Technical Field of the Invention
The present invention relates to rapidly disintegrating tablets of rimonabant for oral administration.
Background of the invention
Oral intake, particularly in the form of tablets, is the most preferred route for administration of wide variety of drugs to produce systemic effects. But, many patients have difficulty in swallowing conventional tablets and even capsules, and consequently do not take medications as prescribed. This is particularly true for pediatric and geriatric patients; mentally ill and developmentally disabled patients and patients who are uncooperative. 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. It is, therefore, desirable to administer drugs to such patients either as liquid dosage forms or as rapidly disintegrating dosage forms.
Rapidly disintegrating tablets, which disintegrate in the oral cavity with or without the aid of any liquid, due to their ease of administration and pleasant taste may encourage patients to adhere to daily medication regimens and, therefore, provide better patient compliance. These dosage forms combine the advantages of both liquid and conventional tablet formulations and also offer advantages over both traditional dosage forms. Rapidly disintegrating tablets, further, offer the convenience of a readily administered dosage form, which can be taken anywhere, anytime, and possibly without water.
Rimonabant is a selective cannabinoid-1 receptor (CB-1) antagonist and is chemically described as 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide. It is indicated as an adjunct to diet and exercise for the treatment of obese patients (BMI>30kg/m2), or overweight patients (BMI>27kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidemia. Rimonabant is also being investigated in smoking cessation treatment and for schizophrenia. Currently, it is marketed under the brand name Acomplia® by Sanofi Aventis as conventional 20mg film coated tablets.
US 5,624,941 discloses rimonabant and processes for its preparation. US 6,893,659 discloses pharmaceutical compositions comprising rimonabant in micronized form, disintegrant and sodium alkyl sulfate prepared by wet granulation in the form of gelatin capsules, tablets, sachets or powders. WO 98/43635 discloses pharmaceutical composition of rimonabant having poloxamer, and formulated in a macroglyceride.
Different technologies have been employed for the formulation of rapidly disintegrating tablets viz. freeze drying, spray drying , tablet molding, vacuum drying and sublimation techniques and are available from manufacturers like Cima Labs, Fuisz Technologies, Prographarm Group, Yamanouchi-Shakles and Cardinal Health.
Zydis™ of Cardinal Health is is a unique, freeze-dried tablet in which the drug is physically entrapped or dissolved within the matrix of fast dissolving carrier material. Lyophilization or freeze drying is an expensive industrial process and incurs high capital cost, complex sophistication of equipment, increased handling and processing time. Other drawbacks include fragility, which makes the use of conventional packaging difficult and poor stability during storage under stressful conditions.
Other technologies which are available include ORASOLV™ and DURASOLV™ from Cima Labs, Inc. ORASOLV™ is an effervescent direct compression tablet that involves incorporating microencapsulated drug ingredients into a tablet that dissolves in the mouth without the need for chewing or water. DURASOLV™ is a high compaction, more durable fast dissolving tablet which combines taste-masked active drug ingredients with a fast dissolving, low effervescence system and is described in US 6,024,981. Fuisz technologies markets FLASHDOSE® direct compression tablet containing a processed excipient called shearform. WOWTAB® by Yamanouchi Pharma Technologies is a fast disintegrating tablet obtained by granulation of a saccharide of low moldability with saccharide of high moldability and then compression molding of the granulation product. Prographarm markets FLASHTAB™, which is a fast melt tablet having coated drug particles, a disintegrating agent and a swelling agent and is described in EP 0548356. However, these processes involve to a greater or lesser extent the following disadvantages: high content of insoluble excipients or microencapsulated active ingredients that give gritty feel and consequently palatability problems, long disintegration times and insufficient mechanical strength.
US 2002/0071864 discloses a tablet for oral administration comprising a therapeutically effective amount of active ingredient, (ii) spray dried mannitol, (iii) crospovidone, and (iv) one or more pharmaceutically acceptable excipients, the tablet containing no microcrystalline cellulose.
US 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 -20cal/g or less and a pH adjusting agent.
WO 99/44580 describes a method for obtaining tablets by direct compression of mixtures that contain atleast 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.
None of the above cited references disclose rapidly disintegrating tablets of rimonabant. Moreover, the above prior art references disclose various methods for preparing rapidly disintegrating tablets that require complicated processing techniques and specialized excipients such as effervescents, highly micronized agents or the like. We have now discovered that rapidly disintegrating tablets of rimonabant can be prepared by simple and economical processes using conventional excipients.
Summary of the Invention
In one general aspect, it relates to a rapidly disintegrating tablet of rimonabant comprising a therapeutically effective amount of rimonabant, a sugar alcohol, a super-disintegrant and one or more pharmaceutically acceptable excipients selected from binders, disintegrants, wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents.
In another general aspect, it relates to a rapidly disintegrating tablet of rimonabant comprising a therapeutically effective amount of rimonabant, spray-dried mannitol, a super-disintegrant and one or more pharmaceutically acceptable excipients selected from binders, disintegrants, wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents.
In another general aspect, it relates to a rapidly disintegrating tablet of rimonabant comprising a therapeutically effective amount of rimonabant, spray-dried mannitol, croscarmellose sodium and one or more pharmaceutically acceptable excipients selected from binders, disintegrants, wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents.
In another general aspect, it relates to a process for preparation of rapidly disintegrating tablet of rimonabant wherein the process comprises mixing a therapeutically effective amount of rimonabant, a sugar alcohol, a super-disintegrant and one or more pharmaceutically acceptable excipients selected from binders, disintegrants, wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents and processing into a tablet.
In another general aspect, it relates to a process for preparation of rapidly disintegrating tablet of rimonabant wherein the process comprises:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents;
and;
b) directly compressing the mixture into a tablet using appropriate tooling.
In another general aspect, it relates to a process for preparation of rapidly disintegrating tablet of rimonabant wherein the process comprises:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) compacting or slugging the material of step (a);
c) sizing the compacted or slugged material of step (b) into granules, and;
d) mixing the sized granules of step (c) with other excipients such as lubricants,
glidants and then compressing into a tablet.
