Patent Description:
Anti-inflammatory drugs are medicaments used to ameliorate muscle pains, sprains, strains, as well as arthritis pains. These drugs can be administered orally (e.g., tablets, liquids, capsules), injected, or applied to the skin. When applied to the skin, such medicaments are referred to as topical anti-inflammatory painkillers. One such group of medicaments, by reason of their chemical structure are usually referred to as topical non-steroidal anti-inflammatory drugs or topical NSAIDS.

When NSAIDS are taken orally they work by inhibiting the cyclo-oxygenate (cox) enzymes which make prostaglandins that are involved in causing pain and inflammation at injured body sites. A reduction in prostaglandins, in turn, results in reduction of pain. Topical NSAIDS function in the same manner, but instead of a systemic effect, the pain relief is provided in the region or area to which the topical preparation has been applied. Upon topical application, the NSAIDS are first absorbed into the skin and then move deeper into an inflamed region of the body and relieve pain and reduce swelling of the affected joints and tissues. As compared to any route of systemic administration, topically applied NSAIDS introduce into the body a relatively low amount of the drug and thus reduce the likelihood of adverse side effects. Yet currently available topical NSAID preparations are relatively slow in releasing the drug into the affected area. <CIT> relates to an aqueous topical gel composition, having a pH value in the range of <NUM> to <NUM> (<NUM> to <NUM>), comprising a non-steroidal anti-inflammatory drug which is an arylalkanoic acid (ketoprofen), a C2 to C8 saturated aliphatic alcohol (ethanol), a aliphatic C8 to C30 esters (isopropyl myristate) and a polymeric skin penetration enhancer (cationic galactomannan gum).

It has now been found, however, that the rate of release of NSAIDS from topical gels can be enhanced by the use of specific aqueous carrier systems for NSAIDS.

The invention relates to an aqueous, topical anti-inflammatory gel composition having a pH value in the range of <NUM> to <NUM>, which comprises:a non-steroidal anti-inflammatory drug (NSAID) which is an arylalkanoic acid, a lactate ester of a C2 to C16 saturated aliphatic alcohol, a monoprotic organic acid having a pKa value in the range of about <NUM> to about <NUM>, a C2 to C8 saturated aliphatic alcohol, a solubility enhancer, and a cationic galactomannan gum,wherein the cationic galactomannan gum content in the composition is in the range of <NUM> to <NUM> percent by weight, based on the total weight of the composition. An arylalkanoic acid non-steroidal anti-inflammatory drug (NSAID) in an aqueous carrier that includes a cationic galactomannan gum system provides a topical composition that enhances skin penetration of the NSAID and is suitable for treating inflammation, mild to moderate pain, and fever.

The arylalkanoic acid can be an arylethanoic acid or its pharmaceutically acceptable salt form, e.g., diclofenac, diclofenac sodium, or an arylpropanoic acid or its pharmaceutically acceptable salt form, e.g., naproxen, naproxen sodium, ketoprofen.

The aqueous carrier system includes, in addition to water, a lactate ester of a C<NUM> to C<NUM> saturated aliphatic alcohol, a monoprotic organic acid having a pKa value in the range of about <NUM> to about <NUM>, a C<NUM> to C<NUM> saturated aliphatic alcohol, a solubility enhancer, and a cationic galactomannan gum.

The topical composition contains the arylalkanoic acid in an amount in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

The topical compositions embodying the present invention are relatively low viscosity gels having a pH value in the range of <NUM> to <NUM>. These gels can be readily dispersed and applied to body regions to be treated in an effective amount without causing irritation, providing enhanced delivery of the NSAID to the affected region for the treatment of inflammation and pain.

Suitable NSAIDS are the arylalkanoic acids, including the pharmaceutically acceptable salts thereof, such as arylethanoic (arylacetic) acids, arylpropanoic acids, and their salts. Illustrative arylethanoic acids are diclofenac, diclofenac sodium, diclofenac potassium, diclofenac diethylamine, diclofenac epolamine, indomethacin sodium, indomethacin meglumine, ketorolac tromethamine, tolmetin sodium, etodolac, sulindac, nabumetone. Illustrative arylpropanoic acids are naproxen, naproxen sodium, naproxen piperazine, ketoprofen, ketoprofen sodium, ketoprofen lysine, ibuprofen, ibuprofen sodium, ibuprofen lysine, fenoprofen, fenoprofen calcium, flurbiprofen.

