DESC:“NOVEL COMPOSITION OF RUCAPARIB OF ORAL SOLID DOSAGE FORM AND METHOD OF MANUFACTURING THEREOF”

FIELD OF THE INVENTION:
The present invention relates to novel oral solid dosage pharmaceutical composition of Rucaparib or pharmaceutically acceptable salts thereof, preferably in a tablet dosage form. Further, the present invention discloses the novel process for preparing the same using wet-granulation technique. The present invention provides an economical and advanced dosage form over existing dosage form.

BACKGROUND OF THE INVENTION:
Rucaparib is tricyclic indole and inhibitor of poly (ADP-ribose) polymerases agent used in the treatment of ovarian, fallopian tube, or primary peritoneal cancer. Structurally, Rucaparib is represented as below:

Rucaparib chemically known as 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one.

Structurally, Rucaparib Camsylate is represented as below:

The chemical formula of Rucaparib camsylate is C19H18FN3O•C10H16O4S the relative molecular mass is 555.67 Daltons.
Rucaparib is disclosed in US6495541 and is marketed under the brand name of RUBRACA®, which is a film coated tablet. The recommended dose of Rucaparib is 600 mg, which should be administered in the form 2 tablets of 300 mg daily or 3 tablets of 200 mg daily. Each film coated tablet contains Rucaparib as Rucaparib camsylate and microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The coating contains Opadry II containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc for the 300 mg tablet.

Ovarian cancer is a cancer that forms in or on an ovary. It results in abnormal cells that have the ability to invade or spread to other parts of the body. In 2012, new cases occurred in approximately 239,000 women in 2015 it was present in 1.2 million women and resulted in 161,100 deaths worldwide. Among women it is the seventh-most common cancer and the eighth-most common cause of death from cancer.

A possible handling of the disease depends on several individual conditions, such as age, general health, the extent of the cancer and possible metastasis. Thus, the decision whether or not to treat ovarian cancer with a curative intent is a personal patient trade-off between the expected beneficial and harmful effects in terms of patient survival and the maintenance of a certain quality of life. According to the USFDA, RUBRACA® is a film coated tablet for oral administration comprising Rucaparib as in Rucaparib camsylate. The dosage form is reported to be used for the treatment of patients with adult patients with recurrent epithelial ovarian, fallopian tube, who are in a complete or partial response to platinum-based chemotherapy.

WO2016/028689 discloses a dry-granulated pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof wherein the composition comprising of excipients such as microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate where the tablet is further coated with polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol.

Rucaparib camsylate formulations available currently in the market are formulated specifically with “dry granulation techniques” and with the excipients as microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The coating contains Opadry II containing polyvinyl alcohol, titanium dioxide, polyethylene glycol/macrogol, and talc.

Dry granulation technique suffers from disadvantages such as requirement of specialized heavy-duty equipment (tablet press / slugging machine / Chilsonator). Further, it does not permit uniform color. It tends to create more dust which in turn increases the potential for contamination and extensive damage to screens and tooling. Also, high compression forces are needed to produce tablets and this may affect their dissolution rate. Dry granulation does not have process control and shows generation of charges of static electricity and lead to reduce flowability which leads to decrease in dissolution of insoluble drugs (lipophilic drug). The process is long and tedious and frequent changeover and maintenance is required specifically for dry granulation. Further, due to the unique and unexpected physicochemical characteristics of Rucaparib camsylate, dry granulation process fails to provide longer stability.

To overcome such instances, the inventors of the present invention has surprisingly developed novel pharmaceutical compositions of Rucaparib with wet granulation process. This process is easily applicable at industrial scale. Further, proper process control is also maintained. Therefore, the inventors of the present invention have developed a technically advanced and improved over the common techniques employed for the formulation of pharmaceutical dosage forms.

Wet granulation technique developed by the inventors of the present invention have provided various advantages including good distribution and uniform content of Rucaparib camsylate with robust process and full control over the in-process parameters necessary for the final formulation. The cohesiveness and the compressibility of the powders are also improved, which may reduce elasticity problems. Wet granulation technique developed by the inventors of the present invention is helpful because final formulation is coated with polymers to increase wettability, which in turn increases dissolution for high dose drug with weak compressibility.

