RU2512757C1 - Antibacterial and regenerative agent presented in form of topical oily gel - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely to a soft dosage form in the form of a topical oily gel used in treating purulent skin infections and containing sodium fusidine, methyluracil (dioxomethyl tetrahydropyrimidine), an oily gel base (mineral oil and polyethylene) and additionally hydroxymethyl quinoxaline dioxide.

EFFECT: developing the preparation for treating purulent wounds, degrees 3-4 burns, decubituses and ulcers, possessing the improved antibacterial effect and regenerative action.

2 cl, 8 ex, 2 tbl

Description

The invention relates to the field of pharmaceutical industry and relates to the creation of an effective drug for the treatment of skin purulent infections.

The technical result of the present invention is to expand the arsenal of topical antibacterial and regenerative drugs for the treatment of purulent infections of open wounds, burns, ulcers, bedsores.

The treatment of painful disorders of the human skin (wounds, burns, ulcers, bedsores, eczema and other manifestations) is one of the most difficult problems for modern medicine. A local medicine for the treatment of wounds should perform several functions:

- prevent infection of wounds by pathogens,

- contribute to drainage of the wound from infiltration,

- prevent drying out of tissues (dehydration of tissues on the periphery of the burn, which slows down the regeneration process),

- reduce inflammation and help improve blood microcirculation.

Currently known drugs for the local treatment of bacterial skin infections containing fusidic acid or its derivatives (RF patents No. 2418806, No. 2180216).

The tool described in patent No. 2418806, contains, along with fusidic acid, corticosteroids, the anti-inflammatory effect of which is generally quite favorable, but can be extremely dangerous in the presence of active infectious agents. With topical use of corticosteroids, side effects can occur that are a manifestation of both local and systemic undesirable effects, including the strengthening of an existing bacterial infection. In addition, side effects, such as inhibition of adrenal function, can occur with excessive and prolonged local use of corticosteroids, especially in pediatric practice.

Closest to the claimed composition of the drug "Fusimet ointment for external use" described in the patent of the Russian Federation No. 2180216. The prototype, containing fusidine sodium, methyluracil, PVP, sodium pyrosulphate and fatty petroleum jelly-lanolin base, has successfully established itself in the Russian pharmaceutical market. It combines the antimicrobial effect of fusidine sodium and the regenerative effect of methyluracil. However, a comprehensive clinical and laboratory study of the effectiveness of the drug "Fusimet Ointment for external use" showed that it is necessary to strengthen its antibacterial and regenerating activity. According to the laboratory of bacteriology, epidemiology and antibiotic therapy NII SP them. N.V. Sklifosovsky, the discharge of burn wounds most often contains staphylococci (almost 75% of cases), a little less often Pseudomonas aeruginosa (about 50%) and much less often other microorganisms. The formation in the wounds of associations of microorganisms with different sensitivity or resistance to antibacterial drugs necessitates the use of complex treatment of burn wounds.

Fusidine sodium is an antibiotic that exhibits high specific antimicrobial activity against staphylococci, meningococci, and gonococci. It has high antimicrobial activity against Staphilococcus epidermidis (methicillin resistant and methicillin sensitive). In medium therapeutic doses, it has a bacteriostatic effect on microorganisms, due to the ability of the drug to disrupt protein synthesis in a microbial cell. Resistance is rare. Fusidine sodium is low toxic.

Methyluracil is a stimulator of cell regeneration, has anabolic and anti-catabolic activity, reduces the healing time of wounds.

When deciding on the use of one or another local external agent, not only the sensitivity of microflora to the antimicrobial component of the drug, but also the nature of the basis, is taken into account. Fat-based ointments do not have osmotic activity, are not able to drain the wound, but, on the contrary, can create the so-called “greenhouse effect”. The prototype is based on the use of a lanolin-vaseline base as an auxiliary agent. Fat-based ointments With antibiotics have only a short-term effect, since such a basis disrupts the outflow of wound discharge, does not provide sufficient release of the active component from the composition, does not contribute to the penetration of the antibiotic deep into the tissues where the microbes are located, which can lead to the transition of acute inflammatory diseases into chronic ones. Lanolin is an organic substance capable of interacting with oxides and basic salts of heavy metals, as well as sensitizing the skin in relation to various substances, causing allergic reactions, especially in dermatological patients. Lanolin is also easily oxidized (rancid). To prevent the oxidation of lanolin in the prototype, an antioxidant (sodium pyrosulphate - preservative E223) is used, which can also cause an allergic reaction in patients sensitive to it.

Known water-glycerin-based gels, when applied, form a thin film on the skin, which has a protective effect in small wounds, but painfully tightens tissues, makes it difficult to drain pus in case of serious skin lesions, increasing the duration of treatment.

The objective of the present invention is to develop an effective drug for the treatment of purulent wounds, burns of 3-4 degrees, bedsores, ulcers, with enhanced regenerative and antibacterial action with the optimal combination of excipients.