The topical compositions contain an arylalkanoic acid in an amount in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

Preferably, the present topical anti-inflammatory compositions also include a photostabilizer which absorbs UVA and UVB ultraviolet radiation, i.e., ultraviolet radiation in the <NUM> to <NUM> nanometer wavelength region. Suitable photostabilizers for the present topical compositions are the benzophenones such as oxybenzone (benzophenone-<NUM>), sulisobenzone (benzophenone-<NUM>), the dibenzoylmethane derivatives such as avobenzone [<NUM>-(<NUM>-methoxyphenyl)-<NUM>-(<NUM>-tert. -butylphenyl)propane-<NUM>,<NUM>-dione)], the cinnnamate derivatives such as ethylhexyl methoxycinnamate, isoamyl methoxycinnamate, the acrylates such as octocrylene (<NUM>-ethylhexyl-<NUM>-cyano-<NUM>,<NUM>-diphenylacrylate, ethyl-<NUM>-cyano-<NUM>,<NUM>-diphenylacrylate), as well as mixtures of the foregoing.

In the present topical compositions the photostabilizer preferably is present in an amount in the range of about <NUM> to about <NUM> percent by weight, more preferably about <NUM> to about <NUM> percent by weight, based on the total weight of the composition.

The photostabilizers may be used with or without a solubilizer such as phenethyl benzoate, dipropylene glycol dibenzoate (DiPG-dibenzoate), <NUM>-(<NUM>-ethoxyethoxy)ethanol (transcutol). Levulinic acid, if present, can also aid in solubilization of a photostabilizer such as oxybenzone.

The present topical anti-inflammatory compositions can also contain crystallization inhibitors such as polymeric precipitation inhibitors, e.g., low molecular weight polyvinylpyrrolidone, hydroxymethyl cellulose, polyethylene glycol poloxamers, polysorbate surfactants, e.g., polyoxyethylene (<NUM>) sorbitan monolaurate, and the like, sugar alcohols such as sorbitol.

In the present topical compositions the photostabilizer can be present preferably in an amount in the range of about <NUM> to about <NUM> percent by weight, based on the total weight of the composition, more preferably about <NUM> to about <NUM> percent by weight, based on the total weight of the composition.

Illustrative lactate esters of a C<NUM> to C<NUM> saturated aliphatic alcohol are ethyl lactate, n-butyl lactate, isoamyl lactate, <NUM>,<NUM>-ethylhexyl lactate, lauryl lactate, myristyl lactate, cetyl lactate.

A preferred lactate ester is lauryl lactate.

The lactate ester content of the present compositions is in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

Suitable monoprotic organic acids are those having a pKa value in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>. Illustrative such acids are lactic acid (pKa <NUM>), hydroxymethyl-butyric acid (pKa <NUM>), levulinic acid (pKa <NUM>), acetic acid (pKa <NUM>), hexanoic (caproic) acid (pKa <NUM>).

The monoprotic organic acid content of the present compositions is in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

Suitable C<NUM> to C<NUM> saturated aliphatic alcohols can be monohydric as well as dihydric. Illustrative C<NUM> to C<NUM> monohydric saturated aliphatic alcohols are ethanol, propanol, isopropanol, n-butanol, the hexanols. Illustrative C<NUM> to C<NUM> dihydric saturated aliphatic alcohols are ethylene glycol, propylene glycol, butylene glycol, hexylene glycol.

The C<NUM> to C<NUM> saturated aliphatic alcohol content of the present compositions is in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition. The present compositions can contain only a monohydric C<NUM> to C<NUM> saturated aliphatic alcohol, only a dihydric C<NUM> to C<NUM> saturated aliphatic alcohol, or a mixture of monohydric and dihydric C<NUM> to C<NUM> saturated aliphatic alcohols. Particularly preferred is a mixture of ethanol and propylene glycol is a respective weight ratio in the range of about <NUM>:<NUM> to about <NUM>:<NUM>.

Suitable solubility enhancers are the monoglycerides such as glycerol monooleate, glycerol monolaurate, glycerol monolinoleate, mixtures thereof. Preferred solubility enhancer is glycerol monolaurate. The solubility enhancer content of the present compositions is in the range of about <NUM> to about <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

Galactomannan gums are polysaccharides having a mannose backbone and galactose side groups such as fenugreek gum (mannose:galactose ~ <NUM>:<NUM>), guar gum (mannose: galactose ~ <NUM>:<NUM>), tara gum (mannose: galactose ~ <NUM>:<NUM>) and locust bean gum (mannose: galactose ~ <NUM>:<NUM>). Suitable for use in the present compositions are cationic galactomannan gums, i.e., galactomannan gums containing cationic groups and/or groups which can be ionized to cationic groups. Preferred cationic groups are primary, secondary, tertiary and/or quaternary amine groups.

