Combined antibacterial preparation for treating acute intestinal infections

IPC classes for russian patent Combined antibacterial preparation for treating acute intestinal infections (RU 2504388):

A61K9/14 - Particulate form, e.g. powders (microcapsules A61K0009500000)

A61K35/74 - Bacteria

A61K31/47 - Quinolines; Isoquinolines

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FIELD: medicine.

SUBSTANCE: invention refers to medicine and biotechnology and concerns treating an antibacterial agent for treating gastrointestinal diseases, preferentially acute intestinal infections, including unexplained. The declared preparation represents a mixture of an antibiotic and probiotic, wherein the antibiotic is presented by ofloxacin, while the probiotic is a bifidus bacterial biomass in the following ratio, mg/capsule: ofloxacin - 200 mg, bifidus bacterial biomass - 200 mg containing min. 2×10⁷ CFU/g living microorganisms.

EFFECT: invention enables reducing the length of recovery in the patients suffering acute intestinal infection considerably.

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The invention relates to medicine and biotechnology and relates to antibacterial agents for the treatment of gastrointestinal diseases, mainly acute intestinal infections, including unknown etiology.

On the use of biologics for the treatment of acute intestinal infections (AII) children and adults has long been known. The first national drug was colibacterin, the current top of which are the bacteria Escherichia coli (Using colibacterin for the prevention and treatment of intestinal diseases and the technology of its production: proceedings of the Moscow and Gorky institutes of epidemiology and Microbiology. - M.: CINTI of Goskomsever, 1967. - 368). However, to combat the OKA more effective was bifidobacteria, the most aggressive selling in relations with pathogenic microorganisms principle of microbial antagonism. The most significant drawback, as with any bacterial drug, is the need for long-term use to achieve a stable bacteriological effect. It is possible that the mix of bacteria with the antibiotic will allow to get rid of this drawback.

The most suitable family of antibiotics for combined preparations against the OKA, in our opinion, is ofloxacin. This antibiotic of the family of forchino the ons has a wide range of actions, affects mostly gram-negative and some gram-positive microorganisms. Effective against microorganisms resistant to most antibiotics and sulfa drugs. Inhibits DNA-girazu, disrupts the process of superspecialization and cross-linking of DNA breaks, inhibits cell division, causing structural changes in the cytoplasm and death of microorganisms. One of the advantages of ofloxacin is its complete absorption from the gastrointestinal tract (GIT). Another advantage is its absolute bioavailability (Register of medicines of Russia radar encyclopedia of medicine. - 14 vol./ CH. edit Glaskowsky. - M.: radar-2006,2005. - s). No less important is the fact that fluoroquinolones because of its specificity not have inhibitory action on Beydaglari person, since the development of the OKA almost always there is the death of bifidobacteria in the result of exposure to pathogenic agents. This property greatly reduces the risk of development of dysbiosis in the result of using ofloxacin for the treatment of diseases. The only disadvantage of this antibiotic is the possibility of its use in humans only 18 years old. But it is possible that in extreme situations this contraindication will not be taken into account. In Primatology (research Institute of medical Primatology of the Russian Academy of medical Sciences, Sochi-Adler,Russia) this antibiotic has been used successfully as a therapeutic agent in OKA unknown etiology (pre-clinical testing of the integrated product and instrumentation Century adolescentis MS-42 / Davydkin C. Y., Jikiza E. K., A. Melikhov Century, the cab T. I., Davydkin, I. Y., Kholodilov L. I. // Matabel. Serosno.-the practical. proc. "Scientific support epidemiological protection of the population"]. 90 anniversary of the Nizhny Novgorod scientific research Institute of epidemiology and Microbiology. academician I. Blokhina Rospotrebnadzor and the 20th anniversary of the Volga regional center for professional and AIDS. - Nizhny Novgorod: Publisher Gladkova, 2009. - s-337).

