WO2013030602A1 - Composition solide à libération prolongée destinée à une administration orale et comprenant de la capécitabine sensiblement amorphe - Google Patents

Composition solide à libération prolongée destinée à une administration orale et comprenant de la capécitabine sensiblement amorphe Download PDF

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WO2013030602A1
WO2013030602A1 PCT/GB2012/052162 GB2012052162W WO2013030602A1 WO 2013030602 A1 WO2013030602 A1 WO 2013030602A1 GB 2012052162 W GB2012052162 W GB 2012052162W WO 2013030602 A1 WO2013030602 A1 WO 2013030602A1
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Prior art keywords
capecitabine
composition
amorphous
extended release
dissolution
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PCT/GB2012/052162
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English (en)
Inventor
Jacob Hendrik Beijnen
Jelte MEULENAAR
Bastiaan Nuijen
Johannes Henricus Matthias Schellens
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Slotervaart Participaties Bv
Stichting Het Nederlands Kanker Instituut
WILSON, Justin
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Publication of WO2013030602A1 publication Critical patent/WO2013030602A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to pharmaceutical compositions.
  • the invention relates to compositions comprising capecitabine for the treatment of neoplastic disease.
  • the invention also relates to methods for treating neoplastic disease.
  • Capecitabine is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers.
  • Capecitabine is a prodrug that is enzymatically converted to 5-fluorouracil in the tumour, where it inhibits DNA synthesis and slows growth of tumour tissue.
  • the activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5- fluorocytidine (5 -DFCR) and 5'-deoxy-5-fluorouridine (5 -DFUR), to form 5-fluorouracil (5-FU).
  • Capecitabine is currently commercially available as an immediate release tablet for oral use (Xeloda ® , Roche), composed of about 80% w/w crystalline capecitabine and about 20% w/w of the following excipients: anhydrous lactose, croscarmellose sodium, hypromellose, microcrystalline cellulose and magnesium stearate.
  • Xeloda ® tablets contain 150 mg or 500 mg active ingredient.
  • the present invention provides a solid pharmaceutical composition for oral administration comprising substantially amorphous capecitabine or an analog thereof.
  • Amorphous capecitabine (e.g. prepared by spray-drying) has slower in vitro dissolution properties compared to crystalline capecitabine. This is a very remarkable and unexpected observation for a component like capecitabine ("small molecule"; Mw 359) because it is common knowledge that the dissolution rate of a crystalline drug can be expected to increase (and not to decrease as observed here for capecitabine) when it is converted from a crystalline form into an amorphous state. This can be explained by the following theory: when a compound is in an amorphous state the molecules are randomly ordered in a higher, and hence less favourable, energetic state than when ordered in a strong lattice in the crystalline form.
  • amorphous capecitabine Without wishing to be held to a particular theory, the inventors believe that the extended release properties of amorphous capecitabine might be explained by the remarkable gelling properties observed for the amorphous drug. In an aqueous environment, amorphous capecitabine immediately forms a gellike phase which may be responsible for the reduced dissolution rate. It appears that this gelling phenomenon as well as the rate and extent of dissolution is highly reproducible. Therefore, this allows amorphous capecitabine to be used in an extended release composition.
  • the composition comprises substantially amorphous capecitabine or an analog thereof.
  • This means that the composition comprises substantially amorphous capecitabine or a substantially amorphous capecitabine analog.
  • Analogs of capecitabine are well known to those skilled in the art. Further, it would be well within the capabilities of a skilled person to test whether a compound is a capecitabine analog.
  • a capecitabine analog is a compound which has a similar structure to capecitabine and which can be broken down in the human body to give 5-fluorouracil (5-FU) or an analog thereof which has anti-cancer properties. In particular, the anti-cancer properties result from the compound being an irreversible inhibitor of thymidylate synthase.
  • the references to capecitabine and substantially amorphous capecitabine are equally applicable to an analog of capecitabine and a substantial amorphous capecitabine analog.
  • the composition comprises substantially amorphous capecitabine.
  • substantially amorphous means that there should be little or no long range order of the position of the capecitabine molecules. The majority of the molecules should be randomly orientated. A completely amorphous structure has no long range order and contains no crystalline structure whatsoever; it is the opposite of a crystalline solid. However, it can be hard to obtain a completely amorphous structure for some solids. Therefore, many "amorphous" structures are not completely amorphous but still contain a certain amount of long range order or crystallinity. For example, a solid may be mainly amorphous but have pockets of crystalline structure or may contain very small crystals so that it is bordering on being truly amorphous.
  • the term "substantially amorphous” encompasses solids which have some amorphous structure but which also have some crystalline structure as well.
  • the crystallinity of the substantially amorphous capecitabine should be less than 50%.
  • the crystallinity of the substantially amorphous capecitabine is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%.
  • the crystallinity of the substantially amorphous capecitabine may be less than 2% or less than 1%.
  • the capecitabine should be completely amorphous (100% amorphous), i.e. have a crystallinity of 0%. Since crystalline capecitabine has a relatively high solubility, the lower the crystallinity of the substantially amorphous capecitabine, the lower the dissolution of the capecitabine and, therefore, the better the extended release properties of the substantially amorphous capecitabine.
  • the degree of crystallinity of the capecitabine may be determined by differential scanning calorimetry, X-ray powder diffraction, near-IR spectrometry or a combination of these techniques.
  • the substantially amorphous capecitabine can be prepared in any suitable manner and techniques would be apparent to those skilled in the art.
  • suitable methods for preparing the amorphous capecitabine include freeze drying, spray drying, spray-freeze drying, vacuum drying, precipitation, supercritical fluid, quench cooling, hot melt extrusion, milling and cryo-milling.
  • the amorphous capecitabine may be prepared using a solvent evaporation method or lyophilisation.
  • the amorphous capecitabine may be prepared by a solvent evaporation method. Suitable solvent evaporation methods are, for example, spray drying and vacuum drying as described in Kawakami (2009) (Journal of Pharmaceutical Sciences. 98(9) 2875-2885.
  • the solvent evaporation method is spray drying.
  • preparing the amorphous capecitabine using a solvent evaporation method, in particular spray drying results in the composition having particularly good extended release properties.
