Technical Field of the Invention
The present invention relates to rapidly disintegrating tablets of risperidone for oral administration prepared by conventional tabletting procedures.
Background of the Invention
Oral intake, particularly in the form of tablets, is the most effective way of administering drugs. But many patients have difficulty in swallowing conventional tablets and hard gelatin capsules, and consequently do not take medications as prescribed. This is particularly true for pediatric and geriatric patients and patients who are bed-ridden. This also holds for some group of patients where swallowing can initiate a nauseating reaction, for example, patients with gastrointestinal disorders, migraine etc. This results in a high incidence of non-compliance and ineffective therapy.
Rapidly disintegrating tablets, which disintegrate in the oral cavity with or without the aid of any liquid, are advantageous over conventional tablets, capsules or extemporary suspensions, and thus are commonly used to enhance patient compliance. Rapid disintegrating tablets also offer the convenience of a readily administered dosage form, which can be taken anywhere, anytime, and possibly without water.
Risperidone is one of a new generation of "atypical" antipsychotic drugs, which offer distinct advantages over older agents, including decreased side effects and improved efficacy in treatment of the negative symptoms of psychosis.
Risperidone is used to treat psychotic disorders and symptoms such as hallucinations, delusions, and hostility and has good activity against various symptoms and signs associated with schizophrenia. It is primarily indicated for acute and chronic schizophrenic psychoses and other psychotic conditions with positive and negative symptoms. It is also indicated for affective symptoms associated with schizophrenia. It is also found to be efficacious in the therapy of acute bipolar affective disorder.
Risperidone is manufactured by Janssen-Cilag and sold under the brand name Risperdal™. US 4,804,663 discloses risperidone and processes for its preparation as well as that of its intermediates. It also discloses film-coated tablet formulation of risperidone comprising a core having a coating, and other formulations such as capsules, oral solution, oral drops, injectable solution and suppositories. But there is no mention with respect to rapidly disintegrating tablet formulation of risperidone.
Different technologies have been developed for obtaining formulations that disintegrate quickly in the oral cavity and are available from manufacturers like Cima Labs, Fuisz Technologies Ltd., Prographarm, Yamanouchi- Shaklee and Cardinal Health.
Zydis™ of Cardinal Health, is a unique freeze dried tablet in which drug is physically entrapped or dissolved within the matrix of fast-dissolving carrier material. Janssen Pharmaceutica discloses a technology of preparing a solid dosage form comprising a porous network of matrix composition that disperses rapidly in water, wherein the dosage form is prepared by subjecting a matrix material solution to either lyophilization, or solid-state dissolution.
Lyophilization or freeze-drying is an expensive industrial process and incurs high capital cost, complex sophistication of equipment, increased handling and processing time and difficulty in packaging. Solid-state dissolution, on the other hand, imposes limitations on the solvents that can be used, as the solidification temperature of the first and the second solvent is a critical factor of consideration. Such limitations confer complexities to such process.
The other technologies which are available include Cima Labs' OraSolv™, which is an effervescent direct compression tablet having an oral dissolution time of five to thirty seconds, and DuraSolv™, which is a direct compression tablet having a taste-masked active agent in the form of coated microparticles. PCT application WO 98/46215 filed by Cima Labs, describes a hard, compressed, fast melt formulation having an active ingredient and a matrix of at least a non-direct compression filler and relatively high amount of lubricant.
Fuisz Technologies markets Flash Dose which is a direct compression tablet containing a processed excipient called shearform.
US 5,464,632 assigned to Prographarm discloses multiparticulate tablet with high disintegration rate in which the active substance is in the form of coated or non-coated microcrystals or microgranules and wherein the excipients or vehicles, comprise generally a disintegrating agent, a swelling agent and a direct compression soluble diluent.
Yamanouchi markets Wowtab™ which is a buccal disintegrating tablet obtained by granulation of a saccharide of low moldability with saccharide of high moldability and then compression molding of the granulation product.
Yamanouchi also has US application 2003/0099701 which describes a quick-disintegrating tablet comprising a drug, a diluent, and a saccharide with a relatively lower melting point than said drug and said diluent, wherein a bridge is formed between said drug and/or said diluent particles by melting and then solidification of the saccharide with a low melting point.
The references above describe direct compression or granulation for preparing rapidly disintegrating tablets, but after some additional or alternative processing instead of simple direct compression or granulation.
PCT application WO 99/44580 describes methods for obtaining tablets by the direct compression of mixtures that contain at least one inorganic excipient that is insoluble in water, for example, calcium phosphate, one or more disintegrants, for example, crospovidone and optionally, water soluble excipients. Said technology is registered as Ziplets™ by Eurand. However, the compositions used contain a high percentage of insoluble excipients, which may leave a high amount of residue in the mouth and give a feeling of grittiness.