There is a method of treatment of intestinal infections in children, including the introduction of tools affecting the level of obligate microorganisms and correcting the deficiency of serum calcium, which is used as a drug, which is a powder mixture of dried microbial mass of live bacteria adsorbed on the particles of activated carbon and calcium gluconate, placed in a sealed packet, containing not less than 5×10⁷SOME of bifidobacteria, immobilized sorbent, 0.5-1 g of calcium gluconate and 0.10-0.12 g of lactose (RU, patent 2227036 C2, A61K 33/06, 35/74, 20.04.2004).

The disadvantage of this method is the lack of antimicrobial activity of the used means.

Known complex bacterial drug interacid P, containing a new strain of Lactobacillus acidophilus In PMBC-6535 (140-160 million living cells/g product) and a strain of Enterococcus faecium VKPM B-2990 (190-210 million living cleto is/g product), with a higher antagonistic activity against some microorganisms and with good survival rate of incoming bacteria in the gastrointestinal tract of fur-bearing animals and dogs (RU, patent 2091075 C1, A61K 35/74, C12N 1/20, 27.09.1997).

A disadvantage of the known complex of the bacterial preparation is that it is intended for the treatment of gastrointestinal diseases only animals, but not humans.

Known means, having antibacterial activity, containing live culture of acidophilic lactobacilli in combination with complex serum immunoglobulins, taken in the same weight units, when the concentration of viable microbial cells 107-10 on the mass of 0.1 g and the percentage of components in the complex of immunoglobulin G:M:A, equal to (55-60):(20-25):(15-20) (RU, patent 1779377 A1, A61K 35/74, 39/395, 07.12.1992).

A disadvantage of the known tool is not wide enough spectrum of antibacterial activity, provide its antimicrobial active substances.

Known for its unique combination of antibacterial drug ANILOX_®(prototype), promoted on the Ukrainian market by Vaishali Pharmaceuticals)and combines the properties of an antibiotic and a probiotic containing the antibiotic amoxicillin and cloxacillin, and to the operation of probiotic containing spores of Lactobacillus sporogenes, used in outpatient and inpatient conditions for empirical treatment of polymicrobial, mixed infections, as well as for treatment of proven or suspected staphylococcal infections http://www.provisor.com.ua/archive/2004/Nl/art_20.php).

The lack of a unique combination of antibacterial drug ANILOX_®is that recommended its use to treat only known intestinal infections (typhoid fever, salmonellosis), i.e. in respect of the OKA he is a drug targeted actions, which does not allow its use for the treatment of acute intestinal infections of unknown etiology.

The basis of the invention is the creation of a combined antibacterial drug for the treatment of acute intestinal infections which may lead to reduced treatment time.

The problem is solved by the fact that the mixture as antibiotic contains ofloxacin, and as a probiotic biomass of bifidobacteria in the following ratio of components, mg/capsule: ofloxacin - 200 mg, dry ground biomass of bifidobacteria 200 mg content of viable microorganisms not less than 2×10⁷CFU/g

Technical result achieved by the creation of a combined preparation for the treatment of the OKA, which is a mixture of ofloxacin and probiotic - dry powdered biome is ssy bifidobacteria is significantly shorter disease primates acute intestinal infection. Recovery animals is on average 1.2 times faster than in the treatment of dry biomass of bifidobacteria Century adolescentis MS-42 with the content of viable microorganisms 2×10⁸CFU/g

The claimed combined antibacterial drug for the treatment of acute intestinal infections, which are new and are not described in literature.

The inventive product is a hard capsule No. 0 for oral administration, contains 200 mg of the substance ofloxacin 200 mg of dry powdered biomass of bifidobacteria with SOME content not less than 2×10⁷/year

The method of obtaining the proposed combined preparation is as follows.