  • the composition for oral administration is in a solid form.
  • the solid composition can be in any suitable form as long as the capecitabine is in a substantially amorphous state.
  • the capecitabine is substantially amorphous in the solid form.
  • the composition preferably has an amoiphous capecitabine content of 34% or more w/w, relative to the total weight of the composition.
  • the amorphous capecitabine content of the composition may be 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more.
  • the amount of amorphous capecitabine in the composition will depend to a certain degree on the desired dissolution characteristics of the composition.
  • the composition has an amorphous capecitabine content of 80% or more w/w, 85% or more, or 90% or more.
  • the composition may have an amorphous capecitabine content of 95% or more, or 98% or more.
  • the composition is an extended release composition.
  • An extended release composition is one which is capable of releasing capecitabine at an adequate rate for therapeutic purposes for a prolonged period of time, for example, a number of hours. This is in contrast to an immediate release composition which releases all the active ingredient in a relatively short period of time, for example, under an hour, once placed into an aqueous environment.
  • the extended release composition of the invention should release no more than 60% of the capecitabine or analog within one hour of being placed into an aqueous environment.
  • the extended release composition should release no more than 50%, 40% or 30% of the capecitabine or analog within one hour of being placed into an aqueous environment.
  • the composition has a dissolution profile so that the capecitabine does not fully dissolve in less than 4 hours.
  • the capecitabine does not fully dissolve in less than 5 hours, less than 6 hours, less than 7 hours, less than 8 hours or less than 9 hours.
  • the capecitabine does not fully dissolve in less than 8 hours or less than 9 hours.
  • the capecitabine fully dissolves in between 8 and 14 hours, between 10 and 14 hours, or between 11 and 13 hours.
  • a composition preferably needs to have release characteristics over a time period of 24 hours or more. Therefore, in one embodiment, the composition has a dissolution profile so that the capecitabine does not fully dissolve in less than 16 hours. In other embodiments, the capecitabine does not fully dissolve in less than 17 hours, less than 18 hours, less than 19 hours, less than 20 hours, less than 21 hours, less than 22 hours, less than 23 hours, or less than 24 hours. Preferably, the capecitabine does not fully dissolve in less than 21 hours, less than 22 hours, less than 23 hours, or less than 24 hours. In some embodiments, the capecitabine fully dissolves in between 18 and 30 hours, between 20 and 28 hours, or between 22 and 26 hours.
  • the term 'fully dissolve' means the point in time at which the capecitabine reaches its peak concentration of dissolved capecitabine. This may be the point in time at which 100% of the capecitabine has dissolved. However, if for some reason not all the capecitabine in the composition dissolves, it is the point at which the amount of capecitabine in solution reaches its maximum level. It would be well within the capabilities of a skilled person to determine the dissolution profile of a composition. For example, dissolution testing can be performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rotations per minute (rpm) paddle speed. Samples can be taken at 0, 10, 15, 20, 30, 45, 60, 90 and 120 minutes. After 120 minutes, samples can be taken every hour until complete dissolution.
  • Capecitabine concentration in the samples can be measured by HPLC (UV detection at 310 nm). Further, using the common general knowledge, a skilled person would be able to obtain a composition with a required dissolution. For example, if the required dissolution profile was longer than that for a particular composition, a skilled person could add one or more extended release excipients to slow down the dissolution of the capecitabine.
  • the composition comprises substantially amorphous capecitabine.
  • the composition may also comprise crystalline capecitabine. This would allow the release characteristics of the composition to be modified.
  • the crystalline capecitabine which dissolves relatively quickly, would give the composition some immediate release characteristics and the substantially amorphous capecitabine, which has a relatively slow dissolution rate, would provide the extended release characteristics.
  • the composition comprises an extended release component.
  • An extended release component is defined as one or more excipients which individually and in combination lead to a slowing in the dissolution rate of the amorphous capecitabine.
  • An extended release component and/or excipient is capable of controlling the release of the capecitabine by influencing one or more of the following mechanisms: diffusion, dissolution, erosion and osmosis. It leads to a further slowing in the dissolution rate of the amorphous capecitabine.
  • Numerous extended release excipients are commercially available and this term would be clear to a person skilled in the art.
  • Suitable extended release components/excipients which are commercially available include Kollidon ® SR (a polyvinyl acetate/povidone excipient manufactured by BASF), Methocel K100 LVCR, Methocel K4M CR, Methocel K15M CR, Methocel K100M CR (all cellulose ether excipients manufactured by Colorcon), Polyox 301, Polyox coagulant (Polyethylene oxide excipients manufactured by Colcoron), Eudragit RS and Eudragit RL (Poly (meth)acrylate excipient manufactured by Evonik).
  • Kollidon ® SR a polyvinyl acetate/povidone excipient manufactured by BASF
  • Methocel K100 LVCR Methocel K4M CR
  • Methocel K15M CR Methocel K100M CR
  • Methocel K100M CR all cellulose ether excipients manufactured by Colorcon
  • the extended release component preferably comprises a polymer and more preferably a hydrophilic polymer.
  • the polymer is an organic polymeric compound capable of at least partial dissolution in aqueous media at pH 7.4 and/or capable of swelling or gelation in such aqueous media.
  • the polymer can be any suitable polymer which reduces the dissolution rate of the capecitabine when the composition dissolves in an aqueous environment.
  • the polymer may be capable of forming a gel or matrix in an aqueous environment. This can reduce the dissolution rate of the capecitabine.
  • the polymer is selected from: polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinylalcohol (PVA); crospovidone (PVP-CL); polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-PVA); poly(ethylene oxide); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate; polyacrylates; polymethacrylates; sugars, polyols and their polymers such as mannitol, sucrose, sorbitol, dextrose and chitosan; and cyclodextrins.
  • PVP polyvinylpyrrolidone
  • PEG polyethylene glycol
  • PVA polyvinylalcohol
  • PVP-CL crospovidone
  • PVP-PVA polyvinylpyrrol
  • the polymer is selected from a cellulose derivative, polymethacrylate, poly(ethylene oxide), polyvinyl acetate, polyvinylpyrrolidone and PVP-PVA.
