Description:FIELD OF INVENTION
The present invention relates to pharmaceutical composition comprising Olaparib or a pharmaceutically acceptable salt thereof.
The invention also relates to a method of preparation of such composition of Olaparib or pharmaceutically acceptable salts or solvate thereof and their use in treatment of cancer.

BACKGROUND OF THE INVENTION
Olaparib (I) is chemically named as 4- [3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin1-one and its structural formula is:

Olaparib (I)
Olaparib is a compound that inhibits cancers in the human with hereditary BRCA1 or BRCA2 mutations, which, include some ovarian, breast, and prostate cancers. It is a PARP inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary BRCA1 or BRCA2 mutations, which, include some ovarian, breast, and prostate cancers. It is marketed in the form of film coating tablets under the trade names Lynparza® (Astrazeneca Pharmaceuticals Lp) for the treatment of certain ovarian, breast, and prostate cancers.
Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility across the physiological pH range. Its molecular weight is C24H23FN4O3.
Film coating tablets are widely used dosage forms of Olaparib for delivery of formulations.
Lynparza® is formulated as film coating tablets to provide 100 mg and 150 mg of Olaparib.
Lynparza film coating tablets for oral administration are available in two dosage strengths containing Olaparib 100 mg and 150 mg. The U.S. Food and Drug administration (FDA) have approved Olaparib as indicated for the treatment of patients with somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer after failure of at least one prior chemotherapy regimen and in combination with bevacizumab is indicated for the first-line treatment of patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer.
Martin et. al. in WO2004080976A1; first disclosed synthesis of Olaparib which are useful in the treatment cancer is breast, ovary, pancreas or prostate cancer.
Bechtold et. al. in US8475842B2; discloses oral formulation of Olaparib containing solid dispersion of Olaparib in copovidone and active agent phase is dispersed in the carrier phase. The weight ratio of Olaparib to copovidone is 1:2.3, prepared by hot-melt extrusion method.
Chao Shen et. al. in CN104434809B; discloses oral formulation of Olaparib containing solid dispersion of Olaparib in povidone, prepared by hot-melt extrusion method.
Bechtold et. al. in WO2010041051A1; discloses various approaches to increase solubility and bioavailability of Olaparib. Based on dissolutions and pharmacokinetic data, the authors infer that for the preparation of a drug form with increased bioavailability conversion of crystalline Olaparib to an amorphous solid solution with polymers exhibiting low hygroscopicity and a high glass transition temperature (Tg) or melting point (Tm), i.e., higher than 100°C, will be most advantageous.
However, the described prior art processes result in composition with Olaparib shows hot-melt extrusion method, tedious and expensive. The present invention provide a film coating tablet comprising Olaparib or a pharmaceutically acceptable salt thereof, wherein the film coating tablet obtained by Rapid mixture granulator method, stable and easy to manufacture, and the composition is scalable on industrial scale with enhanced drug solubility and release profile.
As Olaparib is an important anticancer therapeutic agent. There is still exists a need to develop such unique process for composition/formulation, which is scalable on industrial scale and results in stable pharmaceutical composition. Therefore, inventers of the present invention have developed a commercially viable pharmaceutical composition of Olaparib that is found to be comparable with marketed Lynparza ® film coating tablet.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for preparing film coating tablet containing Olaparib with enhance solubility and dissolution profile obtained by Rapid mixture granulator method.
In one aspects of the present invention, it relates process for manufacturing a film coating tablet, the process comprising the steps of:
a) solubilizing the Olaparib in co-solvent;
b) solubilizing the vitamin - E TPGS and HP ß-CD into step-a);
c) dry mixing the intragranular raw material into Rapid mixture granulator and slowly adding step-b) drug solution into Rapid mixture granulator;
d) kneading and chopping the wet mass and co milled then collecting in FBD;
e) drying the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f) milling of dried granules and loaded into Bin Blender;
g) mixing the extragranular raw materials into step- f);
h) mixing the lubricant into step- g); and
i) lubricated mixture of step- h) compressed to get the film coating tablet.
