Diclofenac Dosage Forms

Abstract

The present invention relates to oral dosage forms of diclofenac, and processes for their manufacture, that provide a rapidly absorbed dose of diclofenac without requiring milling of diclofenac to submicron sizes.

Claims

1. A process of manufacture of a solid dosage form for oral administration comprising the steps of: (i) forming a solution by dissolving diclofenac and a basic sodium or potassium compound in a solvent comprising water, a volatile organic solvent, or a mixture thereof; (ii) applying the solution to a solid substrate comprising one or more pharmaceutically acceptable excipients to form a mixture; (iii) forming a dried mixture by evaporating the solvent from the mixture; and (iv) further processing the dried mixture into a dosage form, optionally with one or more additional pharmaceutically acceptable excipients.

2. The process according to claim 1, wherein the basic sodium or potassium compound is sodium hydroxide or potassium hydroxide.

3. The process according to claim 1, wherein the solvent comprises water, an alcohol, or a mixture thereof.

4. The process according to claim 3, wherein the solvent comprises water.

5. The process according to claim 3, wherein the solvent comprises an alcohol.

6. The process of claim 1, wherein the further processing in step (iv) comprises granulating the dried mixture, optionally with one or more pharmaceutically acceptable excipients.

7. The process according to claim 1, wherein the substrate comprises a disintegrant.

8. The process according to claim 7, wherein the disintegrant comprises croscarmellose sodium.

9. The process according to claim 1, wherein substrate comprises a carbonate.

10. The process according to claim 9, wherein the carbonate is calcium carbonate.

11. The process according to claim 1, wherein the substrate comprises a mixture of a disintegrant and a carbonate.

12. The process according to claim 11, wherein the substrate comprises a mixture of croscarmellose sodium and calcium carbonate.

13. A solid dosage form for the oral administration of diclofenac prepared by: (i) forming a solution by dissolving diclofenac and a basic sodium or potassium compound in a solvent comprising water, a volatile organic solvent, or a mixture thereof; (ii) applying the solution to a solid substrate comprising one or more pharmaceutically acceptable excipients to form a mixture; (iii) forming a dried mixture by evaporating the solvent from the mixture; and (iv) further processing the dried mixture into a dosage form, optionally with one or more additional pharmaceutically acceptable excipients.

14. The solid dosage form of claim 13, wherein the dried mixture is granulated prior to mixing with one or more pharmaceutically acceptable excipients.

15. The solid dosage form of claim 14, wherein the substrate in the dried mixture comprises a disintegrant and a carbonate, and the dried mixture is mixed with a lubricant and a glidant.

16. The solid dosage form of claim 15, wherein the dosage form is a capsule filled with a dried mixture comprising diclofenac sodium and a substrate comprised of a mixture of croscarmellose sodium and calcium carbonate, and the dried mixture is mixed with magnesium stearate and colloidal silicon dioxide.

17. An orally-administrable solid dosage form of diclofenac comprising a substrate coated with a sodium or potassium diclofenac salt, and optionally also comprising, one or more pharmaceutically acceptable excipients.

18. The solid dosage form of claim 17, wherein the substrate is a disintegrant, a carbonate, or a mixture thereof.

19. The solid dosage form of claim 18, wherein the substrate is a mixture of croscarmellose sodium and calcium carbonate.

20. The solid dosage form of claim 17 comprising capsules filled with diclofenac sodium coated onto a solid substrate comprising a mixture of croscarmellose sodium and calcium carbonate, magnesium stearate and colloidal silicon dioxide.

Description

DETAILED DESCRIPTION

[0032] The present invention provides oral dosage forms of diclofenac comprising one or more pharmaceutical excipients coated with a sodium or potassium salt of diclofenac, optionally mixed with one or more additional pharmaceutically acceptable excipients. Through the use of the dosage forms of the present invention, it is possible to provide doses of diclofenac that are rapidly absorbed following administration without requiring the milling of diclofenac to submicron sizes during the manufacturing process. In preferred embodiments of the present invention, there is provided a dosage form that provides equivalent AUC.sub.T and C.sub.max levels of diclofenac to those provided by an equivalent dose of ZORVOLEX capsules without requiring the use of diclofenac that has been milled to submicron sizes.