OBJECT OF THE INVENTION:
The primary object of the present invention is to provide a novel pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof for oral solid dosage form, which is prepared by wet-granulation process.

Another object of the present invention is to provide the pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof for oral solid dosage form, preferably a tablet dosage form.

Another object of the present invention is to provide an economical and advanced dosage form over existing dosage form.

Yet another object of the present invention is to provide a novel process for preparation of oral solid dosage pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof.

Yet another object of the present invention is to provide a pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof having excellent dissolution profile and higher stability with excipients.

Still another object of the present invention is to provide a pharmaceutical composition comprising Rucaparib for the use in treatment of ovarian and fallopian tube cancer.

Another object of the present invention is to provide process for the preparation of pharmaceutical composition comprising Rucaparib camsylate with a wet granulation technique and other suitable excipients, which then was formulated into a tablet dosage form wherein Rucaparib camsylate is in the concentration less than 45%w/w faster dissolution of the Rucaparib is obtained in recommended dissolution media.

SUMMARY OF THE INVENTION:
The present invention discloses a novel pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof preferably oral solid dosage form of a tablet with pharmaceutically acceptable excipients and wet granulation as method of preparation thereof.

The pharmaceutical composition of present invention comprises Rucaparib camsylate with one or more pharmaceutically acceptable excipients selected from the group comprising of at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, wherein the composition comprises a binder.

The pharmaceutical composition of present invention comprises Rucaparib camsylate with one or more pharmaceutically acceptable excipients is prepared with novel wet-granulation process.

The pharmaceutical composition according to the present invention is economical and advanced dosage form over existing dosage form, with less side effects and time efficient, especially for large-scale production, whereby the pharmaceutical composition shows a desired dissolution profile and higher stability with the said excipients.

The inventors of the present invention have surprisingly developed novel pharmaceutical compositions of Rucaparib with wet granulation process wherein the concentration of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino [5,4,3-cd]indol-6-one is in the range of 35%-50% w/w of the total composition. This process is easily applicable at industrial scale. Further, proper process control is also maintained. Therefore, the inventors of the present invention have developed a technically advanced and improved over the common techniques employed for the formulation of pharmaceutical dosage forms.

DETAILED DESCRIPTION OF THE INVENTION:
The following detailed description of the present subject matter the various embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present subject matter. Other embodiments may be utilized and structural, and logical changes may be made without departing from the scope of the present subject matter.

References to “an”, “one”, or “various” embodiments in this disclosure are not necessarily to the same embodiment, and such references contemplate more than one embodiment. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope is defined only by the appended claims, along with the full scope of legal equivalents to which such claims are entitled.

In accordance with the present invention, a pharmaceutical composition of Rucaparib comprising of Rucaparib camsylate as an active ingredient with pharmaceutically acceptable excipients.

The term "drug" or “active ingredient” or “active pharmaceutical ingredient (API)” herein refers to Rucaparib or a pharmaceutically acceptable salt thereof.

The term "Rucaparib" as used herein according to the present invention includes, Rucaparib in the form of free base, a pharmaceutically acceptable salt thereof, amorphous Rucaparib, crystalline Rucaparib, any isomer, derivative, hydrate, solvate or prodrug or a combination thereof.

The term "drug solution" as used herein according to the present invention includes solution obtained by dissolving Rucaparib Camsylate or its pharmaceutically acceptable salt thereof in solvent and (or) mixture of solvents with one or more pharmaceutical acceptable excipients.

The term "granulation" as used herein according to the present invention includes, wet-granulation, dry-granulation or direct compression.

The term "pharmaceutically acceptable excipients" as used herein, refers to excipients those are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise of diluents / fillers, disintegrants, binders, lubricants, vehicles / solubility enhancing agents, stabilizers / anti-oxidants, suspending agents, permeability enhancers, preservatives, glidants, active carriers, anti-caking agents, wetting agents, preservatives, buffering agents and combinations thereof. Each excipient should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the health of the patient.

