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WO2006043025A1 - Compositions granulaires comprenant des granules de fusion solidifies d’un inhibiteur selectif de cox-2 - Google Patents

Compositions granulaires comprenant des granules de fusion solidifies d’un inhibiteur selectif de cox-2 Download PDF

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Publication number
WO2006043025A1
WO2006043025A1 PCT/GB2005/003863 GB2005003863W WO2006043025A1 WO 2006043025 A1 WO2006043025 A1 WO 2006043025A1 GB 2005003863 W GB2005003863 W GB 2005003863W WO 2006043025 A1 WO2006043025 A1 WO 2006043025A1
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WO
WIPO (PCT)
Prior art keywords
cox
drug
composition
granular
melt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2005/003863
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English (en)
Inventor
Robert Sherry
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reckitt Benckiser Healthcare UK Ltd
Reckitt Benckiser Healthcare International Ltd
Original Assignee
Reckitt Benckiser Healthcare UK Ltd
Boots Healthcare International Ltd
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Filing date
Publication date
Application filed by Reckitt Benckiser Healthcare UK Ltd, Boots Healthcare International Ltd filed Critical Reckitt Benckiser Healthcare UK Ltd
Priority to EP05789702A priority Critical patent/EP1811964A1/fr
Publication of WO2006043025A1 publication Critical patent/WO2006043025A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/1617—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
    • A61K9/2022—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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • This invention relates to compositions containing a drug selected from a particular sub-class of non-steroidal anti-inflammatory drugs, to processes to prepare them and to uses thereof.
  • Non-steroidal anti-inflammatory drugs are a widely used class of medicaments. They are a well defined group of compounds and include phenylpropionic acids such as ibuprofen, naproxen, ketoprofen and flurbiprofen. They are primarily used for the treatment of one or more of pain, inflammation and fever, for example rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, post-operative pain, post-partum pain and soft tissue injuries.
  • NSAIDs Non-steroidal anti-inflammatory drugs
  • This invention is concerned with a sub-class of NSAIDs known as Cox-2 drugs.
  • Cyclooxygenase is an enzyme involved in the production of prostaglandins (PG). It has at least two forms, Cox-1 and Cox-2. PGs generated continuously by Cox-1 support normal body functions such as protection of the stomach lining, whereas other PGs, mainly PGE 2 , produce pain, inflammation and fever. These conditions can be treated using NSAIDs such as ibuprofen. Recent developments have produced NSAIDs that are more Cox-2 selective, i.e. are more selective inhibitors of Cox-2, and which theoretically have fewer adverse effects on normal body functions. This class of NSAIDs are known as Cox-2 drugs or simply as Cox-2s.
  • Cox-2 drugs are thought to be able to relieve pain without the gastrointestinal problems of aspirin and some non-Cox-2 specific NSAIDs.
  • Cox-2 drugs include Celecoxib (Celebrex-Pharmacia, co- marketed with Pfizer), which is indicated for the management of osteoarthritis (OA) and rheumatoid arthritis (RA), Rofecoxib (Vioxx-Merck), which is indicated for osteoarthritis and nonarthritic pain.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • Rofecoxib Vioxx-Merck
  • Cox-2 drugs generally exhibit poor solubility in water. They are conveniently administered as an oral pharmaceutical composition in the form of tablets.
  • pharmaceutically acceptable excipients must be chosen for combination with the Cox-2 drug, with which the Cox-2 drug is compatible and with which it can form tablets having a satisfactory hardness and also release the medicament rapidly into the body so that it is readily available for absorption.
  • a major issue in connection with the disorders identified above is to improve the onset of action of the drug, particularly in the treatment of pain. It is believed that rapid disintegration of a formulation releases the drug into the body quickly leading to a more rapid onset of therapeutic action compared with a standard dosage form. Accordingly, it is desired to produce a solid dosage form for oral administration adapted to disintegrate quickly in the gastro- intestinal tract. As Cox-2 drugs generally exhibit poor solubility in water, accordingly, absorption can be a problem in the acidic conditions encountered in the stomach.
  • Cox-2 drugs typically do not lend themselves for compressing directly into tablets.
  • Cox-2 drugs are typically poorly compressible and exhibit relatively poor flow characteristics.
  • compositions comprising a Cox-
  • non-selective NSAIDs we mean NSAIDs which inhibit both Cox-1 and Cox-2 enzymes without selectively targeting one Cox enzyme over another.
  • non-selective NSAIDs and NSAIDs which selectively inhibit Cox-1 include the aryl propionic acids (e.g. ibuprofen, flurbiprofen, fenoprofen, ketoprofen), the acetic acids (e.g. indomethacin, sulindac), the fenamic acids (e.g. mefenamic acid) and the biphenylcarboxylic acids (e.g. diflunisal).
  • WO 01/41733 by The Boots Company PLC discloses that if a disintegrating agent is incorporated into a molten NSAID and intimately combined therewith and then is cooled and milled to produce a granule, a composition capable of tabletting with minimum tabletting excipients and having advantageous tabletting, disintegration and dissolution properties is provided, if silicon dioxide is incorporated therein.
  • This method was substantially improved upon as disclosed in WO 02/098391.
  • the NSAID was formed as a homogenous extrudate in a melt-extrusion process. Preferred cooling and processing conditions are described.
  • the granules typically exhibit improved flow characteristics and improved compressibility compared with the Cox-2 drug alone.
  • the granules formed from a solidified melt of the Cox-2 drug are typically capable of being formed into tablets with minimum tabletting excipients which exhibit advantageous disintegration and dissolution properties.
