RU2296568C1 - Injection medicinal formulation for treatment and prophylaxis of blood-parasitic and invasion diseases - Google Patents

Abstract

FIELD: veterinary medicine, pharmacology.

SUBSTANCE: invention represents injection antiparasitic medicinal agent containing diminazene salts as an active substance and can be used in treatment and prophylaxis of parasitic diseases. Injection medicinal formulation used for treatment and prophylaxis of blood-parasitic and invasion diseases and comprising diminazene as an active substance, organic solvent, stabilizing agent and preserving agent involves additionally a surface-active substance as a solubilizing agent and distilled water as a co-solvent and wherein poly-(1-vinyl-2-pyrrolidone) is used as a stabilizing agent wherein components are taken in the following content, wt.-%: active substance, 1-20; organic solvent, 10-50; co-solubilizing agent, 1-20; stabilizing agent, 1-20; preserving agent, 0.01-1, and co-solvent, up to 100. Proposed medicinal formulation comprises diminazene benzoate or diminazene adipate, or diminazene nicotinate as an active substance. "Cremofor EL" or "Cremofor ELP" (polyoxyethylene-glycerol-trihydroxystearate), or "Tween-80" (polyoxyethylene sorbitan monooleate), or "Solutol HS15" (polyethylene glycol-660 12-hydroxystearate) are used as a co-solubilizing agent. "Collidon 12PF" or "Collidon 17PF" [poly-(1-vinyl-2-pyrrolidone)] are used as a stabilizing agent. Dimethylacetamide or 1-methyl-2-pyrrolidone or "Solufor P" (2-pyrrolidone), or transcutol, or propylene glycol, or ethylene glycol, or glyceroformal, or dimethylsulfoxide are used as a solvent. The proposed injection medicinal formulation comprises additionally phenazone as active substance in the amount 1-10 wt.-%. Invention provides enhancing stability and activity and decreasing toxicity of the medicinal formulation.

EFFECT: improved and valuable properties of formulation.

3 cl, 12 ex

Description

The invention relates to veterinary medicine, namely to pharmacology, and is an injectable antiparasitic drug containing diminazene as an active substance, and can also be used for the treatment and prevention of parasitic diseases.

Diamidines, or aromatic diamidines, is a group of derivatives of diamidine and carbanilide. The first of this group at the beginning of the 50s of the last century by the company Hoechst AG was synthesized diminazene acetate-4,4'-benzinodiazoaminodiamidine diaceturate (US Patent No. 2838485, 1958). The drug showed high activity against blood parasites, and soon the same company developed a convenient dosage form of diminazene in a mixture with antipyrine - berenyl (US. Patent No. 4269830). In 1958, diminazene was re-synthesized in the USSR and was called azidine.

Subsequently, various companies, in addition to diminazene, synthesized some other substances from this group: pentamidine isothionate, phenamidine isothionate, imidocarb dipropionate, amicarbalide diisothionate, dibromopropamide and hexamidine isothionates. Moreover, the first 4 drugs from this group found application in veterinary practice, and the last 2 are used in medicine as antiseptics, because all diamidines have powerful bactericidal activity.

Diminazen diaceturate is the most widely used drug worldwide used to treat diseases caused by both flagellar protozoa (trypanosomes) and representatives of the class Piroplasmida (pyroplasm, babesia, nutallia, francaella, teileria, cytoxozone) in various species of domestic and wild animals.

Known injection drug "Imizol" based on imidocarb dipropionate, which is an injection solution for intramuscular and intravenous administration (Donald K. Plumb. Pharmacological preparations of veterinary use. 2002).

However, this drug has a lower activity compared to diminazene.

Known drug "Berenil" containing 445 mg / g of diminazene acetate and 555 mg / g of phenazone. It is a yellow crystalline powder, dust free. Before use, the drug is dissolved in water (Bauer F. 1955).

There is a preparation “Veriben” containing 44.5% diazoamino-dibenzamidine diaceturate (synonym for diminazene) and auxiliary components. “Veriben” is a sterile granular yellow powder, readily soluble in water (Klenova I.O., Yaremenko N.A. Veterinary preparations in Russia, 2000).

There is a drug "Zolg" containing 96% diamidine. It is a small-crystalline powder of gray-pink color, readily soluble in water (Klenova I.F., Yaremenko N.A., Veterinary preparations in Russia. 2000).

There is a drug "Azidine" containing 99.9% of diminazene acetate. The drug is a sterile orange powder, readily soluble in water (Klenova I.F., Yaremenko N.A. Veterinary preparations in Russia. 2000).

However, the listed diminazene-containing preparations also have low activity. And diminazene in aqueous solution has low stability.