The term "binding agents or binders" as used herein according to the present invention is a material or substance that holds other materials together mechanically, chemically, or as an adhesive, to form a cohesive whole. Binders are loosely classified as organic (bitums, animal and plant glues, polymers) and inorganic (lime, cement, gypsum, liquid glass, etc.). These can be either metallic or ceramic as well as polymeric depending on the nature of the main material.

The nature of the invention is clearly described in the specification. The invention has various components and they are clearly described in the specification. The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.

In accordance with the present invention, a novel pharmaceutical composition comprising Rucaparib as an active ingredient and one or more pharmaceutically acceptable excipients including diluents/filler, disintegrants, binders, lubricants, but not limited thereof.

The present invention discloses a novel pharmaceutical composition of Rucaparib or a pharmaceutically acceptable salt thereof preferably oral solid dosage form of a tablet. The pharmaceutical composition of the present invention comprises Rucaparib camsylate with one or more pharmaceutically acceptable excipients selected from the group consisting of at least one diluent, at least one disintegrant, at least one binder, at least one lubricant, wherein the composition specifically comprises a binder.

Preferably, the pharmaceutical composition comprising Rucaparib according to the present invention may be administered in a solid oral dosage form of a tablet including film coated tablet, sugar coated tablet, chewable tablet, delayed release tablet, multiple compressed tablets, enteric coated tablets, effervescent tablet.

The pharmaceutical composition comprising Rucaparib according to the present invention is administered orally through the solid dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units), MUPS (multiple unit pellet systems), disintegrating tablets, dispersible tablets, granules, and microspheres, multi-particulates, sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, disintegrating tablets, dispersible tablets, granules, and microspheres, multi-particulates), powders for reconstitution and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like.

In accordance with the present invention, a novel pharmaceutical composition comprising Rucaparib as an active ingredient and one or more pharmaceutically acceptable excipients which is formulated with a wet granulation technique.

The present invention discloses an immediate-release formulation of Rucaparib for oral dosage form. Further, in the present invention, camsylate salt is used which exhibited good compression characteristics.

The novel pharmaceutical composition of Rucaparib oral dosage form comprises Rucaparib camsylate as an active ingredient along with pharmaceutically acceptable excipients such as Polyvinylpyrrolidone (PVP), microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate. The coating contains Opadry ready-mix for the pharmaceutical dosage form of Rucaparib.

The inventors of the present invention provide a pharmaceutical composition of Rucaparib which would be considered as patient compliant due its better dissolution profile which ultimately leads to enhanced bioavailability.

The inventors of the present invention have developed the formulation of Rucaparib that comprises Rucaparib, preferably camsylate, with one or more pharmaceutically acceptable excipients selected from at least one diluent, at least one disintegrant, at least one binder, at least one lubricant; wherein diluent is preferably selected from lactose, mannitol, microcrystalline cellulose; binder is preferably selected from Polyvinylpyrrolidone, HPMC; disintegrant is preferably selected from croscarmellose sodium, Polyplasdone® XL (crospovidone), Sodium starch glycolate and lubricant is preferably selected from magnesium stearate, sucrose stearate or sodium stearyl fumarate.

Problem solution approach by the present invention:
Prior experience from the prior-arts taught the inventors of the present invention that it was likely not possible to create a formulation of rucaparib at a dose loading significantly exceeding 32%. The inventors of the present invention also noted that to overcome such limitation, the innovator developed a composition of Rucaparib with high drug loads in excess of 50%; however, limitation of the same is that it can be formulated in a dry granulating manufacturing process. Dry-granulation technique omits use of binder to provide better results. Being a fluffy nature of Rucaparib Camsylate, dry-granulation was the only technique disclosed in prior-arts. The inventors of the present invention have surprisingly developed a pharmaceutical formulation of Rucaparib camsylate wherein 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino [5,4,3-cd]indol-6-one is in the range of 35%-50% w/w of the total composition using wet-granulation technique.

