HK1135905B - Capecitabine pediatric tablets - Google Patents

Description

Capecitabine pediatric tablets

The present invention relates to a new rapidly disintegrating pharmaceutical dosage form having as active ingredient 5' -deoxy-5-fluoro-N- [ (pentyloxy) -carbonyl ] -cytidine (capecitabine). The new dosage form is suitable for any patient, and is particularly suitable for patients who have difficulty swallowing solid oral dosage forms, including pediatric and geriatric populations.

Capecitabine is a fluoropyrimidine carbamate with antitumor activity. It is an orally administered systemic prodrug of: 5 '-deoxy-5-fluorouridine (5' -DFUR), an anti-tumor agent. Capecitabine was obtained by the Roche laboratories as XelodaTrade names are marketed in the united states. The chemical name of capecitabine is 5' -deoxy-5-fluoro-N- [ (pentyloxy) -carbonyl]-cytidine and having the following structural formula:

capecitabine is covered in U.S. patents (including U.S. patent numbers 4,966,891 and 5,472,949) and USSN 60/667,509 filed on 1/4 in 2005. An improved method for producing capecitabine is taught in the following: U.S. patent nos. 5,453,497 and 5,476,932, and application USSN 60/532,266 filed on 12/22/2003. Any or all of the foregoing patents and applications are incorporated herein by reference as needed.

Capecitabine is currently approved for the treatment of colon and breast cancer in the united states. The currently approved/recommended dose of capecitabine in those indications is 1250mg/m²Orally twice daily (corresponding to a total daily dose of 2500 mg/m)²) Up to 14 days followed by a 7 day rest period, provided as long as needed as a 3-week cycle. See approved drug notes. Typically the average treatment duration is 3 to 6 3-week cycles. Currently approved unit dosage forms are light peach-colored film-coated tablets containing 150mg of capecitabine and peach-colored film-coated tablets containing 500mg of capecitabine.

Capecitabine tablets (Xeloda) currently on the marketRoche) typically takes about 7-12 minutes to disintegrate in water (USP disintegration test), depending on the size of the tablet. The conventional excipients currently used in these tablets, such as lactose and croscarmellose sodium, do not, by themselves, overcome the cohesiveness of capecitabine in the tablet. The end result is that the marketed tablets slowly disintegrate by surface erosion and thus are not very easy to rapidly disperse or disintegrate in water prior to oral administration to a swallow-impaired patient.

Thus, the capecitabine tablets currently on the market may be difficult to swallow by pediatric and geriatric populations as well as patients with swallowing disorders and blockages.

Thus, rapidly disintegrating tablets, such as those having a rapidly disintegrating matrix, and more preferably rapidly disintegrating flavored tablets, are desirable to compensate for the aforementioned difficulties of slow tablet erosion in water prior to oral administration.

The present invention provides a rapidly disintegrating pharmaceutical dosage form for oral administration of 5' -deoxy-5-fluoro-N- [ (pentyloxy) -carbonyl ] -cytidine (capecitabine), which is suitable for administration to patients having difficulty swallowing solid oral dosage forms.

The present invention provides a rapidly disintegrating film-coated capecitabine pharmaceutical dosage form suitable for oral administration. Preferably, the tablet disintegrates in water at 37 ℃ in less than about 2 minutes (USP disintegration test), more preferably, in less than about 1 minute (USP disintegration test), and has a hardness of about 8-13scu (strong Cobb-Units, scu). The tablet disintegrates in less than or equal to about 3 minutes upon manual agitation in water at room temperature. In a preferred embodiment, the composition comprises from about 10% to about 50%, more preferably from about 25% to about 35%, and most preferably 30% capecitabine, and from about 10% to about 50%, more preferably from about 20% to about 40%, and most preferably 30% of at least one disintegrant per unit dosage form, based on the total weight of the final unit dosage form.

Yet another preferred embodiment of the present invention relates to a lactose-free tablet composition for use in lactose intolerant individuals, where the lactose is replaced by additional mannitol.

