TOPICAL ANTI-INFLAMMATORY COMPOSITIONS

Abstract: A novel formulation of piroxicam for dermatological administration is disclosed. Pharmaceutical compositions containing proxicam, lower alkanols, water, carboxyvinyl polymer, polyhydric alcohols, alkanolamines and optionally film-forming agents are prepared, said compositions having a pH of from about 6.5 to about 9.0. The novel formulation is characterized by excellent applicability on the skin, skin-­ permeability and good stability. The novel formulation, which is in gel ointment form, is as effective as orally administered piroxicam and is well suited for topical admi­ nistration through skin for the treatment of various types of inflammatory conditions.

Description: This invention relates to new and useful anti-inflammatory compositions for topical administration containing as an active ingredient, piroxicam, viz., N-(2-pyridyl)-methyl-4-hydroxy- 2H-1,2-benzothiazine-3-carboxamide, 1,1-dioxid which is a compound of the formula: More particularly, this invention relates to certain novel anti-inflammatory pharmaceutical compositions for external use comprising an effective anti-inflammatory amount of piroxicam, nontoxic bases for topical formulation and appropriate solvents therefor. Piroxicam is a nonsteroidal anti-inflammatory agent described and claimed under its chemical name by J. G. Lombardino in U.S. Patent No. 3,591,584 and it is highly effective in therapy when administered to mammalian subjects suffering from chronic arthritic rheumatism, arthritis deformans, low back pain, shoulder pain, cerrico-omo-brachial syndrome, trauma or the pain caused by tooth extraction. Piroxicam is sold in capsule form world-wide and it is recognized to be a potent long-acting drug that ensures an effective piroxicam blood level when administerd orally once a day. Some of the above diseases require a relatively long period of treatment in order to avoid or minimize side effects, and it would be desirable that the oral administration be replaced by the topical administration as the disease reaches a recuperative stage. Furthermore, the topical administration is suitable for a mild case or a case where the lesion is localized. This invention is meant to provide anti-inflammatory compositions suitable for topical administration: these compositions are characterized in that they comprise an effective anti-inflammatory amount of piroxicam, nontoxic bases for topical formulation and solvents. Piroxicam is very active as an anti-inflammatory agent, but it is sparingly soluble in water and is not liposoluble. When piroxicam is simply compounded in suspension with conventional bases for ointment or cream, it is poorly absorbed through skin and does not afford expected therapeutical effects. Additionally, the formulation so produced is very sticky and unpleasant to apply to a wide area of the skin. The active ingredients in the formulation may also be lost easily when in contact with clothing. In this connection, it seems possible to apply piroxicam in the form of a tincture after dissolving same in an alcoholic solvent such as ethanol. However, piroxicam will precipitate on the skin due to the evaporation of the solvent and will not be absorbed through the skin. A gel ointment is prepared by adding a polymer to a lower alkanol-water system. It is generally a preferred form for topical administration because it is refreshing and not sticky. Unfortunately, the gel ointment cannot be formulated with piroxicam according to the standard techniques since piroxicam is sparingly soluble in water or any other solvent. Piroxicam, in the presence of moisture, turns into a hydrate thereof which is less soluble than piroxicam itself and this hydrate crystallizes out gradually. This not only reduces the absorbability of piroxicam through skin, but also impairs the coating and stability of the gel ointment. A further problem arises when the gel ointment is applied to the skin in that dermal salt causes crystallization of piroxicam. This hydrate forms a yellow deposit on the skin. The hydrate will also come off when in contact with clothing or other material. A similar problem arises when the gel ointment is applied directly to sweating skin, viz., a polymer gel-forming agent in the ointment is salted out and, as a result, the ointment agglomerates on the skin instead of forming a film layer. This affords unpleasantness to the user and the active ingredient is lost, whereby poor therapeutic effects are obtained. In accordance with the present invention, there has now been developed a novel anti-inflammatory composition for external use that has excellent skin-permeability and none of the defects described above. It has thus been surprisingly found that by combining and blending an effective anti-inflammatory amount of piroxicam with water-soluble bases, solvents, gel-forming agents and, if necessary, an appropriate amount of film-forming agents, one can obtain an anti-inflammatory composition for external use that has an unexpectedly high degree of therapeutic efficacy and good stability. It is, in addition, pleasant to use. Thus according to the present invention there is provided a topical anti-inflamatory composition in gel ointment form in an aqueous system characterised in that it comprises a) 0.3 to 2.0 % by weight of the composition of piroxicam, b) 10 to 50 % by weight of a lower alkanol having from one to four carbon atoms, c) a gel-forming amount of 0.2 to 2.0 % by weight of a carboxyvinyl polymer, d) 5 to 40 % by weight of at least one polyhydric alcohol selected from the lower alkylene glycols having from two to six carbon atoms, glycerine and the polyethylene glycols having an average molecular weight of 200 to 2000, e) a piroxicam-solubilizing amount at a level of up to 3 % by