PCT application WO 03/103629 by Vita Laboratories disclose method for preparation of orally disintegrating tablets which disintegrate in the mouth in less than 30 seconds using a
diluent of high dissolution rate and high compressibility, and limiting the proportion and size of the particle of the insoluble ingredients. The amount and the particle size of the insoluble ingredients are stressed to be critical for compressibility.
PCT application WO 00/57857 by Yuhan Corporation disclose orally disintegrating tablets that disintegrate in the oral cavity leaving no unpleasant water-insoluble residues and has sufficient hardness, and which contain spray-dried mannitol, crospovidone and other excipients, by direct compression.
US application 2003/069213 discloses a method for improving taking ability of an oral administration preparation containing a drug having an unpleasant taste, which is effected by including a sugar alcohol having a heat of dissolution of -20 cal/g or less and a pH adjusting agent.
None of the above cited references disclose rapidly disintegrating composition of risperidone.
We have now discovered that taste-masked, rapidly disintegrating solid oral dosage forms of risperidone can be prepared by conventional tableting procedure using conventional excipients.
Summary of the Invention
In one general aspect, it relates to a rapidly disintegrating tablet of risperidone comprising a therapeutically effective amount of risperidone, a sugar alcohol, a disintegrant, a metal carbonate and one or more of pharmaceutically acceptable excipients like binder, lubricant, glidant, sweeteners, flavors and coloring agents.
In another general aspect, it relates to a rapidly disintegrating tablet of risperidone comprising a therapeutically effective amount of risperidone, mannitol, a disintegrant, a metal carbonate and one or more of pharmaceutically acceptable excipients like binder, lubricant, glidant, sweeteners, flavors and coloring agents.
In another general aspect, it relates to a process for preparation of rapidly disintegrating tablet of risperidone wherein the process comprises mixing a therapeutically effective amount of risperidone, a sugar alcohol, a metal carbonate and one or more of pharmaceutically acceptable excipients like disintegrant, binder, lubricant, glidant, sweeteners, flavors and coloring agents and processing into a tablet by conventional tabletting procedures.
In another general aspect, it relates to a process for preparing rapidly disintegrating tablet of risperidone wherein the process comprises:
a. blending risperidone, a sugar alcohol, a disintegrant, and a metal carbonate and
one or more of pharmaceutically acceptable excipients like binder, lubricant,
glidant, sweeteners, flavors and coloring agents; and
b. compressing the mixture into a tablet using appropriate tooling.
In another general aspect, it relates to a process for preparing rapidly disintegrating tablet of risperidone wherein the process comprises:
a. blending risperidone, a sugar alcohol, a disintegrant and a metal carbonate;
b. compacting or slugging the blend of step (a);
c. sizing the compacts or slugs of step (b) to form granules;
d. mixing the granules obtained in step (c) with one or more of pharmaceutically
acceptable excipients like sugar alcohol, disintegrant, binder, lubricant, glidant,
sweeteners, flavors and coloring agents; and
e. compressing the mixture obtained in step (d) into a tablet using appropriate tooling.
In another general aspect, it relates to a process for preparing rapidly disintegrating tablet of risperidone wherein the process comprises:
a. blending risperidone, a sugar alcohol, a disintegrant and a metal carbonate;
b. granulating blend of step (a) with a granulating liquid;
c. drying and mixing the granules obtained in step (b) with one or more of
pharmaceutically acceptable excipients like sugar alcohol, disintegrant, binder,
lubricant, glidant, sweeteners, flavors, coloring agents and the like; and
d. compressing the mixture obtained in step (c) into a tablet using appropriate tooling.
Detailed Description of the Invention
The term "rapid disintegrating" as used herein is intended for tablets which disintegrate when placed in the oral cavity or in water in less than a minute.
The term "therapeutically effective amount" as used herein is intended to provide from about 0.1 mg to 20 mg of risperidone per tablet, particularly from about 0.1 mg to about 10 mg of risperidone per tablet. Risperidone in the dosage form as described herein may be in a coated or uncoated form.
Risperidone as a drug is unpalatable because of its bitter taste. One of the postulation is that the taste sensation of a drug begins when ions or polar molecules of the drug taken into the mouth stimulate the cells of the taste buds. Retarding the ionization of drug molecules will lead to the decrease in solubility of the drug in the oral cavity and keeping it in a unionized, insoluble form would impart a taste-masking effect. This forms the basis of inclusion of metal carbonate in the formulation. The metal carbonate can be alkali metal carbonate like sodium carbonate, potassium carbonate; an alkaline earth metal carbonate like magnesium carbonate, calcium carbonate and bicarbonates like sodium bicarbonate.
potassium bicarbonate and the like. Particularly suitable is magnesium carbonate. The metal carbonate may be used in an amount ranging from 1 % to 30% w/w of the tablet.