In addition, a directly compressible polyhydric alcohol, such as mannitol, and microcrystalline cellulose are necessary to maintain the strength of the tablet without compromising the disintegration of the tablet. The composition of mannitol constitutes about 2% to about 25%, more preferably about 4% to about 20%, and most preferably 6% to 16%, and microcrystalline cellulose constitutes about 4% to about 30%, more preferably about 8% to about 25%, and most preferably 12% to about 22%, per unit dosage form.

Preferably, the composition contains from about 50mg to about 1500mg, preferably from 100mg to about 750mg, and most preferably from about 125mg to about 500mg of capecitabine. Most preferably, the composition contains 125mg, 150mg, 175mg, 250mg, 350mg or 500mg capecitabine per unit dosage form.

Disintegrants used include, but are not limited to, crospovidone (having a particle size in the 90% range of less than 15 microns to a particle size in the 90% range of less than 400 microns), croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, or any commercially available disintegrant, such as Pharmaburst C^TMIn the United states of AmericaThe mannitol/sorbitol combination disclosed and claimed in patent No. 7,118,765, which is incorporated herein by reference (available from SPI Pharma, neosain, trawa) or any combination thereof.

The pharmaceutical compositions of the present invention may comprise additional therapeutically inert inorganic or organic carriers and excipients. For example, such compositions may include flavorants such as vanillin, bitterness masking blends (Bittermasking Blend), strawberry flavors, or any other flavorant or combination of flavorants typically added to the pharmaceutical preparation to render them palatable for oral administration.

The compositions may also include sweetening agents such as saccharin sodium, aspartame, sucralose, acesulfame-K, and sucrose.

The composition may also include a binder such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, pregelatinized starch, or any other cold swelling corn starch.

The composition may also include fillers such as anhydrous lactose or microcrystalline cellulose.

The compositions may also include colorants, coatings, antioxidants, stabilizers, lubricants (e.g., magnesium stearate), granulation aids, flow aids, and such other agents and materials known to those skilled in the art of making pharmaceutical dosage forms for oral consumption.

In one embodiment, the unit dosage form is a tablet, preferably a film coated tablet. The coating may contain excipients such as film formers (polymers), plasticizers, opacifiers, pigments, colorants, and the like. The selection of such materials and the amounts to be used are considered to be within the scope of the art. The film coating composition may be selected from, for example, hypromellose, polyvinyl alcohol, titanium dioxide, talc, iron oxide pigments with or without plasticizers, such as polyethylene glycol, polysorbate 80, or triacetin.

The following examples illustrate embodiments of unit dosage forms according to the present invention. In each case, the unit dosage form is a film-coated tablet.

Examples 1 to 6

Formulation composition

Examples	#1	#2	#3	#4	#5	#6
							Composition (I)	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet
Capecitabine	125.00	150.00	175.00	250.00	350.00	500.00
							Anhydrous lactose	35.72	42.90	50.06	71.49	100.12	142.88
Hydroxypropyl methylcellulose	3.57	4.28	5.00	7.14	10.00	14.28
							Crosslinked polyvinylpyrrolidone	37.50	45.00	52.50	75.00	105.00	150.00
Pharmaburst C	89.30	107.16	125.00	178.60	250.00	357.20
							Mannitol	23.21	27.85	32.50	46.43	65.00	92.84
Microcrystalline cellulose	46.82	56.18	65.54	93.63	131.08	187.28
							Magnesium stearate	8.22	9.86	11.50	16.43	23.00	32.88
Aspartame	15.54	18.64	21.75	31.07	43.50	62.16
							Saccharin sodium salt	3.22	3.86	4.50	6.43	9.00	12.88
Vanillin	7.86	9.43	11.00	15.71	22.00	31.44
							Bitterness masking blends	1.47	1.76	2.06	2.94	4.12	5.88
Strawberry flavor #915.010	2.97	3.56	4.15	5.93	8.30	11.88
							Pure water1	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Nuclear weight	400.40mg	480.48mg	560.56mg	800.80mg	1121.12mg	1601.60mg
							Opadry (Opadry) pink film coating	8.00	9.61	11.00	16.00	22.00	32.03
Pure water1	44.53	53.44	62.34	89.05	124.67	178.10