  • the present invention provides a granular composition comprising a plurality of solidified melt granules including a Cox-2 drug.
  • melt and "molten”, as used herein, means the Cox-2 drug must melt, either fully or at least partially, during the formation of the granular composition. Preferably, the Cox-2 drug is fully melted during the preparation of the granular composition.
  • solidified melt granules means granules formed by melting the Cox-2 drug, either fully or at least partially, optionally with one or more excipients as defined herein, cooling to a temperature below the melting point of the Cox-2 drug and forming the solid mass into granules.
  • the granular composition comprises a plurality of such granules.
  • the Cox-2 drug is fully melted during the preparation of the granular composition.
  • the granular composition of the present invention typically exhibits improved flow characteristics and it is readily compressible compared with the Cox-2 drug itself.
  • the granular composition may be compressed directly into tablets with minimum, or without any, tabletting excipients.
  • tablets formed from the granular composition typically exhibit increased hardness compared with softer tablets formed from a dry blend of the Cox-2 drug.
  • the tablets formed from the granular composition typically are sufficiently hard to withstand the further rigours of the manufacturing process i.e. film coating.
  • the granular composition lends itself for formulation into solid dosage forms as it is easily compressible and tends not to stick to the punches of a tabletting machine.
  • the throughput of a compression process employing the granular composition of the present invention is substantially increased compared with employing a dry blend of the Cox-2 drug.
  • the granular composition of the present invention offers significant manufacturing advantages for producing solid dosage forms containing a Cox-2 drug as it may permit a reduction in the overall costs and reduce the complexity of the manufacturing process.
  • compositions in particular a solid dosage form for oral administration, prepared from the granular composition of the present invention have valuable disintegrating properties.
  • dissolution results of such pharmaceutical compositions typically exhibit a relatively high level of the Cox-2 drug dissolved in the aqueous medium after relatively short periods of time.
  • the granular composition of the present invention typically provides advantages in processing Cox-2 drugs, improved patient compliance, improved hardness of solid dosage forms with desirable disintegration and dissolution properties, and a lowering of the overall costs and complexity of tablets formed from Cox-2 drugs.
  • Cox-2 drug we mean a compound which selectively inhibits the inducible isoform of cyclooxygenase (Cox-2) compared with the constitutive isoform of cyclooxygenase (Cox-1). Such a compound is commonly known in the art as a “selective Cox-2 inhibitor”.
  • the selectivity of a compound for inhibiting Cox-2 in preference to Cox-1 may be defined by the ratio of the IC 50 for Cox-1 divided by the IC 50 for Cox-2 (IC 50 Cox-1 /IC50 Cox-2).
  • the IC 50 value is the concentration at which the compound achieves 50% of its maximal inhibition of Cox, and is usually expressed in molarity.
  • a compound which has an IC 50 Cox-1 /IC 50 Cox-2 ratio of greater than 1 selectively inhibits Cox-2 compared with Cox-1.
  • the IC 50 ratio of a compound for inhibiting Cox-1 and Cox-2 may be determined by one of the in-vitro, in-vivo or ex-vivo assays as disclosed in US Patent no. 6,846,818B by Pfizer Inc.
  • the Cox-2 drug exhibits an IC 50 Cox-1 /IC 50 Cox-2 ratio of greater than 1 , more preferably greater than or equal to 1.5, even more preferably greater than or equal to 2, even more preferably greater than or equal to 2.5, even more preferably greater than or equal to 3, even more preferably greater than or equal to 5, especially greater than or equal to 25 as determined by one of the in-vitro, in-vivo or ex-vivo assays as disclosed in US Patent no. 6,846,818B by Pfizer Inc.
  • the invention allows the formation of a granular composition comprising a variety of Cox-2 drugs.
  • Cox-2 drugs that can be used in the present invention include Etodolac (available from AHP(shire UK)), Piroxicam, Meloxicam (available from Boehringer Ingelheim), Nimesulide (available form Helsinn), Rofecoxib (available from Merck) Valdecoxib (available from Pfizer), Lumiracoxib (available from Norvartis), Eterocoxib (available from Merck) and Celecoxib (available from Pfizer/Roche).
  • the Cox-2 drug is Etodolac, Meloxicam, Celecoxib or Nimesulide.
  • Cox-2 drug we include all stereoisomers and all optical isomers (e.g. R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
  • the Cox-2 drug may be in the form of a pharmaceutically acceptable salt. Most advantageous results are obtained with racemates, since the heat involved in the melt formation process will tend to transform any single enantiomeric form into the racemate or into an amorphous state.
  • the surface area of the Cox-2 drug in the melt granule is typically significantly greater than that of conventional crystals of the Cox-2 drug.
  • the particle size is typically less than the particle size produced by micronising Cox-2 drug particles which is a conventionally favoured method of improving the dissolution.
  • the invention allows the formulation of any relatively low melting Cox-2 drug into an acceptably tasting, readily disintegrating composition.
  • the melting point of such compounds is generally low enough to allow the melting thereof using standard equipment. It is also important that there is not a deleterious effect on other optional ingredients which may be incorporated in the molten Cox-2 drug, for example a disintegrant.
  • typical melting points of the low melting Cox-2 drug would be expected to fall within the range 30-300 0 C (for example Meloxicam: 254 0 C, Rofecoxib: 207-208°C and Piroxicam: 197- 201 0 C).
  • Preferred Cox-2 drugs have lower melting points so that the melting process does not use significant amounts of energy, which thus has an effect on production costs.
  • Preferred melting points are in the range 30-200 0 C (for example Celecoxib: 157-159 0 C), more preferably 30-150 0 C (for example Etodolac: 145-148X and Nimesulide: 143-144.5 0 C).