In another general aspect, it relates to a process for preparation of rapidly disintegrating tablet of rimonabant wherein the process comprises:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) granulating the blend of step (a) with a granulating solvent or a binder solution;
c) drying and sizing of the granules;
d) mixing the sized granules with other excipients such as lubricants, glidants and
subsequently compressing into a tablet.
Detailed Description of the Invention
The term "rapidly disintegrating tablets" as used herein is intended for tablets that disintegrate within 5 seconds to 2 minutes, when placed either in the oral cavity or in water.
The term "therapeutically effective amount" as used herein refers to the amount which produces the desired therapeutic response upon oral administration and is intended to provide from about 0.1 mg to about 50mg of rimonabant per tablet.
"Rimonabant" as recited herein means rimonabant or a pharmaceutically acceptable form of rimonabant, including without limitation, its pharmaceutically acceptable complexes, salts, solvates, hydrates, and polymorphs. Rimonabant in the dosage form as described herein may be in micronized or un-micronized form.
In a tableting procedure, the choice of excipients is critical to achieve rapid disintegration and suitable physical characteristics like hardness, friability etc. The excipients include diluents, super-disintegrants/disintegrants, binders, wetting agents, lubricants, glidants, sweeteners, flavoring and coloring agents and the like.
The diluent(s) may be selected from calcium phosphate dibasic, microcrystalline cellulose, calcium silicate, maltodextrin, sugar alcohols such as xylitol, erythritol, sorbitol and mannitol and combinations thereof. Particularly preferred diluent is sugar alcohol. Sugar alcohol provides multiple functions to the rapidly disintegrating tablet. It
provides good aesthetic properties to the dissolved oral tablet such as taste (sweetness and coolness due to its endothermal heat of solution) and mouth texture or body and also aids in rapid disintegration. Sugar alcohol may be used in a concentration of 25% to 95%, particularly 40% to 90% w/w of the tablet. Particularly, sugar alcohol is spray-dried mannitol. Spray-dried mannitol is available as Pearlitol SD™ by Roquette. It is a directly compressible, non-hygroscopic and chemically stable sugar. 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 pick-up. 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 exhibits improved flowability and compressibility, thus making it suitable for use in direct compression procedures.
Disintegrants play a major role in the rapid disintegration of tablets as they facilitate the break up of the tablet when it is placed in an aqueous environment, such as the mouth. Disintegrants when in contact with water swell, wick in water or otherwise provide a disruptive force to a tablet causing it to break apart. It is preferred that disintegrant present in the formulations of this invention comprise atleast one super-disintegrant. Suitable super-disintegrants include one or more of croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinyl pyrrolidone. The super-disintegrant may comprise from about 1% to 15%; particularly from 2% to 10% w/w of the tablet. One or more conventional disintegrants may also be included in addition to the super-disintegrant(s). Suitable disintegrants include natural, modified or pregelatinized starch, microcrystalline cellulose, gums especially guargum, alginic acid or salts thereof.
Binders are generally used in a tablet to impart cohesive properties to the tableted blend. Binder may be selected from the group comprising of microcrystalline cellulose, starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxyvinyl polymers like carbomers and other such materials routinely used in the art of solid dosage form manufacturing. Binder may be present in an amount varying from about 1% to about 20% w/w, and particularly from about 3% to about 15% w/w of the tablet. Particularly preferred binder is microcrystalline cellulose.
Suitable wetting agent(s) may be selected from sodium lauryl sulfate, poloxamers, polyoxythylene ethers, polyoxyethylene sorbitan fatty acid esters (polysorbates) and the like. Wetting agent may be comprise from about 0.01 % to about 5% w/w of the tablet.
Suitable lubricant(s) may be selected from talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate and stearic acid. In one embodiment, magnesium stearate is included as a lubricant. Glidant(s) may be selected from talc, colloidal silicon dioxide, and the like. Particularly preferred glidant is colloidal silicon dioxide. The lubricant and glidant may be used in a concentration 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 may be used both as a lubricant and glidant.
Suitable sweetener(s) may be selected from one or more of aspartame, saccharin sodium, dextrose, maltodextrin, fructose, sorbitol and the like. In one embodiment, aspartame is included as a sweetener.
The tablets may also include flavoring and coloring agent(s). Generally, any pharmaceutically acceptable flavoring agent may be used. Suitable flavoring agents include strawberry, peppermint, cherry, mint, caramel, raspberry, lemon, orange or banana. Colors may be selected from the group consisting of ferric oxide, titanium dioxide, F, D & C colors and D & C colors and the like.
The rapidly disintegrating tablets as described herein can be prepared by any of the conventional processing techniques known in the art such as direct compression, dry or wet granulation.
Direct compression method may comprise preparing a blend comprising rimonabant, sugar alcohol, super-disintegrant/disintegrant, binder, wetting agent, lubricant, glidant, sweetener and flavor and compressing the blend into a tablet using appropriate tooling.
Alternatively, dry granulation method may comprise blending rimonabant and one or more pharmaceutically acceptable excipients and granulating using roller compactor or slugging. The resultant material is sized to form granules, which are, optionally, mixed with other excipients and subsequently compressed into a tablet.
Alternatively, wet granulation method may be employed which comprise blending rimonabant and one or more pharmaceutically acceptable excipients in a suitable mixer, granulating with a granulating solvent or a binder solution and drying and sizing of the resultant granules. The granules are then mixed with other excipients and subsequently compressed into a tablet.
In one embodiment, rapidly disintegrating tablets of rimonabant may be prepared as follows:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients such as binder, disintegrant, wetting
agent, lubricant, glidant, sweeteners, flavoring and coloring agents; and;
b) directly compressing the mixture into a tablet using appropriate tooling.
In another embodiment, rapidly disintegrating tablets of rimonabant may be prepared as follows:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) compacting or slugging the material of step (a);
c) sizing the compacted or slugged material of step (b) into granules, and;
d) mixing the sized granules of step (c) with other excipients such as lubricants,
glidants and then compressing into a tablet.
In an alternative embodiment, rapidly disintegrating tablets of rimonabant may be prepared as follows:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) granulating the blend of step (a) with a granulating solvent or a binder solution;
c) drying and sizing of the granules;
d) mixing the sized granules with other excipients such as lubricants, glidants and
subsequently compressing into a tablet.
The tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating
compositions comprising film forming polymers marketed under various trade names,

