Technical Field of the Invention
The present invention relates to a process for the production of a molded dosage form. The said process can be used for the production of both immediate release dosage forms and extended release dosage forms.
Background of the invention
Oral administration constitutes a preferred route of administration for majority of the drugs. Oral dosage forms can be designed as immediate release preparations that are designed to deliver the drug immediately upon administration or as extended release preparations that are designed to deliver the drug over an extended period of time. Several processes are known in the art for the production of these immediate release and extended release solid oral dosage forms like direct compression process, dry granulation, wet granulation, melt granulation and melt extrusion processes etc.
Inventors have now developed a simplified process for the production of a molded dosage form using an efficient continuous system. The process of the present invention is economical, utilizes minimum excipients, involves less number of manufacturing steps and has two-fold application- one, for the production of a molded immediate release dosage form of a poorly soluble drug using a hydrophilic solubilizer that enhances drug solubility/dissolution; and second, for the production of a molded extended release dosage form using a hydrophobic matrix agent.
International Publication Number WO 2005/004917 describes a pharmaceutical composition comprising a poorly soluble drug and polyethylene glycol prepared by wet granulation method or melt granulation method. The said composition exhibits enhanced solubility.
International Publication Number WO 1993/11749 discloses a process for the preparation of a poorly water soluble drug in solid dispersion comprising the steps of (a) blending the drug with a carrier, (b) dissolving a surfactant and a plasticizer/solubilizer in water (c) spraying the surfactant/plasticizer/solubilizer solution onto the drug/carrier mixture in a fluid bed granulator (d) extruding the resultant granulation through a twin screw extruder with one heating zone, and (e) milling the extrudate to a powdery mass of solid dispersion.

Modified release dosage forms prepared via compression method to obtain either diffusional or eroding matrices are exemplified in US Patent No.'s 5,738,874 and 6,294,200 and International Publication Number WO 1999/51209.
International Publication Number WO 2010/022193 describes controlled release pharmaceutical composition comprising modified release multiparticulates into a polymeric or wax-like matrix prepared by extrusion method.
Hydrophobic drugs i.e. drugs having poor solubility in aqueous solution present difficult formulation problems. Moreover, when such poorly soluble drugs are formulated into tablets by conventional compression process, the disintegration/dissolution of these drugs is further reduced. Therefore, to increase the disintegration/dissolution rate, it is a common practice to incorporate relatively large amounts of additional excipients, which in turn, increases the tablet size and causes other excipient and process related challenges. Inventors have now developed a simplified, cost-effective and a relatively continuous process that can be used to produce molded immediate release dosage form comprising a drug and a hydrophilic solubilizer, wherein the resultant dosage form has enhanced solubility/dissolution and hence better bioavailability.
The process of the present invention additionally finds application in the manufacture of extended release dosage forms. It is indeed of great advantage to both the patient and the physician to provide the drug in an extended release dosage form as it not only increases patient compliance due to reduction in frequency of dosing, but also reduces the severity and frequency of side effects by maintaining substantially constant plasma levels. Various types of extended release dosage forms are known in the art like reservoir systems, matrix systems, osmotic pumps etc. of which the matrix system has been most widely utilized. In a hydrophobic matrix system, the drug is dispersed throughout the rate-controlling hydrophobic agent. However, manufacturing of hydrophobic matrix tablets with conventional methods such as compression into tablets or filling into capsules is associated with various problems. These include one or more of the following: (i) sticking of tablets to punches; (ii) lamination of tablets; (iii) need for a slow compression speed to minimize lamination and sticking and (iv) intermittent halting of the compression machine to avoid heating up of the machine which causes softening of the granules. The inventors have found that the process of this invention overcomes some or all of these shortcomings.

Therefore, the process of the present invention is economical, simple and capable of producing both immediate release and extended release molded dosage forms on an efficient continuous system whilst overcoming some or all of the problems associated with the conventional processes.
Summary of the Invention
In one general aspect, it relates to a process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, wherein the process comprises the steps of (i) mixing of the drug and the pharmaceutically acceptable excipient; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
In one embodiment of the above aspect, it relates to a process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, wherein the dosage form is an immediate release dosage form.
In another embodiment of the above aspect, it relates to a process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, wherein the dosage form is an extended release dosage form.
In another general aspect, it relates to a process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipients are selected from hydrophilic solubilizers, hydrophobic agents, diluents, binders, lubricants, glidants, disintegrants, flavoring agents, sweetening agents and coloring agents.
In another general aspect, it relates to a process for the production of a molded dosage form comprising a drug and one or more hydrophilic solubilizers, wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophilic solubilizers having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the

molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
In another general aspect, it relates to a process for the production of a molded dosage form comprising a drug and one or more hydrophobic agents, wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophobic agents having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
In one embodiment of the above aspect, the dosage form may additionally comprise one or more hydrophilic solubilizers.
Detailed Description of the Invention
The present invention relates to a process for the production of a molded dosage form that is advantageous over conventional processes for the following reasons:
1) Simplified and economical process
2) It is a continuous, enclosed process that can be easily translated into an automated process, thereby resulting in reduced manual intervention, lesser variability, higher yields and lower costs
3) Avoidance of the use of solvents or laboratory-intensive drying procedures
4) Involves less number of manufacturing steps and minimum number of excipients
5) Finds application for production of both immediate release and extended release dosage forms
6) Can be used for drugs with wide range of physical and chemical properties
7) Devoid of typical problems associated with hydrophobic matrix tablet manufacture
8) Mold casts can be made attractive (as with jelly, toffee or chocolate) for pediatric use
As used herein, the term "drug" refers to as any compound, medicament, substance or active ingredient having a therapeutic or pharmacological effect, and which is suitable for administration to a mammal, e.g. a human in a dosage form that is particularly suitable for

oral administration. The amount of the drug may vary from about 5% to about 95% by weight of the dosage form.
As used herein, the term "dosage form", refers to physically discrete unit suitable as unitary dosage to mammals, including humans, with each unit containing a predetermined quantity of drug calculated to produce the desired effect in association with other pharmaceutically acceptable excipients, if present. The dosage form in this case may be a tablet, caplet, pellet, pill, jelly or any other suitable unit dosage form. As used herein, the term "immediate release dosage form" means that the drug is released from the dosage form immediately upon administration while the term "extended release dosage form" means that the drug is released from the dosage form over an extended period of time.
As used herein, the term "pharmaceutically acceptable excipient" refers to any physiologically inert and pharmacologically inactive material known in the art. The pharmaceutically acceptable excipients may be selected from hydrophilic solubilizers, hydrophobic agents, diluents, binders, lubricants/glidants, disintegrants, flavoring agents, sweetening agents, coloring agents etc.
As used herein, the term "hydrophilic solubilizer" refers to any pharmaceutically acceptable excipient which possesses hydrophilic groups and is capable of improving the solubility and/or dissolution of the poorly soluble drug. Usually it should be such that it melts and/or soften when heat is applied to allow molding while maintaining good chemical stability and has a melting point greater than about 25°C, preferably greater than about 45°C. Exemplary agents that can be used as hydrophilic solubilizer, include, but are not limited to, polyvinylpyrrolidone; copolymer of polyvinylpyrrolidone with vinyl acetate; polyvinyl alcohol; polyethylene glycol; cyclodextrins; cellulosic derivatives e.g. hydroxypropylmethyl cellulose and hydroxypropyl cellulose etc.; acrylic and methacrylic polymers; polyoxyethylene alkyl ethers; co-block polymers of ethylene oxide and propylene oxide; polyoxyethylene-polyoxypropylene copolymer or the like and the combinations thereof. The amount of hydrophilic solubilizer may vary from about 5% to about 95% by weight of the dosage form.
As used herein, the term "hydrophobic agent" refers to any pharmaceutically acceptable excipient that can retard the release of the drug and is one or more substances that melt and/or soften when heat is applied to allow molding while maintaining good stability.

Usually this agent has a melting point greater than about 25°C, preferably greater than about 45°C. Exemplary agents that may be used as hydrophobic agents, include, but are not limited to, fatty acid glycerides including mono-, di- and tri- glycerides like glyceryl behenate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripaltmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monoluarate, glyceryl didocasanoate, glyceryl tridocasonoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate; glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, and the like; hydrocarbons; hydrogenated fats; hydrogenated vegetable oils such as hydrogenated castor oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soyabean oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and the like; natural or synthetic waxes like spermaceti wax, carnauba wax, japan wax, beeswax, bayberry wax, flax wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, shellac wax, petrolatum and the like; fatty alcohols such as cetyl alcohol, stearyl alcohol, cetostearyl alcohol, myristyl alcohol, lauryl alcohol and the like; fatty acids like stearic acid, palmitic acid, lauric acid, eleostearic acid and the like. Combinations of these agents or their combination with other release controlling agents may also be used. Combination of hydrophobic agents with hydrophilic solubilizers may also be employed to obtain the desired drug release. The amount of hydrophobic agent may vary from about 5% to about 95% by weight of the dosage form.
Exemplary diluents may include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide as well as other conventional diluents well known to the persons skilled in the art.
Exemplary binders may include but are not limited to, acacia, guar gum, alginic acid, carbomer, dextrin, maltodextrin, methylcellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, magnesium aluminum silicate, polymethacrylates, crospovidones, povidones,