  • the extended release component may comprise a plurality of polymers, preferably a plurality of hydrophilic polymers.
  • the extended release component may comprise a plurality of the polymers referred to above.
  • a particular preferred extended release component comprises polyvinyl acetate and polyvinylpyrrolidone. More preferably, the extended release component comprises, by weight, 70-90% polyvinyl acetate, 9-19% polyvinylpyrrolidone, 0- 1.6% sodium lauryl sulfate and 0-0.4% silica.
  • a composition containing amorphous capecitabine requires a lower amount of an extended release component in order to achieve a desired extended release profile.
  • the extended release component relative to the weight of the amorphous capecitabine, may be present in an amount of less than 200% w/w (i.e.
  • the amount of extended release component relative to the weight of the amorphous capecitabine is 0-10% w/w.
  • the amount of extended release component relative to the weight of the amorphous capecitabine may be 0-8%, 0-7%, 0-6%, 0-5%, 0-4%, 0-3%), 0-2%), or 0-1%.
  • the amount of extended release component relative to the weight of the amorphous capecitabine is 1-10% w/w.
  • the amount of extended release component relative to the weight of the amorphous capecitabine is 2-6% w/w. It may be 1-3%. Alternatively, it may be 4-6%.
  • the extended release component may be present in an amount of 0-66% w/w, 0-65%, 0-60%, 0-55%, 0- 50%, 0-45%, 0-40%, 0-35%, 0-30%, 0-25%, 0-20%, 0-15%, 0-10%, 0-7.5%, 0-5%, or 0-2.5%.
  • the amount of extended release component is 0-10% w/w, 0-8%, 0-7%, 0-6%, 0-5%, 0-4%, 0- 3%, 0-2%, or 0-1%.
  • the amount of extended release component is 1-10%.
  • the amount of extended release component is 2-6% w/w. It may be 1-3%. Alternatively, it may be 4-6%.
  • the composition can comprise a physical mixture of amorphous capecitabine and the extended release component.
  • the capecitabine and extended release component are in the form of a solid dispersion.
  • solid dispersion is well known to those skilled in the art and means that the capecitabine and the extended release component are partly molecularly dispersed.
  • a solid dispersion of the capecitabine and the extended release component can be formed by subjecting a solution of capecitabine and the extended release component to one of the following methods: freeze drying, spray drying, spray-freeze drying, vacuum drying, precipitation, supercritical fluid, quench cooling, hot melt extrusion, milling and cryo-milling.
  • the two components may be spray dried together, i.e.
  • the capecitabine and extended release component are in the form of a solid solution.
  • solid solution is well known to those skilled in the art and means that the capecitabine and extended release component are substantially completely molecularly dispersed. It is thought that solid solutions are more amorphous in nature than solid dispersions. Methods of preparing solid dispersions and solid solutions are well known to those skilled in the art (Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci 1999; 88(10): 1058 1066. Karanth H, Shenoy VS, Murthy RR. Industrially feasible alternative approaches in the manufacture of solid dispersions: a technical report.
  • both the capecitabine and extended release component are in an amorphous state.
  • the dissolution rate of the capecitabine is less than a physical mixture of amorphous capecitabine and extended release component.
  • the crystallinity of the solid dispersion or solution should be less than 50%.
  • the crystallinity of the solid dispersion or solution is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%.
  • the crystallinity of the solid dispersion or solution may be less than 2% or less than 1%.
  • the solid dispersion or solution should be completely amorphous (100% amorphous), i.e. have a crystallinity of 0%.
  • the amount of extended release component, relative to the total weight of the capecitabine and extended release component combined may be 0-66% w/w, 0-65%, 0-60%, 0-55%, 0-50%, 0-45%, 0-40%, 0-35%, 0-30%, 0-25%, 0-20%, 0-15%, 0-10%, 0-7.5%, 0-5%, or 0-2.5%.
  • the amount of extended release component is 0-30%, 0-25%, 0-20%, 0-15%, 0-10%, 0-7.5%, 0-5%, or 0-2.5%.
  • the amount of extended release component is 0-10% w/w. More preferably, the amount of extended release component may be 0-8%, 0-7%, 0-6%, 0-5%, 0-4%, 0-3%, 0-2%, or 0-1%.
  • the amount of extended release component is 1-10%.
  • the amount of extended release component is 2-6% w/w. It may be 1-3%. Alternatively, it may be 4-6%.
  • capecitabine has been delivered in chitosan-poly(ethylene oxide-g-acrylamide) microspheres (for example, in Agnihotri and Aminabhavi. International Journal of Pharmaceutics 324 (2006) p. 103- 115).
  • the authors describe the development of a hydrogel formulation for the controlled release of capecitabine.
  • the formulation consists of capecitabine-loaded microspheres composed of selected hydrophilic polymers. Controlled release is achieved by swelling of the polymers in an aqueous environment. The polymers do not dissolve and retain by means of hydrogel formation the entrapped drug, releasing it in a controlled manner. In effect, the polymer microspheres are an extended release component which act to slow down the dissolution of the capecitabine.
  • the formulation including the capecitabine, is in an amorphous form.
  • this finding is not substantiated as no physical mixtures of excipients and capecitabine were assessed. Therefore, the masking of crystalline capecitabine in the formulation by dilution with the intrinsic amorphous polymers cannot be excluded. More importantly, the unique slow-release "gelling" properties of amorphous capecitabine itself are not described or recognised. Additionally, the microsphere formulation reaches a significantly lower drug loading (up to 50% compared to up to 100% in the present invention) and results in significantly shorter capecitabine release profiles ( ⁇ lOh compared to, for example, 24h as for the present invention).
  • the composition of the present invention does not comprises chitosan-poly(ethylene oxide-g-acrylamide) microspheres.
  • the composition does not contain microspheres. The advantage of this is that a simpler composition can be used which does not require the production of microspheres. This makes manufacturing of the composition much easier.
  • composition may further comprise one or more additional pharmaceutically active ingredients.
  • the pharmaceutical composition may comprise additional pharmaceutically acceptable adjuvants and vehicles which are well known to those skilled in the art.