Total tablet weight

408.40mg

490.09mg

571.56mg

816.80mg

1143.12mg

1633.63mg

¹Removed during processing

The method comprises the following steps:

1. mixing capecitabine with anhydrous lactose and a portion of cross-linked polyvinylpyrrolidone

2. Dissolving hypromellose in pure water

3. Granulating the blend from step 1 with the granulating solution from step 2

4. Wet milling of the granules from step 3

5. Drying and grinding the granules from step 4

6. Blending the granulate from step 5 with Pharmaburst C, the remainder of crosslinked polyvinylpyrrolidone, mannitol, microcrystalline cellulose, aspartame, saccharin sodium, vanillin, bittermasking blend, and strawberry flavor

7. Sieving magnesium stearate, adding it to the blend from step 6 and mixing

8. Compression nucleation of the tabletted blend from step 7

9. Film coating suspension prepared by dispersing film coating mixture in pure water

10 film coating the cores with the film coating suspension from step 9

Examples 7 to 12

The following composition represents a preferred formulation on a mg/tablet weight basis, wherein lactose is replaced with mannitol.

Formulation composition

Examples	#7	#8	#9	#10	#11	#12
							Composition (I)	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet
Capecitabine	125.00	150.00	175.00	250.00	350.00	500.00
							Mannitol	58.93	70.75	82.56	117.92	165.12	235.72
Hydroxypropyl methylcellulose	3.57	4.28	5.00	7.14	10.00	14.28
							Crosslinked polyvinylpyrrolidone	37.50	45.00	52.50	75.00	105.00	150.00
Pharmaburst C	89.30	107.16	125.00	178.60	250.00	357.20
							Microcrystalline cellulose	46.82	56.18	65.54	93.63	131.08	187.28
Magnesium stearate	8.22	9.86	11.50	16.43	23.00	32.88
							Aspartame	15.54	18.64	21.75	31.07	43.50	62.16
Saccharin sodium salt	3.22	3.86	4.50	6.43	9.00	12.88

Vanillin	7.86	9.43	11.00	15.71	22.00	31.44
							Bitterness masking blends	1.47	1.76	2.06	2.94	4.12	5.88
Strawberry flavor #915.010	2.97	3.56	4.15	5.93	8.30	11.88
							Pure water1	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
Nuclear weight	400.40mg	480.48mg	560.56mg	800.80mg	1121.12mg	1601.60mg
							Opadry pink film coating	8.00	9.61	11.00	16.00	22.00	32.03
Pure water1	44.53	53.44	62.34	89.05	124.67	178.10
							Total tablet weight	408.40mg	490.09mg	571.56mg	816.80mg	1143.12mg	1633.63mg

¹Removed during processing

The method comprises the following steps: the procedure was analogous to that of examples 1-6, except that mannitol was used instead of anhydrous lactose in step 1.

Examples 13 to 18

The following composition represents the preferred formulation based on mg/tablet weight basis with pharmaburst c and lactose replaced.

Formulation composition

Examples	#13	#14	#15	#16	#17	#18
							Composition (I)	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet	mg/tablet
Capecitabine	125.00	150.00	175.00	250.00	350.00	500.00
							Mannitol	58.93	70.75	82.50	117.86	165.00	235.72
Hydroxypropyl methylcellulose	3.57	4.28	5.00	7.14	10.00	14.28
							Crosslinked polyvinylpyrrolidone	62.50	75.01	87.50	125.00	175.00	250.00
Microcrystalline cellulose	82.26	98.71	115.16	164.52	230.32	329.04

