DESC:FIELD OF INVENTION

The present invention provides premix of pimavanserin tartrate comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient and process for preparation of the premix.

BACKGROUND OF THE INVENTION

Pimavanserin which is marketed under the brand name Nuplazid ® is an atypical antipsychotic drug indicated for the treatment of hallucinations and delusions associated with Parkinson’s diseases psychosis. Nuplazid ® contains the active ingredient as pimavanserin tartrate (I) with chemical name Urea,N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N'-[[4-(2-methylpropoxy) phenyl]methyl] –(2R,3R)-2,3-dihydroxybutanedioate (2:1) and chemical structure as mentioned below.

The patents US 6815458, US 6756393 and US 7601740 mentions pimavanserin and its salts. The patents US 7732615, US 8236960 and US 7923564 mention various polymorphs of pimavanserin tartrate.

Different polymorphs of a compound may provide advantages in a variety of capacities like stability of the compound, stability of the formulation and improved pharmacokinetic profiles. Alternatively premix techniques can also be used to achieve these desired properties. Premixes are characterized by a variety of associated properties such as better stability, flow, and dissolution.

The present invention provides stable amorphous premix of pimavanserin tartrate with at least one pharmaceutically acceptable excipient.

DESCRIPTION OF DRAWING

Figure 1 – X-ray powder diffraction pattern of pimavanserin tartrate premix with aerosil.

SUMMARY OF THE INVENTION

The present invention provides stable amorphous premix of pimavanserin tartrate with at least one pharmaceutically acceptable excipient. The present invention provides process for preparation of stable amorphous premix of pimavanserin tartrate.

DETAILED DESCRIPTION OF THE INVENTION

The term "premix" is used herein to describe combinations of pimavanserin tartrate and at least one pharmaceutically acceptable excipient, wherein individual particles of the components cannot be distinguished using techniques such as optical microscopy and the like. Premixes are not simple or manual mixtures of powdered ingredients.

The term "stable" herein means pimavanserin tartrate that substantially does not convert to any other solid form and fulfill the standard stability criteria given in USP/EP monograph.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes but not limited to filler, diluent, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic. One excipient can perform more than one function.

The excipient include, but not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and .gamma.-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl beta.-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), hypromellose acetate succinate (AQOAT), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co-(lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; gum; Zeolite; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, copovidone, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes; silica excipients like silicon dioxide such as aerosil, syloid, all grades included.

In the first embodiment, the present invention provides stable amorphous pimavanserin tartrate premix comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient.

The present invention provides stable amorphous pimavanserin tartrate premix comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient selected from silicon dioxide or colloidal silicon dioxide.

The present invention provides stable amorphous pimavanserin tartrate premix comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient selected from colloidal silicon dioxide such as aerosil.

The present invention provides stable amorphous pimavanserin tartrate premix comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient selected from colloidal silicon dioxide such as syloid.

In the second embodiment, the present invention provides stable amorphous pimavanserin tartrate premix with aerosil characterized by X-ray diffraction pattern as depicted in Figure 1.

In the third embodiment, the present invention provides a process for the preparation of pimavanserin tartrate premix with at least one pharmaceutically acceptable excipient comprising the steps of:

i) adding pimavanserin tartrate in one or more solvent,
ii) optionally heating the mixture,
iii) adding the excipient, and
iv) isolating pimavanserin tartrate premix.

Pimavanserin tartrate which is used for preparation of premix can be prepared by methods as known in the literature. Pimavanserin tartrate can be crystalline or amorphous.

The solvent can be selected from water; alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane; ketones like acetone, methyl ethyl ketone; other polar solvents like dimethylformamide, dimethyl sulfoxide and mixtures thereof.

The mixture of pimavanserin tartrate and the solvent can be optionally heated to a temperature of 30°C to reflux temperature of the solvent to form a clear solution.

The excipient include, but not limited to mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol, inositol, trehalose, trehalose, maltose, raffinose, .alpha.-, .beta.- and .gamma.-cyclodextrins, gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, xanthan gum, starch, lectins, urea, chitosan, chitosan glutamate, hydroxypropyl beta.-cyclodextrin chitosan, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMC-P), hydroxylpropyl methylcellulose acetate succinate (HPMC-AS), hypromellose acetate succinate (AQOAT), carboxymethylethylcellulose (CMEC), carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, co-(lactic/glycolic)copolymers, poly(orthoester), polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, carbopols, silicon elastomers, polyacrylic polymers, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxylvinyl polymer, polyvinylpyrrolidones (homopolymers or copolymers of N-vinyl pyrrolidone), polyethyleneglycols of various molecular weights, polyethylene-/polypropylene-/polyethylene-oxide block copolymers, polymethacrylates, polyvinylalcohol (PVA) and co-polymers thereof with PVP or with other polymers, polyacrylates, hypromellose phthalates, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyethylene derivatives, organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives; diluents such as starches and derivative thereof, e.g. dextrin, pullulan, corn starch and potato starch pregelatinized starches; gum; Zeolite; lactose, sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol, trehalose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, crystalline cellulose/carmellose sodium, hydroxypropyl cellulose, magnesium aluminometasilicate, binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, a starch, methylcellulose, sodium alginate, sodium carboxymethyl starch, carmellose calcium, carmellose sodium, crystalline cellulose and crystalline cellulose/carmellose sodium, sodium starch glycolate, pregelatinized starches, copovidone, crospovidones, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, talc, light anhydrous silicic acid, calcium stearate, zinc stearate, magnesium oxide, sodium lauryl sulfate, sodium stearyl fumarate, magnesium aluminometasilicate or the like; flavoring agents such as sucrose, aspartame, mannitol, dextran, saccharin, menthol, citric acid, tartaric acid, malic acid, ascorbic acid, sweet hydrangea leaves, fennel, ethanol, fructose, xylitol, glycyrrhizinic acid, purified sucrose, L-glutamine, cyclodextrin, peppermint, methyl salicylate or the like; surfactants such as sodium lauryl sulfate, polysolvate 80, sucrose fatty acid ester, polyoxyl 40 stearate, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate or the like; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes; silica excipients like silicon dioxide such as aerosil, syloid, all grades included.