  • Pharmaceutically acceptable adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminium stearate, magnesium stearate, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate and wool fat.
  • the composition comprises magnesium stearate.
  • the composition may comprise silica.
  • compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, a powder or coated granules.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • other pharmaceutical excipients that can be added are binders, fillers, filler/binders, adsorbents, moistening agents, disintegrants, lubricants, glidants, and the like. Tablets and capsules may be coated to alter the appearance or properties of the tablets and capsules, for example, to alter the taste or to colour coat the tablet or capsule.
  • the composition is in the form of a tablet.
  • the pharmaceutical composition comprises a coating to protect the composition from water.
  • suitable coating agents which can be used to form coatings and which are commercially available include Eudragit E PO (an aminoalkyl acrylic polymer manufactured by Evonik ROHM GmbH), Instamoistshield (a HPMC manufactured by Ideal Cures Pvt.
  • Kollicoat smartseal 30D (a methyl methacrylate (MMA) and diethylaminoethyl methacrylate (DEAEMA) produced by BASF)
  • Kollicoat protect (a polyvinyl alcohol-polyethylene glycol graft copolymer produced by BASF), Opadry03A240005 and Opadry20A240000 (HPMC polymers manufactured by Colorcon)
  • Sepifilm LP010 (a HPMC manufactured bySEPPIC), WT-MP-02005 (a HPMC/ethyl cellulose manufactured by Wincoat), and WT-MPAQ-01001 (a methacrylic acid copolymer type c/HPMC manufactured by Wincoat).
  • the pharmaceutical composition may comprise a coating comprising an extended release component. Suitable extended release components are discussed above.
  • one particular coating may be Kollidon ® SR.
  • the coating acts to further reduce the dissolution rate of the capecitabine by acting as a barrier around the capecitabine.
  • the thickness of the coating will depend on the dissolution properties required for the capecitabine composition. The thicker the coating, the slower the capecitabine will be released. A person skilled in the art will be able to devise a suitable thickness for the coating bearing in mind the desired release properties.
  • the coating may have a thickness of less than 12 mg/cm 2 or less than 9 mg/cm 2 . In some embodiments, the coating has a thickness of less than 6 mg/cm 2 . In particular embodiments, the coating may have a thickness of less than 4 mg/cm 2 . In certain embodiments, the coating may be at least 0.5 mg/cm 2 .
  • the coating may further comprise additives to alter or enhance certain properties of the coating.
  • the coating may comprise a plasticiser to ensure that the coating is uniformly dispersed around the composition.
  • the coating may comprise additives such as a lubricant to enhance lubricity and/or an anti-sticking agent to minimize stickiness of the tablets during the coating process.
  • a particular additive which may be used is talcum.
  • the present invention also provides the above composition for use in therapy.
  • the present invention provides the above composition for use in the treatment of neoplastic disease.
  • the present invention provides the use of the above composition in the manufacture of a medicament for treating a neoplastic disease.
  • the neoplastic disease treated by the present invention is preferably a solid tumour.
  • the solid tumour may be selected from a cancer of the colon, stomach, breast, skin, pancreas, liver, cervix, uterus, ovaries, bladder, small intestine, anus, rectum, oesophagus, head and neck, lung (non-small cell lung and small cell lung cancer), or could be adenocystic carcinoma, or adeno carcinoma of unknown primary site.
  • the solid tumour is preferably selected from colon, stomach and breast cancer.
  • the present invention also provides a method of treatment of a neoplastic disease, the method comprising the administration, to a subject in need of such treatment, of an effective amount of the above composition.
  • the dehydropyrimidine dehydrogenase enzyme which detoxifies 5-FU is more active in humans at night (between about 0000 h and 0400 h). Therefore, if capecitabine is administered in the evening, the initial increase in the plasma concentration of capecitabine and, therefore, 5-FU coincides with the increase in dehydropyrimidine dehydrogenase activity. This leads to reduced severity of side effects and/or fewer side effects.
  • This concept is known as chronotherapy and is described, for example, by Levi et al. (Lancet 1997; 350: 681-86). Therefore, in some embodiments, the composition is administered in a chronotherapeutic dosing regimen so that the initial rise in capecitabine levels coincides with the activity of dehydropyrimidine dehydrogenase.
  • the composition is administered between about 2000 h and about 0600 h. More preferably, the composition is administered between about 2200 h and about 0400 h. More preferably still, the composition is administered between about 2200 h and about 0200 h.
  • the method is used to treat a human subject.
  • Figure 1 shows the dissolution profiles of capecitabine tablets.
  • Figure 2 is an infrared spectrum of crystalline capecitabine.
  • Figure 3 is an infrared spectrum of spray dried capecitabine.
  • Figure 4 is a Differential Scanning Calorimetry thermogram of crystalline capecitabine.
  • Figure 5 is a Differential Scanning Calorimetry thermogram of spray dried capecitabine.
  • Figure 6 is an X-Ray Diffraction spectrum of crystalline capecitabine.
  • Figure 7 is an X-Ray Diffraction spectrum of spray dried capecitabine.
  • Figure 8 is an infrared spectrum of Xeloda ® (powdered tablet).
  • Figure 9 is a differential Scanning Calorimetry thermogram of Xeloda ® (powdered tablet).
  • Figure 10 shows the dissolution profiles of capecitabine tablets.
  • Figure 11 is the implementation of dissolution equation.
  • Figure 12 shows the dissolution profile of Xeloda ® 500 mg.
  • Figure 13 shows the dissolution profile of Xeloda ® 500 mg plotted against the square root of time.
  • Figure 14 shows the simulated plasma profiles for capecitabine after ingestion of Xeloda ® (500 mg) and a theoretical extended release formulation of capecitabine with a Higuchi dissolution constant of 4.5.
  • Figure 15 shows the dissolution profile with a Higuchi dissolution constant of 4.5.
  • Figure 21 shows the dissolution profiles for a storage condition of 2-8°C.
  • Figure 22 shows the dissolution profiles for a storage condition of 25°C 60%RH.
  • Figure 23 shows the dissolution profiles for a storage condition of 40°C 70%RH.