Magnesium stearate	7.41	8.90	10.37	14.82	20.74	29.64
							Aspartame	15.54	18.64	21.76	31.08	43.52	62.16
Saccharin sodium salt	3.22	3.86	4.50	6.44	9.00	12.88
							Vanillin	7.86	9.43	11.00	15.72	22.00	31.44
Bitterness masking blends	1.47	1.76	2.06	2.94	4.12	5.88
							Strawberry flavor #915.010	2.97	3.56	4.15	5.94	8.30	11.88
Pure water1	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of	Proper amount of
							Nuclear weight	370.73mg	444.90mg	519.00mg	741.46mg	1038.00mg	1482.92mg
Opadry pink film coating	7.41	8.90	10.38	14.83	20.76	29.66
							Pure water1	41.99	50.43	58.82	84.04	117.64	168.07
Total tablet weight	378.14mg	453.80mg	529.38mg	756.29mg	1058.76mg	1512.58mg

¹Removed during processing

The method comprises the following steps: the procedure was analogous to that of examples 1-6, except that mannitol was used in place of anhydrous lactose in step 1 and Pharmaburst was removed in step 6.

Disintegration characteristics of dosage forms

The following is a comparison of the disintegration times of the rapidly disintegrating tablets of the invention and the tablets on the market at low and high tablet strengths.

Disintegration times were obtained using a USP disintegration apparatus without discs (discs) and water at 37 ℃. Experimental test methods and resulting observed disintegration times were performed according to the USP disintegration test method (USP 29, General Chapters), Physical Tests (Physical Tests), <709>, which is incorporated herein by reference.

For the purposes of this test, disintegration does not mean complete dissolution of the unit or even complete dissolution of its active ingredient. Complete disintegration is defined as the state in which any residue of the unit remaining on the sieve of the test device, except for insoluble pieces of coating or capsule shell, is a soft substance with no distinct film core.

USP disintegrating device

The device consists of: a basket assembly, 1000-mL, low-profile beaker, 138 to 160mm high and 97 to 115mm internal diameter, for immersion fluid, a thermostatic device for heating said fluid between 35 and 39, and means for raising or lowering said basket in immersion fluid at a rate of constant frequency of 29 to 32 cycles/minute, over a distance of not less than 53mm and not more than 57 mm. The volume of fluid in the vessel is such that at the highest point of the upward stroke the wire screen is maintained at least 15mm below the surface of the fluid and in the downward stroke it descends to no less than 25mm from the bottom of the vessel. The top of the basket assembly should never be submerged. The time required for the upstroke is equal to the time required for the downstroke and the direction change of the stroke is a smooth transition rather than an abrupt reversal of motion. The basket assembly moves vertically along its axis. There is no significant horizontal movement or off-vertical axis movement.

Basket assembly-the basket assembly consists of six open transparent tubes, each tube being 77.5 ± 2.5mm long and having an internal diameter of 20.7 to 23mm and a wall thickness of 1.0 to 2.8 mm; the tube was held in a vertical position by two plates, each 88 to 92mm in diameter and 5 to 8.5mm thick, with six holes, each 22 to 26mm in diameter, equidistant from the center of the plate, and equally spaced from each other. Attached to the lower surface of the lower plate is a woven stainless steel wire cloth with a flat square weave with 1.8-to 2.2-mm holes and wire diameters of 0.57-0.66 mm. The components of the device are assembled and rigidly fixed by means of three bolts passing through the two plates. Suitable means are provided for suspending the basket assembly using a point on its axis to raise and lower the device.

The design of the basket assembly may vary somewhat provided that the size of the glass tube and screen size are maintained.

Disc-no disc is used.

Step (ii) of

Uncoated or coated tablets-1 dosage unit was placed in each of the six tubes of the basket. The device was operated using water or a designated medium as the immersion fluid, maintained at 37 ± 2. At the end of the time period specified in monograph (monograph), the basket was lifted from the fluid and the tablets were observed to see if all had completely disintegrated. If 1 or 2 tablets did not completely disintegrate, the test was repeated on 12 additional tablets. It is desirable if not less than 16 of the total 18 tablets tested are disintegrating.

Disintegration time in water at 37 ℃ (USP disintegration apparatus)

As demonstrated in the above table, the disintegration time of the capecitabine rapidly disintegrating tablets of the invention in water is about 8 to 13 times shorter than the currently marketed tablets, at their low and high dose strengths, respectively.

