Gel system of nimesulide for local use and method of reception (options)

 

(57) Abstract:

The invention can be used in medicine in the treatment of skin inflammations. The claimed preparation of nimesulide for local application in the form of a gel. The product contains 0.5 to 7 wt.% nimesulide, a gelling agent, a solvent, a preservative, and optionally, a stabilizer and a mixture of esters of Caprylic and capric acid with glycerol. Glioblastome agent selected from 0.1 to 5 wt.% carboxyvinyl polymer, neutralized with an aqueous solution of triethanolamine or diisopropanolamine, or 0.5-10 wt.% polyacrylonitrile. The solvent is selected from the group comprising ethanol, isopropanol and monotropy ether of diethylene glycol. The concentration of ethanol and isopropanol in the product is from 5 to 20 wt.%, monoethylene ether of diethylene glycol is from 5 to 40 wt.%, as the water content is from 40 to 95 wt.%. The method of obtaining the drug includes obtaining water dispersed phase containing water-soluble preservatives and carboxyvinyl polymer, adding an alcoholic solvent, the dispersion of nimesulide, water-insoluble preservatives, and optionally additives (wetting agents and amplifiers dermal absorption), neutralizing carboxamidotryptamine aqueous phase, the preparation of the organic phase, dispersing the organic phase in the aqueous phase and neutralization carboxyvinyl polymer, the introduction of triethanolamine or diisopropanolamine. The aqueous phase contains a water-soluble preservatives, a mixture of esters of Caprylic and capric acid with glycerol and homogeneous dispersed carboxyvinyl polymer. The organic phase contains the water-insoluble preservatives, preferably a mixture of parabens, and nimesulide in monoethylene ether of diethylene glycol. The use of nonaqueous solvents in the preparation of the gel system of nimesulide provides improved physico-chemical characteristics of the drug and the characteristics of the release and absorption of nimesulide due to its ability to dissolve the dermal lipid barrier. 3 S. and 4 C.p. f-crystals, 5 PL.

The invention relates to preparations of nimesulide for local use based gel systems.

Nimesulide is known as an anti-inflammatory agent, therapeutic efficacy which opened recently, but the lack of which is in poor physical-chemical properties; main obstacle for the use of nimesulide in preparations for local application t is-breaking materials, usually used in such preparations.

Some drugs nimesulide for external use is described in the publication WO 96/11002; these drugs consist of a dispersion of particles of the active ingredient in the component, which in the case of creams contains a hydrophilic polymer, an oil substance, surface-active agent, a basic compound and water.

In this application not mentioned gel systems, in particular systems in which the active ingredient dispersed in solvents other than water; moreover, the remedies proposed in the publication WO 96/11002 do not solve some of the problems associated with system stability and bioavailability of the active ingredient.

Now, it was established that the Association of a gel based carboxyvinyl polymer or other suitable forming a gel of funds from the dispersion of nimesulide in solvents selected from ethanol, isopropanol or monoethylene ether of diethylene glycol, provides significant advantages both from the point of view of system stability, and from the point of view of the release and absorption of the active ingredient that improves its bioavailability.

Effect of gelation receive preferably Potema acid; as for the base used for neutralization, it is particularly useful is the use of weak bases, such as triethanolamine or diisopropanolamine in equimolar ratio of acid/base 1:1.

Carboxyvinyl polymer, for example, carbomer used in the process of gelation, get, based on acrylic/methacrylic acid. It is used in quantities from 0.1 to 5 wt.%, preferably 0.5 to 2.5 wt.%. On the other hand, polyacrylamidegel, known under the trade name Sepigel (Sepic), in the amount of from 0.5 to 10 wt.%, can also be successfully used as a gelling agent.

The use of nonaqueous solvents in the preparation of the gel of the present invention provides obvious advantages both from the point of view of physical-chemical characteristics, and from the point of view of the characteristics of the release and absorption of nimesulide. In particular, the invention relates to the use of such solvents as ethanol, isopropanol and monotropy ether of diethylene glycol, the latter, as shown particularly effectively increases the absorption of the active ingredient due to its ability to dissolve the dermal lipid barrier. is ü negative impact on the hydration of the skin, compensated film-forming properties and good feeling on the skin of a gel based carboxyvinyl polymer.

The viscosity and pH of the compositions of the present invention may vary within wide limits: viscosity may range from a few centipoise to 100,000, while the preferred range of pH is from 5 to 7. The water content is in the range of from 40 to 95 wt.%, while the number of solvent depending on its contribution to the evaporation of the aqueous phase is from 5 to 20 wt.% for ethanol and isopropanol, preferably about 10%; on the other hand, as for monoethylene ether of diethylene glycol, its diffusion and penetrating properties correlate with concentrations from 5 to 40 wt.%, preferably about 15 wt.%.

The active ingredient nimesulide may be dispersed in a wide range of concentrations, preferably from 0.5 to 7 wt.%.

Compositions of the present invention can also contain lipophilic excipients, such as esters of Caprylic and capric acids or glycerol (8) MA, which have the ability to improve the absorption and characteristics of the final distribution on the skin and "feeling on the skin"materials, acceptable to limit any adverse effects caused by delipidization solvent at the surface level.

The system of preservatives provides microbial protection with broad spectrum antimicrobial agents, such as imidazolidinedione and balanced mixture of parabens; additional guarantee of stability is the presence of pestiviruses agent, such as EDUC (ethylenediaminetetraacetic acid), which has the ability to form chelates with any harmful ions that holds the appropriate viscosity index.

