JP2008535920A - Modified release composition comprising a fluorocytidine derivative for the treatment of cancer - Google Patents

Abstract

The present invention relates to a multiparticulate modified release composition comprising a fluorocytidine derivative, preferably capetitabine, and a modified release composition comprising a modified release coating, a modified release matrix material or both. Following oral delivery, the composition, in operation, delivers the fluorocytidine derivative in a pulsatile manner from about 6 to about 12 hours after administration.
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Description

  The present invention relates to a multiparticulate modified release composition comprising a fluorocytidine derivative, such as capetitabine, suitable for use in the treatment of cancer. In particular, the present invention relates to novel dosage forms for controlled delivery of fluorocytidine derivatives such as capetitabine. Furthermore, the present invention relates to a dosage package designed to enhance patient compliance and therapeutic outcome.

  Many precursors of 5-fluorouracil (5-FU), also called 5-FU prodrugs, are known to be useful as antitumor agents. However, due to intestinal and immunosuppressive toxicity, the bioconversion efficiency of 5-FU precursors is insufficient to treat patients suffering from tumors. Such modifications of the 5-FU precursor have developed fluorocytidine derivatives that exhibit improved bioconversion efficiency and toxicity.

Fluorocytidine derivatives, for example, U.S. Patent No. 4,966,891, "fluorocytidine derivative" and U.S. Patent No. 5,472,949, "N ⁴ - (substituted - oxycarbonyl) -5'-deoxy-5-fluorocytidine compounds, compositions and uses thereof Method "(the entire disclosure of which is fully incorporated herein by reference). US Pat. No. 4,966,891 discloses 5 ′ deoxy-5-fluoro cytidine derivatives, methods for their preparation, anti-tumor compositions containing said derivatives and their use to inhibit tumor growth in a subject. U.S. Patent No. 5,472,949, N ⁴ - (substituted - oxycarbonyl) -5'-deoxy-5-fluorocytidine derivatives, processes for their preparation, their in the treatment of tumors of the antitumor compositions and in the host comprising said derivative The use of is disclosed.

Capetitabine is a fluorocytidine derivative having the chemical name 5 ′ deoxy-5-fluoro-N-[(pentyloxy) carbonyl] -cytidine. Capetitabine has a molecular weight of 359.35 and has the following structural formula:

  Capetitabine is a white to off-white crystalline powder with an aqueous solubility of 26 mg / ml at 20 ° C.

  Capecitabine is enzymatically converted to 5-FU in vivo. Capecitabine is easily absorbed from the gastrointestinal tract. In the liver, the 60 kDa carboxyesterase hydrolyzes many of the compounds to 5'-deoxy-5-fluorocytidine (5'-DFCR). Subsequently, cytidine deaminase, an enzyme found in most tissues including tumors, converts 5'-DFCR to 5'deoxy-5-fluorouridine (5'-DFUR). Thymidine phosphorylase then hydrolyzes 5′-DFUR to the active drug 5′-FU. Many tissues express thymidine phosphorylase. However, human carcinomas express this enzyme at higher concentrations than the surrounding normal tissue.

Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). Their metabolites cause cytotoxicity by two different mechanisms. First, FdUMP and the folate cofactor, N ^5-10 -methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently linked ternary complex. This binding inhibits the formation of thymidylate from 2'-deoxyuridylate. Thymidylate is a necessary precursor of thymidine triphosphate that is essential for DNA synthesis. Therefore, thymidylate deficiency can inhibit cell division. Second, nuclear transcriptase can mistakenly incorporate FUTP instead of uridine triphosphate (UTP) during RNA synthesis. This metabolic error can interfere with RNA processing and protein synthesis, ultimately leading to cell death.