The problem is solved in that the proposed drug is an oily gel and contains fusidine sodium, dioxomethyltetrahydropyrimidine (methyluracil), mineral oil and polyethylene, as well as an additional antimicrobial substance, hydroxymethylquinoxynoxyl dioxide in the following ratio of components, g:

Fusidine sodium 1.0-5.0 Methyluracil (dioxomethyltetrahydropyrimidine) 0.5-10.0 Hydroxymethylquinoxalindioxide 0.5-5.0 Gel base (a mixture of mineral oil and polyethylene) up to 100

When applied to the skin, the oily gel base forms an elastic film that provides a protective effect and does not cause dry skin. Due to its properties, such as low sensitivity in changing the pH of the medium, the stability of physicochemical parameters during storage, the lack of susceptibility to microbial spoilage, and the absence of a specific odor, it makes it possible to exclude stabilizers from the composition of the preparation. The advantage of the oily gel base is also the simplicity of the method for producing a pharmaceutical composition by direct "cold" mixing of the components, eliminating the energy-intensive stage of melting the base, and also preventing the temperature inactivation of the active substances, which, in turn, increases the pharmacological effectiveness of the drug.

Hydroxymethylquinoxalindioxide is a broad-spectrum antimicrobial agent. Active against Proteus vulgaris, Pseudomonas aeruqinosa, Escherichia coli, Staphylococcus spp., Streptococcus spp., Shigella, Frindler's bacillus, pathogenic fungi (Clostridium perfringens). It acts on strains of bacteria resistant to other chemotherapy drugs, including antibiotics. The additional inclusion of hydroxymethylquinoxalindioxide in the composition promotes faster cleaning of the wound surface, stimulates reparative regeneration, marginal epithelization, and favorably affects the course of the wound process.

A method of obtaining a pharmaceutical composition includes the following steps: preparing suspension No. 1 of fusidine sodium; preparing suspension No. 2 of methyluracil; optionally, preparing suspension No. 3 of hydroxymethylquinoxalindioxide; preparing a gel by introducing said suspensions into a base.

Example 1

The estimated amount of gel base (mineral oil and polyethylene) 97.7 g. 1.1 g of fusidine sodium is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 1 with a particle size of not more than 90 microns. Methyluracil 0.6 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 2 with a particle size of not more than 90 microns. Hydroxymethylquinoxalindioxide 0.6 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 3 with a particle size of not more than 90 microns. In the remainder of the calculated amount, part of the gel base is added with stirring suspensions No. 1, 2, 3, the resulting mass is homogenized to homogeneity, and Packed in tubes.

Example 2

Estimated amount of gel base (mineral oil and polyethylene) 80.0 g.

5.0 g of fusidine sodium is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 1 with a particle size of not more than 90 microns. Methyluracil 10.0 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 2 with a particle size of not more than 90 microns. Hydroxymethylquinoxalindioxide 5.0 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 3 with a particle size of not more than 90 microns. In the remainder of the calculated amount, part of the gel base is added with stirring suspensions No. 1, 2, 3, the resulting mass is homogenized to homogeneity, and Packed in tubes.

The resulting drug is stable during storage, meets the requirements of the pharmacopoeia and has a shelf life of 2 years (table 1).

Example 3

Estimated amount of gel base (mineral oil and polyethylene) 96.4 g.

1.8 g of fusidine sodium is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 1 with a particle size of not more than 90 microns. Methyluracil 0.8 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 2 with a particle size of not more than 90 microns. Hydroxymethylquinoxalindioxide 0.8 g is mixed with part of the gel base in a ratio of 1: 3, homogenized to obtain a suspension No. 3 with a particle size of not more than 90 microns. In the remainder of the calculated amount, part of the gel base is added with stirring suspensions No. 1, 2, 3, the resulting mass is homogenized to homogeneity, and Packed in tubes.

The resulting drug is stable during storage, meets the requirements of the pharmacopoeia and has a shelf life of 2 years (table 1).

Example 4

2.0 g of fusidine sodium is mixed with 5.0 g of mineral oil, homogenized to obtain a suspension No. 1 with a particle size of not more than 90 microns. 1.0 g of methyluracil is mixed with 5.0 g of mineral oil, homogenized to obtain a suspension No. 2 with a particle size of not more than 90 microns. 1.0 g of hydroxymethylquinoxalindioxide are mixed with 5.0 g of mineral oil, homogenized to obtain a suspension No. 3 with a particle size of not more than 90 microns. 81.0 g of gel base are batch-mixed with suspension No. 1, suspension No. 2, suspension No. 3, the resulting masses are combined, homogenized to homogeneity, and packaged in tubes.

The resulting drug is stable during storage, meets the requirements of the pharmacopoeia and has a shelf life of 2 years (table 1).

Example 5

Estimated amount of gel base (mineral oil and polyethylene) 97.0 g.

2.0 g of fusidine sodium is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. 1.0 g of methyluracil is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. A suspension of fusidine sodium and a suspension of methyluracil are added to the remainder of the calculated amount of the gel base with stirring, the resulting mass is homogenized to homogeneity, and packaged in tubes.