Given the high percentage of water, it should be recalled that ETUC has a reinforcing effect on the system efficiency preservatives against microorganisms.

Compositions of the present invention can optionally contain: softening/moisturizing agents, such as citylove esters - 1-15 wt.%, cholesterol - 0,3-0,5 wt. % glycerol - 1-30 wt.%, isopropyl ester of myristic acid - 1-10 wt.%, isopropyl ester of palmitic acid is 0.05 to 5.5%, lecithin 1-20 wt.%, lanolin alcohols of 0.5-15 wt.%, vaseline - 4-95 wt.%, soy lipid - 1-20 wt.%, amplifiers dermal absorption, such as 2-peramiho of the invention can be obtained in accordance with the method, which includes:

- receiving the dispersed phase containing carboxyvinyl polymeric gelling agent;

- adding an alcoholic solvent, dispersing the active ingredient of nimesulide, adding preservatives and stabilizing agents:

- neutralizing the resin with the selected base.

In the case of the system in which the solvent is monotropy ether of diethylene glycol, the process can be represented as follows:

- obtaining the aqueous phase containing water-soluble preservatives and homogeneous dispersed carboxyvinyl polymer;

- receive phase containing preservatives (parabens) in monoethylene ether of diethylene glycol and the dispersion of the active ingredient. Add phase containing esters of Caprylic/capric acids and glycerol(8) OE.

to obtain the dispersion suspendirovanie phase containing the active ingredient in an aqueous phase containing carboxyvinyl polymer;

- getting stabilizers, appropriately solubilizing in the aqueous phase;

- neutralizing the resin with the selected base.

Compositions of the present invention have the following advantages:

La;

- the ability to stimulate absorption;

- reduce the induced effect of dehydration.

Compositions of the invention, as shown, have a good tolerance as in the experiments on animals (rabbits and Guinea pigs), and in clinical trials.

The effectiveness of the compositions of the present invention studied using well-known pharmacological tests, such as caused by UV-irradiation erythema in Guinea pigs induced by Croton oil inflammation of the eyes of Guinea pigs induced by carrageenan granuloma in rabbits.

Dermal adsorption was studied using14C-nimesulide as in experiments on rabbits and human volunteers, while in none of the cases was not found significant systemic concentrations of nimesulide.

Compositions of the invention are also tested in a clinical setting on 200 patients with upper extremity tendonitis or sprain of the ankle joint in accordance with a controlled double-blind experiment.

As it turned out, the composition of the present invention in comparison with placebo effective with statistical significance.

In table. 1 shows when the aspersio Carbopol in a solution of water and preservatives receive during the swelling of the gel for two days at room temperature to obtain a homogeneous dispersion. Phase To get in a paddle mixer Gianke and Kunkel Type PM43 when heated on a water bath.

After addition of isopropanol, the mixture is homogenized using a homogenizer Guarniero Mantelli Type F43CV2.

On the other hand, the entire product can be obtained by dispersing Carbopol in water using a turbine in a vacuum, stirring with a blade after you add phase C and homogenize again using turbines in vacuum after addition of isopropanol.

As preservative use paracombe, powdery mixture of methyl-, ethyl-, propyl-, butyl-p-hydroxybenzoate. Methyl-, ethyl - and propyl-p-hydroxybenzoate given in Italian Pharmacopeia IX ed. Butyl p-benzoate described in USP XXIII.

To this mixture was added preservative - imidazolidinedione.

Examples 2-5 explains the table. 2-5.

1. The preparation of nimesulide for local application in the form of a gel containing 0.5-7 wt. % of nimesulide, a gelling agent selected from 0.1 to 5 wt.% carboxyvinyl polymer, neutralized with an aqueous solution of triethanolamine or diisopropanolamine, or 0.5-10 wt.% polyacrylonitrile, the solvent is selected from the group comprising ethanol, isopropanol and monotropy ether of diethylene glycol, and the concentration of ethanol and isopropanol in the product is from 5 to 20 wt.%, monoethylene ether of diethylene glycol is from 5 to 40 wt.%, as the water content is from 40 to 95 wt.%.

2. The drug under item 1, containing ethanol and isopropanol at a concentration of 10 wt.%.

3. The drug under item 1, containing monotropy ether of diethylene glycol at a concentration of 15 wt.%.

4. The drug PCP.1-3, in which preservatives are imidazolidinedione, parabens and Na-salt of ethylenediaminetetraacetic acid.

5. The drug according to any one of paragraphs.1-4, optionally containing additives selected from wetting agents and amplifiers dermal absorption.

6. The method of producing drug for PP.1, 2, 4, and 5, including the production of aqueous disperse phase containing water-soluble preservatives and carboxyvinyl polymer, adding an alcoholic solvent, the dispersion of nimesulide, water-insoluble preservatives, and optionally additives selected from wetting agents and amplifiers dermal absorption, neutralization carboxyvinyl polymer with an aqueous solution of triethanolamine or diisopropanolamine.

7. The method of producing drug for PP.1-5, including the preparation of an aqueous phase containing water-soluble preservatives, a mixture of esters of Caprile the organic phase, containing water-insoluble preservatives, preferably a mixture of parabens, and nimesulide in monoethylene ether of diethylene glycol, dispersing the organic phase in the aqueous phase and neutralization carboxyvinyl polymer introduction triethanolamine or diisopropanolamine.

 

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