, et al. Anti-inflammatory studies on Curcuma longa (turmeric). Ind J Med Res 1971; 59: 1289-1295, Mukhopadhyay A, Basu N, Ghatak N, et al. Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents Actions 1982, 12: 508-515.]. Orally administered curcumin has been shown to be as effective as cortisone or phenylbutazone in acute inflammation and half as weak as these drugs in chronic inflammation, but without side effects [Mukhopadhyay A, Basu N, Ghatak N, et al. Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents Actions 1982; 12: 508-515]. One of the mechanisms of the anti-inflammatory effect of curcumin is probably due to its ability to block the synthesis of pro-inflammatory arachidonic acid. Curcumin significantly inhibited the conversion of dihomo-gamma-linolenic acid to arachidonic acid in the fungus Mortierelle alpina and in rat liver microsomes ²⁴ .

Curcumin also has a choleretic effect. In rats, bile acid synthesis was increased by more than 100% after oral administration of curcumin [Shimizu S, Jareonkitmongkol S, Kawashima H, et al. Inhibitory effect of curcumin on fatty acid desaturation in Mortierella alpina 1S-4 and rat liver microsomes. Lipids 1992; 27: 509-512]. Curcumin also increased the synthesis of other bile elements, including cholesterol, bile salts, and bilirubin [Ramprasad C, Sirsi M. Curcuma longa and bile secretion - Quantitative changes in the bile constituents induced by sodium curcuminate. J Sci Indust Res 1957; 16C: 108-110].

Curcumin and its derivatives showed antitumor activity in in vitro tests [Kuttan R., Bhanumathy P., Nirmala K., George M.C. Potential anti-cancer activity of turmeric (Curcuma longa). Cancer Letters 1985; 29: 197-202], as well as in animals [Mesa M.D., Ramirez-Tortosa M.C., Aguilera C.M., Ramires-Bosca A. in Gil. A. Efectos farmacologicos in nutricionales de los extractos de Curcuma longa L. in de los curcuminoides. Ars Pharmaceutica 2000; 41: 3, 307-321].

An in vitro experiment found that different lines of cancer tumors differ in their sensitivity to curcumin. Cell lines taken from malignant tumors of leukemia, breast, large intestine, hepatocellular and ovarian carcinomas underwent decay (apoptosis) in the presence of curcumin, while lines of tumor cells of the lung, kidney, prostate, cervix, CNS tumors, and melanoma were resistant to cytostatic Curcumin [Khar A, Alt AM, Pardhasaradhi BV, Varalakshmi CH, Anjum R, Kumari AL. Induction of stress response renders human tumor cell lines resistant to curcumin-mediated apoptosis: role of reactive oxygen intermediates. Cell Stress Chaperones 2001; Vol.6 (4): 368-376]. In clinical trials in 15 patients with advanced stage of colon cancer, a high therapeutic activity of turmeric extract, equivalent to 180 mg of curcumin, taken orally was established [Sharma, RA, McLelland, HR, Hill, KA, Ireson, CR, Euden, SA, Manson, MM, Pirmohamed, M., Mamett, LJ, Gescher, AJ, and Steward, WP Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 2001; 7, 1894-1900].

Antimicrobial and antifungal action: curcumin sodium salt in vitro inhibits the growth of Micrococcus pyogenes var. aureus diluted 1: 1,000,000 [Selected medicinal plants in Vietnam / by edition prof. To Dang Hai // National Institute ofmateria medica Hanoi-Vietnam, Vol. I, 440 p. Vol. II, 460 p., 1999].

Turmeric essential oil inhibits Mycobacterium tuberculosis at a minimum concentration of at 1 g / ml, Bacillus mycoides and Candida albicans at a concentration of 1/160 and B. subtilis at 1/250. Turmeron, an essential oil component, inhibits in vitro growth of numerous bacteria and fungi (Mvcobactenum tuberculosis, Shigella dysenteriae, Bacillus mycoides. B subtilis, Proteus vulgaris).