copovidones, gelatin, starch as well as other conventional binders well known to the persons skilled in the art.
Exemplary lubricants/glidants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, stearic acid, colloidal silicon dioxide, glyceryl palmitostearate, vegetable oils, polyethylene glycols, polyvinyl alcohols, talc, sodium benzoate, sodium stearyl fumarate, magnesium oxide, poloxamer, sodium lauryl sulphate, polyoxyethylene monostearate, cocoa butter, hydrogenated vegetable oils, mineral oil, polysaccharides as well as other conventional lubricants/glidants well known to the persons skilled in the art.
Exemplary disintegrants include, but are not limited to, mannitol, alginic acid, carboxymethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium starch glycolate, starch as well as other conventional disintegrants well known to the persons skilled in the art.
Exemplary flavoring agents include, but are not limited to, natural and synthetic flavor liquids like volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof.
Exemplary sweetening agents include, but are not limited to, sucrose, dextrose, invert sugar, fructose, saccharin, aspartame, acesulfame, sucralose, sugar alcohols such as sorbitol, mannitol, xylitol, and the like.
Exemplary coloring agents include, but are not limited to, titanium dioxide pigments, lake colors, iron oxide pigments and the like.
The present invention relates to process for the production of a molded dosage form and may take form of several different embodiments.
In one embodiment, it relates to a process for the production of a molded dosage form comprising a drug and one or more hydrophilic solubilizers, wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophilic solubilizers having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage

form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
In one of the above embodiment, the hydrophilic solubilizer is copovidone.
In another embodiment, the hydrophilic solubilizer is a combination of polyvinylpyrrolidone and cyclodextrin.
In yet another embodiment, the hydrophilic solubilizer is poloxamer.
In still another embodiment, the hydrophilic solubilizer is polyethylene glycol.
In another embodiment, it relates to a process for the production of a molded dosage form comprising a drug and one or more hydrophobic agents, wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophobic agents having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
In one of the above embodiment, the hydrophobic agent is glyceryl behenate.
In another embodiment, the hydrophobic agent is wax.
In yet another embodiment, the hydrophobic agent is hydrogenated vegetable oil.
In the above embodiments, the dosage form may additionally comprise polyethylene glycol in addition to the hydrophobic agents.
In all of the above embodiments, the dosage form is a tablet dosage form.

The process for the production of molded tablets described herein is further illustrated by the following examples, but these should not be construed, as limiting the scope of the invention in any way.
EXAMPLE 1: Production of molded immediate release tablets containing Nisoldipine:
Weighed quantities of nisoldipine and copovidone were sifted through appropriate sieve. The obtained mixture was heated with continuous stirring to get a molten mass. The resultant molten mass was poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLE 2: Production of molded immediate release tablets containing Cilostazole:
Weighed quantities of cilostazole, cyclodextrin and polyvinylpyrrolidone were sifted through appropriate sieve. The obtained mixture was heated with continuous stirring to get a molten mass. The resultant molten mass was poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLES 3-4: Production of molded immediate release tablets containing Carbamezepine:
Weighed quantities of carbamezepine, poloxamer/PEG 8000 are sifted through appropriate sieve. The obtained mixture is heated with continuous stirring to get a molten mass. The resultant molten mass is poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLES 5-6: Production of molded immediate release tablets containing Nisoldipine:
Weighed quantities of nisoldipine, poloxamer/PEG 8000 are sifted through appropriate sieve. The obtained mixture is heated with continuous stirring to get a molten mass. The resultant molten mass is poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLE 7: Production of molded extended release tablets containing pregabalin:
Weighed quantities of pregabalin and glyceryl behenate were sifted through appropriate sieve. The obtained mixture was heated with continuous stirring to get a molten mass. The resultant molten mass was poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLES 8-14: Production of molded extended release tablets containing tramodol hydrochloride:
Weighed quantities of tramodol hydrochloride and glyceryl behenate were sifted through appropriate sieves. The obtained mixture was heated with continuous stirring to get a
molten mass. The resultant molten mass was poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)
EXAMPLES 15-16: Production of molded extended release tablets containing Ibuprofen:
Weighed quantities of ibuprofen and hydrogenated vegetable oil or wax were sifted through appropriate sieve. The obtained mixture was heated with continuous stirring to get a molten mass. The resultant molten mass was poured into blister pocket and then allowed to cool at room temperature.
(Table Removed)

WE CLAIM:
1) A process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, wherein the process comprises the steps of (i) mixing of the drug and the pharmaceutically acceptable excipient; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
2) The process according to Claim 1, wherein the dosage form is an immediate release dosage form.
3) The process according to Claim 1, wherein the dosage form is an extended release dosage form.
4) The process according to Claim 1, wherein the pharmaceutically acceptable excipients are selected from hydrophilic solubilizers, hydrophobic agents, diluents, binders, lubricants, glidants, disintegrants, flavoring agents, sweetening agents and coloring agents.
5) The process according to Claim 1, wherein the process wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophilic solubilizers having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.
6) The process according to Claim 1, wherein the process comprises the steps of (i) mixing of the drug in an amount of from about 5% to about 95% by weight of the dosage form and one or more hydrophobic agents having a melting point above 45°C in an amount of from about 5% to about 95% by weight of the dosage form; (ii) heating of the said admixture to produce a molten mass; (iii) transferring the molten mass to blister pockets (iv) cooling of the molten mass (v) sealing of the blister pockets containing molded dosage form.

7) The process according to Claim 6, wherein the dosage form additionally comprises
one or more hydrophilic solubilizers.
8) A process for the production of a molded dosage form comprising a drug and a pharmaceutically acceptable excipient, substantially as described and exemplified herein.