[0033] In one embodiment of the present invention, a process is provided for the manufacture of solid dosage forms, preferably capsules or tablets, for oral administration comprising the steps of: [0034] (i) forming a solution by dissolving diclofenac and a basic sodium or potassium compound in a solvent comprising water, a volatile organic solvent, or a mixture thereof; [0035] (ii) applying the solution to a solid substrate comprising one or more pharmaceutically acceptable excipients to form a mixture; [0036] (iii) forming a dried mixture by evaporating the solvent from the mixture; and [0037] (iv) further processing the dried mixture into a dosage form, optionally with one or more additional pharmaceutically acceptable excipients.

[0038] Suitable basic sodium or potassium compounds for use with the process of the present invention are those capable of forming a sodium or basic salt with diclofenac. Preferably, the basic sodium or potassium compound is selected from sodium hydroxide and potassium hydroxide.

[0039] Within the present invention, the substrate to which the solution of diclofenac is applied is a pharmaceutical excipient. Preferably, the substrate to which the solution of diclofenac is applied comprises a disintegrant, a carbonate, or a mixture thereof.

[0040] Suitable disintegrants for use within the present invention are those excipients that cause or facilitate breakup of the contents of a dosage form when it comes in contact with liquid. In preferred embodiments, the disintegrant is an excipient that is insoluble in water, but swells when wetted to cause disintegration. Examples of preferred disintegrants for use with the present invention include starches, modified starches, cellulose, modified cellulose, carmellose calcium, croscarmellose sodium, crospovidone, or combinations thereof. A particularly preferred disintegrant is croscarmellose sodium.

[0041] While any pharmaceutically acceptable carbonate may be used with the process of the present invention, the carbonate is preferably calcium carbonate.

[0042] Suitable solvents for use with the processes of the present invention include water and volatile organic solvents. Preferably, the volatile organic solvent is an alcohol, and is most preferably methanol.

[0043] When applying the solution containing diclofenac and the basic sodium or potassium compound to the solid substrate, the substrate and solution can be mixed together, for example, in a standard wet granulation process, or, alternatively, the solution can be applied onto the substrate using other standard methods known to one skilled in the art, such as spray-coating.

[0044] Preferably, the solution is applied to the solid substrate by mixing the solution and solid substrate in a wet granulation process, and then removing the solvent by drying the mixture, thereby allowing the solvent to evaporate. Preferably, the wet granulation process is carried out by applying the solution to the substrate at an elevated temperature, preferably in the range of 55 C. to 70 C.

[0045] Evaporation of the solvent through spray-coating or conventional drying provides a substrate that is coated with a sodium or potassium salt of diclofenac in the form of a dried mixture. This dried mixture can then be further processed into a solid dosage form, such as a capsule or tablet, using common methods of manufacture that would be known to one of skilled in the art.

[0046] Suitable pharmaceutical excipients are those commonly known in the art for the preparation of immediate release dosage forms, and in particular, capsules and tablets, and may be selected from diluents, binders, glidants, disintegrants and lubricants. These excipients and their common methods of use are well-known to the skilled person and are described in common texts, such as The Handbook of Pharmaceutical Excipients and Remington The Science and Practice of Pharmacy. Preferred diluents are selected from dicalcium phosphate, calcium sulfate, lactose, cellulose, mannitol, starch and powdered sugar. Preferred binders are selected from starches, gelatin, sugars, cellulose polymers and polyvinylpyrrolidone. Preferred glidants are selected from colloidal silicon dioxide and talc. Preferred disintegrants are selected from those described above for use as a solid substrate. Preferred lubricants are selected from talc, magnesium stearate, calcium stearate and polyethylene glycol. Optionally, other pharmaceutical excipients, such as coloring agents, can be used.

[0047] Further processing of the dried mixture can involve, for example, deagglomeration. When the further processing step involves deagglomeration, the screen used is suitable for removal of large agglomerates (for example, particles greater than 1,000 m). The dried mixture, with or without further processing, is optionally mixed with one or more pharmaceutically acceptable excipients in the preparation of the oral dosage form, which is preferably a capsule or tablet, and most preferably, a capsule. Capsules can be prepared, for example, by filling capsules with the dried mixture, optionally, with one or more pharmaceutically acceptable excipients. Alternatively, the dried mixture is used in the preparation of mini-tablets, optionally with one or more pharmaceutically acceptable excipients, which are then filled into capsules. Tablets can be prepared, for example, by direct compression, dry granulation or wet granulation of the dried mixture with one or more additional pharmaceutically acceptable excipients. When wet granulation is used, it is preferred that the solvent used does not lead to dissolution of the diclofenac and its salt from the solid substrate. These methods of preparing solid oral dosage forms are well known to the skilled person, and are described in common texts, such as Remington The Science and Practice of Pharmacy.