  • Figure 24 shows the simulated plasma profiles for capecitabine after ingestion of Xeloda ® (500 mg) and a theoretical extended release formulation of capecitabine with a Higuchi dissolution constant of 2.6.
  • Figure 26 shows the dissolution profiles of the theoretical 2.6 Higuchi dissolution constant and 224 mg round tablets from physical mixed crystalline capecitabine with 40% Kollidon ® SR and co-spray dried (CO SD) capecitabine with 2.5% Kollidon ® SR.
  • Figure 27 shows the dissolution profile with a Higuchi dissolution constant of 3.0.
  • Figure 28 shows the simulated plasma profiles for capecitabine after ingestion of Xeloda ® (500 mg) and a theoretical extended release formulation of capecitabine with a Higuchi dissolution constant of 3.0.
  • the simulated curve for the to develop capecitabine formulation can be either obtained from administering 2 tablets of 500 mg capecitabine or once a 1000 mg tablet, (the total dose given per day is 1000 mg for both Xeloda ® and the to develop capecitabine formulation).
  • Figure 29 shows the dissolution profile of tablets containing 500 mg of capecitabine spray dried with 2.5% to 5.5% Kollidon ® S relative to a Higuchi dissolution constant of 3.0.
  • the tablets also contained 2.5% magnesium stearate and 0.5% silica.
  • Figure 30 shows the dissolution profile of tablets containing 500 mg of capecitabine spray dried with 5.5% Kollidon ® SR relative to a Higuchi dissolution constant of 3.0.
  • Figure 31 shows the dissolution profile of tablets containing 1000 mg of capecitabine spray dried with 4.5%) or 5.5%) Kollidon ® SR relative to a Higuchi dissolution constant of 3.0.
  • Figure 32 shows the dissolution profile of tablets containing 1000 mg of capecitabine spray dried with 5.5% Kollidon ® SR relative to a Higuchi dissolution constant of 3.0.
  • Figure 33 shows in vitro dissolution curves of four different ModraCapeOOl formulations that have been tested in a phase 0 clinical trial. These four ModraCapeOOl formulations are referred to as Formulation A, B, C and D and are the first clinically tested products. As shown, instant release of capecitabine was observed for Xeloda ® Formulation A completely releases capecitabine within a period of 18 hours. Capecitabine release was decreased for Formulation B, C and D, in that specific order. Maximum release of capecitabine was 18.43%, 13.68% and 6.53% for respectively Formulation B, C and D at 90h.
  • Figure 34 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation A (ModraCapeOO l) in patient #001.
  • Figure 35 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation A (ModraCapeOO 1 ) in patient #003.
  • Figure 36 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation A (ModraCapeOO 1 ) in patient #004.
  • Figure 37 shows average concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation A (ModraCapeOO l). Error bars represent standard deviations.
  • Figure 38 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation B (ModraCapeOOl) in patient #005.
  • Figure 39 shows concentration-time curves of capecitabine after oral dosage of Xeloda and Formulation B (ModraCapeOOl) in patient #006.
  • Figure 40 shows average concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation B (ModraCapeOOl). Error bars represent standard deviations.
  • Figure 41 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation C (ModraCapeOOl) in patient #007.
  • Figure 42 shows concentration-time curves of capecitabine after oral dosage of Xeloda ® and Formulation D (ModraCapeOOl) in patient #008.
  • Amorphous capecitabine (e.g. prepared by spray-drying) has slower in-vitro dissolution properties compared to crystalline capecitabine. This was an unexpected and surprising observation for a component like capecitabine.
  • amorphous capecitabine The extended release properties of amorphous capecitabine might explained by the remarkable gelling properties observed for the amorphous drug. In an aqueous environment amorphous capecitabine immediately forms a gel which may be responsible for the reduced dissolution rate. From the data shown, it appears that this gelling phenomenon as well as the rate and extent of dissolution is highly reproducible.
  • capecitabine can be further modulated when combined with relatively, very small amounts of controlled release excipients.
  • mixtures of amorphous capecitabine with only minor quantities of Kollidon ® SR commercially available excipient composed of 80% polyvinyl acetate, 19% povidone Ph.Eur./USP, 0.8% of sodium lauryl sulfate and about 0.2% of silica; BASF Technical Information. See http://www.pharma- ingredients.basf om/Statements/Techm ⁇
  • Table 1 shows the usual quantities of Kollidon ® SR used for active ingredients solubility ranges of practically insoluble to freely soluble.
  • Capecitabine is a freely soluble compound (26 mg/ml) in water. So about 40-55 % of Kollidon SR could be expected to be needed for capecitabine, however, the inventors found that only 2-5% was needed before slow release characteristics were provided when co-spray dried with capecitabine.
  • Table 1 Prescribed amounts of Kollidon SR.
  • capecitabine co-spray dried with 2-5% Kollidon ® SR becomes amorphous and possesses slow release characteristics.
  • a controlled release dosage form is developed from the co-spray dried powder. This tablet shows an in vitro release profile of 9 hours. Based on the solubility of capecitabine, the percentage Kollidon ® SR is far below the theoretical percentages used to get a reasonable sustained release.
  • the combination of amorphous capecitabine and Kollidon ® SR (in a physical mixture or co-spray dried) enables extended release dosing of capecitabine over a broad time spectrum with a minimal supplemental addition of excipient, which is highly attractive in view of the size of the final oral dosage form.
  • Co-spray dried with 2.5-5.5% Kollidon ® SR will result in a tablet formulation with a 21-hour release profile and an extended plasma concentration-time profile covering the 24 hours of the day.
  • Crystalline capecitabine was purchased from a commercial supplier. Amorphous capecitabine was prepared by means of spray drying an ethanolic solution of the drug. Both crystalline as well as the spray dried capecitabine were physically characterized by means of X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Fourier transform Infrared (FTIR) spectroscopy.
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • FTIR Fourier transform Infrared
  • tablets composed of amorphous and crystalline capecitabine were prepared using the same excipients as Xeloda ® both qualitatively and quantitatively (w/w ratio to capecitabine). Additional tablets without excipients were made from amorphous capecitabine.
