MXPA00012294A - Delavirdine tablet formulation - Google Patents

Abstract

Disclosed is a non-sustained release pharmaceutical tablet composition which comprises a rapidly precipitating drug in an amount from about 5 to about 60%and at least one member selected from the group consisting of a binder in an amount of from about 2 to about 25%and a superdisintegrant in an amount from about 6 to about 40%where the rapidly precipitating drug,"binder"and superdisintegrant are mixed and compressed into a tablet without heating, solvent or grinding.

Description

FORMULATION OF DELAVIRIDINE IN TABLET BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION The present invention is a tablet formulation that reduces the rate of precipitation of a drug that precipitates rapidly and improves dissolution. 2. DESCRIPTION OF THE RELATED ART U.S. Patent 5,563,142 (EXAMPLE 105) presents delavirdine. International Publication 095/28398 based on PCT patent application PCT / US95 / 02166 discloses delavirdine mesylate in two crystalline forms "S" and "T". U.S. Patent 5,358,941 has a compressed tablet formulation comprising about 0.5% to 40% active ingredient, about 10% to 80% anhydrous lactose, about 5% to 50% by weight microcrystalline cellulose, about 0.5% to 10% by weight of croscarmellose sodium and approximately 0.1% to 5% of magnesium stearate. The pharmaceutical tablet formulation of the present invention does not require lactose. Patent EP 283925 discloses the use of solvent-based polymers under the action of high shear stress so that the precipitation is divided into very small particles to purify resorbable polyester products. The claimed invention does not co-precipitate polymers in any solvent system with the fast precipitating drug, prior to formulation with other ingredients, but rests only in close proximity of the dry binder or superdisintegrant with the fast precipitating drug in a compressed tablet dosage form . The International Journal of Pharmaceutics, 154, 59-66 (1997) presents the use of HPMC, HPC and PVP in a liquid system at various polymer proportions with an attempt to delay precipitation. The methods discussed include the preparation of solid dispersions either by the coprecipitation method or by the precipitation method to improve the dissolution properties. The claimed invention uses the conventional direct compression tablet formulation method and did not use it. none of the solid dispersion techniques, for example, coprecipitation via the use of solvent or by grinding to achieve coprecipitation. The Handbook of Drug Excipient, 2a. Ed., Edited by A. Wade and P. M. Weller. 1994, page 141 and many other pharmaceutical references describe the common use of superdisintegrants, such as eroscarmellose sodium, which are used to help disintegrate the tablet normally in the amount of 1-2% and no more than 5% of the formulation. Larger amounts are not used or recommended due to the gelation of croscarmellose sodium which forms a loose matrix which, it is known, prevents the dissolution of many drug compounds. The present invention uses more than 6% croscarmellose sodium. The Handbook of Drug Excipients, 2a. Ed., Edited by A. Wade and P. J. Weller. 1994, pages 223, 229 and 392 and many other pharmaceutical references describe the common use of water-soluble polymers such as, for example: HPMC, HPC-L and PVP as binders, either as wet binders or dry binders in release tablet formulations sustained and immediate release. For non-sustained release applications, no more than 5% of these binders are used. Larger amounts are not recommended due to the impedance of the dissolution rate for many drugs. Normally amounts greater than 5%, especially HPMC, are used for sustained release dosage forms, and are generally of high molecular weight grades. In the present invention, however, the binder includes use at levels of more than 5%. U.S. Patent 5,225,197 discloses P1158 a chewable tart formulation. The present invention is not a chewable tablet. JP 84-185584 discloses the use of HPC, PVP and other binders together with hardly soluble drugs, by the use of heat. The claimed invention does not use heat.

SUMMARY OF THE INVENTION The present invention is a non-sustained release pharmaceutical tablet composition comprising: a fast precipitating drug in an amount between about 5 and 60%, microcrystalline cellulose and at least one member selected from the group consisting of a binder in an amount of between about 2 and 25% and a superdisintegrant in an amount between about 6 and 40% wherein the fast-precipitating drug, the microcrystalline cellulose, the binder and the superdisintegrant are mixed and compressed into a tablet without heat, solvent or grinding. A pharmaceutical composition in non-sustained release tablet is also presented which is: Quantity% Compound (approximately between:) delavirdine mesylate 10 - 40 hydroxypropyl methylcellulose 5 - 20 P11S8 croscarmellose sodium 6-35 microcrystalline cellulose, 10-50 lactose 0-15 colloidal silicon dioxide 0-5 magnesium stearate? 0-5 wherein delavirdine mesylate, microcrystalline cellulose, hydroxypropyl methylcellulose and croscarmellose sodium are mixed and compressed into a tablet without heating, solvent or grinding.