  • Preferred low-melting Cox-2 drugs are Celecoxib (157-159°C), Etodolac (145- 148°C) and Nimesulide (143-144.5°C) or salts or enantiomers thereof.
  • the Cox-2 drug when the Cox-2 drug is melted a liquid is formed.
  • the Cox-2 drug melts and forms a melt phase having any other optional excipients contained therein.
  • the Cox-2 drug On cooling the molten Cox-2 drug, the Cox-2 drug typically forms a continuous crystalline type solid phase.
  • the solidified melt may be milled directly into a granule that is suitable for compressing directly into a pharmaceutical dosage form with minimal tabletting excipients.
  • the molten Cox-2 drug on cooling forms a single continuous phase, namely a single continuous crystalline solid phase i.e. the crystalline structure of the Cox-2 drug is not interrupted by a different crystalline structure of the Cox-2 drug.
  • Cox- 2 drug is only partially melted where the crystalline structure of the melted Cox- 2 drug is interrupted by the non-melted Cox-2 drug, thus providing that the Cox-2 drug does not have a single crystalline structure as the crystalline structure of the solidified melted Cox-2 drug is different (e.g. particle size) than the crystalline structure of unmelted Cox-2 drug.
  • a resulting pharmaceutical composition i.e. a solid dosage form
  • a pharmaceutical composition formed from a granular composition where the Cox-2 drug is fully melted typically releases a higher concentration of Cox-2 drug in an aqueous medium over a relatively short time compared with a comparable pharmaceutical composition formed from a granular composition where the Cox-2 drug is partially melted.
  • the invention is especially adapted to Cox-2 drugs that have a low aqueous solubility.
  • the granular composition and the melt granules may comprise one or more different Cox-2 drugs as defined herein.
  • the granular composition and the melt granules comprise a single Cox-2 drug.
  • the granular composition and the melt granules comprise a single Cox-2 drug in a single enantiomeric form or as a racemic mixture.
  • the granular composition i.e. the melt granules
  • a pharmaceutical composition formed therefrom may include one or more further pharmaceutically active agents in addition to the Cox-2 drug.
  • a highly preferred granular composition i.e. the melt granules
  • a pharmaceutical composition formed therefrom includes Cox-2 drugs as the only pharmaceutically active agent, most preferably a single Cox-2 drug as defined herein.
  • the melt granules may consist of the Cox-2 drug only.
  • the melt granules may further include one or more excipients as defined herein and/or a further therapeutically active agent as defined herein.
  • excipients as defined herein and/or a further therapeutically active agent as defined herein.
  • a highly preferred expicient for inclusion in the melt granules is a disintegrating agent.
  • the solidified melt granules of the granular composition include one or more disintegrating agents. If a disintegrating agent is incorporated into the molten Cox-2 drug and intimately combined therewith, the melt mixture cooled and milled to produce a plurality of solidified melt granules, a composition capable of tabletting with minimum or without any tabletting excipients and having advantageous tabletting, disintegration and dissolution properties is provided.
  • the granular composition comprises a plurality of solidified melt granules comprising a Cox- 2 drug and a disintegrating agent incorporated therein.
  • the disintegrating agent is uniformly dispersed within the melt granules.
  • a disintegrating agent may also or alternatively be present as an extra-granular component used in tablet formation.
  • the disintegrating agent is present within the granular composition, even more preferably the disintegrating agent is only present within the granular composition.
  • a disintegrating agent is incorporated into the melt, comprising the molten Cox-2 drug, and intimately combined therewith, the mixture cooled and milled to produce a granule, a pharmaceutical composition capable of tabletting with minimum tabletting excipients and having advantageous tabletting, disintegration and dissolution properties is provided.
  • the disintegrating agent has the effect of causing a solid dosage form, such as a tablet, formed from the granular composition to disintegrate quickly under the conditions found in the gastro-intestinal tract.
  • disintegrating agents include one or more of wheat starch, maize starch, potato starch, sodium starch glycolate, low-substituted hydroxy propyl cellulose, alginic acid, cross-linked polyvinylpyrrolidone, magnesium aluminium silicate and croscarmellose sodium.
  • Preferred disintegrating agents are those which swell on the action of water thus causing the ingredients in the granular composition, and solid dosage forms prepared therefrom, to be pushed apart and out into the aqueous disintegration medium.
  • Preferred disintegrating agents comprise one or more of croscarmellose sodium and sodium starch glycolate, especially croscarmellose sodium.
  • the disintegrating agent is present in an amount of less than or equal to 25% by wt, more preferably less than or equal to 23% by wt, even more preferably less than or equal to 20% by wt of the granular composition.
  • the disintegrating agent is present in an amount of greater than or equal to 1 % by wt, more preferably greater than or equal to 2% by wt, more preferably greater than or equal to 5% by wt, most preferably greater than or equal to 8% by wt of the granular composition.
  • the disintegrating agent is present in an amount of less than or equal to 25% by wt, more preferably less than or equal to 23% by wt, even more preferably less than or equal to 20% by wt of the solidified melt granules.
  • the disintegrating agent is present in an amount of greater than or equal to 1 % by wt, more preferably greater than or equal to 2% by wt, even more preferably greater than or equal to 5% by wt, most preferably greater than or equal to 8% by wt of the solidified melt granules.
  • the percent by weight ratio of Cox-2 drug to disintegrating agent in the solidified melt granules is 30:1 to 1 :1 , more preferably 20:1 to 2:1, most preferably 10:1 to 3:1 parts by weight.
