CLIAMS:We Claim-

1) A process for preparing Iloperidone formulation comprising steps of:
a) granulating at least one pharmaceutically acceptable excipients with a solution or dispersion comprising Iloperidone and at least one pharmaceutically acceptable excipient in a solvent in fluid bed granulator,
b) drying the granules obtained from step a),
c) mixing the dried granules of step b) with at least one pharmaceutically acceptable excipients and
d) compressing the resulting blend of step c) in to tablets or filling in to capsules.

2) The process according to claim 1, wherein the solvent is non-aqueous solvent selected from the group consisting of methylene chloride, acetone, ethanol, isopropyl alcohol and the iloperidone is dissolved in the non-aqueous solvent.

3) The process according to claim 1, wherein the solvent is water and the iloperidone is homogenized in the water.

4) The process according to claim 1, wherein the dispersion or solution of iloperidone comprise at least one binder selected from the group consisting of carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin.

5) The process according to claim 1, wherein the iloperidone has a particle size distribution of d(0.1) not more than 2 μm, d(0.5) not more than 6 μm and d(0.9) not more than 10 μm.
,TagSPECI:PROCESS FOR PREPARING FORMULATION OF ILOPERIDONE

FIELD OF INVENTION
The present invention relates to process for preparing formulations of Iloperidone which exhibits desired physico chemical properties.

BACKGROUND OF THE INVENTION
Iloperidone is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4’-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3’methoxyacetophenone. The Iloperidone marketed as Fanapt® is used in the form of a white to off-white finely crystalline powder which is practically insoluble in water, very slightly soluble in 0.1 N HCl and freely soluble in chloroform, ethanol, methanol, and acetonitrile.

Following are the approved formulations of Iloperidone in the USA market:-
Fanapt ® 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg tablets containing Iloperidone with inactive ingredients- lactose monohydrate, microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, magnesium stearate, colloidal silicon dioxide, and purified water (removed during processing). Fanapt® is indicated for the acute treatment of adults with schizophrenia.

USRE39198 the product patent for Iloperidone claims Iloperidone and its metabolites. However, the specification is silent with respect to critical drug properties, critical excipient properties, critical process parameters, ideal formulation properties and the choice of a suitable particle size, which are critical in the formulation in view of Iloperidone belonging to low dose and low solubility class of drugs.

US 20090099232 A1 relates to injectable depot formulations comprising crystals of iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph or stereoisomer of iloperidone or its metabolite wherein the size of Iloperidone crystals is specified. The injectable depot formulations are administered by intramuscular or subcutaneous injection and may not be the first choice dosage forms for administration. There is no teaching of an iloperidone formulation for peroral administration in the specification.

US7767230 describes intramuscular or subcutaneous depot formulation comprising iloperidone and a biodegradable, biocompatible polymer [polylactide-polyglycolide copolymer, polylactide-polyglycolide copolymer etc.]. There is no teaching of an iloperidone formulation for peroral administration in the specification.

CN101822674A as per abstract describes a tablet or capsule dosage form of Iloperidone with a particle size less than 125 μm. The invention of the said application appears to modify the particle size and also uses surfactant for attaining desired dissolution rate.

CN101822673A appears to disclose solid medicinal composition of iloperidone with surfactant as an essential excipient for improvement of dissolution.

Inventors of the present invention has surprisingly found that the formulation of immediate release Iloperidone can be prepared by process of the present invention which exhibits the desired physico chemical properties without any issue of dissolution or content uniformity.

SUMMARY OF THE INVENTION

The present invention relates to process for preparing Iloperidone formulation comprising steps of:
a) granulating at least one pharmaceutically acceptable excipients with a dispersion comprising Iloperidone and at least one pharmaceutically acceptable excipient in a solvent in fluid bed granulator;
b) drying the granules obtained from step a),
c) mixing the dried granules of step b) with at least one pharmaceutically acceptable excipients and
d) compressing the resulting blend of step c) in to tablets or filling in to capsules.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to process for preparing immediate release formulation of Iloperidone which exhibits desired physico chemical properties.