In another aspects of the present invention, it relates a stable pharmaceutical film coating tablet composition of Olaparib comprising:
a) a solubilizing agent selected from hydroxy propyl ß - cyclodextrin (HPßCD), hypromellose phthalate (hydroxypropylmethyl cellulose phthalate, (HPMCP), hypromellose acetate succinate, povidone, (polyvinyl pyrrolidone, PVP homopolymer), hypromellose (hydroxypropylmethyl cellulose, HPMC), polymethacrylates (polymethacrylic acid, methyl methacrylate, vitamin-E TPGS, alcohols, glycols and methyl salicylate in an amount ranging between 15- 40% (w/w);
b) a binding agent selected from L-HPC-21, Povidone K-30 (polyvinylpyrrolidone), PEG, gelatine, cellulose, methyl cellulose, HPMC, sucrose and starch in an amount ranging between 5- 15% (w/w);
c) a superdisintegrating agent selected from croscarmellose sodium, crospovidone, sodium starch glycolate in an amount ranging between 5- 15% (w/w);
d) a diluting agent selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, erythritol, sorbitol, lactose monohydrate and lactose anhydrous in an amount ranging between 10- 20% (w/w);
e) a adsorbing agent selected from calcium silicate, calcium hydrogen phosphate, silica gel, aluminium trisilicate and alumina in an amount ranging between 15- 35% (w/w);
f) a lubricating agent selected from sodium steryl fumarate, magnesium stearate, magnesium lauryl stearate, stearic acid, calcium stearate, and zinc stearate in an amount ranging between 0.2- 2.0% (w/w); and
g) a co-solvent selected from isopropyl alcohol, water, acetone, ethanol, dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane, methanol, tetrachloroethylene, toluene, methyl acetate, ethyl acetate or a mixture thereof in the ratio an amount ranging between 7.0:3.0- 9.5:0.5% (v/v).
Various other specific aspects of the invention are further detailed in the description part of the specification, wherever appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of in vitro dissolution data for pharmaceutical composition comprising of Olaparib 100 mg.
FIG. 2 is an illustration of in vitro dissolution data for pharmaceutical composition comprising of Olaparib 150 mg.
DETAILED DESCRIPTION
The present invention relates to a stable pharmaceutical composition derived from Rapid mixture granulator method, wherein said composition increasing the solubility in co-solvent and which are robust, cost effective, simple to prepare and suitable for use on a commercial scale.
In one embodiment according to present invention, it provides a stable pharmaceutical film coating tablet composition of Olaparib comprising:
a. a solubilizing agent selected from hydroxy propyl ß - cyclodextrin (HPßCD), hypromellose phthalate (hydroxypropylmethyl cellulose phthalate, (HPMCP), hypromellose acetate succinate, povidone, (polyvinyl pyrrolidone, PVP homopolymer), hypromellose (hydroxypropylmethyl cellulose, HPMC), polymethacrylates (polymethacrylic acid, methyl methacrylate, vitamin-E TPGS, alcohols, glycols and methyl salicylate in an amount ranging between 15- 40% (w/w);
b. a binding agent selected from L-HPC-21, Povidone K-30 (polyvinylpyrrolidone), PEG, gelatine, cellulose, methyl cellulose, HPMC, sucrose and starch in an amount ranging between 5- 15% (w/w);
c. a superdisintegrating agent selected from croscarmellose sodium, crospovidone, sodium starch glycolate in an amount ranging between 5- 15% (w/w);
d. a diluting agent selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, erythritol, sorbitol, lactose monohydrate and lactose anhydrous in an amount ranging between 10- 20% (w/w);
e. a adsorbing agent selected from calcium silicate, calcium hydrogen phosphate, silica gel, aluminium trisilicate and alumina in an amount ranging between 15- 35% (w/w);
f. a lubricating agent selected from sodium steryl fumarate, magnesium stearate, magnesium lauryl stearate, stearic acid, calcium stearate, and zinc stearate in an amount ranging between 0.2- 2.0% (w/w); and
g. a co-solvent selected from isopropyl alcohol, water, acetone, ethanol, dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane, methanol, tetrachloroethylene, toluene, methyl acetate, ethyl acetate or a mixture thereof in the ratio an amount ranging between 7.0:3.0- 9.5:0.5% (v/v).