  • the disintegrating agent preferably croscarmellose sodium or sodium starch glycolate (although any known disintegrant may be used), may be the sole excipient incorporated within the Cox-2 drug melt granules.
  • the granular composition i.e. solidified melt granules
  • the granular composition may consist essentially of (i.e. greater than 98% by weight of the composition) a Cox-2 drug and disintegrating agent or it may consist essentially of a Cox-2 drug, a disintegrant, a diluent and optionally a surfactant.
  • the present invention thus preferably provides a granular composition comprising a plurality of solidified melt granules of a Cox-2 drug having a melting point in the range 30-300 0 C and incorporating a disintegrant uniformly dispersed therein.
  • the granules comprise a continuous phase of said Cox-2 drug.
  • the granular composition may be formed into a compressed tablet.
  • a preferred granular composition comprises a plurality of solidified melt granules consisting essentially of a Cox-2 drug as defined herein and a disintegrating agent.
  • An alternative preferred granular composition comprises a plurality of solidified melt granules consisting essentially of a Cox-2 drug (preferably Celecoxib, Etodolac, Nimesulide, Rofecoxib, Piroxicam or Meloxicam), a disintegrant and a surfactant.
  • a further alternative preferred granular composition comprises a plurality of solidified melt granules consisting essentially of a Cox-2 drug (preferably Celecoxib, Etodolac, Nimesulide, Rofecoxib, Piroxicam or Meloxicam), a disintegrant, a diluent and optionally a surfactant.
  • a Cox-2 drug preferably Celecoxib, Etodolac, Nimesulide, Rofecoxib, Piroxicam or Meloxicam
  • Cox-2 drug in the granular composition i.e. the solidified melt granules
  • Low dose drugs such as Meloxicam or Rofecoxib may form as little as 20% by weight of the granular composition in order to provide a unit dosage form prepared therefrom (i.e. a tablet) is not too small.
  • a preferred feature of the present invention is that low melting, high dose Cox-2 drugs, such as Celecoxib, Etodolac or Nimesulide can be formulated into smaller dosage forms.
  • the Cox-2 drug will suitably form greater than or equal to 50% by weight of the granular composition, more preferably greater than or equal to 70% by weight of the granular composition (for example 70 to 99% by weight), preferably 70 to 95%, further preferably 75 to 85% by weight of the granular composition.
  • the granular composition may be prepared in accordance with the present invention by a simple cost- efficient manufacturing process on a large scale. Formulations prepared from the granular composition according to the present invention have been found to be stable on storage and to have advantageous dissolution properties.
  • the " granular composition typically exhibits desirable flow and compressibility characteristics and it may be tabletted using minimum excipients without sticking or capping during the tabletting process to provide a dosage form having suitable hardness properties combined with advantageous disintegration properties. Furthermore, the poor taste associated with certain Cox-2 drugs is significantly improved.
  • the solidified melt granules may be formulated directly or they may be combined with an extra-granular component and formulated into a unit dosage form.
  • the present invention provides a unit dosage form for oral administration comprising a granular composition, as defined herein, including a plurality of solidified melt granules comprising a Cox-2 drug and optionally one or more excipients (i.e. disintegrant incorporated therein).
  • the unit dosage form is a solid unit dosage form.
  • the unit dosage form may be swallowed, dispersed in water prior to ingestion or adapted to disintegrate in the mouth.
  • the unit dosage form is adapted to release the Cox-2 drug in the stomach or the gastro-intestinal tract.
  • the unit dosage form is swallowed by a patient in need thereof.
  • Suitable unit dosage forms include compressed tablets, chewable tablets, effervescent formulations, trouches. Most preferably, the unit dosage form is in the form of a compressed tablet, especially a non-effervescent compressed tablet.
  • the compressed tablet may optionally be coated with a film coat, for example based on a conventional cellulose polymer such as hydroxypropylmethyl cellulose, or a conventional sugar coat, for example base on sucrose or lactose.
  • a film coat for example based on a conventional cellulose polymer such as hydroxypropylmethyl cellulose, or a conventional sugar coat, for example base on sucrose or lactose.
  • the Cox-2 drug may suitably be present in an amount of 5 to 95% by weight, preferably 5 to 90% by weight of the unit dosage form. It will be appreciated that the amount of Cox-2 drug present in the unit dosage form depends to a certain extent on the amount of Cox-2 drug required to induce a therapeutic effect.
  • the Cox-2 drug may be present in an amount of 5 to 20% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • the Cox-2 drug particularly high dose Cox-2 drugs, will suitably form greater than 50% by weight of the unit dosage form, for example 60 to 97% by weight, preferably 70 to 95% by weight, more preferably 70 to 90% by weight and most preferably 75 to 85% by weight of the unit dosage form.
  • Unit dosages for effective therapy are known to those skilled in the art for each Cox-2 drug.
  • they may comprise the Cox-2 drug to an extent of 5mg, 7.5mg, 12.5mg, 25mg, 50mg, 100mg, 150mg, 200mg, 250mg, 300mg and 600mg.
  • the precise unit dosages are chosen to give the equivalent Cox-2 drug doses given above.
  • the maximum daily dose of Rofecoxib is generally 50 mg.
  • a single unit daily dose may be 12.5 mg.
  • Preferred unit doses are in the range 12.5-50 mg, more preferably 12.5-25 mg.
  • the maximum daily dose of Celecoxib is generally 400 mg.
  • a single unit dose may be 100 mg.
  • Preferred unit doses are in the range 100-200 mg, more preferably 200 mg.
  • the maximum daily dose of Meloxicam is generally 15 mg.
  • a single unit daily dose may be 7.5 mg.