  • Table 2 Tablet formulations (Xeloda ® excipients based on patent and percentages used in literature)
  • Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rotations per minute (rpm) paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90 and 120 minutes. After 120 minutes samples were taken every hour until complete dissolution.
  • Capecitabine concentration in the samples was measured by HPLC-UV (detection at 310 nm).
  • dissolution profiles of Xeloda ® tablets 500 mg were also determined.
  • Figure 1 shows the dissolution profiles of formulation A (Xeloda ® 500 mg), B, C and D with a content of 224 mg capecitabine (tablet composition see Table 2). It can be clearly seen that the dissolution rate of tablets containing spray-dried capecitabine is significantly decreased compared to tablets containing the crystalline drug (formulation C approximately eight-fold at 50% and 100% dissolution, formulation D approximately a six-fold at 50% and 100%). No difference in dissolution profile could be observed between the tablets prepared from crystalline capecitabine.
  • FIG. 4 and figure 5 show the Differential Scanning Calorimetry (DSC) thermograms of purchased (crystalline) and spray dried capecitabine.
  • DSC Differential Scanning Calorimetry
  • the DSC thermogram of purchased capecitabine shows a clear melting peak (T m ) at 122°C, indicative for a crystalline state.
  • T m clear melting peak
  • T g glass transition temperature
  • Figure 6 and figure 7 show the XRD spectra of purchased capecitabine (crystalline) and spray dried capecitabine.
  • the XRD spectrum of purchased capecitabine shows peaks that can be related to the crystalline conformation of capecitabine.
  • the XRD spectrum of spray dried capecitabine shows no relevant peaks, indicative for the drug being in an amorphous state. (Peak at 43 2Theta is from the metal of the sample holder).
  • Xeloda ® tablets indeed contain crystalline capecitabine
  • a tablet of Xeloda ® was powdered with mortar and pestle and physically characterized by FTIR and DSC analysis (figure 8 and 9).
  • the FTIR spectrum and DSC thermogram are similar as those obtained with purchased (crystalline) capecitabine (figure 2 and 4), confirming that capecitabine is present in Xeloda as crystalline drug.
  • This experiment was designed to examine the influence of the addition of controlled release excipients on the dissolution characteristics of crystalline and amorphous capecitabine.
  • Table 3 controlled release excipients, composition and manufacturer. Both crystalline and amorphous capecitabine (spray dried) were physically mixed (PM) with the excipients given in table 3. The percentage of controlled release excipient used was 20% w/w, similar to the % weight contribution of excipients in Xeloda ® tablets. Additionally, capecitabine and Kollidon ® SR (4:1 w/w ratio) were co-spray-dried from an ethanolic solution.
  • Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and a 50 rpm paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90 and 120 minutes. After 120 minutes samples were taken every hour until complete dissolution (100% release).
  • Table 4 shows the time until 50% of the capecitabine content of the tablets prepared using different controlled release excipients and crystalline or amorphous capecitabine was dissolved. Also, the found reduction in dissolution time of 50% Of the capecitabine content when using amorphous capecitabine compared to crystalline capecitabine is given.
  • capecitabine and Kollidon ® SR are co-spray dried the dissolution rate can even be further decreased, probably due to the increased homogeneity of the spray dried powder mixture.
  • This experiment was designed to develop a model enabling simulation of the in vivo capecitabine pharmacokinetics (PK) as a function of the in vitro dissolution characteristics of capecitabine in order to obtain the dissolution profile of the extended release capecitabine formulation to be developed.
  • PK pharmacokinetics
  • the capecitabine population PK model as proposed by Urien et al. (Journal of Pharmacokinetics and Pharmacodynamics 2005 Dec; Volume 32; Pages 817-33) was adapted in order to account for a delay in capecitabine to dissolve from its dosage form and become available for absorption (dissolution lag time).
  • the Higuchi dissolution constant was introduced in the model.
  • An in vitro dissolution curve (figure 12) can be plotted as the cumulative amount of drug released in time (Q) versus the square root of time (figure 13).
  • Q square root (Dt(2A - Cw)Cw) a straight line will appear (Higuchi T, Journal of Pharmaceutical Sciences 1963 Dec; Volume 52; Pages 1145-9) (figure 13).
  • the slope (k) of the obtained straight line in which the slope k is the so-called Higuchi dissolution constant, which is a direct measure of the dissolution rate.
  • the model can be used for the simulation of the in vivo capecitabine-PK as a function of the in vitro dissolution characteristics of the dosage form (figure 11).
  • capecitabine 500 mg
  • Table 6 and Figure 16 show the Higuchi dissolution constants as a function of the % (w/w to capecitabine) Kollidon SR of tablets composed of physical mixtures of amorphous and crystalline capecitabine and of co-spray dried material.
  • tablets exhibiting a dissolution profile with a Higuchi dissolution constant of 4.5 can be prepared from physical mixtures of crystalline or amorphous capecitabine or co-spray dried material.
  • the latter composition only requires minimal addition of excipient, which is highly attractive in view of the size of the final oral dosage form.
  • silica (glidant) and magnesium stearate (lubricant) can influence the dissolution characteristics of a tablet
  • tabletting powders of co-spray dried capecitabine and Kollidon ® SR (0%-2.5%) were mixed with percentages (w/w) of silica (0.5%) and magnesium stearate (2.5%) (standard percentages of Si0 2 and magnesium stearate).
  • percentages (w/w) of silica (0.5%) and magnesium stearate (2.5%) standard percentages of Si0 2 and magnesium stearate).
  • the influence on the dissolution of the resistance to crushing was determined by producing tablets with the maximum capable resistance to crushing.
  • Tablets of 16 mm / 8 mm (length / width) oval, a resistance to crushing of 60 N / 140 N and a capecitabine content of 500 mg were prepared. Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rpm paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90, 120 minutes. After 120 minutes samples were taken every hour until complete dissolution (100%).
  • Capecitabine concentration in the samples was measured by HPLC-UV (detection at 310 run).
  • Table 9 shows the Higuchi constants of the dissolution profiles shown in figure 17.
  • the dissolution profile of the tablet containing 2.0% Kollidon ® SR has a Higuchi dissolution constant of 5.03 and gave the best fit for the dissolution constant of 4.5 (figure 18).
