topical formulation containing phosphate buffer as skin permeation enhancer

Abstract: The present invention relates to a novel pharmaceutical formulation for the topical application of drugs, particularly non-steroidal anti-inflammatory drugs (NSAID's), comprising (a) a therapeutically effective amount of a drug; (b) sodium phosphate buffer; and, optionally, (c) an alcoholic solvent.

Description: The present invention relates to a novel pharmaceutical formulation for the topical application of non-steroidal anti-inflammatory drugs (NSAID's). In view of adverse drug reactions associated with oral formulations, NSAID's are administered increasingly by the topical route. A prerequisite for successful topical NSAID medication is that the drug sufficiently permeates across the skin into deeper tissues such as subcutis, fasciae, tendons, ligaments and muscles to treat inflammatory degenerative and posttraumatic alterations of soft tissue structures. Hydroalcoholic formulations, e.g., ethanol/water and propylene glycol/ethanol/water are commonly used formulations for the topical application of NSAID's. In accordance with the present invention it has been found that by the addition of sodium phosphate buffer to such formulations the permeation of the NSAID can be significantly improved. WO 98/27960, which is a prior art document according to Art 54 (3) and 54 (4) EPC for the contracting states AT, BE, CH, LI, DE DK, ES, FI, FR, GB, GR, IE, IT LU, NL, PT, SE, discloses a viscous hydrogel composition comprising an antimicrobially active nitroimidazole drug, a water miscible alkylene glycol, a hydroxyalkyl cellulose gelling agent and water. The composition is buffered to have a physiologically acceptable pH. WO 98/27960 is not concerned with formulations containing NSAID and with the permeability of these drugs, across the skin, into deeper tissues. Accordingly, the invention is concerned with a gel formulation for topical application of non-steroidal anti-inflammatory drugs (NSAID's)as defined in claim 1. The NASAID drug contained in the formulation according to the invention may be any drug that is conventionally applied topically. Drugs of primary interest are naproxen, ibuprofen, indomethacin, diclofenac, piroxicam or etofenamat and pharmaceutically acceptable salts thereof. A preferred NSAID for the purposes of the invention is naproxen. Any salt that is conventionally used in pharmaceutical preparations for NSAID's can be used. Examples of such salts are alkali metal salts such as sodium and potassium salts, and substituted ammonium salts such as salts with alkylamines and hydroxyalkylamines, e.g. diethylamine and triethanolamine. The molarity of the sodium phosphate buffer is suitably in the range of from 10 to 300 mM, preferably 100 to about 200 mM. The pH of the buffer solution is preferably between 5 and 7.5, more preferably 6.0 to 7.5. Most preferred is pH 6.0. The alcoholic solvent can be any such solvent conventionally used in topical formulations. Preferred alcoholic solvents are ethanol, isopropanol, propylene glycol and mixtures thereof. Another example of an alcoholic solvent is glycerol. Preferred alcoholic solvents are mixtures of ethanol and propylene glycol in a ratio of 3:1 parts by weight. Any gel forming agent commonly used in pharmaceutical gel formulations can be used. Examples of gel forming agents are cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; vinyl polymers such as polyvinyl alcohols, polyvinyl pyrrolidones; and polyacryl derivatives such as Carbopol. Further gelling agents that can be used for the compositions in accordance with the invention are pectins, gums, such gum arabic and tragacanth, alginates, carrageenates, agar and gelatine. The preferred gelling agent used in the present invention is hydroxypropylmethyl cellulose (HPMC). Further, the gel formulation of this invention may also contain auxiliary agents commonly used in such formulations such as preservatives, antioxidants, stabilizers, colorants and perfumes. The amount of active ingredient present in the formulations of the present invention is generally the same as in corresponding conventional formulations. The NSAID active ingredient amount may vary, e.g., from 0.1 to 10 g of NSAID per 100 g of finished formulation preferably 0.5-2.5g, most preferably 1g per 100g of finished formulation. In an embodiment according to the present invention, the NSAID active ingredient is naproxene sodium, present preferably in the amount of 1 g per 100 g of finished formulation. The amount of sodium phosphate buffer may vary from 30 to 90 g, preferably 30 to 70 g of a 100-200 mM solution per 100 g of finished formulation. The amount of alcoholic solvent is suitably from 5 to 70 g per 100 g of finished formulation. In a preferred aspect of the invention the alcoholic solvent comprises 20 to 40 g of ethanol and 5 to 30 g of propylene glycol. The amount of gelling agent sufficient to obtain a gel formulation having adequate viscosity for application on the skin depends on the particular gelling agent or agents used and the desired viscosity of the finished gel formulation and can be determined by the pharmaceutical formulation expert depending on the individual requirements. The formulations in accordance with the present invention can be prepared in a conventional manner. For example, the NSAID is dissolved in the aqueous buffer solution and, optionally, alcoholic co-solvents. The obtained solution may then be gelled by adding a gelling agent, e.g., hydroxyethylcellulose or hydroxypropylmethyl cellulose. The following Examples illustrate the invention: Example 1 A gel was prepared from the following constituents: Constituent [gram] Naproxen sodium 1.1 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 200 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 2 A gel was prepared from the following constituents: Constituent [gram] Naproxen sodium 1.1 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 100 mM 50.0 Hydroxypropylmethyl cellulose 2.5 Water q.s. ad 100.0 Example 3 A gel was prepared from the following constituents: Constituent [gram] Naproxen (free acid) 1.0 Triethanolamine 0.65 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 200 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 4 A gel was prepared from the following constituents: Constituent [gram] Naproxen sodium 2.74 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 200 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 5 A gel was prepared from the following constituents: Constituent [gram] Naproxen sodium 5.5 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 200 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 6 A gel was prepared from the following constituents: Constituent [gram] Naproxen sodium 1.1 Ethanol 30.0 Propylene glycol 10.0 Aqueous sodium phosphate buffer pH6.0 100 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 7 A gel can be prepared from the following constituents: Constituent [gram] Naproxen sodium 1.1 Aqueous sodium phosphate buffer pH 7.25 100 mM 50.0 Hydroxyethyl cellulose 1.6 Water q.s. ad 100.0 Example 8 Skin permeation studies Skin permeation of naproxen from formulations in accordance with the invention (Example 1), from a corresponding unbuffered formulation (Formulation B) and from a prior art formulation (NaprosynGEL™,Formulation A) was measured. Formulation A and B were prepared having the composition given below: Formulation A B [gram] Naproxen (free acid) 10.0 - Naproxen sodium - 1.1 Triethanolamine 13.0 - Ethanol 30.0 30.0 Propylene glycol - 10.0 Hydroxyethyl cellulose - 1.6 Carbomer 940 2 - Sodium metabisulfite 0.1 - Rose fragrance 0.03 - Water q.s. ad 100.0 100.0 Skin samples of abdominal skins from human cadavers were dermatomed (0.38 mm) and freezed at -80°C. At the day of experiment the skin samples were thawed and mounted in Franz-type diffusion cells with a diffusional cross-sectional aera of 1 cm 2 and a receptor chamber volume of 5 ml. The receptor compartments, equipped with magnetic stirring bars, were filled with 1 mM phosphated buffered saline, pH 7.4. The diffusion cells were then transferred into a heating box thermostated at 32°C. Following an equilibration period of 3-4 h, 5 mg/cm 2 of the test formulations were applied to epidermal surfaces using micropipets. After 45 h incubation under non-occluded conditions at 32°C the receptor solutions were withdrawn and naproxen concentrations were measured by HPLC. Results are presented in Figure 1.