The present invention relates to a stable pharmaceutical composition derived from Rapid mixture granulator process comprising Olaparib. Wherein said composition comprising Rapid mixture granulator was selected among the various conventional granulation method, (i.e. direct compression, hot-melt extrusion method, dry granulation and wet granulation).
The present invention relates to a stable pharmaceutical composition derived from Rapid mixture granulator process, comprising Olaparib, wherein said composition comprising of one or more pharmaceutically acceptable excipients selected from the group consisting of solubilizing agent, binding agent, super disintegrating agent, diluting agent, adsorbing agent, lubricating agent and co-solvent. Preferably, the pharmaceutical composition of drug product contains all intragranular and extragranular excipients as pre lubricant & lubricant.
The pharmaceutical composition of Olaparib according to present invention involves necessarily use of adsorbent, wherein adsorbing agent selected from calcium silicate, calcium hydrogen phosphate, silica gel, and Alumina in an amount ranging between 15- 35% (w/w);
In a specific embodiment according to present invention the adsorbent used in the pharmaceutical composition was calcium silicate in the intragranular components to make them easy to incorporate in solid dosage forms.
The invention provides that the pharmaceutical composition of Olaparib comprising diluent wherein diluting agent selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, erythritol, sorbitol, lactose monohydrate and lactose anhydrous or combinations thereof in an amount ranging between 10- 20% (w/w).
In a specific embodiment according to present invention the diluent used in the pharmaceutical composition was microcrystalline cellulose, mannitol or combinations thereof to get the bulk volume of mixture and thus the size of the dosage form.
The invention provides that the pharmaceutical composition of Olaparib comprising superdisintegrant wherein superdisintegrating agent selected from croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate in an amount ranging between 5- 15% (w/w).
In a specific embodiment according to present invention the superdisintegrant used in the pharmaceutical composition was croscarmellose sodium or combinations in the intragranular and extragranular components to promote the break-up of the film coating tablet into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the drug substance.
The invention provides that the pharmaceutical composition of Olaparib comprising binder wherein binding agent selected from L-HPC-21, Povidone K-30 (polyvinylpyrrolidone), cellulose, methyl cellulose, PEG, gelatine, HPMC, sucrose and starch in an amount ranging between 5- 15% (w/w).
In a specific embodiment according to present invention the binder used in the pharmaceutical composition was L-HPC-21) and Povidone K-30 (polyvinylpyrrolidone) in the intragranular components to facilitate bonding of powder particles during granulation.
The pharmaceutical composition of Olaparib according to present invention involves necessarily use of lubricant, wherein lubricating agent selected from sodium steryl fumarate, magnesium stearate, magnesium lauryl stearate, stearic acid, calcium stearate, and zinc stearate in an amount ranging between 0.2- 2.0% (w/w).
In a specific embodiment according to present invention the lubricant used in the pharmaceutical composition was sodium steryl fumarate used as the extra granular excipient to improve the flow of powders during the manufacturing of film coating tablets.
Surprisingly, it was found that employing the Rapid mixture granulator
technique for the preparation of the granules of the present invention, comprising stable pharmaceutical composition derived from Rapid mixture granulator comprising Olaparib, solubilizers, adsorbents, superdisintegrant, binder, diluents and lubricant. Wherein the composition is prepared using co-solvent in different ratio (isopropyl alcohol: water). In general, the production costs of a Rapid mixture granulator are lower when compared to a hot-melt extrusion method. Another advantage of the Rapid mixture granulator technique is that it is not relying on the intrinsic properties of the drug and excipients and that, in general, it is easier to obtain maximal film coating tablet stability by using this method.