  Capecitabine is considered a fluorocytidine derivative with high therapeutic value based on its sensitivity to hepatic carboxyesterase, oral bioavailability in monkeys and efficacy in human cancer xenografts. Capetitabine is given orally, resulting in a substantially higher concentration of 5-FU in the tumor than in plasma or normal muscle tissue. Tumor 5-FU levels are also much higher than those achieved by intraperitoneal administration of 5-FU with isotoxic administration. This tumor selective delivery of 5-FU ensures greater efficacy and a more advantageous safety profile than other fluoropyrimidines. In 24 human cancer xenograft model studies, capetitabine was more effective over a wider dosage range than 5-FU, UFT or its intermediate metabolite 5'-DFUR and had a broader spectrum of antitumor activity . The sensitivity of the xenograft to capetitabine correlated with tumor dThdPase levels. Furthermore, the conversion of 5′-DFUR to 5-FU by dThdPase in tumors was insufficient in a xenograft model resistant to capetitabine. In addition, the effectiveness of capetitabine was enhanced by dThdPase upregulators, such as by taxanes and cyclophosphamide, and by X-ray irradiation. The efficacy of capetitabine is therefore optimized by selecting the most appropriate patient population based on dThdPase status and / or by combining it with dThdPase upregulators. Capetitabine has additional features not found in 5-FU, such as potent antimetastatic and anti-cachectic effects in mouse tumor models. Based on their profile, capetitabine may have substantial potential in cancer treatment.

  Capetitabine is provided by Hoffman-La Roche Inc. (Nutley, New Jersey) under the registered trademark XELODA. XELODA® is supplied as a biconvex oval film-coated tablet for oral administration of capetitabine at doses of 150 mg and 500 mg. The film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.

  XELODA® has proven effective in the treatment of colorectal cancer and breast cancer. XELODA® has been shown as the most important treatment for patients with metastatic colorectal cancer where treatment with fluoropyrimidine therapy alone is preferred. Either XELODA® alone or in combination with other anticancer agents such as docetaxel may be effective in the treatment of metastatic breast cancer that is resistant to other chemotherapy measures. Proven.

The recommended dose of XELODA® is 1250 mg / m ² administered orally twice a day (morning and evening; total daily dose equivalent to 2500 mg / m ² ) for 2 weeks Followed by a three week cycle with a rest period of one week. XELODA® tablets are swallowed with water within 30 minutes after a meal. In combination with docetaxel, the recommended dose of XELODA® is 1250 mg / m ² twice a day for 2 weeks, followed by 1 week rest period, 1 hour intravenous infusion every 3 weeks In combination with 75 mg / m ² of docetaxel.

  Fluorocytidine derivatives have high therapeutic value for the treatment of cancer. Administration of fluorocytidine derivatives such as capetitabine requires oral administration twice a day, and the strict patient dosing rate is a significant factor in the effectiveness of fluorocytidine derivatives in the treatment of cancer. Furthermore, such frequency of administration often requires the attention of health care workers and contributes to the high costs associated with treatments for fluorocytidine derivatives such as capetitabine. Thus, there is a need in the art for fluorocytidine derivative compositions that overcome those problems and other problems associated with their use in the treatment of cancer.

Summary of the Invention

One object of the present invention is to provide a multiparticulate modified release composition comprising a fluorocytidine derivative.
Another object of the present invention is to provide a multiparticulate modified release composition that in operation delivers a fluorocytidine derivative in a unimodal manner.
It is a further object of the present invention to provide a multiparticulate modified release composition comprising a fluorocytidine derivative in which its active ingredient is rapidly released after an initial delay period of about 6 to about 12 hours.
Yet another object of the present invention is to provide a multiparticulate modified release composition that is in an erodable, diffusion controlled or osmotic form.
A further object of the present invention substantially mimics the pharmacological and therapeutic effects produced by the administration given over time of two or more immediate release dosage forms comprising a fluorocytidine derivative, It is to provide a multiparticulate modified release composition that is co-administered with an immediate release form of a fluorocytidine derivative.
Yet another object of the present invention is to provide an oral dosage form comprising the multiparticulate modified release composition of the present invention.
It is a further object of the present invention to provide a method for treating cancer by administering a therapeutically effective amount of a multiparticulate modified release composition of the present invention.

  The above objectives are realized by the compositions, dosage forms and methods of the present invention. According to one aspect of the present invention, there is provided a multiparticulate modified release composition comprising a fluorocytidine derivative designed to release all of the active ingredient after about 6 to about 12 hours of administration. When co-administered with an immediate release dosage form comprising a fluorocytidine derivative, the resulting plasma profile is more than one given over time, such as the plasma profile obtained by administration of XELODA® twice daily. Is substantially the same as the plasma profile produced by administration of the immediate release dosage form.