It may also be important to note that dry-granulation technique is more expensive as it uses more expensive equipment like roller compactor and others. Therefore, it requires tremendous investment and thereby providing costlier final product to the mankind in need. In addition, absence of binder in the dry-granulation technique makes final formulation more friable and thereby it faces difficulty during the transportation. Hence, sometimes it is difficult to provide the patient in an intact form to the patient. For that costlier packing material are used which make the final product costliest. Furthermore, the dissolution study of the final product shows slower release rate even after 30 minutes and thereby the drug is not properly bioavailable quickly. This led to delayed onset of the therapeutic effect to the patient.

All problems described below were residing in the prior-arts, are solved by the present invention:
1. Novel & Inventive:
None prior-arts have disclosed or anticipated that Rucaparib can be formulated using techniques other than dry-granulation due to fluffy nature of the API (Active pharmaceutical ingredient). Further, the use of binder in the Rucaparib composition is not known.

Above problem was solved by the present invention by providing compositions of Rucaparib using techniques other than dry-granulation by using binder.

2. Technical Advancement:
Rucaparib itself is in fluffy nature and therefore its composition can be prepared by dry-granulation techniques, only. The products prepared by dry-granulation techniques are more friable and hence, very difficult to transport. In addition, dissolution of the Rucaparib composition using dry-granulation technique shows slower release rate even after 30 minutes and thereby the drug is not properly bioavailable quickly. This led to delayed onset of the therapeutic effect to the patient.

Above problem was solved by the present invention by providing highly bioavailable Rucaparib composition even after storing the same for 6 months at the accelerated stability testing conditions. This proves that the composition as per the present invention is not a mere admixture and bio-available in shorter time span and thereby providing early therapeutic effect.

3. Economical Significance & Industrially Applicable:
Prior-arts have disclosed expensive techniques like dry-granulation. None prior-arts anticipated that Rucaparib composition may be prepared in high drug load using techniques other than dry-granulation.

Above problem was solved by the present invention by using wet-granulation technique which requires use of less expensive machineries and thereby providing more economic final product.

During development of the present invention to provide the solution of the above problems relied in the prior-arts, the inventors of the present invention observed that when the binder concentration of the present invention was increased than 2% w/w, at that time, dissolution of the final composition was reducing in the long-term storage and thereby achieving a low bio-available product. Hence, the inventors of the present invention surprisingly developed a wet-granulated composition of Rucaparib wherein the concentration of binder does not exceed to 2% of the total composition for achieving more bioavailable product in long-term storage as well. Thus, the inventors of the present invention have also proven that the composition as per the present invention is neither a mere admixture nor previously known.

Furthermore, none prior-arts anticipated that wet-granulation techniques may be used for Rucaparib Camsylate due to its fluffy nature as well as what may be the optimum concentration of lubricants and/or glidants are required to prepare the formulation. During the development process, the inventors of the present invention faced difficulty in processing as well as during compression to provide intact final tablet formulation when lubricant and glidants were used in the concertation less than 2% w/w of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd] indol-6-one in the total composition. The inventors of the present invention surprisingly found that when the concentration of lubricants and/or glidants are used more than 2% w/w of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd] indol-6-one in the total composition, at that time, none difficulty is observed during processing. Thus, the inventors of the present invention have also proven once again that the composition as per the present invention is neither a mere admixture nor previously known.

During development of the present invention to provide the solution of the above problems relied in the prior-arts, the inventors of the present invention also observed that when concentration of disintegrants in the present invention was increased than 5% w/w, at that time, dissolution of the final composition was higher however the composition was more prone to friability and thereby achieving a low strength product. Hence, the inventors of the present invention surprisingly developed a wet-granulated composition of Rucaparib wherein the concentration of disintegrant does not exceed to 5% of the total composition for achieving the final product which is a balanced one. Thus, the inventors of the present invention have also proven that the composition as per the present invention is neither a mere admixture nor previously known.