In a tableting procedure, the choice of excipients or tableting aids is critical to achieve rapid disintegration and suitable physical characteristics like hardness, friability, etc. The excipients include diluent, disintegrant, binder, lubricant, glidant, flavors, sweeteners, coloring agents and the like.
Sugar alcohol that may be used include xylitol, erythritol, sorbitol and mannitol. Sugar alcohol may be used in a concentration of 25 % to 95 %, particularly 60% to 90% w/w of the tablet. Particularly suitable sugar alcohol is spray-dried mannitol. Spray dried mannitol is available as Pearlitol™. It is a directly compressible sugar and is nonhygroscopic. It has good dilution capacity due to the size and form of the particle, which makes it possible to accept large amounts of active ingredients that are not easily compressed. It does not add moisture or contribute to moisture pickup. It is also chemically inert. It also has optimum organoleptic properties due to negative dissolution heat and its excellent palatability due to its small particle size. These properties make mannitol a useful excipient for tablets because it protects water-sensitive actives from degradation and does not react with the active. Spray dried mannitol has a particle shape that allows it to be free flowing and easily mixed with other ingredients.
Disintegrants play major role in the disintegration of tablets. To ensure rapid disintegration in the oral cavity, choice of suitable type and an optimal amount of disintegrant is critical. The disintegrant may be selected from cross-linked carboxymethylcellulose and its sodium salt, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium alginate. Particularly suitable disintegrants are cross-linked carboxymethylcellulose sodium and cross-linked polyvinylpyrrolidone. When following the granulation process, the disintegrants may be added either intragranulary or extragranularly or both .The concentration of the disintegrant may vary from 1% to 15 %; particularly from 3% to 10% w/w of the tablet.
Binding agent is generally used in a tablet to impart cohesive properties to the tabletted blend. Binders that may be used are selected from the group consisting of starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymers like carbomers, acrylates like Eudragits and other such materials routinely used in the art of solid dosage form manufacturing for the purposes of binding and preparation of granules. The binding agent may be present in an amount varying from about 1% to about 10% by weight, and particularly from about 3% to about 8% w/w of the tablet.
The granulating liquid may comprise a solution or dispersion of the binder or may be a pharmaceutically acceptable liquid like water, ethanol etc. when binder is premixed with the blend to be granulated.
Lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid; whereas glidants can be selected from talc, colloidal silicon dioxide, and the like. The lubricant and glidant may be used in a concentration of varying from 0.5% to 5% w/w of the tablet. It would be appreciated that a person skilled in the art is cognizant of the fact that certain excipients can be used both as a lubricant and glidant.
Sweeteners may be selected from the group consisting of aspartame, saccharine sodium, sucrose, dextrose, fructose, sorbitol and the like.
The tablets may also include flavorants and coloring agents. Generally any pharmaceutically acceptable flavoring additive can be used such as menthol. Colors may be selected from the group consisting of ferric oxide, titanium dioxide, F.D. & C. and D. & C. dyes and the like.
The tablets as described herein can be prepared by direct compression, compaction or by wet granulation technique.
Direct compression method may comprise preparing a blend comprising risperidone, sugar alcohol, metal carbonate, disintegrant, binder, lubricants, glidants, sweeteners and flavors; and compressing the blend into a tablet using appropriate tooling.
Dry granulation may be carried out by slugging or roller compaction, particularly suitable is roller compaction. The roller compactor functions by uniformly applying pressure on a mixed powder blend by passing the blend between two counter-rotating rollers. The pressure imparted on the blend by the roller compresses the powder into a compact, such as a sheet or ribbon, which is milled to produce granules. In one aspect of the process, risperidone and one or more of pharmaceutical excipient selected from sugar alcohol, metal carbonate, disintegrant, binder, lubricant or glidant are blended and transferred to a roller compactor in a known manner. When in contact with the counter rotating rollers of the roller compactor, the compression force imparted on the blend by the rollers converts the powdered form into a ribbon or compaction sheet. The compact sheet is fed to a mill, such as an oscillatory mill filled with a screen. After passing through the mill and the screen, the compact gets converted into granules of desired particle size distribution. The granules may further be mixed with sugar alcohol, binder, disintegrant, lubricant, glidant, sweeteners and flavors prior to compressing into a tablet or may be compressed as such.