  • Preferred unit doses are in the range 7.5-15 mg, more preferably 7.5 mg.
  • the maximum daily dose of Etodolac is generally 600 mg.
  • a single unit dose may be 600 mg.
  • the maximum daily dose of Nimesulide is generally 200 mg.
  • a single unit daily dose may be 25 mg.
  • Preferred unit doses are in the range of 25-100 mg, more preferably 50 mg.
  • the granular composition as defined herein is combined with an extra-granular component and then formulated into a unit dosage form.
  • the extra-granular component comprises the ingredients incorporated in the unit dosage form which are not contained in the solidified melt granules. They may be mixed with the solidified melt granules simultaneously or at sequential stages in the process to prepare unit dosages.
  • a particular advantage of the present invention is that all of the ingredients of the extra-granular component may be combined with the granular composition at the same time and also there typically does not have to be significant processing of the ingredients in the extra-granular component prior to combining with the granular composition.
  • the melt granules may be combined with the extra-granular component by conventional mixing and blending techniques so as to form a uniform mixture of ingredients. Examples of apparatus which may be used to facilitate this process are: Ribbon Blender, IBC Blender, V-Blender and Plough Blender.
  • the uniform mixture is typically a dry blend which may be compressed into tablets using standard tabletting machines.
  • the present invention provides a pharmaceutical composition comprising:
  • a granular composition as defined herein, comprising a plurality of solidified melt granules comprising a Cox-2 drug and optionally one or more excipients as defined herein;
  • the pharmaceutical composition may be in the form of a dry blend which is suitable for forming into a unit dosage form as defined herein.
  • a preferred unit dosage form as defined herein comprises:
  • a granular composition as defined herein, comprising a plurality of solidified melt granules comprising a Cox-2 drug and optionally one or more excipients; and, (b) an extra-granular component comprising one or more ingredients as defined herein.
  • the unit dosage form (and the pharmaceutical composition) comprises 50 to 99.9% by weight, more preferably 60 to 99% by weight, even more preferably 70 to 99% by weight of the granular composition based on the total weight of the unit dosage form (and the pharmaceutical composition).
  • the unit dosage form (and the pharmaceutical composition) comprises 0.1 to 50% by weight, more preferably 1 to 40% by weight, even more preferably 1 to 30% by weight of the extra-granular component based on the total weight of the unit dosage form (and the pharmaceutical composition).
  • the preferred amounts of Cox-2 drug in the unit dosage form, the amount of Cox-2 drug in the granular composition, the amount of excipients (i.e. disintegrating agents) present in the granular composition, and the ratios of such ingredients, as defined in respect of the granular composition or a unit dosage form prepared from the granular composition, apply equally to the pharmaceutical composition and the unit dosage form formed therefrom.
  • Suitable ingredients which may be present in the extra-granular component, or may be employed as excipients in the granular composition include any of the following:
  • Suitable water-soluble diluent materials include sugars (such as sucrose, fructose, lactose, dextrose), cyclodextrin, maltodextrin and salts of organic acids (e.g. sodium citrate and potassium citrate).
  • Suitable water-insoluble diluent materials include cellulose derivatives (such as microcrystalline cellulose) starch and derivatives thereof (such as pre- gelatinised starch), dicalcium phosphate, tricalcium phosphate, calcium sulphate, calcium carbonate. Microcrystalline cellulose and dicalcium phosphate are preferred water insoluble diluents.
  • the diluent may be present in an amount of 0 to 90% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • the amount of diluent present will depend on whether the Cox-2 drug present in the melt granules is a high dose or low dose drug.
  • the diluent is typically present in an amount of 0 to 25% by weight, more preferably 0 to 15% by weight, preferably 0 to 10% by weight of the unit dosage form.
  • the diluent may be present in an amount of 30 to 90% by weight, more preferably 40 to 80% by weight of the unit dosage form.
  • the diluent may be present in the melt granules and/or the extra- granular component, preferably if the diluent is present it is exclusively within the extra-granular component of the unit dosage form.
  • Preferred surfactants are sodium lauryl sulphate and poloxamer.
  • the surfactant may be used to an extent of 0.05 to 8% by weight, more preferably 0.1 to 5% by weight, most preferably 0.2 to 2% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • the surfactant may be present within the melt granules, preferably if a surfactant is present in the unit dosage form it is present exclusively within the extra-granular component.
  • wicking agent refers to any excipient that forms capillary pathways within a compact, such as a tablet, such that when the compact is placed in an aqueous environment liquid is drawn through the pathways by capillary action, disintegration of the compact occurs as interparticulate bonds are ruptured by the ingress of liquid.
  • the wicking agent is insoluble in water and is preferably present only in an extra-granular composition used in tabletting.
  • the insoluble wicking agent is selected from inorganic materials, starch materials, cellulose materials such as hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), and mixtures thereof.
  • the inorganic material comprises silicon dioxide, PTFE powder, alkali metal silicates, alkaline earth metal silicates, alkali metal carbonates and bicarbonates and alkaline earth metal carbonates. Examples include sodium carbonate, sodium bicarbonate, potassium carbonate, magnesium carbonate, calcium carbonate, PTFE powder, sodium silicate, potassium silicate, magnesium silicate and calcium silicate.
  • the starch material comprises starches such as potato starch, maize starch, rice starch, tapioca starch and starch derivatives including modified starches such as pre-gelatinised starch.
  • the wicking agent comprises at least one of silicon dioxide and/or alkaline earth metal carbonates, especially calcium carbonate, talc, maize starch and pre-gelatinised starch. Most preferably, the wicking agent comprises silicon dioxide.