The term “Iloperidone” as used herein, unless otherwise indicated, includes pharmaceutically acceptable salts or free base or enantiomeric forms of 4’-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3’methoxyacetophenone. In a preferred embodiment, Iloperidone is used in the free base form.

Formulation as used herein is in the form of solid oral pharmaceutical formulation selected from the group consisting of powders, granules, tablet and capsules. Preferably the formulation is in the form of tablets which is either uncoated tablets or film coated tablets or capsules. More preferable formulation is tablet.

Solubility is a most important parameter for the oral bioavailability of poorly soluble drugs such as Iloperidone. Dissolution of drug is the rate determining step for oral absorption of the Iloperidone, which can subsequently affect the in vivo absorption of Iloperidone. One approach to the solubility problem would be to increase the surface area of Iloperidone by micronization. However, very fine particles of Iloperidone can lead to flowability problems. Hence, ascertaining the right particle size distribution for Iloperidone becomes necessary. The preferred particle size distribution of Iloperidone is as below;
d(0.1) = Not more than 2 μm
d(0.5) = Not more than 6 μm
d (0.9) = Not more than 10 μm

The volume median diameter d(0.5) is the diameter where 50% of the distribution is above and 50% is below. d(0.9), 90% of the volume distribution is below this value. d(0.1), 10% of the volume distribution is below this value.

The particle size was reported as an average of the measurements.
The instrument parameters were:
Measuring cell- Scirocco 2000
Particle Refractive Index -1.5
Absorption- 0.1
Obscuration range- 1-10%
Dispersive air pressure-1.5 Bar
Vibration feed rate- 40-50%
Sample measuring time- 6 seconds
Background measuring time- 6 seconds
Number of measurement cycle- 3

Content uniformity can be a major quality issue while preparing solid dosage forms of highly potent drugs like Iloperidone. Since Iloperidone is a low soluble drug, it becomes more difficult to produce a solid dosage form of Iloperidone with ideal physico-chemical properties. In an embodiment, Iloperidone is dissolved in a granulation solution. Solubilising or homogenizing Iloperidone or Iloperidone excipient mixture in a solvent or co-solvents and subsequent adsorption of this liquid containing Iloperidone on pharmaceutically acceptable excipient(s) leads to significant improvement of solubility of Iloperidone. Another advantage of this technique is that solubility and thereby dissolution of Iloperidone in formulation can be modulated based on use of soluble and/or insoluble excipient(s) to achieve desired dissolution profile.

In normal practice, the pharmaceutical compositions of any drug can be prepared by any know techniques to the person skilled in the art like direct compression, dry or wet granulation.

Direct compression generally involves geometrical mixing of drug with diluent and optionally other excipients, mixing the blend with disintegrant, antiadherent, lubricant and optional coloring agents and compressing the blend to form tablets. The tablets can be optionally coated in a coating pan with coating solution or dispersion.

Direct compression with micronized drug may pose problem of blend uniformity and further content uniformity problems leading to undesired variation in the quality of the product.

Dry granulation generally involves mixing of drug with diluent, binder, disintegrating agent, lubricant and/or antiadherent and optionally other excipients; compacting the blend to form a slug or passing it through a roller compactor (chilsonator); screening or milling of the slug or compact to form granules; mixing with lubricant, disintegrating agent and optionally other excipients and compressing to form tablets. The tablets can be optionally coated in a coating pan with coating solution or dispersion.

Wet granulation generally involves mixing of drug and diluent and optionally disintegrant, binder or other excipients to form a blend; preparation of a granulating solution with or without a binder; mixing of the granulating solution with the blend to form a wet mass; coarse screening of the wet mass to form granules; drying the granules; screening of dry granules; mixing of screened granules with lubricant and optionally disintegrant and compressing to form tablets. The tablets can be optionally coated in a coating pan with coating solution or dispersion. The said process may pose content uniformity and dissolution problems as there can be localized over granulation and lump formation, drug losses due to sticking to vessel during dry mixing etc.

