WO2006035414A2

WO2006035414A2 - Carbidopa and levodopa dispersible tablets

Info

Publication number: WO2006035414A2
Application number: PCT/IB2005/053219
Authority: WO
Inventors: Rajeev Shanker Mathur; Sameer Manan; Kamal Mehta
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2004-09-30
Filing date: 2005-09-29
Publication date: 2006-04-06
Anticipated expiration: 2007-03-30
Also published as: WO2006035414A3

Abstract

The present invention relates to a dispersible tablet of levodopa and a decarboxylase inhibitor. The dispersible tablet includes levodopa, the decarboxylase inhibitor, and less than about 30% w/w of filler.

Description

Description CARBIDOPA AND LEVODOPA DISPERSIBLE TABLETS

[1] Technical Field of the Invention

[2] The technical field of the present invention relates to dispersible tablets of levodopa and carbidopa, and to processes for their preparation.

[3] Background of the Invention

[4] Combinations of levodopa with a decarboxylase inhibitor, such as carbidopa or benserazide, are considered to be the most effective treatment for symptoms of Parkinson's disease, which is associated with the depletion of dopamine from cells in the corpus striatum. Levodopa and decarboxylase inhibitors are frequently ad¬ ministered as conventional fixed dose combination tablets having the two drugs in exact unit dosage amounts. Prolonged treatment with conventional levodopa tablets may lead to disabling motor fluctuations in patients that appear as random periods of sudden and unexpected loss of efficacy of levodopa therapy, which may be aggravated with time. This is termed as the 'on-off phenomenon, and is supposed to be directly linked to the plasma levodopa levels. A low absorption rate and high elimination rate of levodopa cause periods of sub-therapeutic plasma levodopa levels, hence treatment becomes ineffective. Some of the approaches used for rapid relief from the 'off state include direct instillation of a slurry of levodopa through a duodenal tube, oral dosing with a dilute aqueous solution of levodopa, and crushing of levodopa tablets before intake. However, these approaches have their own limitations. Hence there is a need for levodopa dosage forms having both quick onset of action as well as accuracy of dosing.

[5] US 6,376,545 discloses dispersible pharmaceutical compositions of L-DOPA ethyl ester and decarboxylase inhibitor. These compositions are characterized by high amounts (35-50% by weight) of filler, in particular microcrystalline cellulose having a low moisture content.

[6] Summary of the Invention

[7] Hence in one general aspect there is provided a dispersible tablet comprising levodopa and one or more decarboxylase inhibitors. In another general aspect there is provided a dispersible tablet comprising levodopa, decarboxylase inhibitor, and less than about 30% w/w filler. In another general aspect there is provided a dispersible tablet comprising about 45% w/w to about 75% w/w levodopa, about 4% w/w to about 20% w/w decarboxylase inhibitor, and about 1% w/w to about 30% w/w filler. In another general aspect there is provided a process for the preparation of dispersible tablet wherein the process includes the steps of wet granulating a blend of levodopa, one or more decarboxylase inhibitors, and one or more fillers. [8] In another general aspect there is provided a process for the preparation of a dispersible tablet, the process including the steps of blending levodopa, decarboxylase inhibitor, intragranular portion of superdisintegrant; wet granulating the blend with a granulating fluid or solution/dispersion of binder in a granulating fluid; blending the granules with an extragranular portion of superdisintegrant; and compressing into tablets. The intragranular and/or extragranular portions may further include one or more pharmaceutically inert excipients. In particular, the process may include the steps of blending levodopa, decarboxylase inhibitor, filler, color, and an intragranular portion of superdisintegrant; wet granulating the blend with a solution/dispersion of binder in a granulating fluid; blending the granules with sweetener, flavor, an ex¬ tragranular portion of superdisintegrant, and lubricant/glidant; and compressing into tablets.

[9] In one general aspect there is provided a dispersible tablet comprising levodopa, at least one decarboxylase inhibitor, and a filler, wherein the tablet comprises less than about 30% w/w filler.

[10] Embodiments of the tablet may include one or more of the following features. For example, the dispersible tablet may disperse to form a solution, or non-gritty suspension or slurry, in less than about three minutes.