While the present invention has been illustrated by reference to specific and preferred embodiments, it will be appreciated by those skilled in the art that variations and modifications may be effected by routine experimentation and practice of the invention. Accordingly, it is not intended that the invention be limited to the above description, but rather that the invention be defined by the appended claims and their equivalents.

Claims (38)

1. A film coated pharmaceutical composition comprising capecitabine in an amount of 10% to 50% based on the total weight of the core composition and at least one disintegrant in an amount of 10% to 50% per unit dosage form, wherein the disintegrant is selected from the group consisting of: crosslinked polyvinylpyrrolidone, Pharmaburst C or a combination thereof, and a directly compressible polyhydroxyl alcohol and 4% to 30% microcrystalline cellulose per unit dosage form, which disintegrates in water at 37 ℃ in less than 2 minutes in a USP disintegration apparatus, and which has a hardness of 8-13 scu.

2. The composition of claim 1 comprising 50mg to 1500mg of capecitabine.

3. The composition of claim 2 comprising 100mg to 750mg of capecitabine.

4. The composition of claim 2, comprising 125mg, 175mg, 250mg, 350mg, or 500mg capecitabine.

5. The pharmaceutical composition of claim 1, wherein the cross-linked polyvinylpyrrolidone has a particle size in the range of 90% less than 15 microns to a particle size in the range of 90% less than 400 microns.

6. The composition of claim 5, wherein the disintegrant is 20 to 40% per unit dosage form.

7. The composition of claim 1, wherein the disintegrant is 30% per unit dosage form.

8. The composition of claim 1, wherein the alcohol is mannitol and comprises 2% to 25% per unit dosage form.

9. The composition of claim 8, wherein the mannitol comprises 4% to 20% per unit dosage form.

10. The composition of claim 9, wherein the mannitol comprises 6% to 16% per unit dosage form.

11. The composition of claim 1 comprising 8% to 25% microcrystalline cellulose per unit dosage form.

12. The composition of claim 11 comprising 12% to 22% microcrystalline cellulose per unit dosage form.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition disintegrates in less than 1 minute.

14. The composition of claim 1, comprising a binder selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, pregelatinized starch, and cold-swelling corn starch.

15. The composition of claim 13, wherein capecitabine comprises 50mg to 1500mg per unit dosage form.

16. The composition of claim 15, wherein capecitabine comprises 100mg to 750mg per unit dosage form.

17. The composition of claim 14, wherein capecitabine comprises 125mg, 150mg, 175mg, 250mg, 350mg or 500mg per unit dosage form.

18. A pharmaceutical composition that disintegrates in water at 37 ℃ in less than 1 minute in a USP disintegration apparatus, the pharmaceutical composition comprising 10% to 50% capecitabine, based upon the total weight of the core composition, 10% to 50% of at least one disintegrant, binder, at least one filler, lubricant, at least one sweetener, and at least one flavorant per unit dosage form, wherein the disintegrant is selected from the group consisting of: crosslinked polyvinylpyrrolidone, Pharmaburst C or a combination thereof, said filler being selected from the group consisting of directly compressible polyhydroxyl alcohols and microcrystalline cellulose.

19. Pharmaceutical composition according to claim 18, characterized in that the pharmaceutical composition is film-coated.

20. Pharmaceutical composition according to claim 1 or 18, characterized in that it is free of lactose.

21. The pharmaceutical composition according to claim 19, said composition comprising 125mg capecitabine, 35.72mg lactose anhydrous, 3.57mg hypromellose, 37.50mg crospovidone, 89.30mg Pharmaburst C, 23.21mg mannitol, 46.82mg microcrystalline cellulose, 8.22mg magnesium stearate, 15.54mg aspartame, 3.22mg saccharin sodium, 7.86mg vanillin, 1.47mg bittermasking blend and 2.97mg strawberry flavor.