The resulting drug is stable during storage, meets the requirements of the Pharmacopoeia and has a shelf life of 2 years (table 2).

Example 6

Estimated amount of gel base (mineral oil and polyethylene) 96.7 g.

2.2 g of fusidine sodium is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. 1.2 g of methyluracil is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. A suspension of fusidine sodium and a suspension of methyluracil are added to the remainder of the calculated amount of the gel base with stirring, the resulting mass is homogenized to homogeneity, and packaged in tubes.

The resulting drug is stable during storage, meets the requirements of the Pharmacopoeia and has a shelf life of 2 years (table 2).

Example 7

Estimated amount of gel base (mineral oil and polyethylene) 97.3 g.

1.8 g of fusidine sodium is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. 0.8 g of methyluracil is mixed with the gel base in a ratio of 1: 3, homogenized to obtain a suspension with a particle size of not more than 90 microns. A suspension of fusidine sodium and a suspension of methyluracil are added to the remainder of the calculated amount of the gel base with stirring, the resulting mass is homogenized to homogeneity, and packaged in tubes.

The resulting drug is stable during storage, meets the requirements of the Pharmacopoeia and has a shelf life of 2 years (table 2).

Example 8

2.0 g of fusidine sodium is mixed with 7.5 g of mineral oil, homogenized to obtain a suspension with a particle size of not more than 90 microns. 1.0 g of methyluracil is mixed with 7.5 g of mineral oil, homogenized to obtain a suspension with a particle size of not more than 90 microns. 82.0 g of the gel base are batchwise mixed with a suspension of fusidine sodium and a suspension of methyluracil, the resulting masses are combined, homogenized to homogeneity, and packed in tubes.

The resulting drug is stable during storage, meets the requirements of the Pharmacopoeia and has a shelf life of 2 years (table 2).

Information sources

1. Patent RU 2180216.

2. Patent RU 2418806.

3. N.M. Vikhrova, M.A. Petrova, I.P. Fomina, S.M. Navashin. "Fusidine and its properties." - Antibiotics, No. 6, 1967, p. 451-454.

4. S.M. Navashin, I.P. Fomina. Handbook of antibiotics. Medicine, 1974.

5. The state register of medicines .

Table 1 Table of analytical data on the quality and stability of the drug Description Microbiological purity Particle size pH quantitation Gel of white with a yellowish tint <10 / <10 / s No more than 90 microns 6.0 to 8.0 fusidine sodium methyluracil hydroxymethylquinoxalindioxide at the time of manufacture Project 1 Correspondingly. Correspondingly. 82.8 7.2 1.10 0.52 0.54 Project 2 Correspondingly. Correspondingly. 81.4 7.8 4.92 9.85 4.95 Project 3 Correspondingly. Correspondingly. 82.5 7.5 1.81 0.88 0.91 Project 4 Correspondingly. Correspondingly. 81.8 7.4 1.98 1,02 0.99 after 2 years of storage - at the end of the expiration date Project 1 Correspondingly. Correspondingly. 82.0 7.3 1.00 0.55 0.51 Project 2 Correspondingly. Correspondingly. 82,2 7.7 4.89 9.92 4.90 Ave.Z Correspondingly. Correspondingly. 83,4 7.7 1.80 0.89 0.91 Project 4 Correspondingly. Correspondingly. 82.9 7.6 2.00 1,02 0.99

table 2 Table of analytical data on the quality and stability of the drug Description Microbiological purity Particle size pH quantitation White gel <10 / <10 / s No more than 90 microns 6.0 to 8.0 fusidine sodium methyluracil at the time of manufacture Ex.5 Correspondingly. Correspondingly. 81.9 7.5 2.02 1,03 Ex.6 Correspondingly. Correspondingly. 82.3 7.5 2.21 1,08 Ex 7 Correspondingly. Correspondingly. 82.0 7.7 1.82 0.91 Ex 8 Correspondingly. Correspondingly. 81.8 7.6 2.00 1,02 after 2 years of storage - at the end of the expiration date Ex.5 Correspondingly. Correspondingly. 82,4 7.7 2.01 1.01 Ex.6 Correspondingly. Correspondingly. 83.0 7.7 2.18 1,1 Ex 7 Correspondingly. Correspondingly. 82.8 7.6 1.81 0.89 Ex 8 Correspondingly. Correspondingly. 83.1 7.5 2.00 0.99

Claims (2)

1. An antibacterial regenerating agent for external use, containing fusidine sodium, methyluracil and an oily gel base, characterized in that the base is a mixture of mineral oil and polyethylene, in the following ratio, g:
fusidine sodium 1.0-5.0 methyluracil (dioxomethyltetrahydropyrimidine) 0.5-10.0 gel base (mineral oil and polyethylene) up to 100 2. The tool according to claim 1, characterized in that it further comprises an antibacterial agent with a wide spectrum of action of hydroxymethylquinoxalindioxide in an amount of from 0.5 g to 5.0 g per 100 g of agent.