  The compositions of the present invention take advantage of modified release features that allow for less frequent administration than with conventional forms of fluorocytidine derivatives, increasing patient convenience and medication rates. The modified release can be achieved, for example, by the use of a formulation such as an erodible formulation, a diffusion controlled formulation or an osmotic controlled formulation. In one embodiment, the invention relates to a multiparticulate modified release composition that in operation delivers a fluorocytidine derivative in a pulsatile manner. When administered at the same time as an immediate release dosage form comprising a fluorocytidine derivative, the composition of the present invention provides a mimicking plasma profile after administration so that a simulated plasma profile is obtained as if the dosage was administered in the morning. The active ingredient is released in about 12 hours.

  In one embodiment, the multiparticulate modified release composition comprises a fluorocytidine derivative, preferably capecitabine. The modified release may be achieved by the use of a modified release coating, a modified release matrix material, or both. Following oral delivery, in operation, the composition delivers the fluorocytidine derivative in a unimodal pulsatile manner. Preferred modified release components include erodible formulations, diffusion controlled formulations and osmotic controlled formulations. Preferably, the composition comprises a fluorocytidine derivative in an amount from about 0.1 mg to about 1 g.

  According to another aspect of the present invention there is provided an oral dosage form comprising the multiparticulate modified release composition of the present invention. The dosage form can be provided in any suitable form, such as a hard or soft gelatin capsule, or as a tablet.

  According to yet another aspect of the present invention, a dosing package comprising one or more dosage forms of the present invention packaged with one or more immediate release forms comprising a fluorocytidine derivative is provided.

  The present invention further provides a method for treating cancer comprising the step of administering a therapeutically effective amount of a composition of the present invention to a cancer patient in need thereof.

  The advantages of the present invention include reducing the dosing frequency required for conventional multiple immediate release dosing procedures while still maintaining the benefits derived from the pulsatile plasma profile. A formulation that can be administered at a reduced frequency is advantageous in terms of patient compliance. The reduction in dosing frequency enabled by the use of the present invention contributes to reducing health care costs by reducing the time spent by health care workers in drug administration.

  Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the claims of the present invention. Other objects, advantages and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.

Detailed Description of the Invention

As used herein in the specification and in the claims, “an” and “the” include plural referents unless the context clearly dictates otherwise.
The term “particulate” as used herein refers to a state of matter characterized by the presence of discrete particles, pellets, beads or granules, regardless of their size, shape or morphology. The term “multiparticulate” as used herein refers to a plurality of discrete or agglomerated particles, pellets, granules or mixtures thereof, regardless of their size, shape or morphology.

  The term “modified release” as used herein means a release that is received not to be immediate, but to include controlled release, sustained release, and delayed release.

  The term “time delay” as used herein refers to the duration between administration of the composition and release of the active ingredient therefrom.

  As used herein, the term “active ingredient” includes one or more fluorocytidine derivatives, preferably capetitabine. The fluorocytidine derivative can be included in a microparticulate drug delivery system wherein the fluorocytidine derivative is encapsulated or encapsulated within it by being attached to the particle or by other bonds.

  The particles of the invention have a modified release component that can include a modified release coating, a modified release matrix material, or both. The modified release particles of the present invention can also be provided in the form disclosed in US Pat. No. 6,228,398 (Devane et al.), Which is hereby incorporated by reference in its entirety. Following oral delivery, the composition of the invention delivers the fluorocytidine derivative in a unimodal manner.

  Modified release of the fluorocytidine derivative from the composition can be achieved by the use of a coating, or matrix material, or both, with a time delay of about 6 to about 12 hours between administration and release of the fluorocytidine derivative. Bring. During the time delay, it can be varied by changing its composition and / or the amount of modified release coating and / or by changing its composition and / or the amount of modified release matrix material used. Suitable formulations for use in changing the time delay include erodible formulations, diffusion controlled formulations and osmotic controlled formulations. The use of such a formulation can be designed to produce the desired plasma profile during the time delay.

  In one embodiment, the composition can be in the form of an erodible formulation in which the structural integrity of the particles changes in the body over time. In one such embodiment, the active ingredient is released over time by the disintegration of the modified release coating and / or matrix material by the action of human ingestion.

  In other embodiments, the composition can be in the form of a diffusion controlled formulation in which the particles are dispersed in a liquid medium. One such embodiment is disclosed in US Pat. No. 6,586,006 (Roser et al.), Which is hereby incorporated by reference in its entirety.