Particularly preferred are cationic guar gums with hydroxypropyltrimethylammonium groups and salts thereof such as guar gum, <NUM>-hydroxy-<NUM>-(trimethylammonium) propyl ether chloride, commercially available under the designation Jaguar C162 from various sources such as Rhodia Operations, <NUM> Aubervilliers Cedex, France, Solvay USA Inc. , Cranbury, NJ, USA.

Suitable cationic guar gums are also described in <CIT>, <CIT>, and <CIT>.

The cationic galactomannan gum content in the present compositions is in the range of <NUM> to <NUM>, preferably about <NUM> to about <NUM>, percent by weight, based on the total weight of the composition.

The topical compositions described herein can be prepared in the following manner.

A cationic guar gum is dispersed in water with agitation at room temperature. In a separate vessel the NSAID is combined with a lactate ester, the monoprotic organic acid, the C<NUM> to C<NUM> saturated aliphatic alcohol, and a solubility enhancer. An aliquot of water is added after the monoprotic organic acid has been dissolved, and the resulting solution is agitated thoroughly. The photostabilizer, if desired, is added concurrently.

Thereafter the solution is transferred quantitatively to the aqueous dispersion of the cationic guar gum with vigorous agitation for a time period of at least two hours until a substantially homogeneous gel is achieved. The obtained gel is then left standing before packaging for a time period sufficient for entrained air bubbles to disperse.

Skin permeation studies of illustrative topical compositions embodying the invention were performed using dermatomed human male cadaver skin pieces from the back (Science Care, Aurora, CO; <NUM> micrometers thick), Franz cells (<NUM> volume, <NUM><NUM> surface area) at <NUM>° C using heating/stirring blocks. Receptor compartment contained saline with sodium azide (pH <NUM>).

Four or five replicates (<NUM> and <NUM> control) were prepared for each sample. Sampling volume was <NUM>. Fresh buffer was replaced after each sample removal. The samples were assayed using high performance liquid chromatography (HPLC).

For naproxen the control was Apronax® gel (<NUM>% naproxen sodium) or Flanax® gel (<NUM>% naproxen sodium), Bayer de Mexico S. , Lerma, Mexico.

For diclofenac the control was Voltaren® gel (<NUM>% diclofenac sodium), Novartis Pharma Productions GmbH, Wehr, Germany.

For ibuprofen the control was Ibutop™ Schmerzgel gel (<NUM>% ibuprofen), Axicorp Pharma GmbH, Friedrichsdorf, Germany, or Ibuleve™, DDD Limited, <NUM> Rickmansworth Road, Watford, Herts, U.

Results of the skin permeation studies are presented below.

Topical compositions shown in Table <NUM>, below, and containing about <NUM> percent by weight naproxen or sodium salt of naproxen were compared with Apronax® gel containing about <NUM> percent by weight naproxen sodium. Skin permeation results are presented in Table <NUM>, below, and in <FIG>.

The above skin permeation data show that the present compositions, containing a relatively lower concentration of naproxen provided more skin penetration of naproxen that a commercially available naproxen sodium gel having a relatively higher naproxen concentration. The data further show that the skin penetration of naproxen sodium and naproxen was about the same.

Topical compositions shown in Table <NUM>, below, and containing about <NUM> percent by weight of diclofenac, diclofenac sodium, or diclofenac diethylamine were evaluated for skin permeation and compared with Voltaren® Gel performance. The observed results are presented in Table <NUM>, below, and in <FIG>.

The above skin penetration data show significant enhancement of diclofenac delivery by the topical compositions containing a cationic guar gum as compared to Voltaren® gel, a commercially available product containing about the same amount of diclofenac.

The compositions listed in Table <NUM> and containing about <NUM> percent by weight of ibuprofen were evaluated for skin permeation performance and compared to Ibuleve™ gel. The observed results are presented in Table <NUM>, below, and in <FIG>.

The above skin permeation data show significant enhancement of ibuprofen delivery by the topical compositions containing a cationic guar gum as compared to Ibutop™ gel, a commercial product containing about the same amount of ibuprofen.

Tables <NUM> and <NUM>, below, illustrate the effect of cationic guar gum on skin permeation.