Inventors of the present invention have found a simple yet robust process for preparing Iloperidone formulation. The said process surprisingly resulted in formulation with desired physico-chemical properties without any issue of content uniformity and dissolution.

In an embodiment, Iloperidone is included in the granulating solution instead of dry mixing with the other excipients and wherein the iloperidone was solubilized or homogenized with the solvent and the tablets were prepared by the fluid bed granulation process. This approach led to a faster dissolution profile without any issue of content uniformity.

As per main embodiment, a process for preparing Iloperidone formulation comprising steps of:
a) granulating at least one pharmaceutically acceptable excipients with a solution or dispersion comprising Iloperidone and at least one pharmaceutically acceptable excipient in a solvent in fluid bed granulator,
b) drying the granules obtained from step a),
c) mixing the dried granules of step b) with at least one pharmaceutically acceptable excipients and
d) compressing the resulting blend of step c) in to tablets or filling in to capsules.

Various suitable pharmaceutically acceptable excipients known to a person skilled in the art can be suitably chosen to prepare the formulation of the invention. They include diluents, binders, disintegrants, antiadherents, lubricants, coloring agents and the like.

Suitable diluents in a composition of the present invention may be one or more compounds which are capable of providing bulk to obtain a desired tablet mass and include inorganic phosphates such as dibasic calcium phosphate; sugars such as lactose hydrous or lactose anhydrous; and cellulose or cellulose derivatives such as microcrystalline cellulose and the like. The diluent can be present in a suitable amount from about 10-95 % w/w or about 50- 95 % w/w or about 70-95 % w/w of the total composition.

Suitable solvents used for dissolving or dispersing or homogenizing Iloperidone can be selected from water, methylene chloride, acetone, ethanol, isopropyl alcohol and the like or mixtures thereof.

Suitable binder in a composition of the present invention may be one or more compounds which are capable of facilitating granulation of Iloperidone into aggregates and/or more free-flowing particles and include carboxymethylcellulose sodium, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch, alginic acid, sodium alginate, gelatin and the like. The binder can be present in a suitable amount from 0.1-10 % w/w or 0.1- 5 % w/w or 0.1-3 % w/w of the total composition. Binder may be present in the dry form or in the solution.

Suitable disintegrant in a composition of the present invention may be one or more compounds which are capable of facilitating the break up of a tablet prepared from the composition when placed in contact with an aqueous medium and include carboxymethylcellulose sodium, microcrystalline cellulose, croscarmellose sodium, alginic acid, sodium alginate, crospovidone (cross-linked homopolymer of N-vinyl-2-pyrrolidinone), pregelatinized starch, sodium starch glycolate, starch and the like. The disintegrant can be present in a suitable amount from 0.1-20 % w/w or 0.1- 15 % w/w of the total composition.

Suitable antiadherent in a composition of the present invention may be one or more compounds capable of prevent sticking to punch faces such as silicon dioxide, magnesium trisilicate, talc and the like. The antiadherent can be present in a suitable amount from 0.1-7 % w/w or 0.1-5 % w/w or 0.1-2 % w/w of the total composition.

Suitable lubricant in a composition of the present invention may be one or more compounds capable to decrease friction at the interface between the tablet surface and the die wall during ejection and include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talc and the like. The lubricant can be present in a suitable amount from 0.1-7 % w/w or 0.1-5 % w/w or 0.1-2 % w/w of the total composition.

Suitable coloring agent in a suitable amount in a composition of the present invention may be one or more compounds which impart a desired color to a tablet prepared from the composition and include FDA approved colors for oral use such as ferric oxides.

An optional film coating can be applied using the materials and methods known to a person skilled in the art. Examples of film coating material includes Opadry® which is Colorcon’s customized, one-step film coating system which combines polymer, plasticizer and pigment, as required, in a dry concentrate. For example, Opadry® white YS-1-7040 contains hydroxypropylmethylcellulose, polyethylene glycol, talc and titanium dioxide. The film coating can be applied in an amount up to about 5% w/w of the formulation.