In a particular embodiment, it provides to a process for manufacturing a film coating tablet, the process comprising the steps of:

In an embodiment according to the present invention in step a) solubilize the Olaparib in required amount of IPA: water in a beaker at temperature 50 to 80°C until clear solution is not obtained, in step b) solubilizing the Vitamin - E TPGS and HP ß-CD into step-a) with continuous stirring till clear transparent solution obtained and continuously stirring until clear solution is not obtained.
According to the present invention of step c) dry mix the intragranular raw material (calcium silicate, L-HPC-21, croscarmellose sodium and Povidone K-30) into Rapid mixture granulator for 5 to 10 minutes and slowly adding step-b) drug solution into Rapid mixture granulator;
According to the present invention of step d) kneading and chopping the wet mass and co milled then collecting in FBD.
According to the present invention of step e) drying the wet granules at temperature of 30 - 50 °C till desire LOD achieved ranging between 2.0 to 3.5%;
According to the present invention of step f) milling of dried granules and loaded into Bin Blender;
According to the present invention of step g) mixing the extragranular raw materials (croscarmellose sodium, microcrystalline cellulose and mannitol) into step- f);
According to the present invention of step h) mixing the lubricant (sodium steryl fumarate) into step- g); and
According to the present invention of step i) lubricated mixture of step- h) compressed to get the film coating tablet.
Based on context of discussion, the term "% w/w" refers to the relative value to total weight of granules or to total weight of pharmaceutical composition and “% v/v” refers to volume by total volume percentage.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
EXAMPLES
Examples 1: Film coating tablet composition of Olaparib
Sr. No. Ingredients (100 mg)
ACTIVE SOLUTION
1. Olaparib 100.000
2. Vitamin E polyethylene glycol succinate (Vitamin E TPGS) 50.000
3. Hydroxypropyl Beta- Cyclodextrin 100.000
4. Isopropyl Alcohol: Water 1mL
INTRAGRANULAR
5. Calcium Silicate 140.000
6. Low-substituted Hydroxy propyl cellulose LH 21 40.000
7. Croscarmellose Sodium 24.000
8. Povidone K30 8.00
EXTRAGRANULAR
9. Croscarmellose Sodium 28.000
10. Microcrystalline Cellulose PH 112* 38.000
11. Mannitol 36.000
12. Sodium Stearyl Fumarate 6.000
Core Weight 570.00

a. solubilize the Olaparib in co-solvent (ratio IPA: water) at a temperature 65-80°c;
b. solubilize the Vitamin - E TPGS and HP ß-CD into step-a);
c. dry mix the intragranular raw material into Rapid mixture granulator for 10 min and slowly adding step-b) drug solution into Rapid mixture granulator;
d. kneading and chopping the wet mass and co milled then collecting in FBD;
e. dry the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f. milling of dried granules and loaded into Bin Blender;
g. mix the extragranular raw materials into step- f);
h. mix the lubricant into step- g); and
i. lubricated mixture of step- h) compressed to get the film coating tablet.
Examples 2: Film coating tablet composition of Olaparib
Sr. No. Ingredients (150 mg)
ACTIVE SOLUTION
1. Olaparib$ 150.000
2. Vitamin E polyethylene glycol succinate (Vitamin E TPGS) 75.000
3. Hydroxypropyl Beta- Cyclodextrin 150.000
4. Isopropyl Alcohol: Water 1.5 mL
INTRAGRANULAR
5. Calcium Silicate 210.00
6. Low-substituted Hydroxy propyl cellulose LH 21 60.000
7. Croscarmellose Sodium 36.000
8. Povidone K30 12.00
EXTRAGRANULAR
9. Croscarmellose Sodium 42.000
10. Microcrystalline Cellulose PH 112* 57.00
11. Mannitol 54.000
12. Sodium Stearyl Fumarate 9.000
Core Weight 855.00

a. solubilize the Olaparib in co-solvent (ratio IPA: water) at a temperature 65-80°c;
b. solubilize the Vitamin - E TPGS and HP ß-CD into step-a);
c. dry mix the intragranular raw material into Rapid mixture granulator for 10 min and slowly adding step-b) drug solution into Rapid mixture granulator;
d. kneading and chopping the wet mass and co milled then collecting in FBD;
e. dry the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f. milling of dried granules and loaded into Bin Blender;
g. mix the extragranular raw materials into step- f);
h. mix the lubricant into step- g); and
i. lubricated mixture of step- h) compressed to get the film coating tablet.