22. The pharmaceutical composition according to claim 19, comprising 150mg of capecitabine, 42.90mg of lactose anhydrous, 4.28mg of hypromellose, 45.00mg of crospovidone, 107.16mg of Pharmaburst C, 27.85mg of mannitol, 56.18mg of microcrystalline cellulose, 9.86mg of magnesium stearate, 18.64mg of aspartame, 3.86mg of saccharin sodium, 9.43mg of vanillin, 1.76mg of bittermasking blend and 3.56mg of strawberry flavor.

23. The pharmaceutical composition according to claim 19, comprising 175mg of capecitabine, 50.06mg of lactose anhydrous, 5.00mg of hypromellose, 52.50mg of crospovidone, 125.00mg of Pharmaburst C, 32.50mg of mannitol, 65.54mg of microcrystalline cellulose, 11.50mg of magnesium stearate, 21.75mg of aspartame, 4.50mg of saccharin sodium, 11.00mg of vanillin, 2.06mg of bittermasking blend and 4.15mg of strawberry flavor.

24. The pharmaceutical composition according to claim 19, comprising 250mg of capecitabine, 71.49mg of lactose anhydrous, 7.14mg of hypromellose, 75.00mg of crospovidone, 178.60mg of Pharmaburst C, 46.43mg of mannitol, 93.63mg of microcrystalline cellulose, 16.43mg of magnesium stearate, 31.07mg of aspartame, 6.43mg of saccharin sodium, 15.71mg of vanillin, 2.94mg of bittermasking blend and 5.93mg of strawberry flavor.

25. The pharmaceutical composition according to claim 19, comprising 350mg of capecitabine, 100.12mg of lactose anhydrous, 10.00mg of hypromellose, 105.00mg of crospovidone, 250.00mg of Pharmaburst C, 65.00mg of mannitol, 131.08mg of microcrystalline cellulose, 23.00mg of magnesium stearate, 43.50mg of aspartame, 9.00mg of saccharin sodium, 22.00mg of vanillin, 4.12mg of bittermasking blend and 8.30mg of strawberry flavor.

26. The pharmaceutical composition according to claim 19, comprising 500mg of capecitabine, 142.88mg of lactose anhydrous, 14.28mg of hypromellose, 150.00mg of crospovidone, 357.20mg of Pharmaburst C, 92.84mg of mannitol, 187.28mg of microcrystalline cellulose, 32.88mg of magnesium stearate, 62.16mg of aspartame, 12.88mg of saccharin sodium, 31.44mg of vanillin, 5.88mg of bittermasking blend and 11.88mg of strawberry flavor.

27. The pharmaceutical composition according to claim 1, comprising 125.00mg capecitabine, 3.57mg hypromellose, 37.50mg crospovidone, 89.30mg pharmaburst C, 58.93mg mannitol, 46.82mg microcrystalline cellulose, 8.22mg magnesium stearate, 15.54mg aspartame, 3.22mg saccharin sodium, 7.86mg vanillin, 1.47mg bittermasking blend and 2.97mg strawberry flavor.

28. The pharmaceutical composition according to claim 1, comprising 150.00mg of capecitabine, 4.28mg of hypromellose, 45.00mg of crospovidone, 107.16mg of Pharmaburst C, 70.75mg of mannitol, 56.18mg of microcrystalline cellulose, 9.86mg of magnesium stearate, 18.64mg of aspartame, 3.86mg of saccharin sodium, 9.43mg of vanillin, 1.76mg of bittermasking blend and 3.56mg of strawberry flavor.

29. The pharmaceutical composition according to claim 1, comprising 175.00mg of capecitabine, 5.00mg of hypromellose, 52.50mg of crospovidone, 125.00mg of Pharmaburst C, 82.56mg of mannitol, 65.54mg of microcrystalline cellulose, 11.50mg of magnesium stearate, 21.75mg of aspartame, 4.50mg of saccharin sodium, 11.00mg of vanillin, 2.06mg of bittermasking blend and 4.15mg of strawberry flavor.