In wet granulation, risperidone, a disintegrant, sugar alcohol and metal carbonate are granulated with a solution/dispersion of the binder. Alternatively, the binder is added to the above blend and the resulting blend is granulated with a suitable solvent. The granules are dried and may be mixed with other excipients like sugar alcohol, binder, disintegrant, lubricant, glidant, sweeteners and flavors and compressed into tablets using appropriate tooling.
In one embodiment, rapid disintegrating tablets of risperidone may be prepared by:
blending risperidone, mannitol, a disintegrant and a metal carbonate with binder, lubricant, glidants, sweeteners, flavors and coloring agents; and compressing the mixture into a tablet using appropriate tooling;
In another embodiment, rapid disintegrating tablets of risperidone may be prepared by:
blending risperidone, mannitol, a disintegrant and a metal carbonate;
compacting the above blend with a roller compactor and sizing the compacts to
form granules;
mixing the granules with mannitol, disintegrant, binder, lubricants, glidants,
sweeteners, flavors and coloring agents; and
compressing the mixture thus obtained into a tablet using appropriate tooling.
In yet another embodiment, rapid disintegrating tablets of risperidone may be prepared by: blending risperidone, mannitol and a metal carbonate; granulating the blend with a granulating liquid;
drying and mixing the granules with mannitol, disintegrant, binder, lubricant, glidants, sweeteners, flavors and coloring agents; and compressing the mixture thus obtained into a tablet using appropriate tooling.
The invention described herein is further illustrated by the following examples but these should not be construed as limiting the scope of the invention:
(TABLE REMOVED)
Procedure: Risperidone, spray-dried mannitol, magnesium carbonate, menthol and iron oxide red were sifted. IVIagnesium carbonate was mixed geometrically with risperidone, menthol and iron oxide red and the blend was further mixed with spray-dried mannitol. Croscarmellose sodium, L-HPC, sodium saccharin, aspartame, flavors, talc and colloidal silicon dioxide were sifted and mixed with the blend obtained above. Magnesium stearate was sifted and added to the resultant blend and the lubricated blend was subsequently compressed into tablets using suitable tooling.
(TABLE REMOVED)
Procedure: Risperidone, spray-dried mannitol, croscarmellose sodium and magnesium carbonate were sifted and mixed in a blender. The blend was compacted using roll compactor and the compacted material was passed through a sieve to obtain granules. Aspartame, saccharin sodium, talc, colloidal silicon dioxide, L-HPC, magnesium stearate, flavors and the remaining amount of croscarmellose sodium and spray-dried mannitol were mixed with compacted granules, and subsequently compressed into tablets using suitable flat bevelled tooling.
(TABLE REMOVED)
Procedure: Risperidone, spray-dried mannitol, croscarmellose sodium and magnesium carbonate were sifted and mixed in a blender. Tlie blend was compacted using roll compactor and the compacted material was passed through a sieve to obtain granules. Aspartame, saccharin sodium, talc, colloidal silicon dioxide, L-HPC, magnesium stearate, sodium stearyl fumarate, flavors and the remaining amount of croscarmellose sodium and spray-dried mannitol were mixed with compacted granules, and subsequently compressed into tablets using suitable flat bevelled tooling.
(TABLE REMOVED)
Procedure: Risperidone, spray-dried mannitol, crospovidone and magnesium carbonate were sifted and mixed in a blender. Tlie blend was compacted using roll compactor and compacted material was passed through a sieve to obtain granules. Aspartame, saccharin sodium, talc, colloidal silicon dioxide, L-HPC, magnesium stearate, flavors and the remaining amount of crospovidone and spray-dried mannitol were mixed with compacted granules, and subsequently compressed into tablets using suitable flat bevelled tooling.
(TABLE REMOVED)
Procedure: Menthol and Eudragit E 100 were dissolved in a mixture of acetone and water. Risperidone, spray-dried mannitol, magnesium carbonate and ferric oxide were sifted and mixed in a blender. This blend was granulated with Eudragit solution and granules were dried in a fluidized bed drier. The granules were passed through a sieve. Croscarmellose sodium, L-HPC, aspartame, saccharin sodium, talc, silicon dioxide, magnesium stearate, flavors and the remaining amount of ferric oxide and spray-dried mannitol were mixed with granules, and subsequently compressed into tablets using suitable flat bevelled tooling.

WE CLAIM:
1. A rapidly disintegrating tablet of risperidone comprising a therapeutically effective amount of risperidone, a sugar alcohol, a disintegrant, a metal carbonate and one or more of pharmaceutically acceptable excipients like binder, lubricant, glidant, sweeteners, flavors and coloring agents.