Curcumin inhibits the in vitro growth of Mycobacterium tuberculosis at a minimum concentration of 25 g / ml. Salmonella paratyphi - 50 g / ml, Staphylococcus aureus - 50 g / ml [Selected medicinal plants in Vietnam / by edition prof. To Dang Hai // National Institute of materia medica Hanoi-Vietnam, Vol. I, 440 p. Vol. II, 460 p., 1999].

Curcumin has an antiulcer effect, suppressing Helicobacter pylori (Helicobacter pylori).

Curcumin, which is part of the rhizomes, reduces the level of bad cholesterol (low density lipoproteins) in the blood and normalizes the composition of bile.

Turmeric not only cleanses and improves blood circulation, but also stimulates the formation of red blood cells. This plant regulates the metabolism, adjusting both the redundancy and insufficiency of metabolic processes, and promotes the absorption of protein.

The immunomodulatory property of curcumin has been established. Under the influence of this substance, the total number of leukocytes and antibody-forming cells increases, and the phagocytic activity of macrophages also increases [Selected medicinal plants in Vietnam / by edition prof. To Dang Hai // National Institute ofmateria medica Hanoi-Vietnam, Vol. I, 440 p. Vol.II, 460 p., 1999, Mesa M.D., Ramirez-Tortosa M.C., Aguilera C.M., Ramires-Bosca A. in Gil. A. Efectos farmacologicos in nutricionales de los extractos de Curcuma longa L. in de los curcuminoides. Ars Pharmaceutica 2000; 41: 3, 307-321].

The invention is illustrated by the following examples.

The presented examples differ in that the curcumin content in children's candles is 25 mg and 50 mg, and in adults - 100 mg.

Example 1. To 925 g of molten fat base (cocoa butter or vitepsol), heated to a temperature of 40-45 ° C, add 50 g of dry extract of long turmeric rhizome containing 50% curcumin, 25 g of anesthetic (benzocaine), and mix thoroughly in a mixer until a uniform distribution of the substances in the base. The resulting candle mass is poured into a cooled mold for casting 1000 candles of 1 g each.

Example 2. To 875 g of a molten fat base (cocoa butter or vitepsol), heated to a temperature of 40-45 ° C, add 100 g of dry extract of rhizomes of long turmeric containing 50% curcumin, 25 g of anesthetic (benzocaine), and mix thoroughly in stirrer until the distribution of substances in the base is even. The resulting candle mass is poured into a cooled mold for casting 1000 candles of 1 g each.

Example 3. To 775 g of molten fat base (cocoa butter or vitepsol), heated to a temperature of 40-45 ° C, add 200 g of dry extract of rhizome of long turmeric containing 50% curcumin, 25 g of anesthetic (benzocaine), and mix thoroughly in stirrer until the distribution of substances in the base is even. The resulting candle mass is poured into a cooled mold for casting 1000 candles of 1 g each.

The resulting suppositories are orange in color, torpedo-shaped, with possible interspersed yellow.

Store in a dry, dark place at a temperature not exceeding 25 ° C. Shelf life: 2 years. After the expiration date, do not use the drug.

Contraindications:

- pregnancy;

- breast-feeding;

- children's age up to 1 year;

hypersensitivity to the components of the drug.

Clinical trials were conducted on volunteers.

Suppositories have been prescribed for adults and children with inflammatory diseases of the pelvic organs (prostatitis, vesiculitis, adnexitis, metritis, salpingoophoritis), moderate and mild hemorrhoids, proctitis, proctosigmoid and paraproctitis, as well as cracks, fistulas and tumors of the rectum).

Dosage and administration.

Before the introduction of the suppository, it is necessary to empty the intestines. Enter the suppository into the anus with a pointed end, as deep as possible. For a more convenient administration of the suppository, it is recommended to bend down, squat down or lie on your side, legs tightened. With careless handling, suppositories can leave orange stains on underwear.