  • Figure 19 shows the dissolution profiles of tablets with a resistance to crushing of 60 and 140 N. No difference in dissolution properties are seen between the 60 and 140 N tablets.
  • the tablets were stored in blisters (PVC/alu) at 4 storage conditions.
  • the storage conditions are -20°C; 2- 8°C; 25°C 60%RH and 40°C 70%RH.
  • the tablets were examined during storage for dissolution characteristics and physical stability by visual inspection for deformation and colour changes.
  • Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rpm paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90, 120 minutes. After 120 minutes samples were taken every hour until complete dissolution (100%).
  • the reference dissolution profile was obtained from the dissolution test performed at the start of the stability study.
  • the dissolution profile of the tablets stored at -20°C and 2-8°C does not change for at least 19 weeks of storage at the respective storage conditions (figures 20, 21).
  • the tablets After 10 and 19 weeks of storage at 25°C 60%RH, the tablets show a decrease in dissolution rate in the first 90 minutes and an increase in the dissolution rate after this time point compared to the reference dissolution profile.
  • the dissolution end point (100% release) remain at 180 minutes (figure 22).
  • the tablets dissolve at a similar rate as at the start of the stability study, however the dissolution end point (100% release of capecitabine) is not reached due to chemical degradation of the capecitabine (figure 23).
  • Tablets stored at -20°C and 2-8°C were physically stable upon visual examination (no deformation or colour changes) for at least 19 weeks of storage. Tablets stored at 25°C 60%RH showed slight deformation after 10 weeks of storage.
  • Tablets stored at 40°C 75%RH showed significant deformation and colour change after 10 weeks of storage and were completely liquified (melted) after 19 weeks.
  • Table 10 Overview of the stability results, showing dissolution and physical stability.
  • capecitabine tablets tested are stable with respect to dissolution characteristics and physical appearance for at least 19 weeks when stored at -20°C and 2-8°C, packed in PVC/alu blisters.
  • the capecitabine tablets stored at 25°C 60%RH and 40°C 75%RH are not stable with respect to physical appearance (25°C 60%RH, 40°C 75%RH) or dissolution characteristics (40°C 75%RH).
  • Example 7 Extended Release Formulation For Once Daily Dosing 1 It was investigated if release of capecitabine over a 24 hour period from tablets composed of either a physical mixture of crystalline capecitabine with Kollidon ® SR or co-spray dried capecitabine with Kollidon ® SR is feasible.
  • crystalline (physically mixed, PM) and amorphous (co-spray dried) capecitabine a percentage of 40% w/w and 2.5% w/w Kollidon ® SR, respectively, is theoretically needed to obtain a Higuchi constant of 2.6.
  • 0.5% w/w of colloidal silicium oxide and 2.5% w/w magnesium stearate were added as glidant and lubricant, respectively.
  • Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rpm paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90, 120 minutes. After 120 minutes samples were taken every hour until complete dissolution (100% release).
  • Figure 26 shows the dissolution curves of the tablets with crystalline (40% Kollidon ® SR) and co-spray dried (2.5% Kollidon ® SR) capecitabine.
  • the size of the tablet containing physically mixed crystalline capecitabine and Kollidon SR is 1.8 fold the size of the tablet containing co-spray dried capecitabine and Kollidon ® SR.
  • Oblong tablets of 15.8 mm length and 8.4 mm width, a resistance to crushing of 60 N and a capecitabine content of 500 mg were prepared.
  • Dissolution testing of the tablets was performed using USP apparatus 2, water at 37°C as dissolution medium and 50 rpm paddle speed. Samples were taken at 0, 10, 15, 20, 30, 45, 60, 90, 120 minutes. After 120 minutes samples were taken every hour until complete dissolution (100%). Capecitabine concentrations were analyzed by HPLC-UV (detection at 310 nm).
  • Figure 29 shows the dissolution curves of the 500 mg capecitabine tablets with 2.5-5.5% co-spray dried Kollidon ® SR. It can be seen that the tablets containing 4.5 and 5.5% w/w co-spray dried Kollidon ® SR fit the reference dissolution curve with a Higuchi coefficient of 3.0 adequately. Based on this result, 1000 mg capecitabine tablets containing 4.5 and 5.5% w/w co-spray dried Kollidon SR were prepared (oblong tablets of 22.1 mm length, 11.7 mm width, resistance to crushing of 60 N) and tested for dissolution characteristics as described above. Formulations also contained 0.5% w/w of colloidal silicium oxide and 2.5% w/w magnesium stearate as glidant and lubricant, respectively.
  • Figure 30 shows that 1000 mg capecitabine tablets containing 4.5-5.5% w/w co-spray dried Kollidon ® SR fit the reference dissolution curve with a Higuchi coefficient of 3.0 adequately.
  • the ModraCapeOOl formulation consists of an amorphous tablet core containing capecitabine in combination with a variable percentage of Kollidon ® SR, a commonly applied slow-release excipient, prepared by co-spray drying. This tablet core is coated with Kollidon ® SR with a variable layer thickness.
  • the inventors have discovered that amorphous capecitabine in itself has unique slow-release characteristics. The hypothesis which is tested in this clinical proof of concept study is that the release of capecitabine from the ModraCapeOOl formulation can be modulated by the addition and variation of the percentages of Kollidon ® SR in the tablet core (matrix) and the thickness of the Kollidon ® SR coating layer.
  • Patient characteristics and administered study drugs are shown in Table 12.
  • Patient #002 met the inclusion criteria during the screening procedure, but was eventually excluded from the study due to deterioration of his clinical status.
  • the result section is divided in subsections wherein the pharmacokinetic results are shown for each specific ModraCapeOOl formulation.
  • Patient #007 and #008 have been exposed to Xeloda ® (study day 1). On study day 2, patient #007 received ModraCapeOOl Formulation C and patient #008 received ModraCapeOOl Formulation D. Concentration-time curves for capecitabine are shown in Figure 41 (patient #007) and Figure 42 (patient #008). No capecitabine uptake is observed after oral dosage of Formulation C and D.