Dry biomass Bifidobacterium bifidum 1 received in accordance with VFS 42-3378-99 on Bifidumbacterin dry. The content of viable microorganisms in dry biomass was 2×10⁹CFU/g freeze-dried biomass of bifidobacteria was ground in a rotary mill or electromagnetic apparatus to highest values of maximum bulk density of chopped biomass, as described in the work (Davydkin YOU, Davydkin V.Y., Melikhova AV Rational approach to grinding // Matabel. Serosno.-the practical. proc. "Scientific support epidemiological protection of the population"]. 90 anniversary of the Nizhny Novgorod scientific research Institute of epidemiology and Microbiology. academician I. Blokhina Resotre the supervision and the 20th anniversary of the Volga district center by Prof. and control of AIDS. - Nizhny Novgorod: Publisher Gladkova, 2009. - s-347). The content of viable microorganisms in powdered biomass remained the same as in the dry and was 2×10⁹CFU/g

Substance ofloxacin (manufacturer NANJING FOREIGN ECONOMIC &TRADE DEVELOPMENT CO., LTD, CHINA) grinding is not exposed. The content of active substance in the substance was 99.4%.

Shredded biomass of bifidobacteria and substance ofloxacin mixed in the apparatus of periodic action CM-30 in a predetermined ratio, and the mixture was packaged in hard gelatin capsules No. 0 so that each capsule contained 200 mg ofloxacin 200 mg powdered biomass of bifidobacteria with the content of live bifidobacteria not less than 2×10⁷CFU/g

Preclinical study of therapeutic efficacy of the claimed combined drug capsules in the treatment of acute intestinal infections in monkeys was carried out at research Institute of medical Primatology of the Russian Academy of medical Sciences (Sochi-Adler).

Testing of the developed drug was carried out on monkeys species rhesus monkeys of both sexes of different ages (from 1.3 to 18.3 years) weighing 2.5 to 10.0 kg, spontaneously ill OKA with severe diarrhoeal syndrome. Diarrhoeal syndrome is a frequent liquid chair with fetid odor without pathological impurities from 6 to 8 times per day, moderate reduced activity.

All of the LM is now fished out of a group of cells and the enclosure and placed in individual. Animal comparison groups were selected by the method of free samples that were representative in terms of age, weight and sex. Animals were kept on briquetted feed, produced by briquetting plant genetics, Institute of medical Primatology of the Russian Academy of medical Sciences according to a formulation developed by the company "Altrogge" for primates.

Each monkey received one capsule claimed the drug in the day. The duration of treatment was 7 days. The follow - up period was 14 days. As the comparison drug used capsules with dry biomass of bifidobacteria Century adolescentis MS-42 with the content of viable microorganisms 2×10⁸CFU/g at a dose of 1 capsule 1 monkey in the day.

The results of these studies, representing a comparison of the average duration in days of the clinical manifestations of the disease in primates, are presented in the table.

Compare medications	Part of the preparation	Duration (days) clinical manifestations (including monkeys)	The average duration of clinical manifestations of the disease (days)
Known	Capsule: dry biomass Century adolescentis MS-42 2×10⁸CFU/g	4(1)-8(1)-10(2)-121)-15(2)	11,4
Declare	Capsules: ofloxacin 200 mg + shredded biomass Century bifidum 1 - 200 mg 2×10⁷CFU/g	8(3)-9(1)-10(2)-11(1)	9,1

As follows from the analysis of the data presented in the table, the combined preparation, which is a dry mixture in hard gelatin capsules containing 200 mg ofloxacin 200 mg of dry powdered biomass of bifidobacteria with a content of viable bacteria of at least 2×10⁷CFU/g, provides the reduction of 1.2 times the duration of clinical manifestations of the disease in primates compared with known drug bifidobacteria in capsules containing 2×10⁸CFU/g of viable microorganisms, and hence a corresponding reduction in the treatment time of the apes from acute enteric infections.

Combined antibacterial drug for the treatment of acute intestinal infections, which are a mixture of antibiotic and probiotic, characterized in that the quality of the antibiotic mixture contains ofloxacin, and as a probiotic biomass of bifidobacteria with SOME content not less than 2·10⁷CFU/g in the following ratio of components, mg/capsule:

ofloxa the Ying	200
biomass of bifidobacteria	200