Antineoplastic product, use and formulation thereof

An antineoplastic product is comprised of at least three dosages forms, each of which has a different release profile, with the C max for the antineoplastic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a C max at different times.

The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight. Immediate Release Component Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. 1 Example 1: Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5 Example 2: Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10 Example 3: Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 4: Fluorouracil 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 5: Fluorouracil 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6: Dexamethasone 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 7: Dexamethasone 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 8: Dexamethasone 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 9: Dexamethasone 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 10: Valrubicin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11: Valrubicin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12: Valrubicin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5 Example 13: Cirpofloxacin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 14: Tretinoin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 15: Tretinoin 75% (W/W) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5 Non pH Sensitive Delayed Release Component Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. 2 Ingredient Conc. (% W/W) Example 16: Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5 Example 17: Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example 18: Fluorouracil 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 19 Fluorouracil 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 20: Fluorouracil 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Example 21: Dexamethasone 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 22: Dexamethasone 75% (W/W) Polyox 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 23: Dexamethasone 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 24: Dexamethasone 80% (W/W) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5 Example 25: Valrubicin 65% (W/W) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL 30D 5 Example 26: Valrubicin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 27: Valrubicin 80% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5 Eudgragit RL 30D 5 Example 28: Valrubicin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Example 29: Tretinoin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 30: Tretinoin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5 Enteric Release Component Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. 3 Ingredient Conc. (% W/W) Example 31: Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 32: Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 33: Fluorouracil 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5 Example 34: Fluorouracil 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5 Example 35: Fluorouracil 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 36: Dexamethasone 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 37: Dexamethasone 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5 Example 38: Dexamethasone 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 15 Example 39: Dexamethasone 40% (W/W) Lactose 50 Eudgragit L 30D 10 Example 40: Valrubicin 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 41: Valrubicin 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 42: Valrubicin 80% (W/W) Lactose 10 Eudragit L 30D 10 Example 43: Valrubicin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 44: Tretinoin 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L 30D 10 Example 45: Tretinoin 70% (W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10 Sustained Release Component Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. 4 Ingredient Conc. (% W/W) Example 46: Fluorouracil 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 47: Fluorouracil 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 48: Fluorouracil 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 49: Dexamethasone 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 50: Dexamethasone 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5 Example 51: Dexamethasone 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5 Example 52: Valrubicin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 53: Valrubicin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 54: Tretinoin 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 55: Tretinoin 75% (W/W) Lactose 15 Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5 Example 56: Dexamethasone 40% (W/W) Eudragit S100 50 Triethyl Citrate 10 Example 57: Dexamethasone 50% (W/W) Sureteric 50 Example 58: Dexamethasone 50% (W/W) Eudragit S100 45 Triethyl Citrate 5 Three Pulses 
 EXAMPLE 59 1. Antineoplastic Agent Matrix Pellet Formulation and Preparation Procedure (Immediate Release) A. Pellet Formulation The composition of the antineoplastic agent matrix pellets provided in Table 1. 5 TABLE 1 Composition of Antineoplastic Pellets Component Percentage (%) Antineoplastic agent 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing. B. Preparation Procedure for Antineoplastic Agent Matrix Pellets 1.2.1 Blend antineoplastic agent and Avicel® PH 101 using a Robot Coupe high shear granulator. 1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm. 1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. 1.2.5 Dry the spheronized pellets at 50° C. overnight. 1.2.6 Pellets between 16 and 30 Mesh were collected for further processing. 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion A. Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the antineoplastic agent matrix pellets is provided below in Table 2. 6 TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9 B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 1.3.1 Suspend triethyl citrate and talc in deionized water. 1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. 1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the antineoplastic agent matrix pellets. 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion A. Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the antineoplastic agent matrix pellets is provided below in Table 3. 7 TABLE 3 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%) Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0 B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part I: (i) Dispense Eudragit® S 100 powder in deionized water with stirring. (ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring. (iii) Allow the partially neutralized dispersion to stir for 60 minutes. (iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. Part II: (i) Disperse talc in the required amount of water (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer. (iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating. 8 Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45° C. Outlet Air 30 to 33° C. Temperature Atomization Air 1.8 Bar Pressure Pump Rate 2 gram per minute (i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets. (ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. 1.6 Encapsulation of the Antineoplastic agent Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%: Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S 100 coated pellets respectively. The capsule is filled with the three different pellets to achieve the desired dosage. Three Pulses 