  In other embodiments, the composition can be in the form of a osmotic controlled formulation in which the release of the active ingredient from the composition is controlled by osmosis. One such embodiment is disclosed in US Pat. No. 6,110,498 (Rudnic et al.), Which is hereby incorporated by reference in its entirety, which has limited water solubility in soluble form. The release of therapeutic agents having The delivery system includes a core that is free of swellable polymers and includes a nonswelling solubilizer and a wicking agent. The soluble therapeutic agent is delivered through a passageway in the semipermeable coating of the tablet.

  US Pat. No. 5,814,979 B2 (Rudnic et al.), Which is hereby incorporated by reference in its entirety, discloses an osmotic drug delivery system comprising: (a) During drug delivery A semi-permeable wall whose integrity is maintained and having at least one passage therethrough; (b) a single uniform composition inside said wall, said composition essentially consisting of Consisting of: (i) a pharmaceutically active agent; (ii) at least one non-swelling solubilizer that enhances the solubility of the pharmaceutically active agent; (iii) at least one A non-swellable osmotic agent; and (iv) a non-swellable wicking agent dispersed throughout the composition that enhances the surface area of the pharmaceutical agent in contact with the incoming water-soluble liquid ( wicking agent).

  The composition may further comprise additional components, such as enhancer compounds or sensitizing compounds, for modifying the bioavailability or therapeutic effect of the fluorocytidine derivative.

As used herein, the term “enhancer” enhances absorption and / or bioavailability of active ingredients by facilitating net transport across the gastrointestinal tract of animals such as humans. A compound that can be produced. Suitable enhancers include either alone or in combination,
Medium chain fatty acids and salts, esters, ethers and other derivatives thereof including glycerides and triglycerides; such as those that can be prepared by reacting ethylene oxide with fatty acid esters of fatty acids, fatty alcohols, alkylphenols or sorbitan or glycerol, Ionic and nonionic surfactants; cytochrome P450 inhibitors; bile salts and bile acids: micelle chelators; P-glycoprotein inhibitors and the like.

  The plasma profile associated with administration of the composition can be described as a “pulsatile profile” in which one or more peaks of the plasma concentration of the active ingredient are observed. A pulsatile profile containing one peak can be described as `` unimodal '', and a pulsatile profile containing two peaks separated by a low concentration depression is `` bimodal ( A pulsatile profile that includes three or more peaks, each adjacent pair separated by a low concentration depression, should be described as `` multimodal ''. Can do.

  Conventional frequency dosage regimens in which immediate release (IR) dosage forms are administered at periodic intervals typically produce a pulsatile plasma profile. The peak of drug concentration in plasma is observed after each dose of IR dose with a dent that develops between successive dose points. The plasma profile produced by co-administration of a modified release composition at the same time as the immediate release composition is substantially similar to the plasma profile produced by administration of two or more immediate release dosage forms given over time.

  In one embodiment, the active fluorocytidine derivative is capetitabine, and the composition delivers capetitabine in operation in a unimodal manner. In other embodiments, the active fluorocytidine derivative is capetitabine, and the modified release composition is co-administered with an immediate release form of capetitabine in the evening, eg A plasma profile is produced that substantially mimics the plasma profile obtained by sequential administration of amounts.

  The release characteristics of the composition can be altered, for example, by changing the amount and / or type of coating and / or matrix material used in the composition. As noted above, the release profile can be further controlled by selective use of erodible formulations, diffusion controlled formulations or osmotic controlled formulations. Similarly, the plasma concentration curve produced by administration of the composition can be altered, for example, by changing the amount and / or type of coating and / or matrix material used in the composition. Depending on the duration of the time delay of the modified release composition, the pulses in the plasma profile produced by the simultaneous administration of the modified release and immediate release forms can be well separated and clearly defined (eg, the modified release composition If the time delay of the object is long), or the pulse can be overwritten to some extent (eg, if the time delay of the modified release composition is short).

  In one embodiment, the modified release composition of the present invention has a single modified release component whose modified release is realized by the use of a modified release coating, a modified release matrix material, or both. In operation, co-administration of such a modified release composition with an immediate release form is characterized by a first peak in the plasma profile associated with the immediate release form and a second peak in the plasma profile associated with the modified release component. Resulting in a pulsatile plasma profile. Embodiments of the invention in which two or more modified release components are present show additional peaks in the plasma profile.