[11] The tablet may include less than about 20% w/w filler or from about 1% w/w to about 20% w/w filler. The filler may include or be microcrystalline cellulose.

[12] The decarboxylase inhibitor may be carbidopa or benserazide. The tablet may include from about 45% w/w to about 75% w/w levodopa and from about 4% w/w to about 20% w/w decarboxylase inhibitor. The tablet may include about 54% w/w to about 70% w/w levodopa and from about 5% w/w to about 18% w/w decarboxylase inhibitor.

[13] The dispersible tablet may further include one or more pharmaceutically inert excipients selected from superdisintegrants, binders, suspending agents, sweeteners, surfactants, colors, flavors, and lubricants/glidants. The filler may be microcrystalline cellulose, the superdisintegrant may be one or both of croscarmellose sodium and crospovidone, and the binder may be starch. The tablet may include from about 5% w/ w to about 15% w/w superdisintegrant, and/or from about 3% w/w to about 10% w/w binder.

[14] In another general aspect there is provided a process for the preparation of a dispersible tablet of levodopa and one or more decarboxylase inhibitors. The process includes the steps of wet granulating a blend comprising levodopa, one or more de¬ carboxylase inhibitors, and one or more fillers; and compressing the granules into tablets. The tablets include less than about 30% w/w of filler.

[15] Embodiments of the process may include one or more of the following features or those described above. For example, the tablet may include less than about 20% w/w filler or from about 1 % w/w to about 20% w/w filler. The filler may include or be mi- crocrystalline cellulose. The granulation may be carried out with a granulating fluid or a solution/dispersion of binder in a granulating fluid. The granulating fluid may be one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water.

[16] In another general aspect there is provided a method for the treatment of Parkinson's disease in a mammal by administering to the mammal a dispersible tablet that includes levodopa, at least one decarboxylase inhibitor, and a filler, with the tablet including less than about 30% w/w filler.

[17] Embodiments of the method may include one or more of the following features or those described above. For example, the tablet may disperse to form a solution, or non- gritty suspension or slurry, in less than about three minutes.

[18] The details of one or more embodiments of the inventions are set forth in the de¬ scription below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

[19] Detailed Description of the Invention [20] Dispersible tablets of levodopa and a decarboxylase inhibitor that are prepared using large amounts of filler yielded tablets with unsatisfactory dissolution charac¬ teristics. In stark contrast, we have surprisingly discovered that decreasing the amount of filler increased the dissolution of both levodopa and the decarboxylase inhibitor. The present invention therefore includes dispersible tablets of levodopa and a de¬ carboxylase inhibitor using large amounts of levodopa and the decarboxylase inhibitor or low amounts of excipients, particularly low amounts of filler.

[21] Dispersible tablets of levodopa and carbidopa were prepared using different amounts of filler and the in vitrorelease of both carbidopa and levodopa was studied in 750 ml of acidic media (0.1 N HCl), using USP I dissolution apparatus, at a paddle speed of 50 rpm. The results of the study are provided in the following table.

[22]

[23] The above results clearly show that higher percentages of filler in the formulation hinder the in vitro release of both carbidopa and levodopa from the tablets. However, the release is increased with the gradual decrease in concentration of filler, i.e., to less than about 30% w/w.

[24] The dispersible tablets of the present invention completely disperses in water in a short period of less than about three minutes to form a solution, or non-gritty suspension or slurry. All the particles of the slurry easily pass through sieve #22 (BSS), as per the Pharmacopoeial requirements. Formation of a slurry with such fine particles and free of any lumps provides a smooth feeling to the patient. Besides providing the accuracy of dose of a tablet dosage form, the drug from a dispersible tablet is actually administered in a solution or suspension form, which helps to achieve quick plasma levodopa levels. Further, dispersible tablets provide an added advantage of drug ad¬ ministration to patients having problems in swallowing whole tablets, particularly the pediatric and geriatric population, and even to those suffering from concomitant vomiting or diarrhea. In addition the dispersible tablets may provide a quick onset of action and thereby proper relief from the so called 'off state phenomenon.

[25] In one of the embodiments the dispersible tablet may comprise levodopa, de¬ carboxylase inhibitor, and one or more pharmaceutically inert excipients.

