TOPICAL COMPOSITIONS CONTAINING DICLOFENAC

Abstract: The invention relates to pharmaceutical compositions comprising a non-steroid antiinflammatory drug, namely diclofenac hydroxy­ ethylpyrrolidine (DIEP), suitably carried by lipid substances of amphipathic character to allow topical application, with adequate cutaneous absorption.

Description: Those substances which possess maximum cutaneous absorption levels are known to present amphipathic characteristics of between 4 and 15 expressed as the HLB (hydrophil-lipophil balance) value (Remington's Pharmaceutical Sciences, Easton Penna, 1975, USA) and a very low degree of ionization. EP-A-271.709 discloses diclofenac salt of hydroxyethylpyrrolidine (DIEP) which is soluble in water. Diclofenac hydroxyethylpyrrolidine (DIEP) is soluble in water to concentrations exceeding 50% (w/v) in which it ionizes practically totally, but is only slightly soluble in polar organic solvents, and is practically insoluble in apolar organic solvents. These physico-chemical characteristics mean that a product dissolved in a water phase cannot be satisfactorily absorbed by the cutis, as demonstrated by the insufficient antiinflammatory activity obtained when DIEP is applied in the form of medicated gels based on cellulose or acrylic derivatives, such as those of the following compositions. Composition I: DIEP 1.32% Neutralized polymerized acrylic acid 2.00% Isopropyl alcohol 10.00% Demineralized water to make up to 100.00% Composition II: DIEP 1.32% Glycerin 25.00% Hydroxyethylcellulose 2.00% Parabens 0.80% Demineralized water to make up to 100.00% In fact EP-A-271.709 describes pharmaceutical formulations of DIEP for oral use only. We have now discovered new pharmaceutical compositions for topical use able to act as improved vehicles for diclofenac hydroxyethylpyrrolidine (DIEP). Said compositions comprise: diclofenac hydroxyethylpyrrolidine (DIEP), lipid substances of amphipathic character with high cutaneous absorption, suitable surfactants, co-solvents and additives of common pharmaceutical use suitable for topical application, incorporated in a viscous hydrophilic support (gel). Said compositions are prepared by dissolving the DIEP in the lipid substances in the presence of surfactants, co-solvents and additives, and emulsifying the obtained mixture together with the viscous hydrophilic support. The compositions obtained have physico-chemical characteristics which indicate their suitability for cutaneous absorption and are easy to apply locally. The characteristics and advantages of the pharmaceutical compositions for topical use according to the invention will be more apparent from the following detailed description. Said compositions comprise diclofenac hydroxyethylpyrrolidine (DIEP) as active principle and, as vehicles, lipid substances of amphipathic character, surfactants, co-solvents and additives of common pharmaceutical use, and are incorporated in a viscous hydrophilic support (gel). Of the possible lipid substances which can be used, those pertaining to the following four groups are preferred: 1) Cetyl and stearyl esters of ethylhexanoic acid which have been made hydrophilic by surfactants, and have an HLB of between 10 and 12; 2) C₈-C₁₈ mono and/or di and/or triglycerides with different polyoxyethylenated/glycolyzed aliphatic chains, and having an HLB of between 4 and 14; 3) Phospholipids of vegetable origin having an HLB of between 12 and 14; 4) Lanolin esters having an HLB of 9. The dissolving of the DIEP in said lipid compounds is aided by adding non-ionic surfactants having an HLB of between 10 and 13, such as polyethyleneglycol stearates, cetomacrogols etc. The co-solvents used can be glycols, ethyldiglycol or low molecular-weight polyethyleneglycols, which also perform a wetting action in the complete formulation. The lipid solutions obtained are emulsified in a transparent hydrophilic gel consisting of suitably neutralized polymerized acrylic acid. A gel is obtained having a milky or transparent appearance, and of suitable viscosity and consistency for application to the skin. The composition is completed by the addition of additives of common pharmaceutical use such as antimicrobials, for example nipaginics, isopropyl alcohol or perfumes. In the compositions of the present invention the various components are contained in the following weight proportions: DIEP between 0.5 and 2%, lipids between 1 and 5%, surfactants between 1 and 10%, co-solvents between 3 and 12%, acrylic acid between 0.5 and 3%, and other commonly used additives between 7 and 15%, the difference to 100% being demineralized water. When used topically, the compositions prepared in this manner are easily absorbed to carry the DIEP into the dermis where it efficiently performs its pharmacological action. The following examples of compositions according to the present invention are given for illustrative purposes. EXAMPLE 1 % by weight DIEP 0.5- 2 acetylstearyl-2-ethylhexanoate 1 - 4 polyethyleneglycol 400 stearate 1 - 2 polyethyleneglycol 300 or propyleneglycol 5 - 10 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 demineralized water to make up to 100 EXAMPLE 2 % by weight DIEP 0.5- 2 cetylstearyl-2-ethylhexanoate 1 - 2 cetomacrogol