weight of at least one alkanolamine selected from the monoalkanolamines having from one to four carbon atoms, the dialkanolamines having from two to eight carbon atoms and the trialkanolamines having from three to twelve carbon atoms, f) a film-forming amount at a level of 0.2 to 2.0 % by weight of at least one film-forming agent selected from carboxymethyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone and g) 30 to 60 % by weight of water to total 100 %, said composition having a pH range of from 6.5 to 9.0. Also encompassed by this invention is an anti-inflammatory composition for external use which contains in addition to the above-stated ingredients, an effective amount of a film-forming agent selected from carboxymethyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone, said composition having a pH range of from 6.5 to 9.0. The effective anti-inflammatory amount of piroxicam in the composition from 0.3% to 2.0% by weight, of the total composition. Use of a lower piroxicam level affords unsatisfactory anti-inflammatory effects but, on the other hand, use of higher levels is not preferred for economic reasons. The lower alkanols used in this invention are, for example, methanol, ethanol, isopropanol and butanol. The lower alkylene glycol having from two to six carbons which can be used includes ethylene glycol, propylene glycol and butylene glycol. Glycerine or polyethylene glycol having an average molecualr weight of from 200 to 2000 can also be used in place of glycol. It is possible to use only one kind of such polyhydric alcohol, but more than one kind may also be used. The amount of the polyhydric alcohol is from 5% to 40% by weight of the composition. Use of the polyhydric alcohol level greater than 40% is not preferred, since the formulation gives unpleasant feelings such as stickiness after use. Although these polyhydric alcohols are known to dissolve active ingredients in bases, it is a particularly surprising feature of this invention that the polyhydric alcohols in combination with the above-mentioned alkanolamines prevent the conversion of piroxicam into its hydrate, thereby precluding the formation of the previously-mentioned yellow deposit on the skin. As Table 1 below indicates, it will be understood that when the polyhydric alcohols are not present in the composition, piroxicam crystallizes out as a yellow deposit on the skin: This invention employs a solubilizing agent to dissolve piroxicam in bases for formulation; the piroxicam-solubilizing agent is an alkanolamine. It has been discovered that monoalkanolamine, dialkanolamine and trialkanolamine are highly effective for increasing the solubility of piroxicam in the composition, as well as enchancing the skin-permeability of piroxicam. The monoalkanolamines have from one to four carbon atoms and include methanolamine, ethanolamine, propanolamine and butanolamine. The dialkanolamine have from two to eight carbon atoms and include dimethanolamine, diethanolamine, dipropanolamine and dibutanolamine. The trialkanolamines have from three to twelve carbon atoms and include trimethanolamine, triethanolamine, tripropanolamine and tributanolamine. The marked solubilizing power of these alkanolamine has been demonstrated by reference to testing results where the ability of these amines to dissolve piroxicam is compared with that of other solubilizers listed in the table below (Table 2): It possible to use only one kind of the alkanolamines, but more than one kind may also be used. A preferred amount of the alkanolamine is up to 3% by weight of the composition: this amount is sufficient to dissolve piroxicam in the ointment bases, but levels of the alkanolamines are not limited to this range. In accordance with this invention, carboxyvinyl polymers are used as gel-forming agents. Carboxyvinyl polymers are hydrophilic polymers and prepared by polymerizing monomers principally consisting of acrylic acid. They are commercially available from Goodrich Chemicals, U.S.A., under the trade name of Carbopole 934,940 or 941 and also from Wako Pure Chemicals, Japan under the trade name of HIVISWAKO 103, 104 or 105. An aqueous solution containing the carboxyvinyl polymer is acidic, since the polymer has free carboxylic acid residues. Neutralization of the aqueous solution with an appropriate base furnishes a viscous gel with desired viscosity. The appropriate bases are the aforementioned alkanolamines. A preferred amount of the gel-forming agent is from 0.2% to 2.0% by weight of the composition. A gel ointment formulation containing carboxyvinyl polymer is generally stable. It has a constant viscosity with very little variation due to temperature or time. However, as previously described herein, several problems arise when the compositions of this invention containing carboxyvinyl polymer are applied to the skin. It sometimes happens that the polymer is salted out by the salt contained in sweat and forms soft agglomerates which disintegrate easily. In such a case, the active ingredient may be lost before it is absorbed through skin and the formulation affords an unpleasant feeling on administration. Accordingly, the formulation must be administered after the area of application is wiped and cleaned. It has been discovered that if certain hydrophilic polymers are incorporated in the formulation, the ointment can be administered topically even on the sweating skin to form a suitable film without the above problems. Japanese Published Patent Application No. 55-40,604 describes a similar phenomenon and teaches a method for preventing the same with the use of hydroxypropyl cellulose has, however, turned out to be ineffective when combined with the compositions of this invention. For the purpose of this invention polyvinylpyrrolidone, carboxymethyl cellulose