  Where it is desired to deliver two (or more) pulses of the active ingredient, administration of the immediate release form and the at least one modified release form is over time of two (or more) dosage units. There is no need for administration, which is advantageous. Furthermore, in the case of cancer treatment, it is particularly useful for producing such bimodal or multimodal plasma profiles. For example, typical treatment with capetitabine consists of the administration of two doses of an immediate release dosage formulation given about 6 to about 12 hours apart. This type of measure has been found to be therapeutically effective and is widely used.

  Any coating material that modifies the release of the fluorocytidine derivative in the desired manner can be used. In particular, coating materials suitable for use in the practice of the present invention include cellulose acetate phthalate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, poly (vinyl acetate) phthalate, and the trademark Eudragit ( R) Ammonio methacrylic acid copolymers such as those sold under RS and RL, poly (acrylic acid) and polyacrylates and methacrylic acid copolymers such as those sold under the trademark Eudragit® S and L , Poly (vinyl acetal diethylamino) acetate, hydroxypropyl methylcellulose acetate succinate, shellac, hydrogels and gel-forming substances such as carboxyvinyl polymer, sodium alginate, sodium carmellose, calcium Carmellose, sodium carboxymethyl starch, poly (vinyl alcohol), hydroxyethylcellulose, methylcellulose, gelatin, starch, and cellulose-based cross-linked polymers that have a low degree of cross-linking to promote water adsorption and polymer matrix expansion , Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylic acid copolymer (Eudragit (R) RS-PM, Rohm & Haas), pullulan, collagen, casein, agar Gum arabic, sodium carboxymethyl cellulose, expandable hydrophilic polymer, poly (hydroxyalkyl methacrylate) (m. Wt. To 5 k-5,000 k), polyvinyl pyrrolidone (m. Wt. ~ 10 k-360 k), expandable mixture of agar and carboxymethylcellulose, maleic anhydride and styrene, ethylene, propylene or isobutylene copolymers, polysaccharides such as acacia, karaya, tragacanth, algin and guar, poly Acrylamide, polyox (R) polyethylene oxide (m. Wt. ~ 100 k-5,000 k), AquaKeep (R) acrylate polymer, diester of polyglucan, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone Sodium starch glucolate (eg Explotab®, Edward Mandell C. Ltd.), hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, nitrocellulose, carboxymethylcellulose, cellulose ether, poly Ethylene oxide (for example, Polyox®, Union Carbide), methyl ethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, Polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid (eg Eudragit®, Rohm and Haas), other acrylic acid derivatives, sorbitan esters, natural rubber, lecithin, pectin, Alginate, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar, and , Gum arabic, karaya gum, locust bean gum, gum tragacanth, Karagengomu, guar gum, xanthan gum, curable rubbers and rubber such as a mixture and blend thereof include polymer coating materials such as. As will be apparent to those skilled in the art, excipients such as plasticizers, lubricants, solvents, etc. may also be added to the coating. Suitable plasticizers include, for example, acetylated monoglyceride; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; Diacetylene; dibutyl phthalate; acetyl monoglyceride; polyethylene glycol; castor oil; triethyl citrate; polyhydric alcohol, glycerol, acetate ester, glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl Octyl phthalate, dioctyl azelate, epoxy disedtalate, triisooctyltri Retate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimelli Tate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.

  Where the modified release component comprises a modified release matrix material, any suitable modified release matrix material or combination of suitable modified release matrix materials can be used. The term “modified release matrix material” as used herein includes hydrophilic polymers, hydrophobic polymers and mixtures thereof that can modify the release of the fluorocytidine derivative dispersed therein. Modified release matrix materials suitable for the practice of the present invention include, but are not limited to, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, polyethylene oxide, methylcellulose and Alkyl celluloses such as ethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkyl methacrylate, polyvinyl acetate and mixtures thereof are included.

  The modified release composition of the present invention may be incorporated into any suitable dosage form that facilitates release of the active ingredient in a pulsatile manner. In one embodiment, the dosage form comprises fluorocytidine derivative-containing particles packed in a suitable capsule, such as a hard or soft gelatin capsule. Alternatively, the fluorocytidine derivative-containing particles may be compressed (optionally with additional excipients) into small tablets that can be subsequently filled into capsules. Another suitable dosage form is a tablet. The fluorocytidine derivative-containing particles that make up the compositions of the present invention can be further included in rapidly dissolving dosage forms, such as effervescent dosage forms or fast-melt dosage forms. You can also.