stearyl alcohol 1 - 2 polyethyleneglycol 300 or propyleneglycol 5 - 10 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 demineralized water to make up to 100 EXAMPLE 3 % by weight DIEP 0.5- 2 polyoxyethylenated C₁₂-C₁₈ glycerides 1 - 4 ethyldiglycol 3 - 8 polyethyleneglycol 400 stearate 1 - 2 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 demineralized water to make up to 100 EXAMPLE 4 % by weight DIEP 0.5- 2 polyoxyethylenated ricinoleic triglyceride 0.5- 5 polyethyleneglycol 400 stearate 1 - 2 propyleneglycol 5 - 10 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 demineralized water to make up to 100 EXAMPLE 5 % by weight DIEP 0.5- 2 soya lecithin 2 - 5 polyethyleneglycol 400 stearate 1 - 2 glycerin 5 - 10 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 demineralized water to make up to 100 EXAMPLE 6 % by weight DIEP 0.5- 2 isopropyl lanolate 1 - 4 glyceryl monostearate or polyethyleneglycol 400 stearate 1 - 4 propyleneglycol 6 - 12 polymerized acrylic acid 0.5- 3 triethanolamine 1 - 4 isopropanol 6 - 10 perfume 0.1- 0.2 dimineralized water to make up to 100 By way of example, the antiinflammatory activity results obtained experimentally in the rat by applying 1 gram of some of the aforesaid preparations indicated with 1-4-5 are shown hereinafter, compared with those of a hydrophilic gel containing the same concentration of DIEP (Composition I of the known art). Preparation DIEP concentration Quantity applied to rat No. of rats Analgesic/peripheral anti-inflammatory activity (Randall-Selitto test) 1 1.32% 1 g 5 65% 4 1.32% 1 g 5 72% 5 1.32% 1 g 5 68% Hydrophilic gel (Composition I) 1.32% 1 g 5 22% These results clearly indicate the considerable increase in absorption of the active principle obtained with the compositions according to the present invention.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Pharmaceutical compositions for topical use able to act as vehicles for diclofenac hydroxyethylpyrrolidine (DIEP) characterized in that they comprise: a) diclofenac hydroxyethylpyrrolidine (DIEP) as active principle; b) lipid substances of amphipathic character with high cutaneous absorption, selected from the classis of cetyl and stearyl esters of ethylhexanoic acid made hydrophilic by surfactants and havig a HLB between 10 and 12; C₈ ÷ C₁₈ mono- and/or di- and/or tri-glycerides with different poly oxyethylenated/glycolyzed aliphatic chains, with an HLB of between 4 and 14; phospholipids of vegetable origin with an HLB between 12 and 14; lanolin esters with an HLB of 9; c) a surfactant of non-ionic type with an HLB of between 10 and 13 d) a viscous hydrophilic support consisting of neutralized polymerized acrylic acid e) co-solvents selected from: glycols, ethyldiglycol and low molecular weight polyethyleneglycols. Compositions as claimed in claim 1, characterised in that said surfactants are polyethyleneglycol stearates and cetomacrogols. Compositions as claimed in claim 1, characterised by comprising the various components in the following weight proportions: DIEP between 0.5 and 2%, lipids between 1 and 5%, surfactants between 1 and 10%, co-solvents between 3 and 12%, acrylic acid between 0,5 and 3% and other commonly used additives between 7 and 15%, the difference to 100% being demineralized water. A method for preparing the compositions claimed in claim 1, characterised in that the DIEP is dissolved in the lipid substances in the presence of the surfactants, co-solvents and additives, the mixture obtained then being emulsified with the viscous hydrophilic support. Claims for the following Contracting States : ES, GR Process for preparing pharmaceutical compositions for topical use, containing as active principle diclofenac hydroxyethylpyrrolidine (DIEP), which comprises the following steps: a) dissolving DIEP in a lipid substance of amphipathic character having high cutaneous absorption, selected from the classis of: cetyl and stearyl esters of ethylhexanoic acid made hydrophilic by surfactants and having a HLB between 10 and 12; C₈ +C₁₈ mono- and/or di- and/or tri-glycerides with different poly oxyethylenated/glycolyzed aliphatic chains, with an HLB of between 4 and 14; phospholipids of vegetable origin with an HLB between 12 and 14; lanolin esters with a HLB of 9; in combination with a co-solvent selected from: glycols, ethyldiglycol and low molecular weight polyethylenglycols and with a surfactant of non-ionic type having an HLB between 10 and 13; b) emulsifying the lipid solution of DIEP with a hydrophilic gel consisting of neutralized polymerized acrylic acid. Process according to claim 1 wherein the various components are used in the following weight proportions: DIEP between 0.5 and 2%, lipids between 1 and 5%, surfactants beween 1 and 10%, co-solvents between 3 and 12%, acrylic acid between 0.5 and 3% and furthermore commonly used additives, the difference to 100% being demineralized water, and commonly used additives. Process according to claim 1 wherein the surfactant of non-ionic type are selected from polyethylenglycol stearates and cetomacrogols.

Inventors: DONATI-PEDEMONTI, ELISABETTA, LUALDI, PAOLO
Applicants: ALTERGON S.A.
Application year: 1989
Main classification: A61K31
IPC codes: A61K47, A61K31, A61K9