Claims: A gel formulation for topical application comprising per 100 g formulation: a) 0.1 to 10 g of NSAID; b) 30 to 90 g of 10-300 mM aqueous sodium phosphate buffer pH 5 to 7.5; c) 5 to 70 g of an alcoholic solvent; d) at least one gelling agent in an amount sufficient to obtain a gel formulation having adequate viscosity for application to the skin. A gel formulation as in claim 1 comprising per 100 g of formulation (a) 0.1 to 10 g of NSAID (b) 30 to 70 g of 100-200 mM sodium phosphate buffer pH 6-7.5; (c1) 20 to 40 g of ethanol and/or isopropanol; (c2) 5 to 30 g of propylene glycol; and (d) at least one gelling agent in an amount sufficient to obtain a gel formulation having adequate viscosity for application to the skin. A gel formulation as in claim 1 or 2 wherein the sodium posphate buffer has a pH value of 6. A gel formulation as in any preceding claim wherein the gelling agent is hydroxypropylmethyl cellulose. A gel formulation as in any preceding claim wherein the NSAID is naproxen sodium A gel formulation as in any claim 1 to 4 wherein the NSAID is present in an amount of about 1 %. A gel formulation as in claim 5 wherein the NSAID is about 1% naproxen sodium.

Inventors: SUPERSAXO ANDREAS, SUPERSAXO, ANDREAS
Applicants: ROCHE CONSUMER HEALTH WORLDWID, ROCHE CONSUMER HEALTH (WORLDWIDE) SA
Application year: 1998
Main classification: A61K47
IPC codes: A61K47, A61K31, A61K9