  • the wicking agent especially silicon dioxide
  • the wicking agent is present in an amount of 0.05 to 10% by weight, more preferably 0.05 to 5% by weight, even more preferably 0.1 to 3% by weight, most preferably 0.2 to 1% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • the wicking agent is present exclusively within the extra- granular component.
  • Conventional lubricants for ibuprofen tablets may be used for example stearic acid, sodium lauryl sulphate, polyethylene glycol, hydrogenated vegetable oil, sodium stearyl fumarate, magnesium stearate or calcium stearate. These may be incorporated in the unit dosage form in amounts of 0.05 to 5% by weight, preferably 0.1 to 3% by weight based on the total weight of the unit dosage form.
  • the lubricant if present in the unit dosage form, may be incorporated in the solidified melt granules and/or the extra-granular component, preferably the lubricant is only present within the extra-granular component.
  • a further pharmacologically active ingredient and/or enhancing agent is a pharmacologically active ingredient and/or enhancing agent
  • Suitable agents may include any other ingredient commonly used in a composition useful to treat pain, inflammation and/or fever, for example caffeine or another xanthine derivative, another analgesic, for example codeine or paracetamol, another non-selective NSAID or Cox-1 selective NSAID, for example ibuprofen, a skeletal muscle relaxant: an antihistamine (e.g.
  • acrivastine astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine, dexbromopheniramine, dexchloropheniramine, diphenhydramine, ebastine, ketotifen, Iodoxamide, loratidine, levocabastine, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setastine, tazifylline, warmthlastine, terfenidine, tripelennamine or triprolidine (preferably non-sedating antihistamines are employed)); a decongestant (e.g.
  • pseudoephedrine — phenylpropanolamine and phenylephrine
  • a cough suppressant e.g. caramiphen, codeine or dextromethorpan
  • an expectorant e.g. guaifenesin, potassium citrate, potassium guaiacolsuphonate, potassium sulphate and terpin hydrate
  • an anti-ulcer histamine antagonist e.g. misoprostol
  • an anti-nausea drug e.g. domperidone.
  • the further pharmacologically active ingredient and/or enhancing agent may be incorporated in the melt granules and/or the extra-granular component.
  • a highly preferred further pharmacologically active ingredient comprises paracetamol or ibuprofen.
  • Such extra active ingredients and/or enhancing agents may be incorporated in the melt granules or in the extra-granular component which is combined with the melt granule prior to formulation into a compressed tablet.
  • Celecoxib, Etodolac or Nimesulide include: codeine phosphate (preferably 5-30 mg, more preferably 10-15 mg); ephidrine (preferably 7.5 - 60 mg, more preferably 15 - 30 mg); pseudoephidrine (preferably 7.5 - 60 mg, more preferably 15 - 30 mg); caffeine (preferably 7.5 - 50 mg, more preferably 15 - 30 mg); ascorbic acid (preferably 20 - 200 mg, more preferably 40 -100 mg); phenylpropanolamine (e.g. as the hydrochloride) (preferably 6.25 - 50 mg, more preferably 12.5 - 25 mg); diphenhydramine (e.g.
  • hydrochloride preferably 6.25 - 50 mg, more preferably 12.5 - 25 mg
  • phenylephrine e.g. as the hydrochloride
  • misoprostol preferably 200 mg
  • paracetamol preferably 125-500 mg, more preferably 250-500 mg
  • ibuprofen preferably 200 to 400 mg
  • Preferred dosage forms comprising a Cox-2 drug and another pharmaceutically active ingredient and/or enhancing agent include:
  • Celecoxib, Etodolac or Nimesulide and 5.0-10% w/w diphenylhydramine
  • the ratio of Cox-2 drug to the further pharmacologically active ingredient or ingredients will depend on the proportion and type of the Cox-2 drug in the dosage form. Thus, depending on the dosage of the drug, it can be expected to fall in the range 20:1 to 1 :100, conveniently 5:1 to 1 :40.
  • the ratio of Cox-2 drug to further pharmacologically active ingredient or ingredients may preferably be in the range 1:5 to 1:25, more preferably 1 :6 to 1 :20.
  • the ratio of Cox-2 drug to further pharmacologically active ingredient may suitably be 10:1 to 1 :10, preferably 1 :4 to 4:1 parts by weight.
  • the further pharmacologically active ingredient or ingredients is present in the granular component of the formulation it is typically combined with the Cox-2 drug in the solid state. Typically, the mixture is then heated to melt at least the Cox-2 drug. A melt liquid is formed.
  • the further pharmacologically active ingredient or ingredients may be soluble or insoluble in the Cox-2 drug melt. Accordingly, the further pharmacologically active ingredient or ingredients may dissolve or be dispersed within the liquid Cox-2 drug melt.
  • the liquid melt is cooled until solidified melt is formed. As the mixture cools, it becomes more viscous. The mixture is allowed to cool by methods hereinafter discussed until a solid is produced.
  • the melt granules may be formed before, during or after the Cox-2 drug solidifies.
  • solidified melt granules means granules formed by combining a further pharmacologically active ingredient with a molten Cox-2 drug, cooling the mixture to form a solidified melt and forming the solidified melt into a plurality of melt granules.
  • the further pharmacologically active ingredient or ingredients component may be the sole ingredient incorporated within the Cox-2 drug melt granules or it may be combined with a disintegrant and/or a diluent and optionally a surfactant and other tabletting excipients. Accordingly, in one preferred embodiment, the granules may comprise greater than 80% w/w of the Cox-2 drug and further pharmacologically active ingredient or ingredients (i.e. 80-100 % w/w). Preferred melt granules comprise a Cox-2 drug, further pharmacologically active ingredient or ingredients, a disintegrant and optionally a surfactant and/or a diluent.