The composition of the present invention includes excipients such as Polyvinylpyrrolidone (PVP or PVP K-30). This excipient helped the present invention in achieving good dissolution profile. Therefore, stability of solid dosage forms of the present invention is quite higher than prior-art formulations.

In further aspect of the present invention, diluents may be selected from the group consisting of dextrin, dextrose, fructose, 1-O-a-D-glucopyranosyl-D-mannitol, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, lactose monohydrate, maltitol, mannitol, maltodextrin, maltose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer), pregelatinized starch, microcrystalline cellulose, sorbitol, dicalcium phosphate, starches, sucrose, talc and xylitol or a mixture of one or more of said diluents.

Disintegrants used for the preparation of solid oral dosage form are selected from the group consisting of carboxymethyl cellulose, low substituted hydroxypropyl cellulose, powdered cellulose, croscarmellose sodium, Polyplasdone® XL (crospovidone), sodium starch glycolate, polacrilin potassium, sodium alginate or a mixture of one or more of said disintegrants.

The binders may be selected from the group consisting of hydroxyl propyl methyl cellulose (HPMC or Hypromellose), polyvinylpyrrolidone (povidone or PVP or PVP K-30), hydroxyl propyl cellulose, polyvinyl alcohol, methyl cellulose, ethyl cellulose, gum Arabic, alginic acid, polyethylene glycol (PEG), pregelatinized starch (PGS) and the like.

Glidants or lubricants may be selected from the group consisting of colloidal silica, glyceryl palmitostearate, sodium benzoate, sodium stearyl fumarate, stearic acid, magnesium stearate; calcium stearate; zinc stearate; hydrophobic colloidal silica and magnesium trisilicate, such as talc; preferably, the glidants are selected from the group consisting of magnesium stearate, colloidal silica and hydrophobic colloidal silica.

The amount of lubricant magnesium stearate and glidant colloidal silicon dioxide in the tablet of the present invention is adjusted to avoid sticking to the tableting tools. Further, the film coated tablet of the present invention facilitate swallowing and patient compliance.

Coating mixture Opadry® or Tabcoat® of present invention is consisting of Hypromellose as film-forming agent, macrogol as plasticizer and polysorbate 80 as wetting agent. Further, titanium dioxide, yellow ferric oxide and red ferric oxide are used as colorants.

The present invention thus provides a pharmaceutical composition comprising Rucaparib is formulated in such a way that lead to provide better dissolution profile and solubility of the drug.

The present invention can be described by way of example or strategy only. It is to be recognized that modifications falling within the scope and spirit of the description or claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this disclosure.

EXAMPLES:

Example-1:
Sr.
No. Ingredients For 200 mg / Tablet Range (%w/w)
1. Rucaparib Camsylate 343.64 72.68
2. PVP K-30 6.87 1.45
3. Microcrystalline cellulose 98.19 20.67
4. Sodium starch glycolate 18.93 4.00
5. Colloidal silicon dioxide 2.37 0.50
6. Magnesium Stearate 3.33 0.70

Manufacturing process for Rucaparib composition (Example: 1)
1) Rucaparib camsylate API, Microcrystalline cellulose (MCC), Colloidal silicon dioxide and Sodium starch glycolate (SSG) were sifted using appropriate size sieve and transferred to rapid mixer granulator (RMG). Then, dry mixing was done of the blend for 5 minutes.
2) Dry blend was granulated in rapid mixer granulator (RMG) by adding binder solution of PVP K30 at an impeller speed of 75-190 RPM and chopper speed of 1400-1500 RPM. Wet granules prepared were kneaded for 30 seconds in rapid mixer granulator (RMG).
3) After completing the granulation, the wet granules prepared were dried in the fluid bed processor (FBP) at inlet air temperature 55 to 65°C till loss on drying (LOD) of the granules is less than 1.5 %.
4) Then after, dried granules prepared were sifted using 30# sieve, milling of the oversize granules were done using clit mill.
5) Lubricant magnesium stearate was added in the blend prepared in step (4) and lubrication was carried out for 3 minutes.
6) Lubricated blend was compressed using suitable punch set at 200 mg and 300 mg tablet weight.
7) Then, coating of core tablets was carried out using coating mixture of Opadry® II 85F505266 Blue till the desired weight gain.