Pimavanserin tartrate premix can be isolated from the mixture by techniques known in art like filtration, concentration, removal of solvent by evaporation, distillation, centrifugation, cooling, drying on rotavapor, agitated thin film drying, spray drying.
The process for the preparation of pimavanserin tartrate premix with at least one pharmaceutically acceptable excipient comprising the steps of mixing pimavanserin tartrate in one or more solvent; optionally heating the mixture from a temperature of 30°C to reflux temperature of the solvent to form a solution and filtering the solution to remove any suspended particles and cooling the solution to a temperature of below 30°C; adding the excipient such as silicon dioxide selected from aerosil or syloid and isolating pimavanserin tartrate premix by techniques known in the art.

The present invention provides a stable pimavanserin tartrate premix having enhanced flow property, stability that can be easily formulated into pharmaceutical compositions. The pimavanserin tartrate premix of the present invention can be formulated into various pharmaceutical compositions like powder, granules, capsules, tablets, pellets etc. The pharmaceutical composition of the invention can be formed by various methods known in the art such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering and the like, preparation of compositions such as tablets, capsules, pellets are well known in the art. The pimavanserin tartrate premix formulation of the present invention can be utilized for the treatment of neuropsychiatric diseases and neurodegenerative diseases in a subject in need of such treatment.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

The X-ray powder diffraction pattern was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

EXAMPLES
Example 1:
A mixture of methanol (1400 ml), water (300 ml) and pimavanserin tartrate (100 g) was heated to 45-50°C and stirred for 30 minutes. The mixture was cooled to 25-30° and filtered through micron filter. The filtrate was collected and colloidal silicon dioxide (Aerosil) (100 g) and methanol (100 ml) was also added to it. The mixture was subjected to spray drying to obtain pimavanserin tartrate premix with aerosil. Yield: 160 g and X-ray diffraction pattern as in figure-1.
,CLAIMS:1. A stable amorphous pimavanserin tartrate premix comprising pimavanserin tartrate and at least one pharmaceutically acceptable excipient.

2. The stable amorphous pimavanserin tartrate premix of claim 1, wherein the pharmaceutically acceptable excipient is silicon dioxide or colloidal silicon dioxide.

3. The stable amorphous pimavanserin tartrate premix of claim 2, wherein the pharmaceutically acceptable excipient, silicon dioxide or colloidal silicon dioxide is aerosil.

4. The stable amorphous pimavanserin tartrate premix of claim 2, wherein the pharmaceutically acceptable excipient, silicon dioxide or colloidal silicon dioxide is syloid.

5. The stable amorphous pimavanserin tartrate premix with aerosil of claim 3, having X-ray diffraction pattern of Figure 1.

6. A process for the preparation of pimavanserin tartrate premix with at least one pharmaceutically acceptable excipient comprising the steps of:
i) adding pimavanserin tartrate in one or more solvent,
ii) optionally heating the mixture,
iii) adding the excipient, and
iv) isolating pimavanserin tartrate premix.

7. A process for the preparation of pimavanserin tartrate premix of claim 6, wherein the pharmaceutically acceptable excipient is silicon dioxide or colloidal silicon dioxide.

8. A process for the preparation of pimavanserin tartrate premix of claim 7, wherein the pharmaceutically acceptable excipient, silicon dioxide or colloidal silicon dioxide is aerosil.

9. A process for the preparation of pimavanserin tartrate premix of claim 7, wherein the pharmaceutically acceptable excipient, silicon dioxide or colloidal silicon dioxide is syloid.

10. A process for the preparation of pimavanserin tartrate premix of claim 6, wherein the solvent is water, alcohol, nitrile, ether, ketone, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

11. A process for the preparation of pimavanserin tartrate premix of claim 10, wherein alcohols is methanol, ethanol, butanol, propanol; nitrile is acetonitrile, propionitrile, butyronitrile; ether is tetrahydrofuran, dioxane, dimethoxyethane; ketone is acetone, methyl ethyl ketone.