  • the formulation comprises 90% -100% w/w (preferably 95-100% w/w) of the combination of Cox-2 drug, further pharmacologically active ingredient or ingredients and disintegrant.
  • the formulation consists essentially of (98-100% w/w) of the combination of Cox-2 drug, further pharmacologically active ingredient or ingredients and a disintegrant.
  • Further preferred melt granules consist essentially of a Cox-2 drug, further pharmacologically active ingredient or ingredients, a disintegrant and a surfactant.
  • a further preferred granular component consists essentially a Cox- 2 drug, further pharmacologically active ingredient or ingredients, a disintegrant, a surfactant and a diluent.
  • the Cox-2 drug is selected from the lower melting point materials Celecoxib, Etodolac or Nimesulide.
  • Formulations prepared according to the present invention have valuable disintegrating properties, an unexpectedly high level of the Cox-2 drug is dissolved in an aqueous medium after relatively short periods of time.
  • a preferred pharmaceutical composition i.e. a unit dosage form, especially a compressed tablet, comprises:
  • an extra-granular component comprising an insoluble wicking agent, as defined herein, present in an amount of 0.05 to 5.0% by weight based on the total weight of the unit dosage form.
  • a further preferred pharmaceutical composition i.e. a unit dosage form, especially a compressed tablet composition, comprises:
  • an extra-granular component comprising an insoluble wicking agent present in an amount of 0.05 to 5.0% by weight based on the total weight of the unit dosage form.
  • the insoluble wicking agent comprises silicon dioxide.
  • the extra-granular component further includes a diluent as defined therein.
  • the granular composition as defined hereinbefore is present in an amount of 50 to 99.9% by weight, more preferably 60 to 99% by weight, even more preferably 70 to 99%, even more preferably 80 to 99.9% by weight and most preferably 95 to 99.9% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • the extra-granular component as defined hereinbefore is present in an amount of 0.1 to 50% by weight, more preferably 1 to 40% by weight, even more preferably 1 to 30% by weight, even more preferably 1 to 20% by weight and most preferably 1 to 5% by weight of the unit dosage form based on the total weight of the unit dosage form.
  • Cox-2 drug and the disintegrating agent may be present in the amounts as defined hereinbefore.
  • solidified melt granules comprising 70-97% Etodolac by weight of the granule (preferably 70-95% by weight), 3-25% croscarmellose sodium by weight of the granule (preferably 5-20% by weight) and 0-20% diluent by weight of the granule (preferably 8-16% by weight) uniformly dispersed therein, the Etodolac being present as a continuous phase;
  • a granular composition comprising: i) 70-90% w/w Etodolac, said Etodolac being present as a continuous phase; ii) 8-20% w/w croscarmellose sodium; iii) 0-20% w/w diluent; and
  • an extra-granular composition comprising: iv) 0.5%-2% w/w insoluble wicking agent; and v) 0.1-2.5% w/w surfactant. the sum of components (i) to (v) being greater than 99% by weight of the formulation.
  • the Etodolac may be replaced in whole or part by one or more alternative Cox-2 drugs, in particular high dose Cox-2 drugs such as Celecoxib and Nimesulide.
  • Cox-2 drugs are primarily anti-inflammatory and analgesic agents, with some anti-pyretic activity. Their use has also been proposed for other therapeutic areas, including the treatment of various forms of cancer, Alzheimer's Disease, periodontal bone loss and pruritus.
  • the dosage forms of the present invention are therefore indicated for use in the treatment of all therapeutic uses for which cyclooxygenase Il inhibitors are effective, including rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. They may also be used in the treatment of pyrexia, acute pain, primary dysmenorrhoea and cancer.
  • the present invention provides a granular composition as defined herein or a unit dosage form as defined herein for use in medicine.
  • the present invention provides a granular composition as defined herein or a unit dosage form as defined herein for use in the treatment of pain and/or inflammation and/or fever and/or cancer.
  • the present invention provides a method of treating pain and/or inflammation and/or fever and/or cancer comprising the administration of a granular composition as defined herein or a unit dosage form as defined herein to a mammal in need thereof.
  • the present invention provides the use of a granular composition as defined herein in the manufacture of a medicament for treating pain and/or inflammation and/or fever and/or cancer.
  • the present invention provides the use of a unit dosage form as defined herein in the manufacture of a medicament for treating pain and/or inflammation and/or fever and/or cancer
  • the present invention provides a process for producing a granular composition as defined herein comprising a plurality of solidified melt granules including a Cox-2 drug, the process comprising the steps of:
  • step (a) of the above process takes place in a melt extruder.
  • the melt is cooled below the melting point of the Cox-2 drug to form a solidified melt and the solidified melt is formed into a plurality of solidified melt granules.
  • the plurality of solidified melt granules may be formed by comminuting the solidified melt.
  • the melt comprises a homogeneous melt material which is formed into two or more thin ribbons, having a depth of 10 mm or less, preferably 0.1 to 6 mm, more preferably 0.5 to 5 mm, for example 3 to 4 mm and most preferably 1-3 mm, for example 2 mm and which solidify in 5 minutes or less, preferably 1 minute or less.
  • Cox-2 drug in addition to the Cox-2 drug that may be present in the granules of the present invention are described above.
  • Such components include but are not limited to additional pharmacologically active agents, disintegrants, diluents, lubricants and the acid or basic component of an effervescent couple.