DETAILED DESCRIPTION OF THE INVENTION The tablets of the present invention require a drug of rapid precipitation (5 to 60%), microcrystalline cellulose (10-50%), a binder (2-25%) and a superdisintegrant (6-40%) ). While not required, the use of one or more of the following pharmaceutical ingredients is often highly desirable: microcrystalline cellulose (0-50%), lactose (0-80), a fluid agent (0-5) and a lubricant (0-5%). A fast-precipitating drug is a pharmaceutical compound or its form in a salt that, when introduced into water or simulated physiological fluids, at room temperature, begins to dissolve rather quickly and then begins to precipitate rapidly, within 60 minutes, of a solution to a less soluble form that P1158 __ «__. it provides a concentration that is not entirely therapeutic. This precipitation results in a slow and incomplete dissolution. In most cases, the amount that is precipitated may be more than 90% or more, leaving approximately 10% or less available for therapeutic activity. It is preferred that the fast precipitation drug be a highly soluble or fairly soluble salt form of a sparingly soluble free base or a free acid drug or an anhydrous form of a sparingly soluble free base or a free acid drug. Rapid precipitation drugs are prone to supersaturation, as those skilled in the art know. It is preferred that the fast-precipitating drug be selected from the group consisting of: delavirdine mesylate, phenytoin, furosemide, pseudoephedrine, clindamycin hydrochloride, chloridine hydrochloride, diphenhydramine hydrochloride, fluphenazine hydrochloride, griseofulvin, hydromorphone hydrochloride, hydrochloride naloxone, oxytetracycline hydrochloride, phenylephrine hydrochloride, pheniramine maleate, tetracycline hydrochloride, verapamil hydrochloride, propoxyphene hydrochloride, propoxyphen napsylate, hydrocodine bitartrate, sodium acyclovir, albuterol sulfate, ampicillin sodium, benzotropine mesylate, hydrochloride benzfetamine, bupivacaine hydrochloride, bupropin hydrochloride, chlorphenamine maleate, chlorpromazine hydrochloride. What is most preferred is that the drug of rapid precipitation is delavirdine mesylate. The rapid precipitation drug should be present in an amount of between about 5% and 60%, preferably, in an amount between about 10% and 40%. Delavirdine, 1- [5-methanesulfonamidoindolyl-2-carbonyl] -4- [3- (1-methylethylamino) -2-pyridinyl] piperazine, is known, see U.S. Patent 5,563,142 (EXAMPLE 105). Delavirdine mesylate is also known in two different forms of crystal "S" and "T", see International Publication W095 / 28398 based on PCT patent application PCT / US95 / 02166. The tablet formulation of the present invention is a non-sustained release pharmaceutical tablet composition, comprising a fast-precipitating drug in an amount of between about 5% and 60%, microcrystalline cellulose (10% -50%) and therefore minus one member selected from the group consisting of a binder in an amount of between about 2% and 25% and a superdisintegrant in an amount between about 6% and 40%, when the fast-precipitating drug, the microcrystalline cellulose, the binder and the superdisintegrant are mixed and compressed into a tablet without heating, solvent or grinding. It is preferred that the binder, the microcrystalline cellulose and the superdisintegrant are all present. The tablet formulation of the present invention may utilize a binder. The binder is preferably selected from the group consisting of: hydroxypropyl methylcellulose, PVP, hydroxypropyl cellulose, microcrystalline cellulose, hydroxymethylcellulose, carbopol and sodium carboxymethylcellulose.; more preferably, the binder is selected from the group consisting of hydroxypropyl methylcellulose and more preferably, from USP 2910 of 3 cps. PVP is also preferred. It is preferred that the binder is present in an amount of hydroxypropyl methylcellulose of between about 5% and 20%, PVP of between about 2% and 15%, of hydroxypropyl cellulose or hydroxyethylcellulose of between about 5% and 20%, carbopol, methylcellulose and sodium carboxymethylcellulose of between about 3% and 20%. It is obvious to the person skilled in the art, that the binders of the present invention are polymeric binders, since they are opposed to non-polymeric binders. The superdisintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, L-hydroxypropyl cellulose; it is preferred that the superdisintegrant be croscarmellose. The superdisintegrant should be present in an amount between about 6% and 40%. It is preferred that the superdisintegrant be present in an amount between about 6% and 35%; it is more preferred that the superdisintegrant be present in an amount between 10% and 30%. This is one of the agents responsible for retarding the precipitation of the rapid precipitation drug. Microcrystalline cellulose is not absolutely necessary to prepare the tablet formulation of the present invention. However, it is very desirable that it be present in most cases. The tablet formulation may use a microcrystalline cellulose diluent. When present, it is preferable that it be selected from the group consisting of coarse powder of microcrystalline cellulose, medium powder of microcrystalline cellulose and microcrystalline cellulose 200; it is more preferred that the microcrystalline cellulose be coarse powder of microcrystalline cellulose N.F. The microcrystalline cellulose must be present in an amount between about 5% and 50%. It is preferred that the microcrystalline cellulose be present in an amount of between about 10% and 50%. Lactose is not absolutely necessary to prepare the tablet formulation of the present invention. However, it is highly desirable that it be present in the majority of cases, in an amount of up to about 80%. When present, it is preferred that it be selected from the group consisting of the lactose monohydrate serving as the N.F. for the spraying process, lactose monohydrate, lactose anhydrous, lactose dihydrate, lactose DMV; it is more preferred that the lactose be lactose monohydrate which serves as a standard for the N.F. The lactose may be present in an amount between about 0% and 80%. It is preferred that the lactose be present in an amount between about 5% and 20%. The fluid agent is not absolutely necessary to prepare the tablet formulation of the present invention. However, it is highly desirable that it be present in most cases. When present, it is preferred that it be selected from the group consisting of colloidal silicon dioxide and talc; it is more preferred that the flow agent be selected from the group consisting of colloidal silicon dioxide N.F .. When present, the fluid agent must be present in an amount of up to about 5%. It is preferred that the fluid agent be present in an amount between about 0.25% and about 2%. The lubricant is not absolutely necessary to prepare the tablet formulation of the present invention. However, it is very desirable that it be present in most cases. When present, it is preferred that the lubricant be selected from the group consisting of magnesium stearate and stearic acid; it is more preferred that the lubricant be magnesium stearate. When present, the lubricant should be present in an amount of up to 5%, approximately. It is preferred that the lubricant be present in an amount of 0.25% to 2%. As is known to those skilled in the art, the tablet can be colored, flavored and / or coated with a film. The tablet composition of the present invention is prepared as known to those skilled in the art, by direct compression. It is preferred to first mix the rapid precipitation drug with the microcrystalline cellulose, perfectly and by methods well known to those skilled in the art, preferably, by the use of a shear mixer. Hydroxypropyl methylcellulose, croscarmellose, lactose and sieved colloidal silicon dioxide are mixed separately, preferably in a high shear mixer and P1158 added to the microcrystalline cellulose-drug mixture and all the ingredients are mixed perfectly, preferably, in a high shear mixer. The magnesium stearate is screened and added to the drug mixture and mixed well. The resulting mixture is compressed by methods well known to those skilled in the art to produce tablets containing the desired amount of the active pharmaceutical agent. These tablets can then be coated and polished, as is well known to those skilled in the art. These tablets comply with the requirements / applicable laws of the F.D.A and the U.S.P. and they are very convenient for commercial production and use. Alternatively, but with less preference, the binder can be solvated and used in a wet granulation process.

DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms, as used throughout this document, including both the specification and the claims.

I. DEFINITIONS Delavirdine refers to 1- [5-methanesulfonamidoindolyl-2-carbonyl] -4- [3- (2- P1158 ^ gjr methylethylamino) -2-pyridinyl] piperazine. Delavirdine mesylate refers to the mesylate salt of 1- [5-methanesulfonamidoindolyl-2-carbonyl] -4- [3- (2-methylethylamino) -2-pyridinyl] piperazine. A "rapid precipitation drug" is a pharmaceutical compound or its salt form, which when introduced into water or physiologically simulated fluids at body temperature, begins to dissolve rather quickly and then begins to rapidly precipitate out of the solution into the cells. 60 min to a less soluble form that provides a concentration that is less than therapeutic. All temperatures are in degrees Celsius. Pharmaceutically acceptable refers to those properties and / or substances that are acceptable to the patient from a pharmacological / toxicological point of view and for pharmaceutical chemical processing from a physical / chemical point of view with respect to composition, formulation, stability, bioavailability and patient acceptance. When two or more solids are used in a mixture, these are expressed as weight / weight designated w / w or p.p. PVP refers to polyvinyl pyrrolidone.

P1158 EXAMPLES Without further elaboration, it is believed that a person skilled in the art can, using the foregoing description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and / or develop the various processes of the invention and will be interpreted as merely illustrative and not as limitations of the preceding disclosure in any way. Those skilled in the art will immediately recognize appropriate variations from the procedures as well as for the reactants as well as for the reaction conditions and techniques. EXAMPLE 1 Formulation of the Delavirdine Mesylate 200 mg tablet. 200 mg tablet Quantity / Compound tablet%. (weight / weight) delavirdine mesylate 200.00 mg 30.2 coarse cellulose powder 198.76 mg 30.0 microcrystalline N.F. lactose monohydrate for 71.29 mg 10.7 pattern of the spray process N.F. hydroxypropyl methylcellulose 2910 75.00 mg 11.3 P1158 ? * £ l U.S.P. 3 cps croscarmellose sodium N.F. of 110.00 mg 16.6 Type A colloidal silicon dioxide N.F. 1.50 mg 0.23 magnesium stearate powder N.F. 5.00 mg 0.76 food grade, V, sieved The previous tablets were made by mixing with intensity delavirdine mesylate and microcrystalline cellulose in a high shear mixer. Add and then mix the hydroxypropyl methylcellulose, croscarmellose, lactose and sieved colloidal silicon dioxide in a high shear mixer. Finally, add sifted magnesium stearate and lubricate in a shear mixer.

The resulting mixture is compressed, film coated and polished in the manner known to those skilled in the art to provide tablets having approximately 200 mg of delavirdine mesylate / tablet and to meet the requirements of the U.S.P. and / or the F.D.A.

P1158

Claims (3)