®
such as Opadryand Eudragit.

The invention described herein is further illustrated by the following examples but it should not be construed as limiting the scope of the invention.
EXAMPLES 1-3:
Procedure: All ingredients except flavor, magnesium stearate and colloidal silicon dioxide were blended for 5-10 minutes. This blend was then mixed with flavor, magnesium stearate, and colloidal silicon dioxide for 5 minutes and subsequently compressed to obtain rapidly disintegrating tablets.

WE CLAIM:
1) A rapidly disintegrating tablet of rimonabant comprising a therapeutically
effective amount of rimonabant, a sugar alcohol, a super-disintegrant and one or
more of pharmaceutically acceptable excipients selected from binders,
disintegrants, wetting agents, lubricants, glidants, sweeteners, coloring and
flavoring agents.
2) The rapidly disintegrating tablet according to Claim 1, wherein rimonabant is
present in an amount ranging from about 0.1 mg to about 50mg per tablet.
3) The rapidly disintegrating tablet according to Claim 1, wherein sugar alcohol is
selected from the group comprising of xylitol, erythritol, sorbitol and mannitol.
4) The rapidly disintegrating tablet according to Claim 1, wherein the super-
disintegrant is selected from the group comprising of croscarmellose sodium
sodium starch glycolate, and cross-linked polyvinyl pyrrolidone.
5) A process for the preparation of rapidly disintegrating tablet of Claim 1, wherein
the process comprises blending rimonabant, a sugar alcohol, a super-
disintegrant with one or more of pharmaceutically acceptable excipients selected
• from binders, disintegrants, wetting agents, lubricants, glidants, sweeteners, coloring and flavoring agents; and compressing the mixture into a tablet using appropriate tooling.
6) A process for the preparation of rapidly disintegrating tablet of Claim 1, wherein
the process comprises the steps of:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) compacting or slugging the material of step (a);
c) sizing the compacted or slugged material of step (b) into granules, and;
d) mixing the sized granules of step (c) with other excipients such as lubricants,
glidants and then compressing into a tablet.

7) A process for the preparation of rapidly disintegrating tablet of Claim 1, wherein
the process comprises the steps of:
a) blending rimonabant, a sugar alcohol, a super-disintegrant and one or more
pharmaceutically acceptable excipients selected from binders, disintegrants,
wetting agents, sweeteners, flavoring and coloring agents;
b) granulating the blend of step (a) with a granulating solvent or a binder
solution;
c) drying and sizing of the granules;
d) mixing the sized granules with other excipients such as lubricants, glidants
and subsequently compressing into a tablet.

8) A rapidly disintegrating tablet according to Claim 1, comprising rimonabant,
mannitol, microcrystalline cellulose, croscarmellose sodium, lubricant/glidant,
sweetener and flavoring agent prepared by direct compression method.
9) A rapidly disintegrating tablet of rimonabant and process for the preparation
thereof substantially as described and illustrated by the examples herein.