[26] The term 'levodopa' as used herein includes levodopa as well as its pharma¬ ceutically acceptable salts. The term 'decarboxylase inhibitor' as used herein includes carbidopa, benserazide; and pharmaceutically acceptable salts thereof. In particular, carbidopa may be used. The amount of levodopa and decarboxylase inhibitor in the dispersible tablet may vary from about 45% w/w to about 75% w/w and from about 4% w/w to about 20% w/w, respectively. In particular, the amounts may vary from about 54% w/w to about 70% w/w and from about 5% w/w to about 18% w/w, re¬ spectively.

[27] The term 'pharmaceutically inert excipient¹ as used herein includes all physio¬ logically inert excipients used in the pharmaceutical art of dispensing. Examples include superdisintegrants, binders, fillers, suspending agents, sweeteners, surfactants, colors, flavors, lubricants/glidants, and the like. [28] Specific examples of superdisintegrants include sodium starch glycolate, croscarmellose sodium, crospovidone, and low-substituted hydroxypropylcellulose. Superdisntegrants may be used either in the intragranular portion or extragranular portion or both. The extragranular disintegrant aids in quick disintegration of the dispersible tablet into granules, and the intragranular disintegrant aids into disin¬ tegration into individual particles. Use of an excessively great amount of disintegrant may make the tablet extremely moisture sensitive, and fragile. On the other hand lower amounts of disintegrant may delay complete disintegrations. Selection of an optimum amount is therefore desired. The amount of superdisintegrant in the dispersible tablet may vary from about 5% w/w to about 15% w/w, in particular from about 7% w/w to about 10% w/w.

[29] Specific examples of binders include starch; gelatin; sugars such as molasses, lactose, glucose, dextrose and sucrose; and natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, methylcellulose, polyvinyl pyrrolidone and veegum. In particular pregelatinized starch may be used. The amount of binder in the dispersible tablet may vary from about 3% w/w to about 10% w/w, in particular from about 5% w/w to about 8% w/w.

[30] Specific examples of fillers include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrins, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, sugar compressible, and sugar confectioners. In particular, micro- crystalline cellulose may be used. The amount of filler in the dispersible tablet may be as low as about 1% to less than about 30%, in particular less than about 20% w/w.

[31] Specific examples of suspending agents include microcrystalline cellulose, sodium carboxy methylcellulose, colloidal anhydrous silica, mannitol, povidone, sodium starch glycolate, and veegum.

[32] Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions. These include polyethoxylated fatty acids and their derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol - 20 glyceryl stearate; alcohol - oil transester- ification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as 'poloxamer'; ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.

[33] Specific examples of lubricants/glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, and white beeswax.

[34] Examples of colors, flavors and sweeteners include any approved color, flavor, or sweetener for oral use.

[35] The dispersible tablet may be prepared by any of the conventional technique used in the pharmaceutical industry such as spray drying, freeze drying, direct compression, dry granulation, melt molding, wet granulation and the like. Each of these techniques has its own limitations and drawbacks. In particular wet granulation methods may be used which help to achieve soft and porous granules which disintegrate readily to form a smooth suspension or slurry free of lumps in water.

[36] In one of the embodiments dispersible tablets of levodopa and carbidopa may be prepared by blending levodopa, carbidopa, filler, color, and an intragranular portion of superdisintegrant; wet granulating the blend with a solution/dispersion of binder in a granulating fluid; blending the granules with sweetener, flavor, an extragranular portion of superdisintegrant, and lubricant/glidant; and compressing into tablets.

[37] In another embodiment dispersible tablets of levodopa and carbidopa may be prepared by blending levodopa, carbidopa, binder, filler, color, and an intragranular portion of superdisintegrant; wet granulating the blend with a granulating fluid; blending the granules with sweetener, flavor, an extragranular portion of superdis¬ integrant, and lubricant/glidant; and compressing into tablets.

[38] In another embodiment dispersible tablets may be compressed using suitable tooling to produce a scored tablet. Scored tablets may be easily divided into smaller pieces to provide a lower dose. In particular, the tablet may be scored through its center so that it can be easily divided into two equal halves.

[39] Specific examples of solvents used as granulating fluid and for preparing a solution/ dispersion of binder include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water. In particular, water may be used.