1. CLAIMS: 1. A non-sustained release pharmaceutical tablet composition, comprising: a fast-precipitating drug in an amount between about 5% and 60%, microcrystalline cellulose and at least one member selected from the group consisting of: binder in an amount of between about 2% and 25% and a superdisintegrant in an amount between about 6% and 40%, wherein the fast-precipitating drug, microcrystalline cellulose, binder and superdisintegrant are mixed and compressed into a tablet without heating, solvent or grinding.
2. 2. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the binder is selected from the group consisting of: hydroxypropyl methylcellulose, PVP, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, carbopol, sodium carboxymethylcellulose. 3. A non-sustained release pharmaceutical tablet composition according to claim 2, wherein the binder is hydroxypropyl methylcellulose. 4. A non-sustained release pharmaceutical tablet composition according to claim 2, wherein the binder is PVP. 5. A non-sustained release pharmaceutical tablet composition according to claim 2, wherein the binder is present in the amounts detailed below: between about 5% and 20% hydroxypropyl methylcellulose, between about 2% and 15% PVP, between about 5% and 20% of hydroxypropyl cellulose, between about 5% and 20% of methylcellulose, between about 5% and 20% of hydroxyethylcellulose, between about 3% and 20% of carbopol, between about 3% and 20% of sodium carboxymethylcellulose. 6. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the superdisintegrant is croscarmellose sodium, sodium starch glycolate, L-hydroxypropyl cellulose. 7. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein P1158 the superdisintegrant is present in an amount between about 6% and 35%. 8. A non-sustained release pharmaceutical tablet composition according to claim 7, wherein the superdisintegrant is present in an amount of between about 10% and 30%. 9. A non-sustained release pharmaceutical tablet composition according to claim 1, containing microcrystalline cellulose in an amount up to about 50%. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the microcrystalline cellulose is selected from the group consisting of: coarse microcrystalline cellulose powder, microcrystalline cellulose medium powder and microcrystalline cellulose 200. 11. A composition of pharmaceutical tablet of non-sustained release according to claim 9, wherein the microcrystalline cellulose is coarse powder of microcrystalline cellulose NF 12. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the microcrystalline cellulose is present in an amount of between about 10% and 40%. P1158 13. A non-sustained release pharmaceutical tablet composition according to claim 1, containing lactose in an amount of up to about 80%. 14. A non-sustained release pharmaceutical tablet composition according to claim 13, wherein the lactose is selected from the group consisting of the lactose monohydrate which serves as the standard for the spray process NF, lactose monohydrate, lactose anhydrous, dihydrate lactose, lactose DMV. 15. A non-sustained release pharmaceutical tablet composition according to claim 13, wherein the lactose is lactose monohydrate which serves as the standard for the N.F. 16. A non-sustained release pharmaceutical tablet composition according to claim 12, wherein the lactose is present in an amount of between about 5% and 20%. 17. A non-sustained release pharmaceutical tablet composition according to claim 1, which contains a flow agent in an amount of up to 5%. 18. A non-sustained release pharmaceutical tablet composition according to claim 17, wherein the flow agent is selected from the group consisting of colloidal silicon dioxide and talc. P1158 19. A non-sustained release pharmaceutical tablet composition according to claim 17, wherein the flow agent is dioxide N.F. of colloidal silicone. 20. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the flow agent is present in an amount of between about 0.25% to about 2%. 21. A non-sustained release pharmaceutical tablet composition according to claim 1, containing a lubricant in an amount of up to 5%. 22. A non-sustained release pharmaceutical tablet composition according to claim 21, wherein the lubricant is selected from the group consisting of magnesium stearate and stearic acid. 23. A non-sustained release pharmaceutical tablet composition according to claim 21, wherein the lubricant is magnesium stearate. 24. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the lubricant is present in an amount from 0.25% to about 2%. 25. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the rapid precipitation drug is selected from the group P1158 consisting of delavirdine mesylate, phenytoin, furosemide, pseudoephedrine, clindamycin hydrochloride, chloridine hydrochloride, diphenhydramine hydrochloride, fluphenazine hydrochloride, griseofulvin, hydromorphone hydrochloride, naloxone hydrochloride, oxytetracycline hydrochloride, phenylephrine hydrochloride, maleate pheniramine, tetracycline hydrochloride, verapamil hydrochloride, propoxyphene hydrochloride, propoxyphen napsylate, hydrocodine bitartrate, sodium acyclovir, albuterol sulfate, ampicillin sodium, benztropine mesylate, benzfetamine hydrochloride, bupivacaine hydrochloride, bupropin hydrochloride, maleate chlorpheniramine, chlorpromazine hydrochloride. 26. A non-sustained release pharmaceutical tablet composition according to claim 1, wherein the fast precipitating drug is present in an amount of between about 10% and 40%. 27. A non-sustained release pharmaceutical tablet composition according to claim 25, wherein the fast dissolving drug is delavirdine mesylate. 28. A non-sustained release pharmaceutical tablet composition according to claim 27, wherein the delavirdine mesylate is present in an amount between about 50 and 300 mg / tablet. P1158 • A non-sustained release pharmaceutical tablet composition according to claim 27, wherein the delavirdine mesylate is present in an amount of about 200 or 300 mg / tablet. 30. A non-sustained release pharmaceutical tablet composition according to claim 1, which contains both a binder and a superdisintegrant. 31. A non-sustained release pharmaceutical tablet composition that is: Amount% Compound (between approximately) delavirdine mesylate 10-40 hydroxypropyl methylcellulose 5-20 croscarmellose sodium 6-35 microcrystalline cellulose 10-50 lactose 0-15 colloidal silicon dioxide 0-5 magnesium stearate 0-5 where mesylate delavirdine, microcrystalline cellulose, hydroxypropyl methylcellulose and croscarmellose sodium are mixed and compressed into a tablet without heating, solvent or grinding. 32. A non-sustained release pharmaceutical tablet composition according to claim 31, which is: P1158 Compound Amount% (between approximately) delavirdine mesylate 30.2 hydroxypropyl methylcellulose 2910 11.
3. 3 U.S.P. 3 cps croscarmellose sodium N.F. Type A 16.6 coarse cellulose powder 30.0 microcrystalline N.F. lactose monohydrate N.F. for 10.7 pattern of spray process colloidal silicon dioxide N.F. 0.23 magnesium stearate powder 0.76 N.F. V food grade united P1158