[0048] Optionally, immediate release coatings can be applied to either the dried mixture, granules formed from the dried mixture and other pharmaceutically acceptable excipients, mini-tablets or tablets. Suitable immediate release coatings (i.e., coatings not intended to delay the release of diclofenac for the formulation) are well known to those skilled in the art, and are described, for example, in common texts, such as Remington The Science and Practice of Pharmacy.

[0049] In a preferred embodiment of the invention, the dried mixture is agglomerated prior to being mixed with a lubricant and a glidant. Preferably, the lubricant is magnesium stearate and the glidant is colloidal silicon dioxide. After mixing the deagglomerated dried mixture with these excipients, the mixture is filled into capsules to provide a dosage form having 18 mg or 35 mg diclofenac.

[0050] In a further preferred embodiment of the present invention, the oral dosage form provides equivalent AUC.sub.T and C.sub.max levels to those provided by ZORVOLEX capsules.

[0051] AUC.sub.T as used herein is defined as the area under the curve of serum concentration versus time for a chosen period of time after ingestion, such as, for example 24 hours. AUC.sub.T ratio as used herein is defined as the ratio of mean AUC.sub.T provided by the test product to the mean AUC.sub.T provided by the reference product.

[0052] C.sub.max as used herein is defined as the peak serum concentration. C.sub.max ratio as used herein is defined as the ratio of mean C.sub.max provided by the test product to the mean C.sub.max provided by the reference product.

[0053] Oral dosage forms of the present invention are considered to provide equivalent AUC.sub.T and C.sub.max levels to those provided by ZORVOLEX capsules if the C.sub.max and AUC.sub.T ratios are within the range of 80% to 125%.

[0054] In a further embodiment of the invention, oral dosage forms are provided comprising a combination of a first and second dose of diclofenac. The first dose of diclofenac is an amount of a dried mixture of diclofenac sodium or potassium coated on a solid substrate to provide a first, rapidly absorbed, dose of diclofenac. If desired, the dried mixture is further processed, for example, by wet or dry granulation with one or more additional pharmaceutically acceptable excipients, before being combined with the second dose of diclofenac to prepare the oral dosage form. The second dose of diclofenac is an amount of diclofenac, or a pharmaceutically acceptable salt thereof, in the form of extended release granules, pellets or mini-tablets.

[0055] The extended release character of the second dose of diclofenac can be provided through the use of extended release matrices or extended release coatings. If desired, delayed release coatings can also be used to provide a delayed release of the second dose of diclofenac such that the second dose provides either delayed release followed by extended release, or delayed release followed by immediate release. Excipients known to provide extended and delayed release, as well as the preparation of extended and delayed release dosage forms are well known to the skilled person, and are described, for example, in common texts, such as The Handbook of Pharmaceutical Excipients and Remington The Science and Practice of Pharmacy.

EXAMPLES

[0056] The following examples are illustrative of the aspects and embodiments of the invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 1

[0057] 7.96 kilos of diclofenac and 1.1 kilos of sodium hydroxide were dissolved in 13.65 kilos of methanol to form a solution. The solution was blended into a mixture of 22.8 kilos of croscarmellose sodium (a disintegrant) and 7.59 kilos of calcium carbonate 90% (an alkaline powder) at 55-70 C. to form granules. The granules were dried, and the dried granules were deagglomerated using a Comil equipped with a 0.039R (1,000 m) screen. 0.32 kilos of magnesium stearate (a lubricant) and 0.08 kilos of colloidal silicon dioxide (a glidant) were added to the granules and a final mixing was performed. The final weight was thus about 39.8 kilos comprising about 7.96 kilos (20.0%) of diclofenac as the sodium salt.

Example 2

[0058] The final mixture from Example 1 was filled into size 3 hard gelatin capsules at a net fill of 175 mg per capsule. Each capsule thus contained about 35 mg of diclofenac as diclofenac sodium.

Example 3

[0059] Comparative bioavailability studies were performed using the capsules of Example 2 and ZORVOLEX capsules, both of 35 mg strength.

[0060] The results from a comparative bioavailability study in 35 subjects in the fasted state were: AUC.sub.T ratio: 101.7% and C.sub.max ratio 88.0%.

[0061] The results from a comparative bioavailability study in 36 subjects in the fed state were: AUC.sub.T ratio: 100.4% and C.sub.max ratio 91.1%.

[0062] The capsules of Example 2 are thus considered to provide equivalent AUC.sub.T and C.sub.max levels to those provided by ZORVOLEX capsules.