Known antiparasitic composition, which is an aqueous solution of diminazene acetate, which includes the active substance - pentamidine and phenazone, and a stabilizer - glycerol and cellulose ethers (Patent DE No. 19530708, IPC: A 61 K 31/655)

However, this composition has several disadvantages, the most significant of which is its lack of stability.

Known composition for the treatment of protozoid diseases, containing particles associated with the lipid matrix for the controlled release of the active ingredient. The composition is a hydrophobic salt of diminazene (diminazen oleinate, diminazen stearate, etc.) (US Patent No. 6770299, IPC: A 61 K 9/14).

However, this drug is an anhydrous (oil) form, difficult to manufacture, is expensive and can cause unwanted side effects.

Closest to the claimed form is a pharmacological preparation with trypanocidal properties for the treatment of diseases caused by the blood parasitic family, containing diminazene diaceturate as an active substance, glycerin as a stabilizer, N-methylpyrrolidone as a solvent and preservative (Patent DE No. 19826263, IPC: A 61K 31/655).

This drug is intended for injection, but it is an anhydrous form, which, when used, can cause irritation of the skin, inflammation and other side effects. In addition, it is known that N-methylpyrrolidone causes toxic effects in the body.

The above drugs are intended for the treatment of diseases mainly of blood parasitic etiology, because for the treatment of invasive diseases caused by flagellar and ciliary protozoa, an increase in the dosage of the drug is required, which leads to toxic effects.

The objective of the present invention is to increase the activity and stability of a combined injectable preparation based on diminazene for the treatment of diseases of not only blood parasitic etiology, but also invasive diseases caused by flagellar and ciliary protozoa, without increasing the dosage.

The problem is solved in that the injectable dosage form for the treatment and prevention of blood-parasitic and invasive diseases, including diminazene as an active substance, an organic solvent, stabilizer, preservative, according to the proposed solution additionally contains a surfactant as a solubilizer and distilled water as co-solvent, and as a stabilizer use poly- (1-vinyl-2-pyrrolidone), with the following components wt.%:

Active substance 1-20 Organic solvent 10-50 Solubilizer 1-20 Stabilizer 1-20 Preservative 0.01-1 Co-solvent Up to 100

Moreover, its hydrophobic mono- and disubstituted derivatives are used as diminazene.

As a solubilizer, use Cremofor EL, or Cremofor ELP (polyoxyethylene glycerol trihydroxy triricinoleate), or Cremofor RH40 (polyoxyethylene glycerol trihydroxy stearate), or Tween 80 (polyoxyethylene sorbitan monooleol hydrochloride) 6, 1260 Solut stearate); as stabilizer use Collidone 12PF or Collidone 17PF (poly- (1-vinyl-2-pyrrolidone)); dimethylacetamide, or 1-methyl-2-pyrrolidone, or Solufor P (2-pyrrolidone), or transcutol, or propylene glycol, or ethylene glycol, or glyceroformal, or dimethyl sulfoxide are used as an organic solvent.

As an active substance, it additionally contains phenazone in an amount of 1-10 wt.%.

Thus, the preparation may be an aqueous solution of hydrophobic salts of diminazene, for the stabilization of which a solubilizer (Cremofor EL, or Cremofor ELP (polyoxyethylene-glycerol-trihydroxy-tricinoleate), or Cremofor RH40 (polyoxyethylene-glycerol-trihydroxy-stee) is used 80 (polyoxyethylene sorbitan monooleate), or Solutol HS15 (polyethylene glycol 660 12-hydroxy-stearate)) and a stabilizer (Kollidon 12PF or Kollidon 17PF (poly- (1-vinyl-2-pyrrolidone), as well as an organic solvent (dimethylacetamide, or 1- methyl 2-pyrrolidone, or Solufor P (2-pyrrole he) or Transcutol, or propylene glycol, or ethylene glycol, or glitseroformal or dimethyl sulphoxide) and a preservative (benzyl alcohol or parabens), and may include phenazone.

The resulting dosage form was prepared as follows.

A weighed portion of an organic solvent, for example, Solufor P, was prepared, after which diminazene was dissolved in it with constant stirring. A solubilizer, for example Tween 80, and benzyl alcohol as a preservative were added to the resulting solution. The composition was mixed until completely dissolved. To the resulting solution, a stabilizer, for example Collidone 12 PF, and phenazone, previously dissolved in the required volume of water, were added with constant stirring. The finished product was filtered.

Example 1

The formulation of the drug with a high content of micelle-forming component is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen benzoate 7 Organic solvent Solufor p fifty Solubilizer Tween 80 twenty Stabilizer Collidon 12PF 7 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water Up to 100

An increase in the concentration of Tween 80 in the preparation leads to delamination of the solution.

Example 2

The formulation with a reduced concentration of solubilizer is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen benzoate 7 Organic solvent Dimethylacetamide fifty Solubilizer Cremofor EL one Stabilizer Collidon 12PF twenty Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Lowering the concentration of Cremofor EL in the preparation leads to instability of the solution.