[40] The invention is further illustrated by the following examples which should not be construed as limiting the scope of the invention.

[41] Examples

[42]

[43] Procedure:

[44] 1) All the ingredients were sieved to the appropriate size and the required amounts were weighed out. [45] 2) Levodopa, carbidopa, microcrystalline cellulose, color, and intragranular croscarmellose sodium were blended in a rapid mixer granulator. [46] 3) Pregelatinized starch was dispersed in purified water to form a slurry.

[47] 4) The blend of step 2 was granulated with the slurry of step 3.

[48] 5) The granules of step 4 were dried in a fluidized bed dryer and sized through sieve

# 44 BSS. [49] 6) The granules of step 5 were blended with crospovidone, aspartame, flavor, colloidal anhydrous silica, talc, and extragranular croscarmellose sodium in a non- shear blender.

[50] 7) The blend of step 6 was finally blended with magnesium stearate and compressed into tablets using suitable tooling.

[51] The formulations of the above examples were tested for their dispersion properties and found to disperse completely to form a solution, or non-gritty suspension or slurry, in less than three minutes.

[52] While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. Ac¬ cordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

[I] A dispersible tablet comprising levodopa, at least one decarboxylase inhibitor, and a filler, wherein the tablet comprises less than about 30% w/w filler.

[2] The dispersible tablet according to claim 1 wherein the tablet comprises less than about 20% w/w filler.

[3] The dispersible tablet according to claim 1 wherein the tablet comprises from about 1% w/w to about 20% w/w filler.

[4] The dispersible tablet according to claim 1 wherein the filler comprises micro- crystalline cellulose.

[5] The dispersible tablet according to claim 1 wherein the tablet disperses to form a solution, or non-gritty suspension or slurry, in less than about three minutes.

[6] The dispersible tablet according to claim 1 wherein the decarboxylase inhibitor comprises carbidopa or benserazide.

[7] The dispersible tablet according to claim 1 wherein the tablet comprises from about 45% w/w to about 75% w/w levodopa and from about 4% w/w to about 20% w/w decarboxylase inhibitor.

[8] The dispersible tablet according to claim 1 wherein the tablet comprises about

54% w/w to about 70% w/w levodopa and from about 5% w/w to about 18% w/ w decarboxylase inhibitor.

[9] The dispersible tablet according to claim 1 wherein the tablet further comprises one or more pharmaceutically inert excipients selected from superdisintegrants, binders, suspending agents, sweeteners, surfactants, colors, flavors, and lubricants/glidants.

[10] The dispersible tablet according to claim 9, wherein the filler comprises micro- crystalline cellulose, the superdisintegrant comprises one or both of croscarmellose sodium and crospovidone, and the binder comprises starch.

[I I] The dispersible tablet according to claim 9 wherein the tablet comprises from about 5% w/w to about 15% w/w superdisintegrant.

[12] The dispersible tablet according to claim 9 wherein the tablet comprises from about 3% w/w to about 10% w/w binder.

[13] A process for the preparation of a dispersible tablet of levodopa and one or more decarboxylase inhibitors, the process comprising the steps of a) wet granulating a blend comprising levodopa, one or more de¬ carboxylase inhibitors, and one or more fillers; and b) compressing the granules into tablet, wherein the tablet comprises less than about 30% w/w of filler.

[14] The process according to claim 13 wherein the tablet comprises less than about 20% w/w filler.

[15] The process according to claim 13 wherein the tablet comprises from about 1% w/w to about 20% w/w filler.

[16] The process according to claim 13 wherein the filler comprises microcrystalline cellulose.

[17] The process according to claim 13 wherein the granulation is carried out with a granulating fluid or a solution/dispersion of binder in a granulating fluid.

[18] The process according to claim 17 wherein the granulating fluid comprises one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, and water.

[19] A method for the treatment of Parkinson's disease in a mammal by administering to the mammal a dispersible tablet comprising levodopa, at least one de¬ carboxylase inhibitor, and a filler, wherein the tablet comprises less than about 30% w/w filler.

[20] The method of claim 19 wherein the tablet disperses to form a solution, or non- gritty suspension or slurry, in less than about three minutes.