2. The rapidly disintegrating tablet according to claim 1, wherein risperidone is present in amount ranging from 0.1 mg to 20 mg per tablet.
3. The rapidly disintegrating tablet according to claim 2, wherein risperidone is present in amount ranging from 0.1 mg to 10 mg per tablet.
4. The rapidly disintegrating tablet according to claim 1, wherein sugar alcohol is selected from the group consisting of xylitol, erythritol, sorbitol and mannitol.
5. The rapidly disintegrating tablet according to claim 4, wherein the sugar alcohol is mannitol.
6. The rapidly disintegrating tablet according to claim 1, wherein the disintegrant is selected from the group consisting of cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium alginate.
7. The rapidly disintegrating tablet according to claim 6, wherein the disintegrant is cross-linked carboxymethylcellulose sodium.
8. The rapidly disintegrating tablet according to claim 1, wherein the disintegrant is present in an amount ranging from 1% to 15% w/w of the tablet.
9. The rapidly disintegrating tablet according to claim 1, wherein the metal carbonate is selected form a group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
10. The rapidly disintegrating tablet according to claim 9, wherein the metal carbonate is magnesium carbonate.
11. The rapidly disintegrating tablet according to claim 1, wherein metal carbonate is present in an amount ranging from 1 % to 30 % w/w of the tablet.
12. The rapidly disintegrating tablet according to claim 1, wherein the binder is selected from the group consisting of starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymers and acrylates.
13. The rapidly disintegrating tablet according to claim 1, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid.
14. The rapidly disintegrating tablet according to claim 1, wherein glidant is selected from a group consisting of talc and colloidal silicon dioxide.
15. The rapidly disintegrating tablet according to claim 1, wherein sweeteners are selected from the group consisting of aspartame and saccharine sodium.
16. A rapidly disintegrating tablet of risperidone comprising a therapeutically effective amount of risperidone, mannitol, cross-linked carboxymethylcellulose sodium and magnesium carbonate.
17. A process for preparation of rapidly disintegrating tablet of risperidone wherein the process comprises mixing a therapeutically effective amount of risperidone, a sugar alcohol, a metal carbonate and one or more of pharmaceutically acceptable
excipients like disintegrant, binder, lubricant, glidant, sweeteners, flavors and coloring agents and processing into a tablet by conventional tabletting procedures.
18. The process according to claim 17, wherein risperidone is present in amount ranging from 0.1 mg to 20 mg per tablet.
19. The process according to claim 18, wherein risperidone is present in amount ranging from 0.1 mg to 10 mg per tablet.
20. The process according to claim 17, wherein sugar alcohol is selected from a group consisting of xylitol, erythritol, sorbitol and mannitol.
21. The process according to claim 20, wherein the sugar alcohol is mannitol.
22. The process according to claim 17, wherein the metal carbonate is selected from a group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
23. The process according to claim 22, wherein the metal carbonate is magnesium carbonate.
24. The process according to claim 17, wherein metal carbonate is present in an amount ranging from 1 % to 30% w/w of the tablet.
25. The process according to claim 17, wherein the disintegrant is selected from the group consisting of cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium alginate.
26. The process according to claim 25, wherein the disintegrant is cross-linked carboxymethylcellulose sodium.
27. The process according to claim 17, wherein the disintegrant is present in an amount ranging from 1% to 15% w/w of the tablet.
28. The process according to claim 17, wherein the binder is selected from the group consisting of starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxyvinyl polymers and acrylates.
29. The process according to claim 17, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid.
30. The process according to claim 17, wherein glidant is selected from a group consisting of talc and colloidal silicon dioxide.
31. The process according to claim 17, wherein sweeteners are selected from the group consisting of aspartame and saccharine sodium.
32. The process according to claim 17, wherein the tabletting procedure comprises direct compression.
33. The process according to claim 17, wherein the tabletting procedure comprises dry granulation.
34. The process according to claim 33, wherein the dry granulation is carried out by roller compaction.
35. The process according to claim 33, wherein the dry granulation is carried out by slugging.
36. The process according to claim 17, wherein the tabletting procedure comprises wet granulation.
37. A process for preparation of rapidly disintegrating tablet of risperidone wherein the process comprises blending risperidone, mannitol, cross-linked carboxymethylcellulose sodium, magnesium carbonate and one or more of pharmaceutically acceptable excipients like binder, lubricant, glidant, sweetener, flavor and coloring agent; and compressing the mixture into a tablet.
38. A process for the preparation of rapidly disintegrating tablet of risperidone as substantially exemplified and described herein.