and hydroxyethyl cellulose are satifactory. The film-forming ability of these hydrophilic polymers has been illustrated in the test results of Table 3, as shown below, where the use of film-forming polymers in the compositions of this invention are observed to afford very favorable effects: It is possible to use only one kind of the film-forming agents, but more than one kind may also be used. The anti-inflammatory compositions of this invention have a pH range of from 6.5 to 9.0, and preferably from 6.5 to 8.0. In general, it is believed that the percutaneous absorption or skin-penetration of a given drug is dependent upon the ratio of lipophilicity to water solubility (partition coefficient) and that a high ratio is preferred, but too high a ratio adversely decreases the absorption and skin-penetration. Piroxicam has a pKa value of from 1.5 to 5.1. A preferred pH range for the compositions of this invention is from 6.5 to 8.0, since it is inthis range that piroxicam is present partially in a dissociated form and the alkanolamines can also be used. At a higher pH than 9.0, piroxicam is chemically unstable and may even decompose or deteriorate in quality. Accordingly, the compositions of this invention can be prepared in the manner described below: 1. dispersing carboxyvinyl polymer and, if desired, a film-forming agent in distilled water; 2. blending the above with lower alkanols, glycols, glycerine or polyethlene glycols uniformly; 3. independently dissolving piroxicam in an aqueous solution of alkanolamine until it is completely dissolved and, if necessary adding a neutralizing agent thereto; and 4. adding the resulting mixture of step 3 to the mixture obtained in step 2 and mixing under constant agitation to form a gel ointment. The composition of this invention so produced are stable even after storage for a prolonged period of time and exhibit excellent anti-inflammatory activity, as is evident from the following examples. These examples further illustrate this invention, but are not to be construed as limiting the same. Example 1 The following ingredients were combined and blended uniformly together to produce an ointment formulation having a pH of 7.9: Example 2 The following ingredients were combined and blended uniformly together produce an ointment formulation having a pH of 8.0: Example 3 The following ingredients were combined and blended uniformly together to produce an ointment formulation having a pH of 7.7: The following ingredients were combined and blended uniformly together to produce an ointment formulation having a pH of 8.2:

Claims: Claim for the following Contracting States : BE, CH, DE, FR, GB, LI, NL, SE 1. A topical anti-inflammatory composition in gel ointment form in an aqueous system characterized in that it comprises a) 0.3 to 2.0 % by weight of the composition of piroxicam, b) 10 to 50 % by weight of a lower alkanol having from one to four carbon atoms, c) a gel-forming amount of 0.2 to 2.0 % by weight of a carboxyvinyl polymer, d) 5 to 40 % by weight of at least one polyhydric alcohol selected from the lower alkylene glycols having from two to six carbon atoms, glycerine and the polyethylene glycols having an average molecular weight of 200 to 2000, e) a piroxicam-solubilizing amount at a level of up to 3 % by weight of at least one alkanolamine selected from the monoalkanolamines having from one to four carbon atoms, the dialkanolamines having from two to eight carbon atoms and the trialkanolamines having from three to twelve carbon atoms, f) a film-forming amount at a level of 0.2 to 2.0 % by weight of at least one film-forming agent selected from carboxymethyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone and g) 30 to 60 % by weight of water to total 100 %, said composition having a pH range of from 6.5 to 9.0. Claim for the following Contracting State : AT 1. A process for preparing a topical anti-inflammatory composition in gel ointment form in an aqueous system characeterized by the steps of: a) dispersing a carboxyvinyl polymer in water together with a film-forming amount of 0.2 % to 2.0 % by weight of the composition of at least one film-forming agent selected from carboxymethyl cellulose, hydroxyethyl cellulose and polyvinylpyrrolidone; b) blending the resulting aqueous dispersion with a lower alkanol having from one to four carbon atoms and at least one polyhydric alcohol selected from the lower alkylene glycols having from two to six carbon atoms, glycerine and the polyethylene glycols having an average molecular weight of from 200 to 2,000; c) dissolving piroxicam in an aqueous solution of a piroxicam-solubilizing amount at a concentration level of up to 3.0 % by weight of the composition of at least one alkanolamine selected from the monoalkanolamines having from one to four carbon atoms, the dialkanolamines having from two to eight carbon atoms and the trialkanolamines having from three to twelve carbon atoms; d) combining the aqueous solution obtained in step (c) and the alcoholic mixture obtained in step (b) and thereafter subjecting the resulting mixture to constant agitation to form a gel ointment; the amounts of the ingredients being such as to provide in the gel ointment so formed a gel-forming amount of 0.2 % to 2.0 % by weight of the composition of carboxyvinyl polymer, from 10 % to 50 % of lower alkanol, from 5 % to 40 % by weight of polyhydric alcohol, an effective anti-inflammatory amount of 0.3 % to 2.0 % by weight of the composition of piroxicam, 30 % to 60 % by weight of the composition water to total 100 %, and a pH in the range from 6.5 to 9.0.

Inventors: KAWAZOE, TOSHIJI, NOZAWA, SHIGENORI, OHAYA, KATSUMI
Applicants: PFIZER CORPORATION
Application year: 1983
Main classification: A61K9
IPC codes: A61K47, A61K31, A61P29, A61K9, A61P25