 EXAMPLE 60 Antineoplastic Agent Pellet Formulation and Preparation Procedure 60.1 Pellet Formulations for Subsequent Coating The composition of the Antineoplastic agent trihydrate matrix pellets provided in Table 4. 9 TABLE 4 Composition of Antineoplastic agent Matrix Pellets Component Percentage (%) Antineoplastic agent Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing. 60.2 Preparation Procedure for Antineoplastic agent Matrix Pellets 60.2.1 Blend Antineoplastic agent and Avicel® PH 101 using a low shear blender. 60.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm. 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate. 60.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. 60.2.6 Pellets between 20 and 40 Mesh were collected for further processing. 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 60.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the antineoplastic agent matrix pellets is provided below in Table 5. 10 TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5 60.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 60.4.1 Suspend triethyl citrate and talc in deionized water. 60.4.2 The TEC/talc suspension is mixed using laboratory mixer. 60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. 60.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antineoplastic agent matrix pellets. 60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 60.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the Antineoplastic agent matrix pellets is provided below in Table 6. 11 TABLE 6 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%) Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0 Polymer Content 10.0 60.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 60.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. 60.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. 60.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. 60.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B. Part B: 60.6.5 Disperse talc in the required amount of water 60.6.6 Stir the dispersion using an overhead laboratory mixer. 60.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 60.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes. 12 Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram per minute 60.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets. 60.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets. 60.8 Preparation of Antineoplastic Agent Granulation (Immediate Release Component) for Tabletting 13 TABLE 7 Composition of Antineoplastic agent Granulation Component Percentage (%) Antineoplastic agent Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing. 60.8.2 Blend Antineoplastic agent and Avicel® PH 101 using a low shear blender. 60.8.3 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. 60.8.4 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. 60.8.5 Granules between 20 and 40 Mesh are collected for further processing. 60.9 Tabletting of the Antineoplastic Agent Pellets 14 TABLE 8 Composition of Antineoplastic agent Tablets Component Percentage (%) Antineoplastic agent granules 32.5 Avicel PH 200 5.0 Antineoplastic agent L30D-55 coated pellets 30 Antineoplastic agent S100 coated pellets 30 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 100 60.9.1 Blend the Antineoplastic agent granules, Avicel PH-200, Antineoplastic agent pellets and colloidal silicon dioxide for 15 minutes in a tumble blender. 60.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes. 60.9.3 Compress the blend on a rotary tablet press. 60.9.4 The fill weight should be adjusted to achieve the desired dosage. Four Pulses 
 EXAMPLE 61 1 Antineoplastic Matrix Pellet Formulation and Preparation Procedure 61.1 Pellet Formulation The composition of the antineoplastic agent matrix pellets provided in Table 9. 15 TABLE 9 Composition of Antineoplastic agent Pellets Component Percentage (%) Antineoplastic agent 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing. 61.2 Preparation Procedure for Antineoplastic Agent Matrix Pellets 61.2.1 Blend antineoplastic agent and Avicel® PH 101 using a Robot Coupe high shear granulator. 61.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. 61.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm. 61.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. 61.2.5 Dry the spheronized pellets at 50° C. overnight. 61.2.6 Pellets between 16 and 30 Mesh were collected for further processing. 61.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 61.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the antineoplastic agent matrix pellets is provided below in Table 1 0. 16 TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0 Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9 61.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 61.4.1 Suspend triethyl citrate and talc in deionized water. 61.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. 61.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. 61.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antineoplastic agent matrix pellets. 61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 61.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the antineoplastic agent matrix pellets is provided below in Table 11. 17 TABLE 11 Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%) Part A Eudargit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate 6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0 61.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 61.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. 61.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. 61.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. 61.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. Part B: 61.6.5 Disperse talc in the required amount of water 61.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer. 61.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 61.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings. 18 Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per minute 61.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets. 61.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets. 61.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. 61.8 Encapsulation of the Antineoplastic agent Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively. The capsule is filled with the four different pellets to achieve the desired dosage. The present invention is particularly advantageous in that there is provided an antineoplastic product which provides an improvement over twice a day administration of the antineoplastic and an improvement over a once a day administration of such agent. Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described.