  The amount of fluorocytidine derivative present in the dosage form is a therapeutically effective amount that varies according to other things, the specific type of cancer being treated, the sensitivity of the patient, and other factors known to those skilled in the art. . In one embodiment, the amount of fluorocytidine derivative present in the dosage form is about 0.1 mg to about 1 g, preferably about 150 mg to about 500 mg.

  The present invention further provides a method for treating cancer comprising the step of administering a therapeutically effective amount of the composition of the present invention. In one such embodiment, the composition comprises capetitabine delivered in a pulsatile manner.

[Example 1]
Multiparticulate modified release composition containing capetitabine The multiparticulate modified release composition of the present invention is prepared as follows.

(a) Preparation of capetitabine-containing particles A solution of capetitabine (50:50 racemic mixture) is prepared according to any recipe shown in Table 1. The capetitabine solution is then coated with nonpareil seeds to a level of about 16.9% solids weight gain using, for example, a Glatt GPCG3 (Glatt, Protech Ltd., Leicester, UK) fluid bed coater. Form contained particles.

(b) Preparation of modified release capetitabine-containing particles Capetitabine-containing modified release particles were prepared by coating the capetitabine-containing particles prepared according to Example 1 (a) above with the modified release coating solution detailed in Table 2. Is done. The capetitabine-containing particles are coated to a level that varies up to about a 30% weight gain using, for example, a fluid bed coater.

(c) Encapsulation of modified release particles The modified release particles prepared according to Examples 1 (a) and (b) above, use a Bosch GKLF 4000S encapsulation apparatus for an overall 150 mg dose strength. And enclosed in size 2 hard gelatin capsules. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover modifications and variations of this invention provided that they come within the scope of the following claims and their equivalents.

Claims (28)

  A fluorocytidine derivative and a modified release coating or alternatively or additionally comprising a modified release matrix material such that the composition delivers the fluorocytidine derivative in a pulsatile manner following oral delivery to a subject. Multiparticulate modified release composition.   The composition of claim 1, wherein the fluorocytidine derivative is capetitabine.   The composition of claim 1, wherein the modified release component comprises an erodible formulation.   The composition of claim 1, wherein the modified release component comprises a diffusion controlled formulation.   The composition of claim 1, wherein the modified release component comprises a controlled permeability formulation.   The composition of claim 1, wherein the modified release component comprises a modified release coating. The composition of claim 1, wherein the modified release component comprises a modified release matrix material.   The composition of claim 1, wherein the amount of the fluorocytidine derivative is from about 0.1 mg to about 1 g.   9. The composition of claim 8, wherein the amount of the fluorocytidine derivative is about 150 mg or about 500 mg.   The composition of claim 1, wherein substantially all of the fluorocytidine derivative is released from about 6 to about 12 hours after administration to the patient.   The composition of claim 1, wherein the modified release component comprises a pH-dependent polymer coating capable of releasing a pulse of fluorocytidine derivative following a time delay of about 6 to about 12 hours after administration to a patient. object.   The composition of claim 11, wherein the polymer coating comprises a methacrylic acid copolymer.   13. The composition of claim 12, wherein the polymer coating comprises a mixture of methacrylic acid and ammonio methacrylic acid copolymer.   14. The composition of claim 13, wherein the ratio of methacrylic acid to ammonio methacrylic acid copolymer is about 1: 1.   A dosage form comprising the composition of claim 1.   A dosage form comprising the composition of claim 2.   The dosage form of claim 15, wherein the composition is provided in a hard or soft gelatin capsule.   The dosage form of claim 17, wherein the composition is in the form of a mini-tablet.   16. The dosage form of claim 15, wherein the composition is compressed into a tablet form.   The dosage form of claim 15, wherein the composition is provided in a fast dissolving dosage form.   21. The dosage form of claim 20, wherein the composition is provided as a fast melting tablet.   A method of treating cancer comprising the step of administering a therapeutically effective amount of the composition of claim 1.   A method of treating cancer comprising the step of administering a therapeutically effective amount of the composition of claim 2.   24. The method of claim 23, wherein substantially all capetitabine is released from about 6 to about 12 hours after administration of the composition.   25. The method of claim 24, further comprising co-administering a therapeutically effective amount of an immediate release composition of capetitabine.   26. The method of claim 25, wherein the composition is administered once daily.   26. The method of claim 25, wherein the composition is administered in the evening.   A combination dosage package comprising an immediate release dosage form of capetitabine and the dosage form of claim 16, wherein the dosage form is packaged together.