The coating solutions may be applied using techniques, such as spray coating in a conventional coating pan or fluidized bed processor or dip coating as known to person skilled in the art.

Suitable solvents for the formulation processes such as granulation and coating can be selected from solvents such as purified water, isopropanol, ethanol, dichloromethane and the like. Preferable solvent for granulation is purified water.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The examples mentioned below, demonstrate some illustrative procedures for preparing the pharmaceutical formulations as described herein. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

The dissolution studies of the formulations of the present invention can be performed by suitable dissolution methods as per US pharmacopoeia such as for example, the dissolution studies of tablet formulations can be performed using USP apparatus II (Paddle), at 50 rpm using 500 ml 0.1 N HCl as a medium.

Example 1
Iloperidone Tablets: 1 mg and 12 mg (Direct compression)
S. No. Name of Ingredients mg/tab %w/w mg/tab %w/w
1 Iloperidone 1.00 1.18 12.00 5.00
2 Lactose monohydrate 70.00 82.35 194.20 80.92
3 Microcrystalline cellulose 9.50 11.18 24.00 10.00
4 Crospovidone 2.80 3.29 5.00 2.08
5 Colloidal silicon dioxide 0.85 1.00 2.40 1.00
6 Magnesium stearate 0.85 1.00 2.40 1.00
Total 85.00 100.00 240.00 100.00

Procedure:
1) All the material were dispensed as per mentioned in the formula.
2) Geometrically mixing of Iloperidone, lactose monohydrate and microcrystalline cellulose were performed by sifting through 40 mesh screen.
3) Crospovidone and colloidal silicon dioxide were sifted through 40 mesh screen.
4) Magnesium stearate was sifted through 60 mesh screen.
5) Ingredients of step 3 and step 4 were mixed with step 2 blend.
6) Lubricated material was compressed by using suitable punch to form tablets.

Dissolution Data for tablets of example 1
Time in minutes % of drug released
(1 mg strength) % of drug released
(12 mg strength)
15 38 40
30 47 53
45 59 63
60 65 71

Example 2
Iloperidone Tablets: 1 mg and 12 mg (Wet granulation)
S. No. Name of Ingredients mg/tab %w/w mg/tab %w/w
1 Iloperidone 1.00 1.18 12.00 5.00
2 Lactose monohydrate 68.5 80.59 187.00 78.00
3 Microcrystalline cellulose 8.50 10.00 24.00 10.00
4 Hydroxypropylmethylcellulose 6cps 2.80 3.29 7.20 3.00
5 Purified water q.s q.s q.s q.s
6 Crospovidone 2.50 2.94 5.00 2.08
7 Colloidal silicon dioxide 0.85 1.00 2.40 1.00
8 Magnesium stearate 0.85 1.00 2.40 1.00
Total 85.00 100.00 240.00 100.00

Procedure:
Stage A: Dry Mixing
1) All the material were dispensed as per mentioned in the formula.
2) Geometrically mixing of Iloperidone, lactose monohydrate and microcrystalline cellulose were performed by sifting through 40 mesh screen.
Stage B: Granulation
3) Binder solution was prepared by dissolving hydroxypropylmethylcellulose in purified water.
4) Granulation of above mixture (step 2) was performed in RMG with hydroxypropylmethylcellulose binder solution.
5) Wet granules were passed through 10 mesh screen.
6) Granules were dried at an inlet temperature not more than 60º C.
7) Dried granules were passed through 24 mesh screen.
Stage C: Blending and Lubrication
8) Crospovidone and colloidal silicon dioxide were sifted through 40 mesh screen.
9) Magnesium stearate was sifted through 60 mesh screen.
10) Dried granules (step 7) were mixed properly with above sifted materials (step 8 & 9).
11) Lubricated material was compressed using suitable punch to form tablets.

Dissolution Data for tablets of example 2
Time in minutes % of drug released
(1 mg strength) % of drug released
(12 mg strength)
15 45 49
30 65 69
45 80 84
60 92 96


Example 3
Iloperidone Tablets: 1 mg and 12 mg (Fluid bed granulation)
S. No. Name of Ingredients mg/tab %w/w mg/tab %w/w
1 Lactose monohydrate 64.45 75.82 187.00 78.00
2 Microcrystalline cellulose 8.50 10.00 24.00 10.00
3 Hydroxypropylmethylcellulose 6cps 2.55 3.00 7.20 3.00
4 Iloperidone 1.00 1.18 12.00 5.00
5 Dichloromethane q.s q.s q.s q.s
6 Crospovidone 6.80 8.00 5.00 2.08
7 Colloidal Silicon Dioxide 0.85 1.00 2.40 1.00
8 Magnesium Stearate 0.85 1.00 2.40 1.00
Total 85.00 100.00 240.00 100.00

Procedure:
Stage A: Solution Preparation
1) Iloperidone was dissolved in sufficient amount of dichloromethane.
2) Hydroxypropylmethylcellulose 6cps was dissolved in dichloromethane, to make a clear solution.
3) Drug solution (step 1) was added to HPMC binder solution (step 2) by proper stirring.
Stage B: Blending & Granulation
4) Lactose monohydrate and microcrystalline cellulose were sifted through 40 mesh and mixed properly in fluid bed processor.
5) The blend was granulated by spraying solution of step 3) in fluid bed processor at inlet temperature 45-65°C.
Stage C: Drying & Sifting
6) After completion of spray, the mass was dried at inlet Temperature 45-65°C till LOD was achieved to NMT 2.0 % w/w and dried granules were passed through 24 mesh.
Stage D: Lubrication
7) Granules of step 5) were mixed with Colloidal Silicon Dioxide and Crospovidone (sifted through # 30 mesh) in blender for 10 min.
8) Granules of step 7) were lubricated with magnesium stearate (sifted through # 60 mesh) for 5 min.
9) Lubricated granules were compressed by using suitable punches and dies to form tablets.

Dissolution Data for tablets of example 3
Time in minutes % of drug released
(1 mg strength) % of drug released
(12 mg strength)
15 75 77
30 90 92
45 98 96
60 98 102

Example 4
Iloperidone Tablets: 12 mg (Fluid bed granulation)
S. No. Name of Ingredients mg/tab %w/w
1 Iloperidone 12.00 5.00
2 Hydroxypropylmethylcellulose 3 cps 7.20 3.00
3 Purified water q.s. q.s.
4 Lactose monohydrate 187.00 78.00
5 Microcrystalline cellulose 24.00 10.00
6 Crospovidone 5.00 2.08
7 Colloidal silicon dioxide 2.40 1.00
8 Magnesium Stearate 2.40 1.00
Total 240.00 100.00

Procedure:
Stage A: Drug suspension Preparation
1) Iloperidone was homogenized in sufficient amount of purified water.
2) Hydroxypropylmethylcellulose 3cps was dissolved in purified water, to make a clear solution.
3) Drug solution (step 1) was added to HPMC binder solution (step 2) by proper stirring.
Stage B: Blending & Granulation
4) Lactose monohydrate and microcrystalline cellulose were sifted through 40 mesh and mixed properly in fluid bed processor.
5) Blend was granulated by spraying solution of step 3) in fluid bed processor at inlet temperature 45-65°C.
Stage C: Drying & Sifting
6) After completion of spray, the mass was dried at inlet Temperature 45-65°C till LOD was achieved to NMT 2.0 % w/w and passed the dried granules through 24 mesh.
Stage D: Lubrication
7) Granules of step 5 were mixed with Colloidal Silicon Dioxide and Crospovidone (sifted through # 30 mesh) in blender for 10 min.
8) Granules of step 7) were lubricated with magnesium stearate (sifted through # 60 mesh) for 5 min.
9) Lubricated granules were compressed by using suitable punches and dies to form tablets.

Dissolution Data for tablets of example 4
Time in minutes % of drug released
15 101
30 102
45 103
60 102

Example 5
Iloperidone Tablets: 1 mg (Fluid bed granulation)
S. No. Name of Ingredients mg/tab %w/w
1 Lactose monohydrate 60.325 70.97
2 Microcrystalline cellulose 6.250 7.35
3 Crospovidone 5.100 6.00
4 Iloperidone 1.000 1.18
5 Hydroxypropylmethylcellulose 3 cps 3.825 4.50
6 Purified water q.s -
7 Crospovidone 5.100 6.00
8 Colloidal silicon dioxide 1.700 2.00
9 Magnesium Stearate 1.700 2.00
Total 85.000 100.00

Procedure:
Stage A: Drug suspension Preparation
1) Hydroxypropylmethylcellulose 3cps was dissolved in purified water, to make a clear solution.
2) Iloperidone was suspended and homogenized in purified water and added to solution of step 1) with stirring.
Stage B: Blending
3) lactose monohydrate, microcrystalline cellulose were sifted through 40 mesh and crospovidone through 30 mesh screen and mixed properly in fluid bed processor.
4) Blend was granulated by spraying solution of step 2) in fluid bed processor at inlet temperature 45-65°C.
Stage C: Drying & Sifting
5) After completion of spray, the mass was dried at inlet Temperature 45-65°C till LOD was achieved to NMT 2.0 % w/w and passed the dried granules through 24 mesh.
Stage D: Lubrication
6) Granules of step 5) were mixed with Colloidal Silicon Dioxide and Crospovidone (sifted through # 30 mesh) in blender for 10 min.
7) Granules of step 6) were lubricated with magnesium stearate (sifted through # 60 mesh) for 5 min.
8) Lubricated granules were compressed by using suitable punches and dies to form tablets.
Dissolution Data for tablets of example 5 compared with FANAPT®
Time in minutes % of drug released
Example 5 FANAPT® 1 mg Tablets
15 99 98
30 101 97
45 103 98
60 103 98

Stability data for tablets of example 5 compared with FANAPT®
Parameter 1 mg tablets of example 5 FANAPT®
1 mg Tablets
Initial 3M at 40oC/75% RH Initial 3M at 40oC/75% RH
Time in minutes Dissolution
15 99 98 98 96
30 101 100 97 96
45 103 102 98 95
60 103 104 98 95
Related substance
Impurity I
(NMT 0.5%) 0.000 0.079 0.000 0.000
Impurity II
(NMT 0.5%) 0.017 0.116 0.039 0.000
Impurity III
(NMT 0.5%) 0.065 0.138 0.315 0.363
Impurity IV
(NMT 0.5%) 0.002 0.000 0.000 0.006
Impurity V
(NMT 0.5%) 0.000 0.007 0.000 0.004
Max unknown
(NMT 0.2%) 0.028 0.065 0.513 0.520
Total Impurity
(NMT 1.5%) 0.204 0.640 1.212 1.592

Example 6
In vivo study was conducted in human volunteers to assess bioequivalence of Iloperidone tablets of present invention with a reference treatment with FANAPT® Tablets.

Study parameters

Type of study: Fasting and Fed
Study design: Open label, balanced, randomized two-treatment, two-sequence, two-period, single-dose, crossover oral bioequivalence study.

Fasted study result
PK Parameter No. of subject %Ratio
(T/R) Power
Cmax (pg/ml) 9 93.49 60.79
AUC0-t
(pg*hr/ml) 9 104.65 85.67
AUC0-infi
(pg*hr/ml) 9 105.58 87.94

Fed study result
PK Parameter No. of subject %Ratio
(T/R) Power
Cmax (pg/ml) 13 93.17 84.94
AUC0-t
(pg*hr/ml) 13 97.77 99.83
AUC0-infi
(pg*hr/ml) 13 99.86 97.48