Example-2:
Sr.
No. Ingredients For 300 mg / Tablet Range (%w/w)
1. Rucaparib Camsylate 516.00 72.68
2. PVP K-30 10.30 1.45
3. Microcrystalline cellulose 146.75 20.67
4. Sodium starch glycolate 28.40 4.00
5. Colloidal silicon dioxide 3.55 0.50
6. Magnesium Stearate 5.00 0.70

Manufacturing process for Rucaparib composition (Example: 2)
1) Rucaparib camsylate API, MCC, Colloidal silicon dioxide and SSG were sifted using appropriate size sieve and transferred to rapid mixer granulator (RMG). Then, dry mixing was done of the blend for 5 minutes.
2) Dry blend was granulated in rapid mixer granulator (RMG) by adding binder solution of PVP K30 at an impeller speed of 75-190 RPM and chopper speed of 1400-1500 RPM. Wet granules prepared were kneaded for 30 seconds in rapid mixer granulator (RMG).
3) After completing the granulation, the wet granules prepared were dried in the fluid bed processor (FBP) at inlet air temperature 55 to 65°C till loss on drying (LOD) of the granules is less than 1.5 %.
4) Then after, dried granules prepared were sifted using 30# sieve, milling of the oversize granules were done using clit mill.
5) Lubricant magnesium stearate was added in the blend prepared in step (4) and lubrication was carried out for 3 minutes.
6) Lubricated blend was compressed using suitable punch set at 200 mg and 300 mg tablet weight.
7) Then, coating of core tablets was carried out using coating mixture of Opadry® II 85F520440 yellow till the desired weight gain.

Example-3:

Example 3A 3B 3C
Sr. No. Ingredients 200 mg Tablet 250 mg Tablet 300 mg Tablet
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 91.69 114.63 137.55
4. Sodium starch glycolate 18.93 23.67 28.40
5. Colloidal silicon dioxide 2.37 2.96 3.55
6. Magnesium Stearate 9.47 11.83 14.20
Total Weight 473.33 591.67 710.00

Manufacturing process for Rucaparib composition (Example: 3)
1) Rucaparib camsylate API was weighed and sieved to obtain dry blend ready for granulation;
2) binder solution was prepared my dissolving PVP K30 in purified water;
3) binder solution obtained in step-2 was then added to the dry blend obtained in step-1 for granulation using rapid mixer granulator or fluidized bed granulator;
4) granules obtained in step-3 was then dried;
5) dried granules obtained in step-4 was then blended with excipients Microcrystalline cellulose and sodium starch glycolate;
6) blend obtained in step-5 was then lubricated with magnesium stearate and Colloidal silicon dioxide to obtain final blend;
7) blend obtained in step-6 was then compressed to form tablets;
8) optionally, coating of above tablets obtained in step-7 using Opadry II 85F520440 yellow (for 300 mg), Opadry II 85F505266 Blue (for 200 mg), Opadry 85F18422 White (for 250 mg).

Example-4:
Example 4A 4B 4C
Sr. No. Ingredients 200 mg Tablet 250 mg Tablet 300 mg Tablet
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 167.40 209.25 251.10
4. Sodium starch glycolate 21.80 27.25 32.70
5. Colloidal silicon dioxide 2.67 3.33 4.00
6. Magnesium Stearate 3.93 4.91 5.90
Total Weight 546.67 683.32 820.00

Manufacturing process for Rucaparib composition (Example: 4)
1) Rucaparib camsylate API was weighed and sieved to obtain dry blend ready for granulation;
2) binder solution was prepared my dissolving PVP K30 in purified water;
3) binder solution obtained in step-2 was then added to the dry blend obtained in step-1 for granulation using rapid mixer granulator or fluidized bed granulator;
4) granules obtained in step-3 was then dried;
5) dried granules obtained in step-4 was then blended with excipients Microcrystalline cellulose and sodium starch glycolate;
6) blend obtained in step-5 was then lubricated with magnesium stearate and Colloidal silicon dioxide to obtain final blend;
7) blend obtained in step-6 was then compressed to form tablets;
8) optionally, coating of above tablets obtained in step-7 using Opadry II 85F520440 yellow (for 300 mg), Opadry II 85F505266 Blue (for 200 mg), Opadry 85F18422 White (for 250 mg).