The compositions shown in Table <NUM> were applied to cadaver skin from the back of a <NUM>-year old male, weighing <NUM> pounds, in a Franz cell skin permeation study. The results are shown in Table <NUM>, below.

The foregoing data indicate that stain permeation is enhanced by the presence of the cationic guar gum.

The use of crystallization inhibitors in the present naproxen compositions is illustrated in Tables <NUM>-<NUM>, below.

The compositions shown in Table <NUM> were applied to cadaver skin from the back of a <NUM>-year old male, weighing <NUM> pounds, in a Franz cell skin permeation study. The results are shown in Table <NUM>, below, and in <FIG>.

The compositions shown in Table were applied to cadaver skin from the back of a <NUM>-year old male, weighing <NUM> pounds, in a Franz cell skin permeation study. The results are shown in Table <NUM>, below, and in <FIG>.

The effect of lactic acid on skin permeation performance of naproxen compositions is illustrated in Tables <NUM>-<NUM>, below, and in <FIG> and <FIG>.

The results shown in Table <NUM> indicate that elimination of lactic acid resulted in reduced skin permeation of the composition.

The data in Table <NUM> indicate that omission of lactic acid from the composition reduces skin permeation.

Oxybenzone was added to naproxen containing compositions as a photostabilizer, and skin permeation performance of these compositions was evaluated.

Data in Table <NUM> indicate that the presence of a photostabilizer does not materially affect the skin permeation of the naproxen compositions.

Oxybenzone was added to diclofenac-containing compositions as a photostabilizer, and skin permeation performance of these compositions was evaluated.

The compositions shown in Table <NUM>, above, were applied to cadaver skin from the thigh of a <NUM>-year old female, weighing <NUM> pounds, in a Franz cell skin permeation study. The results are shown in Table <NUM>, below, and in <FIG>.

Data in Table <NUM> indicate that the presence of a photostabilizer does not materially affect the skin permeation of the diclofenac compositions.

The stability and photostability of the prepared diclofenac containing compositions was evaluated at <NUM>° C. and after <NUM>-minute UV light exposure using a Fusion UV system with F6005 bulb at <NUM> watts/cm. The results are shown in Table <NUM>, below.

The data in Table <NUM>, above, demonstrate that oxybenzone enhances the photostability of diclofenac-containing compositions.

Oxybenzone was added to ibuprofen-containing compositions as a photostabilizer, and skin permeation performance of these compositions was evaluated. The compositions are shown in Table <NUM>, below.

The compositions shown in Table <NUM>, above, were applied to cadaver skin from the thigh of a <NUM>-year old male, weighing <NUM> pounds, in a Franz cell skin permeation study. The observed results are shown in Table <NUM>, below.

The stability and photostability of the prepared ibuprofen compositions shown in Table <NUM>, above, was evaluated at <NUM>° C. and after a <NUM>-minute UV light exposure using a Fusion UV system with F6005 bulb at <NUM> watts/cm. The results are shown in Table <NUM>, below.

Topical compositions containing diclofenac and oxybenzone shown in Table <NUM>, below, were prepared for stability testing.

The prepared compositions were transparent gels, and were evaluated for stability at <NUM>° C. with and without <NUM>-minute UV light exposure using a Fusion UV system with F6005 bulb at <NUM> watts/cm. The results are shown in Table <NUM>, below.

Topical compositions containing naproxen and naproxen sodium shown in Table <NUM>, below, were prepared for stability testing.

Sulisobenzone was added to ibuprofen-containing topical compositions as photostabilizer, and skin permeation performance of those topical compositions was evaluated. The compositions are shown in Table <NUM>, below.

Compositions AZ, BA and BB shown in Table <NUM>, above, were applied to cadaver skin from the thigh of a <NUM>-year old male, weighing <NUM> pounds, in a Franz cell skin permeation study. The observed results are shown in Table <NUM>, below.

Claim 1:
An aqueous, topical anti-inflammatory gel composition having a pH value in the range of <NUM> to <NUM>, which comprises:
a non-steroidal anti-inflammatory drug (NSAID) which is an arylalkanoic acid, a lactate ester of a C<NUM> to C<NUM> saturated aliphatic alcohol, a monoprotic organic acid having a pKa value in the range of about <NUM> to about <NUM>, a C<NUM> to C<NUM> saturated aliphatic alcohol, a solubility enhancer, and a cationic galactomannan gum,
wherein the cationic galactomannan gum content in the composition is in the range of <NUM> to <NUM> percent by weight, based on the total weight of the composition.