  • DSC Differential Scanning Calorimetry
  • Capecitabine API shows a (endothermic) melting peak at 117.41°C when heated to 130°C. The absence of other exothermic peaks and glass transitions confirm that the capecitabine is in a (100%) crystalline form.
  • capecitabine When the quick cooled sample of capecitabine is reheated again by MDSC, a glass transition at 33.69°C appears indicating amorphous content in the sample. Further heating of capecitabine gives no other thermodynamic occurrences. This implies that the amorphous capecitabine is not able to crystallise. Further, the absence of any endothermic melting peaks shows that the sample was 100% amorphous before reheating. The inability of amorphous capecitabine to crystallise during heating is an important finding.
  • Re-heating the slowly cooled substance will not show a glass transition if the substance has become fully (100%) crystalline. If this crystallization occurs during cooling then at higher temperatures (e.g. the melting temperature) an endothermic melting peak will be shown for the crystallized substance. Exothermic crystallization peaks can be identified at temperatures above the glass transition temperature if the substance is partially crystalline. The remaining amorphous part will then turn in a crystalline substance again.
  • capecitabine When the slowly cooled sample of capecitabine was reheated again by MDSC, a glass transition at 35.39°C appeared indicating amorphous content in the sample. Further heating of capecitabine gave (again) no other thermodynamic occurrences, thus implying that the amorphous capecitabine is not able to crystallise. This also shows that the sample was 100% amorphous before reheating as no endothermic melting peaks were shown. The inability of melted capecitabine to crystallise during a slow cooling process and amorphous capecitabine to crystallise during heating is an important finding.
  • Capecitabine was spray dried from a MeOH solution. After spray drying, thermograms were recorded by MDSC to characterise the spray dried powders. A solution of capecitabine in MeOH (300gr/L) was prepared. The spray dryer was equipped with a high performance cyclone and adequate components. The aspirators were adjusted as the settings during ModraCapeOOl production (spray dryer 50% / stand-alone 50%). The temperature of the inlet air was at a constant 20°C. The measured outlet temperature was 11-15°C. The settings for the solution pump (20%) and the nitrogen flow (50mm, bottom of the ball) were adjusted for spray drying pure MeOH.
  • Spray dried capecitabine shows a glass transition at 18.14°C. Further heating of spray dried capecitabine gives no other thermodynamic occurrences. It seems that the amorphous capecitabine is not able to crystallise. Also, this shows that the sample was 100% amorphous before reheating as no endothermic melting peaks were shown.
  • the glass transition is about 15°C lower than the glass transition of the amorphous capecitabine from the melted and cooled samples but in agreement with the glass transition temperature determined from the ModraCapeOOl spray dried capecitabine from an ethanolic solution. Possibly a little bit of residual solvent or water (+/-l-3%) in the powder gives a decrease in the glass transition temperature.
  • amorphous capecitabine can be produced with a Tg around 19°C by spray drying a MeOH solution. Also, the relatively high in- and outlet (20°C/11-15°C) with respect to the Tg (19°C) during spray drying of capecitabine is noteworthy as no amorphous powder has been produced with other drugs such as paracetamol and doxifluridine while the system temperatures were far below theoretically Tg's.
  • an amorphous substance tends to return to its most favourable crystalline form (lowest internal thermodynamic energy) even below the glass transition temperature so that it eventually becomes fully crystalline.
  • the amorphous substance may need a small amount of initializing energy at the onset for the rest of the sample to crystallise.
  • an amorphous sample is heated above its Tg, energy is supplied and the substance can crystallise. The higher the temperature above the Tg, the faster and easier the onset of crystallisation of the amorphous substance will be.
  • the different amorphous capecitabine samples were heated to 60°C by MDSC to again identify the Tg and to check the amorphous nature of the sample. At 60°C, the temperature was held isothermally for 48 hours.
  • a sample of amorphous capecitabine that had previously been melted and fast cooled was isothermally heated at 60°C.
  • the quick cooled sample of capecitabine was reheated by MDSC to 60°C a glass transition at 34.09°C appeared indicating the amorphous content of the sample. This was in accordance with the previously found glass transition of 33.69°C.
  • no exothermic peaks were identified, indicating that there was no crystallization of capecitabine during heating.
  • capecitabine After heating the spray dried sample of capecitabine to 60°C, the heat flow of the sample over the course of 2 days (2880 minutes) was zero. There was no exo- or endothermic energy release. This means that the capecitabine does not crystallises. It is very unexpected that the spray dried sample of capecitabine is not able to crystallise over a period of days, especially given that the difference between the glass transition and final isothermal temperature is an extra 10°C for this sample. This may help to explain why amorphous capecitabine gels after wetting and has a slower dissolution compared to crystalline capecitabine.

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Abstract

La présente invention concerne une composition pharmaceutique solide à libération prolongée destinée à une administration orale et comprenant de la capécitabine sensiblement amorphe ou un analogue de celle-ci et facultativement un composant à libération prolongée, le composant à libération prolongée étant présent en une quantité inférieure à 200% p/p, par rapport au poids total de la capécitabine ou d'un analogue de celle-ci. La présente invention concerne en outre une composition pharmaceutique solide à libération prolongée destinée à une administration orale et comprenant de la capécitabine substantiellement amorphe ou un analogue de celle-ci, la teneur en capécitabine amorphe étant de 34 % ou plus, par rapport au poids total de la composition. La présente invention concerne en outre l'utilisation des compositions en thérapie, en particulier pour le traitement d'une maladie néoplasique et dans des procédés thérapeutiques.
PCT/GB2012/052162 2011-09-02 2012-09-03 Composition solide à libération prolongée destinée à une administration orale et comprenant de la capécitabine sensiblement amorphe WO2013030602A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104739800A (zh) * 2015-02-03 2015-07-01 吉林修正药业新药开发有限公司 一种卡培他滨片组合物及其制备方法
WO2017025894A1 (fr) * 2015-08-10 2017-02-16 Intas Pharmaceuticals Ltd. Comprimés de capécitabine à libération prolongée

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WO2017025894A1 (fr) * 2015-08-10 2017-02-16 Intas Pharmaceuticals Ltd. Comprimés de capécitabine à libération prolongée

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