Example-5:
Example 5A 5B 5C
Sr. No. Ingredients 200 mg Tablet 250 mg Tablet 300 mg Tablet
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 27.00 33.75 40.50
4. Sodium starch glycolate 16.00 20.00 24.00
5. Colloidal silicon dioxide 2.00 2.50 3.00
6. Magnesium Stearate 2.80 3.50 4.20
Total Weight 398.67 498.33 598.00

Manufacturing process for Rucaparib composition (Example: 5)
1) Rucaparib camsylate API was weighed and sieved to obtain dry blend ready for granulation;
2) binder solution was prepared my dissolving PVP K30 in purified water;
3) binder solution obtained in step-2 was then added to the dry blend obtained in step-1 for granulation using rapid mixer granulator or fluidized bed granulator;
4) granules obtained in step-3 was then dried;
5) dried granules obtained in step-4 was then blended with excipients Microcrystalline cellulose and sodium starch glycolate;
6) blend obtained in step-5 was then lubricated with magnesium stearate and Colloidal silicon dioxide to obtain final blend;
7) blend obtained in step-6 was then compressed to form tablets;
8) optionally, coating of above tablets obtained in step-7 using Opadry II 85F520440 yellow (for 300 mg), Opadry II 85F505266 Blue (for 200 mg), Opadry 85F18422 White (for 250 mg).

Test Example-1: Comparative Dissolution Profile:
Dissolution rate is a critical property that need to study for final dosage form Comparative dissolution profile of the product of present invention with a reference product (tablet) was studied. Dissolution study of the pharmaceutical dosage of the present invention was carried out by HPLC.

Comparative Dissolution Profile
Media 0.1 N HCl
Volume 900 ml
USP apparatus Type II (paddle) with sinker
Time
(minutes) Reference product Dissolution
(%) Examples of the present invention
Ex. 1
(%) Ex. 2
(%) Ex. 4A
(%) Ex. 4C
(%)
5 70.40 78.70 78.00 75.10 77.90
10 85.70 95.40 92.10 80.00 81.10
15 92.60 96.50 96.20 83.40 82.90
20 94.80 96.10 97.60 85.90 84.50
30 95.00 97.80 98.90 97.40 98.10

The dissolution method employed in the present invention was performed in USP Apparatus II (paddle) with sinker in 0.1 N HCl for 60 min of time duration at (37 ± 0.5) ºC. Samples were taken at 5, 10, 15, 20 and 30 minutes. These samples were filtered through a 0.45 µm syringe filter, transferred to HPLC vials and analyzed by HPLC.

Surprisingly, it was found from the above data for the Rucaparib tablets of the present invention that the tablets underwent rapid and complete dissolution initially compare to innovator product and even after 1 month when tested using the USP Apparatus (II). An increase in the solubility and dissolution rates leads to improvement in the bioavailability of the drug with consistency and uniformity. Similar results were obtained with all the examples described in the present invention.

Test Example-2: Accelerated Stability Testing:
Example-3C of the present invention was placed under accelerated stability testing at conditions of 40°C and 75% RH.
Accelerated Stability Testing
Parameter Initial After 1 month After 3 months After 6 months
% Assay 99.57 106.44 98.92 100.11
Dissolution Profile
30 min 98.6 103.6 101.7 92.4
45 min 99.2 102.9 102.5 95.9

Inventors of the present invention surprisingly found from the above data that Rucaparib tablets prepared as per the present invention underwent rapid and complete dissolution even after 6 months of storage at accelerated stability testing. In addition, % assay of the composition as per the present invention shown consistency proving it a stable dosage form in long term storage as well. Similar results were obtained with all the examples described in the present invention.