Examples 3: Film coating tablet composition of Olaparib
Sr. No. Ingredients (100 mg)
ACTIVE SOLUTION
1. Olaparib 100.00
2. Vitamin E TPGS 50.00
3. Hydroxy propyl ß - Cyclodextrin 100.00
4. IPA : Water 1.25mL
INTRAGRANULAR
5. Calcium Silicate 145.50
6. L-HPC-21 30.00
7. Croscarmellose Sodium 24.00
EXTRAGRANULAR
8. Croscarmellose Sodium 28.00
9. Microcrystalline Cellulose 112* 48.25
10. Mannitol 48.25
11. Sodium Steryl Fumarate 6.00
Core Weight 580.00
a. solubilize the Olaparib in co-solvent (ratio IPA: water) at a temperature 65-80°c;
b. solubilize the Vitamin - E TPGS and HP ß-CD into step-a);
c. dry mix the intragranular raw material into Rapid mixture granulator for 10 min and slowly adding step-b) drug solution into Rapid mixture granulator;
d. kneading and chopping the wet mass and co milled then collecting in FBD;
e. dry the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f. milling of dried granules and loaded into Bin Blender;
g. mix the extragranular raw materials into step- f);
h. mix the lubricant into step- g); and
i. lubricated mixture of step- h) compressed to get the film coating tablet.
Examples 4: Film coating tablet composition of Olaparib
Sr. No. Ingredients (150 mg)
ACTIVE SOLUTION
1. Olaparib 150.00
2. Vitamin E TPGS 75.00
3. Hydroxy propyl ß - Cyclodextrin 150.00
4. IPA : Water 1.88 mL
INTRAGRANULAR
5. Calcium Silicate 218.25
6. L-HPC-21 45.00
7. Croscarmellose Sodium 36.00
EXTRAGRANULAR
8. Croscarmellose Sodium 42.00
9. Microcrystalline Cellulose 112* 72.38
10. Mannitol 72.38
11. Sodium Steryl Fumarate 9.00
Core Weight 870.00

a. solubilize the Olaparib in co-solvent (ratio IPA: water) at a temperature 65-80°c;
b. solubilize the Vitamin - E TPGS and HP ß-CD into step-a);
c. dry mix the intragranular raw material into Rapid mixture granulator for 10 min and slowly adding step-b) drug solution into Rapid mixture granulator;
d. kneading and chopping the wet mass and co milled then collecting in FBD;
e. dry the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f. milling of dried granules and loaded into Bin Blender;
g. mix the extragranular raw materials into step- f);
h. mix the lubricant into step- g); and
i. lubricated mixture of step- h) compressed to get the film coating tablet.
In vitro dissolution study
The dissolution study in USP apparatus type-I Basket at 100 RPM for 45 minutes and dissolution medium 900ml of distilled water with 0.5% SLS at 37 ± 0.5 °C.
Table 05: Dissolution in 900ml of distilled with 0.5% SLS at 37 ± 0.5 °C, Basket type-I at 100 RPM

Time (Minutes) Examples 1
Cumulative % of Drug Dissolved (100 mg) Examples 2
Cumulative % of Drug Dissolved (150 mg)
10 32.06 18.36
20 50.63 31.02
30 87.65 63.21
45 98.21 87.21
60 99.41 95.97

The above mentioned examples, which are provided by the way of illustration, should not be constructed as limiting the scope of the invention with respect to parameter/s, ingredient/s or quantities used in any manner.
