Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present invention relates to nimesulide topical formulations based on gel systems.
• Nimesulide is a known antiinflammatory agent whose therapeutical efficacy has been proved for some time, but which has the drawback of having unfavourable chemical-physical characteristics; the main obstacle to the use of nimesulide in topical formulations is in fact its insolubility in water and, on the other hand, its poor solubility in the solvents/raw materials usually employed in such formulations.
• nimesulide for the external use are described in WO 96/11002; said formulations consist in dispersions of particles of the active ingredient throughout a component which, in the case of creams, comprises a hydrophilic polymer, an oily substance, a surfactant agent, a basic substance and water.
• the gel-forming action is obtained preferably through neutralization of the carboxyvinylpolymer resin in the acidic form, which chemically behaves as a weak acid; as regards the base to employ in the neutralization, the use of weak bases such as triethanolamine or diisopropanolamine, in a 1:1 acid/base equivalent ratio, turned out to be particularly successful.
• weak bases such as triethanolamine or diisopropanolamine
• the carboxyvinylpolymer used in the gelling process is obtained starting from acrylic/methacrylic acid, and it is used in amounts ranging from 0.1% to 5% by weight, preferably 0.5%-2.5%.
• a polyacrylamide-isoparaffin known under the commercial name Sepigel (Sepic) in amounts ranging from 0.5 to 10% by weight, can be used advantageously as the gel-forming agent.
• non aqueous solvents in the preparation of the gel systems of the invention, involves undoubtable advantages both in terms of chemical-physical characteristics and of release and absorption properties of nimesulide.
• the invention relates to the use of the solvents ethanol, isopropanol and diethylene glycol monoethyl ether, the latter proving to be particularly effective in increasing the absorption of the active ingredient, thanks to its solvent effect on the lipidic dermal barrier.
• Viscosity and pH of the compositions of the present invention can vary within wide ranges: from a few cps to above 100,000 as regards viscosity, whereas the preferred pH range is from 5 to 7.
• the amount of water can range from 40% to 95% by weight, whereas the amount of solvent, also depending on its contribute to the evaporation of the aqueous phase, is comprised from 5% to 20% by weight for ethanol and isopropanol, preferably about 10%; on the other hand, as far as diethylene glycol monoethyl ether is concerned, the diffusion and permeation properties thereof are related to concentrations from 5% to 40% by weight, preferably about 15%.
• the active ingredient nimesulide can be dispersed in a wide range of concentrations, preferably from 0.5% to 7% by weight.
• compositions of the invention can also contain lipophilic excipients, such as caprylic or capric esters, or gliceryl(8)0E, which are capable of improving both the absorption and the final spreadability and “skin-feel” characteristics.
• lipophilic excipients such as caprylic or capric esters, or gliceryl(8)0E, which are capable of improving both the absorption and the final spreadability and “skin-feel” characteristics.
• the preservant system provides a microbiological protection by means of wide spectrum antimicrobials, such as imidazolidinyl urea and a balanced parabens mixture; a further guarantee of stability is the presence of a sequestrating agent such as EDTA which is capable of chelating any dangerous ions to keep an appropriate viscosity index.
• wide spectrum antimicrobials such as imidazolidinyl urea and a balanced parabens mixture
• a further guarantee of stability is the presence of a sequestrating agent such as EDTA which is capable of chelating any dangerous ions to keep an appropriate viscosity index.
• compositions of the invention can further comprise emollients/humectants, such as cetyl esters 1-15% by weight, cholesterol 0.3-0.5% by weight, glycerin 1-30% by weight, isopropyl myristate 1-10% by weight, isopropyl palmitate 0.05-5.5% by weight, lecithin 1-20% by weight, lanolin alcohols 0.5-15% by weight, vaseline 4-95% by weight, soy lipids 1-20% by weight, as well as dermal absorption enhancers such as 2-pyrrolidone 0.1-10% by weight, propylene glycol 5-50% by weight, pyrrolidone derivatives 0.1-10% by weight.
• emollients/humectants such as cetyl esters 1-15% by weight, cholesterol 0.3-0.5% by weight, glycerin 1-30% by weight, isopropyl myristate 1-10% by weight, isopropyl palmitate 0.05-5.5% by weight, lecit
• compositions of the invention can be prepared according to a process comprising:
• phase containing the preservatives (parabens) in diethylene glycol monoethyl ether and dispersion of the active ingredient.
• phase consisting of caprylic/capric esters and glyceryl(8)0E;
• compositions of the invention have the following advantages:
• compositions of the invention proved to be well tolerated, both in animals (rabbit and guinea pig) and in clinical studies.
• compositions of the invention has been tested using well-known pharmacological tests, such as the UV-induced erythema in guinea pigs, the croton oil-induced inflammation of the guinea pig ear, the carrageenin-induced granuloma in the rat.
• compositions of the invention were also clinically tested on 200 patients affected with tendinitis of the upper limb or with benign ankle sprains, according to a controlled, double-blind experimental design.
• compositions of the invention turned out to be effective in a statistically significant way, in comparison with placebo.
• Phase Ingredient % w/w Phase A Purified water q.s. Imidazolidinyl urea 0.20 EDTA tetrasodium salt 0.10 Phase B Carbomer (CARBOPOL 1382) 1.20 Phase C Mix parabens 0.20 Vaseline 1.00 Phase D Isopropanol 10.00 Phase E Nimesulide — Phase F Purified water 10.00 Triethanolamine 0.60
• the formulation was prepared at four nimesulide concentrations, i.e. 2, 3, 4, 5% w/w, each concentration in 3 different 5 kg batches
• Phase A+B i.e. the dispersion of Carbopol in the solution of water and preservatives, was obtained by swelling the gel for two days at room temperature until reaching a homogeneous dispersion.
• Phase C was prepared in a Gianke & Kunkel Type PM43 paddle mixer heated on a water bath.
• the whole preparation can be performed dispersing Carbopol in water by means of a turbine under vacuum, mixing with paddles after addition of phase C and homogenizing again with the turbine under vacuum after addition of isopropanol.
• % w/w Water 83.40 Isopropanol 10.00 Nimesulide 3.00 Carbomer (CARBOPOL 1382) 1.40 Petrolatum 1.00 Triethanolamine 0.60 Imidazolidinyl urea 0.20 Methyl, ethyl, propyl parabens 0.20 Tetrasodium EDTA 0.10
• the formulation was prepared at four nimesulide concentrations, i.e. 2%, 3%, 4%, 5% w/w, each concentration in 3 different 5 kg batches.
• % w/w Water 83.40 Diethylene glycol monoethyl ether 15.00 Nimesulide 3.00 Carbomer (CARBOPOL 940) 1.00 PEG-8 Caprylic/capric glycerids 2.00 Triethanolamine 0.50 Imidazolidinyl urea 0.20 Methyl, ethyl, propyl parabens 0.20 Tetrasodium EDTA 0.10

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Engineering & Computer Science (AREA)
• Dermatology (AREA)
• Inorganic Chemistry (AREA)
• Organic Chemistry (AREA)
• Rheumatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pain & Pain Management (AREA)
• Medicinal Preparation (AREA)
• Cosmetics (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Orthopedics, Nursing, And Contraception (AREA)
• Medicines Containing Plant Substances (AREA)

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• 1997
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• 1998
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