Dosage regimen:

Adults are prescribed 1 suppository (100 mg) 2 times a day, in the morning and at night; maximum single dose - 200 mg; the maximum daily dose is 200 mg.

Children aged 1-7 years are prescribed 1 suppository (25 mg) 2 times a day, in the morning and at night; maximum single dose - 50 mg; the maximum daily dose is 50 mg.

Children aged 7-12 years are prescribed 1 suppository (50 mg) 2 times a day, in the morning and at night; maximum single dose - 100 mg; the maximum daily dose is 100 mg.

Children over 12 years of age are prescribed 1 suppository (100 mg) 2 times a day, in the morning and at night; maximum single dose - 200 mg; the maximum daily dose is 200 mg.

The duration of the drug treatment for inflammatory diseases is from 7 to 30 days, depending on the severity of the disease. With cancer, there are no restrictions on the duration of the drug.

Side effect: When applied according to indications in recommended doses, no side effects were detected.

Interaction with other drugs: with the simultaneous use of suppositories weaken the effect of chlorpromazine and barbiturates.

With increased sensitivity to the drug, irritation of the rectal mucosa is possible, in some cases pain in the rectal area.

The combined preparation for local use has a pronounced anti-inflammatory, antimicrobial, immunomodulatory, reparative, antioxidant, analgesic and antitumor effects.

The combination of turmeric extract with an anesthetic helps to achieve high results in the treatment of difficult diseases such as cracks, ulcers and fistulas of the anal canal. These diseases are difficult to treat with therapeutic treatment, since the pain symptom characteristic of these diseases causes spasm of the mouse of the rectum, disrupting the blood circulation of this organ and, thereby, preventing the healing of its injuries.

Due to the analgesic effect, anesthetic (benzocaine) present in suppositories leads to muscle relaxation and, as a result, to weakening of the peristalsis of the rectum and restoration of blood circulation. Due to this effect, the movement of feces in the colon is slowed down and the prolonged action of the second component of suppositories - curcumin is achieved. Curcumin has a strong anti-inflammatory and reparative effect on damaged tissues. This combination of pharmacological properties of the above components allows you to get a more effective therapeutic effect in comparison with monotherapy with a similar purpose.

Claims (9)

1. An agent for the prevention and treatment of inflammatory diseases of the pelvic organs and diseases of the rectum, characterized in that it contains a dry extract of rhizomes of long turmeric (Curcuma longa L.), standardized for curcumin, anesthetic and pharmaceutically acceptable excipients. 2. The tool according to claim 1, made in the form of a suppository. 3. The tool according to claim 1, as anesthetic contains benzocaine. 4. The tool according to claim 1, contains a dry extract of rhizome of turmeric long, standardized for curcumin, benzocaine and a suppository base in a ratio of 1 suppository weighing 1 g: Dry extract of turmeric rhizome long 25-100 mg Benzocaine 25 mg Suppository base Rest 5. The tool according to claim 1, where as a suppository base contains vitepsol or cocoa butter. 6. A method of obtaining funds for the prevention and treatment of diseases of the pelvic organs and diseases of the rectum, characterized in that the dry extract of turmeric rhizomes of long, standardized curcumin is mixed with an anesthetic and a pharmaceutically acceptable excipient. 7. A method for the prevention and treatment of diseases of the pelvic organs and diseases of the rectum, characterized in that they use the tool according to claim 1 or 4. 8. The method according to claim 7, the tool is used for the prevention and treatment of diseases of the pelvic organs - prostatitis, vesiculitis, adnexitis, metritis, salpingo-oophoritis. 9. The method according to claim 7, the tool is used for the prevention and treatment of hemorrhoids, prostatitis, proxigmoiditis, paraproctitis, fissures, fistulas, tumors of the rectum.