, Claims:We Claim
1. A process for manufacturing a film coating tablet, the process comprising the steps of:
a. solubilizing the Olaparib in co-solvent;
b. solubilizing the vitamin - E TPGS and HP ß-CD into step-a);
c. dry mixing the intragranular raw material into Rapid mixture granulator and slowly adding step-b) drug solution into Rapid mixture granulator;
d. kneading and chopping the wet mass and co milled then collecting in FBD;
e. drying the wet granules in FBD and LOD ranging between 2.0 to 3.5%;
f. milling of dried granules and loaded into Bin Blender;
g. mixing the extragranular raw materials into step- f);
h. mixing the lubricant into step- g); and
i. lubricated mixture of step- h) compressed to get the film coating tablet.
2. The process for manufacturing a film coating tablet of Olaparib as claimed in claim 1, wherein the ratio of co-solvents ranges from 7.0:3.0 to 9.5:0.5.
3. A film coating tablet composition of Olaparib comprising:
a. a solubilizing agent selected from hydroxy propyl ß - cyclodextrin (HPßCD), hypromellose phthalate (hydroxypropylmethyl cellulose phthalate, (HPMCP), hypromellose acetate succinate, povidone, (polyvinyl pyrrolidone, PVP homopolymer), hypromellose (hydroxypropylmethyl cellulose, HPMC), polymethacrylates (polymethacrylic acid, methyl methacrylate, vitamin-E TPGS, alcohols, glycols and methyl salicylate in an amount ranging between 15- 40% (w/w);
b. a binding agent selected from L-HPC-21, Povidone K-30 (polyvinylpyrrolidone), PEG, gelatine, cellulose, methyl cellulose, HPMC, sucrose and starch in an amount ranging between 5- 15% (w/w);
c. a superdisintegrating agent selected from croscarmellose sodium, crospovidone, sodium starch glycolate in an amount ranging between 5- 15% (w/w);
d. a diluting agent selected from microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, erythritol, sorbitol, lactose monohydrate and lactose anhydrous in an amount ranging between 10- 20% (w/w);
e. a adsorbing agent selected from calcium silicate, calcium hydrogen phosphate, silica gel, aluminium trisilicate and alumina in an amount ranging between 15- 35% (w/w);
f. a lubricating agent selected from sodium steryl fumarate, magnesium stearate, magnesium lauryl stearate, stearic acid, calcium stearate, and zinc stearate in an amount ranging between 0.2- 2.0% (w/w); and
g. a co-solvent selected from isopropyl alcohol, water, acetone, ethanol, dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane, methanol, tetrachloroethylene, toluene, methyl acetate, ethyl acetate or a mixture thereof in the ratio an amount ranging between 7.0:3.0- 9.5:0.5% (v/v).
4. The process for manufacturing a film coating tablet as claimed in claim 2, wherein the co-solvent is a mixture of isopropyl alcohol and water.
5. A film coating tablet composition of Olaparib or a pharmaceutically acceptable salt thereof, wherein Olaparib film coating tablet is obtained by Rapid mixture granulator.
6. The film coating tablet composition of Olaparib as claimed in claim 3, comprising:
Olaparib 10 - 25% (w/w)
Vitamin - E TPGS 5 - 15% (w/w)
Hydroxy propyl ß - Cyclodextrin 10 - 25% (w/w)
IPA: water 7.0:3.0 - 9.5:0.5% (v/v)
Calcium Silicate 15 - 35% (w/w)
Low-substituted Hydroxy propyl cellulose LH -21 5 - 10% (w/w)
Croscarmellose Sodium 5 - 15% (w/w)
Microcrystalline Cellulose 5 - 10% (w/w)
Mannitol 5 - 10% (w/w)
Povidone K-30 1 - 5% (w/w)
Sodium Steryl Fumarate 0.2 - 2.0% (w/w)
7. The film coating tablet composition of Olaparib as claimed in claim 3, for use in the treatment of cancer.
8. The film coating tablet composition of Olaparib as claimed in claim 3, further comprising one or more pharmaceutically acceptable excipients.