Therefore, the inventors of the present invention have herein disclosed the problems in the prior-art and provided a solution to the same. Further, the inventors of the present invention have proved by testing study data that the present invention is not a mere admixture but it is technical advancement over the prior-art. In addition, wet-granulation process is conventional and require less investment than dry-granulation process disclosed in prior-arts. Thus, the inventors of the present invention have provided an invention which is economically significant than prior-art. Hence, the inventors of the present invention have crossed all the barriers for the patentability including novelty, inventive step, industrial applicability and non-patentable subject matters.

The invention described herein comprises in various objects as mentioned above and their description in relation to characteristics, compositions and process adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
,CLAIMS:We Claim:

1. A wet-granulated composition of Rucaparib Camsylate comprising at least one binding agent is having concentration not more than 2% w/w and 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino [5,4,3-cd]indol-6-one is in the range of 35%-50% w/w of the total composition.

2. A wet-granulated composition of Rucaparib Camsylate as claimed in claim 1, wherein the binding agent is Polyvinylpyrrolidone having concentration not more than 2% w/w of the total composition.

3. A wet-granulated composition of Rucaparib Camsylate as claimed in claim 1, wherein the composition further comprises disintegrating agent in the concentration not more than 5% w/w of the total composition.

4. A wet-granulated composition of Rucaparib Camsylate as claimed in claim 3, wherein disintegrating agents are selected from the group of sodium starch glycolate, croscarmellose sodium and crospovidone in the concentration not more than 5% w/w of the total composition.

5. A wet-granulated composition of Rucaparib Camsylate as claimed in claim 1, wherein the composition further comprises lubricants and/or glidants in the concentration not less than 2% w/w of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd] indol-6-one in the total composition.

6. A wet-granulated composition of Rucaparib Camsylate as claimed in claim 5, wherein lubricants and/or glidants are selected from the group of magnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide and talc in the concentration not less than 2% w/w of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd] indol-6-one in the total composition.

7. A wet-granulated composition of Rucaparib Camsylate comprising of following formula:
Sr. No. Ingredients 200 mg 250 mg 300 mg
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 91.69 114.63 137.55
4. Sodium starch glycolate 18.93 23.67 28.40
5. Colloidal silicon dioxide 2.37 2.96 3.55
6. Magnesium Stearate 9.47 11.83 14.20

8. A wet-granulated composition of Rucaparib Camsylate comprising of following formula:
Sr. No. Ingredients 200 mg 250 mg 300 mg
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 167.40 209.25 251.10
4. Sodium starch glycolate 21.80 27.25 32.70
5. Colloidal silicon dioxide 2.67 3.33 4.00
6. Magnesium Stearate 3.93 4.91 5.90

9. A wet-granulated composition of Rucaparib Camsylate comprising of following formula:
Sr. No. Ingredients 200 mg 250 mg 300 mg
1. Rucaparib Camsylate 344.00 430.00 516.00
2. PVP K-30 6.87 8.58 10.30
3. Microcrystalline cellulose 27.00 33.75 40.50
4. Sodium starch glycolate 16.00 20.00 24.00
5. Colloidal silicon dioxide 2.00 2.50 3.00
6. Magnesium Stearate 2.80 3.50 4.20

10. A wet-granulated composition of Rucaparib Camsylate prepared by the process for preparation of composition comprises following steps:
a) sieving of Rucaparib camsylate to obtain dry blend ready for granulation;
b) binder solution was prepared my dissolving PVP K30 in purified water;
c) binder solution obtained in step-b was then added to the dry blend obtained in step-a for granulation using rapid mixer granulator or fluidized bed granulator;
d) granules obtained in step-c was then dried;
e) dried granules obtained in step-d was then blended with excipients Microcrystalline cellulose and sodium starch glycolate;
f) blend obtained in step-e was then lubricated with magnesium stearate and Colloidal silicon dioxide to obtain final blend;
g) blend obtained in step-f was then compressed to form tablets;
h) optionally, coating of above tablets obtained in step-f to form final formulation.