30. The pharmaceutical composition according to claim 1, comprising 250.00mg of capecitabine, 7.14mg of hypromellose, 75.00mg of crospovidone, 178.60mg of Pharmaburst C, 117.92mg of mannitol, 93.63mg of microcrystalline cellulose, 16.43mg of magnesium stearate, 31.07mg of aspartame, 6.43mg of saccharin sodium, 15.71mg of vanillin, 2.94mg of bittermasking blend and 5.93mg of strawberry flavor.

31. The pharmaceutical composition according to claim 1, comprising 350.00mg of capecitabine, 10.00mg of hypromellose, 105.00mg of crospovidone, 250.00mg of Pharmaburst C, 165.12mg of mannitol, 131.08mg of microcrystalline cellulose, 23.00mg of magnesium stearate, 43.50mg of aspartame, 9.00mg of saccharin sodium, 22.00mg of vanillin, 4.12mg of bittermasking blend and 8.30mg of strawberry flavor.

32. The pharmaceutical composition according to claim 1, comprising 500.00mg of capecitabine, 14.28mg of hypromellose, 150.00mg of crospovidone, 357.20mg of Pharmaburst C, 235.72mg of mannitol, 187.28mg of microcrystalline cellulose, 32.88mg of magnesium stearate, 62.16mg of aspartame, 12.88mg of saccharin sodium, 31.44mg of vanillin, 5.88mg of bittermasking blend and 11.88mg of strawberry flavor.

33. The pharmaceutical composition according to claim 1, comprising 125.00mg of capecitabine, 3.57mg of hypromellose, 62.50mg of crospovidone, 58.93mg of mannitol, 82.26mg of microcrystalline cellulose, 7.41mg of magnesium stearate, 15.54mg of aspartame, 3.22mg of saccharin sodium, 7.86mg of vanillin, 1.47mg of bittermasking blend and 2.97mg of strawberry flavor.

34. The pharmaceutical composition according to claim 1, comprising 150.00mg of capecitabine, 4.28mg of hypromellose, 75.01mg of crospovidone, 70.75mg of mannitol, 98.71mg of microcrystalline cellulose, 8.90mg of magnesium stearate, 18.64mg of aspartame, 3.86mg of saccharin sodium, 9.43mg of vanillin, 1.76mg of bittermasking blend and 3.56mg of strawberry flavor.

35. The pharmaceutical composition according to claim 1, comprising 175.00mg of capecitabine, 5.00mg of hypromellose, 87.50mg of crospovidone, 82.50mg of mannitol, 115.16mg of microcrystalline cellulose, 10.37mg of magnesium stearate, 21.76mg of aspartame, 4.50mg of saccharin sodium, 11.00mg of vanillin, 2.06mg of bittermasking blend and 4.15mg of strawberry flavor.

36. The pharmaceutical composition according to claim 1, comprising 250.00mg of capecitabine, 7.14mg of hypromellose, 125.00mg of crospovidone, 117.86mg of mannitol, 164.52mg of microcrystalline cellulose, 14.82mg of magnesium stearate, 31.08mg of aspartame, 6.44mg of saccharin sodium, 15.72mg of vanillin, 2.94mg of bittermasking blend and 5.94mg of strawberry flavor.

37. The pharmaceutical composition according to claim 1, comprising 350.00mg of capecitabine, 10.00mg of hypromellose, 175.00mg of crospovidone, 165.00mg of mannitol, 230.32mg of microcrystalline cellulose, 20.74mg of magnesium stearate, 43.52mg of aspartame, 9.00mg of saccharin sodium, 22.00mg of vanillin, 4.12mg of bittermasking blend and 8.30mg of strawberry flavor.

38. The pharmaceutical composition according to claim 1, comprising 500.00mg of capecitabine, 14.28mg of hypromellose, 250.00mg of crospovidone, 235.72mg of mannitol, 329.04mg of microcrystalline cellulose, 29.64mg of magnesium stearate, 62.16mg of aspartame, 12.88mg of saccharin sodium, 31.44mg of vanillin, 5.88mg of bittermasking blend and 11.88mg of strawberry flavor.