Example 3

The formulation with a high content of diminazene in the preparation is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen benzoate 10 Organic solvent Propylene glycol fifty Solubilizer Cremofor rh fifteen Stabilizer Collidon 17PF 10 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

An increase in the concentration of diminazene benzoate in the preparation leads to precipitation, i.e. to the instability of the solution.

Example 4

The formulation with a reduced content of diminazene in the preparation is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen benzoate one Organic solvent Dimethyl sulfoxide twenty Solubilizer Solutol hs 10 Stabilizer Collidon 17PF 5 Additional ADV / stabilizer Phenazone 5 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

A decrease in the concentration of diminazene benzoate in the drug leads to a decrease in therapeutic efficacy.

In the above examples of dosage forms, diminazene benzoate was used as the active substance.

The following examples provide formulations using other salts of diminazene (lauric, adipic, nicotinic acid salts)

Example 5

The formulation of the drug with a high content of micelle-forming component and with diminazene adipinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen adipate 7 Organic solvent Solufor p fifty Solubilizer Tween 80 twenty Stabilizer Collidon 12PF 7 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 6

A formulation with a reduced solubilizer concentration and with diminazene adipinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen adipate 7 Organic solvent Dimethylacetamide fifty Solubilizer Cremofor EL one Stabilizer Collidon 12PF twenty Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 7

A formulation with a high content of diminazene in the preparation and with diminazene adipinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen adipate 10 Organic solvent Propylene glycol fifty Solubilizer Cremofor rh fifteen Stabilizer Collidon 17PF 10 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 8

A formulation with a reduced content of diminazene in the preparation and with diminazene adipinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen adipate one Organic solvent Dimethyl sulfoxide twenty Solubilizer Solutol hs 10 Stabilizer Collidon 17PF 5 Additional ADV / stabilizer Phenazone 5 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 9

The formulation of the drug with a high content of micelle-forming component and with diminazene nicotinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen nicotinate 7 Organic solvent Solufor p fifty Solubilizer Tween 80 twenty Stabilizer Collidon 12PF 7 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one

Example 10

A formulation with a reduced concentration of the solubilizer and with diminazene nicotinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen nicotinate 7 Organic solvent Dimethylacetamide fifty Solubilizer Cremofor EL one Stabilizer Collidon 12PF twenty Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 11

The formulation with a high content of diminazene in the preparation and with diminazene nicotinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen nicotinate 10 Organic solvent Propylene glycol fifty Solubilizer Cremofor rh fifteen Stabilizer Collidon 17PF 10 Additional ADV / stabilizer Phenazone 7 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Example 12

A formulation with a reduced content of diminazene in the preparation and with diminazene nicotinate as an active substance is given.

Functionality of the component Component Example The concentration of components, wt.% Actively active substance (ADV) Diminazen nicotinate one Organic solvent Dimethyl sulfoxide twenty Solubilizer Solutol hs 10 Stabilizer Collidon 17PF 5 Additional ADV / stabilizer Phenazone 5 Preservative Benzyl alcohol one Additional solvent Distilled water up to 100

Claims (3)

1. Injectable dosage form for the treatment and prevention of blood-parasitic and invasive diseases, including a diminazene derivative as an active substance, an organic solvent, stabilizer, preservative, characterized in that it contains diminazene benzoate or diminazene adipinate, or diminazene nicotine diminazene benzyl alcohol as a preservative and poly- (1-vinyl-2-pyrrolidone) as a stabilizer, and in addition a surfactant as solubi an ionizer and distilled water as a co-solvent in the following components, wt.%: Diminazen benzoate, or diminazen adipate, or diminazen nicotinate 1-20 Organic solvent 10-50 Surface-active substance 1-20 Poly- (1-vinyl-2-pyrrolidone) 1-20 Benzyl alcohol 0.01-1 Distilled water Up to 100 2. The dosage form according to claim 1, characterized in that as a solubilizer contains Cremofor EL or Cremofor ELP (polyoxyethylene glycerol trihydroxy triricinoleate), or Cremofor RH40 (polyoxyethylene glycerol trihydroxy stearate), or Tween 80 (polyoxyethylene monooleate), or Solutol HS15 (polyethylene glycol 660 12-hydroxy-stearate); as stabilizer use Collidone 12PF or Collidone 17PF (poly- (1-vinyl-2-pyrrolidone)); as an organic solvent, dimethylacetamide or 1-methyl-2-pyrrolidone, or Solufor P (2-pyrrolidone), or transcutol, or propylene glycol, or ethylene glycol, or glyceroformal, or dimethyl sulfoxide are used. 3. The dosage form according to claim 1, characterized in that as an active substance it additionally contains phenazone in an amount of 1-10 wt.%.