  • the Cox-2 drug and any additional component to be included in the melt granules may be mixed in the solid state prior to melting the Cox-2 drug.
  • the additional component(s) of the melt granules may be added to the melted Cox-2 drug.
  • Processes in which one or more additional components are mixed with the Cox-2 drug prior to the melting of that drug and in which one or more further additional components are added to the molten Cox-2 drug are also within the scope of the present invention.
  • the Cox-2 drug is heated in a suitable vessel until molten. Any excipient may then be added to the molten mass and thoroughly combined therewith to form a homogeneous mixture. Optional additional components may be blended into the molten Cox-2 drug simultaneously or sequentially.
  • the molten mixture may then be discharged into an appropriate cooling system, for example a cooled belt which may continuously rotate and deliver the cooled melt to a comminuting device such as a scraper bar and/or a mill.
  • the granular composition is formed by a melt extrusion process.
  • a melt extrusion process Such apparatus is commonly used and is familiar to those skilled in the art.
  • a suitable extruder for use in the present invention is disclosed in WO 02/098391 and is available from APV, UK, Ltd model number APV MPC40.
  • the Cox-2 drug and any additional component are fed into an extruder type system (preferably having first been combined by blending together).
  • the materials are heated and mixed in the extruder until the Cox-2 drug is molten (preferably fully molten) and a uniform mixture is produced.
  • the Cox-2 drug and any additional component are extruded and the extrudate cooled.
  • the Cox-2 drug and any additional component are extruded in a twin screw extruder.
  • the hot mass (comprising the Cox-2 drug and any additional component) extruded forms an agglomerated mass which may be collected and, if desired, milled to form granules.
  • the Cox-2 drug is melted. Under pressurised conditions, the drug may be melted at a temperature below its normal melting point. Melting may be carried out according to known methods, including for example, heating in a vessel to a temperature above the melting point of the Cox-2 drug or by extrusion in a heated extruder. Under conditions of pressure, the drug may be melted at a temperature below its normal melting point. The maximum temperature is determined by the stability of the molten drug and ingredients combined therewith. The drug may be heated to any convenient temperature. Generally, the higher the temperature, the more quickly the drug will melt although this must be balanced by the energy input required to heat the drug.
  • the Cox-2 drug will be heated to not more than 50 0 C, preferably not more than 25 0 C, for example not more than 1 to 25°C, preferably 5-20 0 C, most preferably 5 -10 0 C, above its melting point to keep energy costs to a minimum.
  • the extruder is heated to a given temperature.
  • the work on the Cox-2 drug by the screw configuration in the extruder will also contribute to melting the Cox-2 drug thereby reducing its external applied temperature requirement.
  • the extruder barrel may be heated to a temperature less than the melting point of the Cox-2 drug.
  • the normal melting point of Celecoxib is 157- 159°C, however under conditions of force/pressure (such as may be encountered in an extruder or similar processing device), the external applied heat necessary to melt the Celecoxib may be reduced significantly through the mechanical heat generated by the intense mixing action within the extruder.
  • the extruder will be heated to a temperature not less than 25"C below the melting point of the drug, preferably in the range from 2O 0 C below the melting point of the drug to 5O 0 C above the melting point of the drug, more preferably from 15 0 C below the melting point of the drug to 25 0 C above its melting point and most preferably to a temperature in the range of 10 0 C on each side of the melting point of the drug.
  • Some extruders allow different zones to be heated to different temperatures in the extruder. These temperatures can be chosen as desired to ensure that the Cox-2 drug is fully melted.
  • the drug and optional excipients are heated to a temperature in the range 100-250 0 C, more preferably 120-200°C to melt said drug.
  • the Cox-2 drug is Etodolac it may conveniently be heated in the range 130-145 0 C, more preferably 135- 140 0 C.
  • the Etodolac may also be heated and subjected to conditions of force, such as by heat-extruding the Etodolac, for example in a twin-screw extruder.
  • the temperature of the Etodolac in the extruder barrel is preferably 135°C.
  • the Cox-2 drug is preferably melted in a heated extruder barrel having an inlet for the solid drug and an outlet for the molten extrudate.
  • the barrel may be divided into different heating zones as desired.
  • the extruder may also have one or more cooling zones. The cooling zones may be necessary to remove the heat generated by the kneading action on the material being extruded, particularly to ensure that there is a good flow of material into the extruder and out from the extruder.
  • the extruder is provided with a cooling zone and a heating zone. Further preferably, there is provided a cooling zone at the inlet portion of the extruder so that the material entering the extruder may be conveyed or transferred along the extruder to a heated zone. In the cooling zone, the internal heat generated within the material being extruded is carried away so that partial melting of the Cox-2 drug cannot occur which may be detrimental to the throughput of material in the extruder.
  • the extruder is provided with a cooled transfer zone and a heated melting zone.
  • a heated zone at an end portion of the extruder at or adjacent the outlet.
  • the extruded material may be heated to ensure that the extrudate passing through the extruder outlet is sufficiently heated so that the temperature difference between the molten extrudate and extrudate cooling means is maximised as appropriate to optimise the cooling process.
  • the barrel may be heated to cause the extrudate passing through the outlet to be preferably fully molten or substantially fully molten.
  • the pressure within the extruder may cause a lowering of the melting point of the Cox-2 drug.
  • the temperature of the extrudate passing through the outlet is in the range of 2O 0 C on each side of the normal melting point of the drug, preferably within 1O 0 C on each side of the melting point of the drug.
  • the extruder is suitably provided with at least one screw shaft provided with means arranged to generate heat within the Cox-2 drug. This may usually be achieved by a combination of kneading paddles and helical screws. