“Oral Suspension of Capecitabine”

RELATED APPLICATIONS This application is related to Indian Provisional Application No. IN201921033487 filed on 20 ^th Aug, 2019 is incorporated herein in its entirety.

FIELD OF THE INVENTION The present invention relates to a new dosage form of Capecitabine in form of suspension for oral administration. Further, the present invention discloses process for the preparation of the said suspension.

BACKGROUND OF THE INVENTION

Capecitabine is a fluoropyrimidine carbamate having antineoplastic activity. It is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which is converted to fluorouracil. Molecular formula of Capecitabine is C15H22FN3O6 and the molecular weight is 359.35 and has following chemical structure:

(Capecitabine)

US4966891 and US5472949 discloses Fluorocytidine derivatives and N ⁴ - (substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds respectively which cover Capecitabine and methods of using same. Capecitabine is marketed as immediate release tablet comprising 150 or 500 mg Capecitabine for oral administration under trade name XELODA ^® by Roche. The inactive ingredients in XELODA ^® include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides. Capecitabine is indicated for colon cancer, metastatic colorectal cancer and metastatic breast cancer as monotherapy or combination therapy.

W02020039264 discloses suspension composition comprising an anti-cancer active pharmaceutical ingredient; water; a suspending agent; a buffering agent; and one or more of a wetting agent and a binder/filler. Specifically, W02020039264 discloses compositions which are supplied as liquid dosage form i.e. the supplied composition is ready for administration to the patient in need thereof which does not require reconstitution. Further, to prepare suspension of anti-cancer agents this disclosure requires buffer and wetting agent.

Recommended standard starting dose of Capecitabine is 1250 mg/m ² administered orally twice daily (morning and evening; equivalent to 2500 mg/m ² total daily dose) for 2 weeks followed by a 1-week rest period given as 3 -week cycles. In combination with docetaxel, the recommended dose of Capecitabine is 1250 mg/m ² twice daily for 2 weeks followed by a 1-week rest period, combined with docetaxel at 75 mg/m ² as a 1-hour intravenous infusion every 3 weeks. The currently marketed product XELODA ^® is available as immediate release tablet dosage form and has dosage administration instruction “XELODA ^® tablets should be swallowed whole with water within 30 minutes after a meal.” Many patients face difficulty in swallowing while taking tablets as whole, specifically the cancer patients. Further, based on body surface area, patient needs to take more than one tablet at a time as shown in below Table 1. Currently, based on body surface area, a patient needs to take at least three tablets and a maximum of seven tablets. Table: 1 Capecitabine dose calculation according to body surface area

*Total Daily Dose divided by 2 to allow equal morning and evening doses

Oral suspension is a dosage form in which active pharmaceutical ingredient (API) is dispersed throughout a liquid vehicle with or without stabilizers and other pharmaceutical additives. A powder mixture / granules containing the API and suitable excipients like suspending and dispersing agents, which upon dilution and agitation with a specified quantity of vehicle (i.e. purified water) results in the formation of the final suspension suitable for administration.

For many patients, the liquid dosage form (i.e. suspension) is preferred over the solid forms (i.e. tablets and capsules) due to ease of swallowing especially in cancer patients. Further, the suspension dosage form gives a greater flexibility in dose administration especially for exceedingly large doses.

Currently, for patient with swallowing problem Capecitabine tablets are dissolved in water to prepare solution / suspension of Capecitabine. The solution / suspension should be swallowed by the patient. But till date no suspension dosage form is available. Hence, there is a need to develop suspension dosage form of Capecitabine which overcomes problems associated with currently available immediate release tablets dosage form and provides ease of swallowing and a greater flexibility in dose administration.

OBJECT OF THE INVENTION

It is therefore, object of the invention is to provide a new dosage form of Capecitabine in the form of suspension for oral administration, and process for the preparation of the said suspension.

Another object of the present invention is to provide composition of Capecitabine which is administered as suspension to the patient.

Another object of the present invention is to provide a granular composition of Capecitabine, which upon reconstitution with specified quantity of vehicle gives a suspension dosage form.

Another object of the present invention is to provide a granular composition of Capecitabine, which upon reconstitution with specified quantity of water gives a suspension dosage form.

Another object of the present invention is to provide a granular powder composition of Capecitabine, which upon reconstitution with specified quantity of vehicle gives a suspension dosage form.

Another object of the present invention is to provide a powder composition of Capecitabine, which upon reconstitution with specified quantity of vehicle gives suspension dosage form.

Another object of the present invention is to provide a powder composition of Capecitabine, which upon reconstitution with specified quantity of water gives suspension dosage form.

Another object of the present invention is to provide a suspension dosage form of Capecitabine. Another object of the invention is to provide a dry suspension of Capecitabine which needs to be reconstituted with suitable vehicle.

Another object of the invention is to provide a dry suspension of Capecitabine, which upon mixing with specified quantity of vehicle gives suspension ready for swallowing by the patient.

Another object of the invention is to provide a suspension of Capecitabine, which upon mixing with specified quantity of vehicle gives suspension ready for swallowing by the patient, wherein the suspension is not prepared by dissolving Capecitabine tablets currently available in market (i.e. 150/300/500 mg Capecitabine film coated tablets) in water.

Another object of the invention is to provide a suspension of Capecitabine, which upon mixing with specified quantity of vehicle gives suspension ready for swallowing by the patient, wherein the said suspension is used for the treatment of cancer in pediatric patients.

Another object of the present invention is to provide a kit comprising a suspension of Capecitabine and a vehicle, wherein the said suspension is mixed with a vehicle just before administration.

Another object of the present invention is to provide process for the preparation of a suspension dosage form of Capecitabine.

SUMMARY OF THE INVENTION

Present invention provides a new dosage form of Capecitabine in form of suspension for oral administration. Further, the present invention provides process for the preparation of the said suspension. DETAILED DESCRIPTION OF THE INVENTION

Present invention provides suspension dosage form of Capecitabine. The suspension dosage form can be prepared before administration by reconstitution of Capecitabine composition with suitable vehicle or the suspension dosage form is readily provided as finished product which does not require any further reconstitution with vehicle (i.e. no processing required before administration). Further, the present invention provides process for the preparation of the said suspension.

In another embodiment, the present invention provides a new dosage form of Capecitabine in form of suspension and process for the preparation of the said suspension.

In another embodiment, the present invention provides a composition of Capecitabine, which is administered as an oral suspension to the patient in need thereof.

In another embodiment, the present invention provides a granular composition of Capecitabine which upon reconstitution with specified quantity of vehicle gives suspension dosage form.

In another embodiment, the present invention provides a granular composition of Capecitabine which upon reconstitution with specified quantity of water gives suspension dosage form.

In another embodiment, the present invention provides a granular powder composition of Capecitabine which upon reconstitution with specified quantity of vehicle gives suspension dosage form. In another embodiment, the present invention provides a powder composition of Capecitabine which upon reconstitution with specified quantity of vehicle gives suspension dosage form.

In another embodiment, the present invention provides a powder composition of Capecitabine which upon reconstitution with specified quantity of water gives suspension dosage form.

In another embodiment, the present invention provides a suspension dosage form of Capecitabine.

In another embodiment, the invention provides a dry suspension of Capecitabine.

In another embodiment, the invention provides a dry suspension of Capecitabine, which upon mixing / reconstitution with specified quantity of suitable vehicle gives reconstituted suspension ready for swallowing / administration to a patient in need thereof.

In another embodiment, the invention provides a suspension of Capecitabine, which upon mixing with specified quantity of vehicle gives suspension ready for swallowing by the patient, wherein the suspension is not prepared by dissolving Capecitabine tablets currently available in market in water.

In another embodiment, the invention provides a suspension of Capecitabine, which upon mixing with specified quantity of vehicle gives suspension ready for swallowing by the patient, wherein the said suspension is used for the treatment of cancer in pediatric patients.

In another embodiment, the invention provides a kit comprising a suspension of Capecitabine and a vehicle, wherein the said suspension is mixed with a vehicle just before administration. The term "kit" refers to a packaging system comprising at least dual chambers, wherein one chamber comprises a suspension and another chamber comprises a vehicle. At the time of administration of the said suspension, the contents of both the chambers of the kit are mixed together to obtain a final suspension which is ready for swallowing by the patient.

One of the examples of the kit is a dual chamber packaging system comprising a bottle with a cap, wherein the suspension is kept in a chamber in the cap, and the vehicle is present in the bottle. During administration, the cap of the bottle is twisted to tighten the cap which causes the chamber in the cap to break or puncture and releases the suspension in the bottle comprising the vehicle. By gentle shaking the contents of the suspension get mixed with the vehicle. The cap of the bottle is opened, and the final suspension is administered to the patient conveniently.

In another embodiment, the present invention provides a process for the preparation of Capecitabine suspension.

The suspension according to present invention comprises of Capecitabine with suitable excipients. The suitable excipients may include, but not limited to diluent, binder, preservative, suspending agent, viscosity enhancer, sweetener, glidant, antioxidant, flavoring agent, vehicle and like thereof.

In another embodiment, the present invention provides Capecitabine suspension comprising (a) amount of Capecitabine ranging from 25-70 % w/w (b) amount of diluent ranging from 10-70 % w/w (c) amount of binder ranging from 0-5 % w/w (d) amount of viscosity enhancer ranging from 0.02-5 % w/w (e) amount of sweetener ranging from 0.01-5 % w/w (f) amount of flavoring agent ranging from 0.05-5 % w/w, where in amount of all the ingredients are measured on dry basis. In another embodiment, the present invention provides Capecitabine suspension, wherein the suspension is immediate release suspension.

In another embodiment, the present invention provides Capecitabine suspension, wherein the suspension is devoid of buffer and wetting agent.

In another embodiment, the present invention provides Capecitabine suspension comprising (a) amount of Capecitabine ranging from 25-70 % w/w (b) amount of diluent ranging from 10-70 % w/w (c) amount of binder ranging from 0-5 % w/w (d) amount of viscosity enhancer ranging from 0.02-5 % w/w (e) amount of sweetener ranging from 0.01-5 % w/w (f) amount of flavoring agent ranging from 0.05-5 % w/w, where in amount of all the ingredients are measured on dry basis, wherein the suspension is immediate release suspension and the suspension is devoid of buffer and wetting agent.

For the purpose of this specification, the term “suspension” means a pharmaceutical dosage form which can be supplied as granular / powder composition which is reconstituted with vehicle before administration to the patient, or can be supplied as liquid suspension as finished product which does not require further reconstitution with vehicle before administration to the patient.

For the purpose of this specification, “dry suspension” means a solid pharmaceutical dosage form which can be supplied as granular / powder composition in sachet or bottle or pouch or vial or any other suitable chamber / container to hold the solid material, wherein the granular / powder composition is mixed with vehicle before administration to the patient. For the purpose of this specification, “reconstitution” means dry suspension composition of the present invention is mixed with suitable vehicle to obtain liquid suspension prior to administration to the patient in need thereof.

For the purpose of this specification, the term “diluent” means filler or bulking agent which are used to make up the volume (i.e. to increase the bulk) of the composition.

For the purpose of this specification, the term “binder” means a binding agent or any material or substance that holds or draws other materials together.

For the purpose of this specification, the term “preservative” means any substance added to the composition to prevent or inhibit microbial growth. An ideal preservative would be effective at low concentrations against all possible micro-organism, be nontoxic and compatible with other constituent of the composition and be stable for the shelf-life of the preparation.

For the purpose of this specification, the term “suspending agent” means ingredient added to the composition to promote particle suspension or dispersion and which reduces sedimentation.

For the purpose of this specification, the term “viscosity enhancer” means ingredient added to the composition which increases the viscosity of the composition. The viscosity enhancer also increase the thickness of the composition and thereby keeping the active ingredient suspended to allow accurate dosing.

For the purpose of this specification, the term “sweetener” means ingredient added to the composition to increase the palatability of the composition. For the purpose of this specification, the term “glidant”, “antioxidant” and “flavoring agent” and “vehicle” has plain meaning known to person skilled in the art in pharmaceutical technology field with common general knowledge.

According to present invention, diluent may include, but not limited to xylitol, sorbitol, maltitol, dextrose, fructose, sucrose and the like, or mixtures thereof. The amount of diluent that can be used in the present invention ranges from about 10 % to about 70 %, weight by weight of the composition.

According to present invention, binder may include, but not limited to acacia, carbomer, carboxymethylcellulose, cellulose microcrystalline, copovidone, gelatin, guar gum, hydroxypropyl cellulose, low -substituted hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose acetate succinate, methyl cellulose, ethyl cellulose, polyethylene oxide, povidone, starch, pregelatinized starch, ammonia methacrylate copolymer and the like, or mixtures thereof. The amount of binders that can be used in the present invention ranges from about 0.05 % to about 5 %, weight by weight of the composition.

According to present invention, preservative may include, but not limited to benzalkonium chloride, benzoic acid, boric acid, butylparaben, chlorhexidine, citric acid, methylparaben, monothioglycerol, potassium benzoate, potassium metabisulfite, propionic acid, propylparaben, propylparaben sodium, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sorbic acid, sulfur dioxide and the like, or mixtures thereof. The amount of preservatives that can be used in the present invention ranges from about 0.001 % to about 2 %, weight by weight of the composition.

According to present invention, suspending agent may include, but not limited to acacia, agar, alginic acid, bentonite, carbomer, carboxymethylcellulose, carboxymethylcellulose sodium, carrageenan, cellulose, microcrystalline cellulose, ceratonia, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, kaolin, magnesium aluminum silicate, medium-chain triglycerides, methylcellulose, polyoxyethylene, potassium alginate, povidone, propylene glycol alginate, sodium alginate, tragacanth, xanthan gum and the like, or mixtures thereof. The amount of suspending agent that can be used in the present invention ranges from about 0.1 % to about 5 %, weight by weight of the composition.

According to present invention, viscosity enhancer may include, but not limited to acacia, carboxymethylcellulose, carrageenan, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, maltodextrin, methylcellulose, sodium alginate, tragacanth, xanthan gum and the like, or mixtures thereof. The amount of viscosity enhancer that can be used in the present invention ranges from about 0.02 % to about 5 %, weight by weight of the composition.

According to present invention, sweeteners may include, but not limited to sugar alcohols such as mannitol, sorbitol or mixtures thereof, natural sweeteners such as sugars e.g. fructose, glucose, sucrose, and artificial sweeteners such as sodium saccharine, sodium cyclamate, aspartame and the like, or mixtures thereof. The amount of sweeteners that can be used in the present invention ranges from about 0.01 % to about 5 %, weight by weight of the composition.

According to present invention, antioxidant may include, but not limited to alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene and the like, or mixtures thereof. The amount of antioxidant that can be used in the present invention ranges from about 0.05 % to about 2 %, weight by weight of the composition.

According to present invention, flavoring agent may include, but not limited to N&A gum fruit flavor, artificial cream flavor, banana flavor, artificial strawberry flavor and the like, or mixtures thereof. The amount of flavoring agent that can be used in the present invention ranges from about 0.05 % to about 5 %, weight by weight of the composition.

According to present invention, glidant may include, but not limited to calcium silicate, magnesium silicate, colloidal silicon dioxide, talc and the like, or mixtures thereof. The amount of glidant that can be used in the present invention ranges from about 0.01 % to about 5 %, weight by weight of the composition.

In another embodiment, the suspension dosage form can be prepared before administration to the patient by reconstitution of Capecitabine composition according to the present invention with suitable vehicle.

In another embodiment, the present invention provides Capecitabine suspension, wherein the suspension is immediate release suspension.

According to present invention, vehicle may include, but not limited to water, purified water and the like, or mixtures thereof. The amount of vehicle can be decided based on final strength requirement of Capecitabine in the suspension.

In another embodiment, the present invention provides Suspension dosage form as finished product which does not require any further reconstitution with vehicle (i.e. no processing required before administration).

In another embodiment, the present invention provides stable Capecitabine suspension, wherein the total amount of impurities is not more than 1.5 % after subjecting the said suspension at 40 °C temperature and 75% relative humidity for a time period of 1 month.

In another embodiment, the present invention provides stable Capecitabine suspension, wherein individual unspecified impurity is not more than 0.1 % after subjecting the said suspension at 40 °C temperature and 75% relative humidity for a time period of 1 month.

In another embodiment, the present invention provides stable Capecitabine suspension, wherein total amount of impurities is not more than 1.5 % and individual unspecified impurity is not more than 0.1 % after subjecting the said suspension at 40 °C temperature and 75% relative humidity for a time period of 1 month.

According to present invention, the suspension can be supplied as dry suspension which is further constituted with vehicle i.e. water and then given to the patient for administration as per required dose or alternatively the suspension can be supplied as finished product which does not require further reconstitution with vehicle.

According to present invention, the suspension dosage form can be prepared by the process known to the person skilled in the art.

According to present invention, process of the preparation of the suspension of the invention involves granulation step.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto falling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.

EXAMPLE 1: Capecitabine for oral suspension 200 mg/ml

Process for the preparation of Capecitabine suspension:

1. Co-sift Capecitabine, diluent, through suitable sieve.

2. Prepare binder solution in purified water.

3. Granulate the sifted material of step 1 with binder solution of step 2 in suitable granulator.

4. Dry the granules obtained in step 3.

5. Sift the dried granules through sifter.

6. Shift viscosity enhancer, sweetener, flavoring agent and glidant through suitable sieve.

7. Blend the materials of step 5 and 6.

8. Fill predetermined amount of lubricated blend into HDPE bottle.

Method of reconstitution (before administration to patient):

9. Take predetermined amount of vehicle (water).

10. Add approximately half the total amount of water for reconstitution to the bottle filled in step 8 and shake well.

11. Add the remaining quantity of water and shake well.

For preparation of Capecitabine suspension as finished product (wherein no reconstitution is required before administration) step 9 to 11 are done at manufacturing site with modification as per need of bulk production. EXAMPLE 2: Composition of Capecitabine suspension 200 mg/ml

Process for preparation:

1. Capecitabine and sorbitol were co-sifted through suitable sieve and were transferred into fluidized bed processor.

2. Binder solution was prepared by adding low viscosity grade hypromellose and methylparaben sodium in purified water.

3. Co- sifted material of step 1 was granulated with binder solution of step 2 in fluidized bed processor.

4. Granules obtained in step 3 were dried in fluidized bed processor to get loss on drying (LOD) not more than 2 % w/w.

5. Dried granules obtained in step 4 were sifted.

6. Microcrystalline cellulose and carboxymethylcellulose sodium, xanthan gum, aspartame, fruit flavor and colloidal anhydrous silica were passed through sieve.

7. Sifted granules obtained in step 5 and materials obtained in step 6 were blended for specified period of time.

8. Lubricated blend was filled into HDPE bottle. Method of reconstitution:

1. 135 ml of potable water was taken in glass. 2. Approximately half the total amount of water for reconstitution was added to bottle and shaken well.

3. Remaining quantity of water was added and shaken well to obtain Capecitabine suspension 200 mg/ml.

EXAMPLE 3: Composition of Capecitabine suspension 200 mg/ml

Process for preparation:

1. Capecitabine and sorbitol were co-sifted through suitable sieve and were transferred into fluidized bed processor.

2. Binder solution was prepared by adding low viscosity grade hypromellose and methylparaben sodium in purified water.

3. Co-sifted material of step 1 was granulated with binder solution of step 2 in fluidized bed processor.

4. Granules obtained in step 3 were dried in fluidized bed processor to get loss on drying (LOD) not more than 2 % w/w.

5. Dried granules obtained in step 4 were sifted.

6. Xanthan gum, aspartame, fruit flavor, colloidal anhydrous silica and butylated hydroxytoluene were passed through sieve.

7. Sifted granules obtained in step 5 and materials obtained in step 6 were blended for specified period of time. 8. Lubricated blend was filled into HDPE bottle.

Method of reconstitution:

1. 135 ml of potable water was taken in glass.

2. Approximately half the total amount of water for reconstitution was added to bottle and shaken well.

3. Remaining quantity of water was added and shaken well to obtain Capecitabine suspension 200 mg/ml.

EXAMPLE 4: Composition of Capecitabine suspension 200 mg/ml

Process for preparation:

1. Capecitabine and sorbitol were co-sifted through suitable sieve and were transferred into fluidized bed processor.

2. Binder solution was prepared by adding low viscosity grade hypromellose in purified water.

3. Co-sifted material of step 1 was granulated with binder solution of step 2 in fluidized bed processor.

4. Granules obtained in step 3 were dried in fluidized bed processor to get loss on drying (LOD) not more than 2 % w/w.

5. Dried granules obtained in step 4 were sifted.

6. Xanthan gum, aspartame, fruit flavor and colloidal anhydrous silica were passed through sieve. 7. Sifted granules obtained in step 5 and materials obtained in step 6 were blended for specified period of time.

8. Lubricated blend was filled into HDPE bottle.

Method of reconstitution: 1. 135 ml of potable water was taken in glass.

2. Approximately half the total amount of water for reconstitution was added to bottle and shaken well.

3. Remaining quantity of water was added and shaken well to obtain Capecitabine suspension 200 mg/ml.

Analysis results: The Capecitabine suspension obtained in example 2-4 were analyzed initially for various parameters and the obtained results are tabulated below. The analyses for below parameters were performed as per method (where applicable) given in pharmacopoeia (i.e. USP/EP/IP).

LOD: Loss on drying; BQL: Below quantifiable limit; ND: Not detected EXAMPLE 5: Capecitabine for oral suspension 200 mg/ml

Process for preparation:

Process for preparation of Capecitabine suspension is similar to the process of example 3.

Method of reconstitution:

Method of reconstitution is similar to the method of example 3.

EXAMPLE 6: Composition of Capecitabine suspension 200 mg/ml

Process for preparation: Process for preparation of Capecitabine suspension is similar to the process of example 3. Method of reconstitution: Method of reconstitution is similar to the method of example 3.

Stability study of Example 6:

The stability study was carried out for Capecitabine suspension obtained in Example 6 at 40 °C temperature and 75% relative humidity for time periods of 1 month. The obtained stability study results are shown in below table. NMT: Not more than; ND: Not detected

From the above stability data, it can be concluded that Capecitabine suspension of the present invention is found stable. Thus, the new dosage form of Capecitabine in form of suspension can be prepared according to the present invention.