| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | November 17, 1992 |
| PATENT TITLE |
Process for preparing piroxicam/cyclodextrin complexes, the products obtained and their pharmaceutical compositions |
| PATENT ABSTRACT | A process for preparing complexes of piroxicam with cyclodextrins in which the two components in the powder state are premixed and then co-ground in a high energy mill in the presence of steam. The products obtained have technological, physical and biopharmacological characteristics which are advantageous compared with those of liquid-state complexes obtained by traditional methods, and are suitable for preparing pharmaceutical compositions for oral, rectal and topical use |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | March 27, 1991 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Szejtli, Cyclodextrin Technology, pp. 279-281 (1988). Duchene et al, Acta Pharmaceutica Technol., vol. 36, No. 1, pp. 1-6 (1990). |
| PATENT CLAIMS |
We claim: 1. A process for preparing piroxicam-cyclodextrin complexes which comprise: a) mixing piroxicam and a cyclodextrin together in a solid state to produce a mixture; b) co-grinding said mixture in a high energy mill, wherein the grinding chamber is saturated with steam to produce a product. c) drying said product under vacuum, and d) screening the thus produced dried product to eliminate aggregates. 2. The process as claimed in claim 1, wherein the weight ratio of cyclodextrin to piroxicam is between 10:1 and 1:1. 3. The process as claimed in claim 1, wherein the co-grinding is conducted for a time of between 0.10 and 48 hours. 4. The process as claimed in claim 1, wherein the co-grinding is conducted for a time of between 0.25 and 4 hours. 5. A piroxicam/cyclodextrin complex obtained by the process of claim 1. 6. A pharmaceutical composition with analgesic, anti-inflammatory and antirheumatic activity which comprises as an active ingredient the complex of claim 5, together with a pharmaceutical excipient. 7. The composition as claimed in claim 6 which is suitable for oral or rectal administration containing between 10 and 50 mg of said complex per unit dose. 8. The composition as claimed in claim 6 which is suitable for topical administration containing between 0.2 and 5% by weight of said complex. 9. The composition as claimed in claim 6 in the form a of tablet comprising said piroxicam/cyclodextrin complex in an amount of between 40 and 60% by weight and a pharmaceutically acceptable excipient selected from the group consisting of colloidal silica, lactose, cross linked polyvinylpyrrolidone, magnesium stearate, starch and carboxy-methyl starch. 10. The process according to claim 1, wherein said mixture is degassed |
| PATENT DESCRIPTION |
Piroxicam is a non-steroidal anti-inflammatory drug with considerable analgesic and anti-inflammatory activity. It is poorly soluble in water and in biological fluids at physiological pH values. Piroxicam is characterised by a slow and gradual absorption via both the oral and rectal routes and this involves a delayed onset of anti-inflammatory and analgesic effect. The aforegoing underlines the interesting method to ameliorate biopharmaceutical properties is based on including the drug in cyclodextrins, water-soluble natural glycosidic cyclic compounds. Italian patent 1,196,033 filed on Feb. 22, 1984 describes inclusion complexes of piroxicam and cyclodextrins in a molar ratio between 1:1 and 1:10, preferably 1:2.5. This complex results in much higher solubility than piroxicam alone, improved pharmacokinetic characteristics and improved gastric tolerability. The processes described in said patent for preparing inclusion complexes of piroxicam in cyclodextrins are all based on the liquid state, comprising dissolving the two components (piroxicam and cyclodextrin) in a suitable solvent and then separating the complexes obtained in the solid state by drying, crystallization, freeze-drying or air-flow atomization (spray-drying). SUMMARY OF THE INVENTION A new process has now been found for preparing piroxicam-cyclodextrin complexes characterised in that: a) piroxicam and cyclodextrin both in powder form are mixed together in the solid state and optionally degassed; b) the mixture obtained is co-ground in a high energy mill whose grinding chamber is saturated with steam; c) the product obtained is dried under vacuum and screened to eliminate any aggregates. The product obtained is a piroxicam/cyclodextrin complex of high density and large surface area which, combined with its extremely fine particle size, make it particularly advantageous in the preparation of pharmaceutical compositions for oral, rectal and topical administration. DETAILED DESCRIPTION OF THE INVENTION The characteristics and advantages of the process for preparing piroxicam-cyclodextrin complexes, the product obtained and the relative pharmaceutical compositions according to the present invention will be more apparent from the following detailed description. Said process is based on dry preparation. In a first stage the piroxicam and cyclodextrin both in the finely divided powder state are mixed together in a powder mixer, the mixture optionally being degassed under vacuum at room temperature or with slight heating. In a second stage the mixture of piroxicam and cyclodextrin is co-ground in a high energy mill with the grinding chamber saturated with steam. In a third stage the product obtained is dried under vacuum at room temperature or with slight heating and sieved to eliminate any aggregates. The piroxicam and cyclodextrin used in the process have a particle size less than 60 mesh and are fed to the mill in a weight ratio of cyclodextrin to piroxicam between 10:1 and 1:1. The co-grinding is conducted for a time of between 0.10 and 48 hours and preferably for a time between 0.25 and 4 hours. The product obtained is screened through a 60 mesh screen and homogenized by mixing. The product is characterized by a high density, a large surface area and an extremely fine particle size, good solubility and a low water contact angle. It consists of a piroxicam/cyclodextrin molecular inclusion complex, as demonstrated by IR spectrophotometry and DSC (differential scanning calorimetry) analysis. Because of its characteristics, the piroxicam/cyclodextrin complex according to the invention can be advantageously used to prepare pharmaceutical compositions having analgesic, anti-inflammatory and antirheumatic activity, for oral, rectal and topical administration. For example, tablets prepared with the complex of the present invention have a much higher dissolution rate than commercial formulations containing piroxicam alone. "In vivo" trials have shown that the complexes of the invention provide more rapid absorption than commercial formulations of uncomplexed piroxicam. Compositions for oral or rectal administration contain between 10 and 50 mg of said complex per unit dose, while compositions for topical administration contain between 0.2 and 5% by weight of said complex. Using the complex of the present invention, tablets of rapid disintegration and high dissolution rate can be specifically prepared in which the content of the piroxicam-cyclodextrin complex is between 40 and 60% by weight, with colloidal silica, lactose, crospovidone, magnesium stearate and optionally starch and carboxymethylstarch as excipients. Finally, in addition to the aforesaid advantages it must be emphasized that the process according to the invention results in considerable cost and industrial advantages due to the simplicity of the operations and equipment. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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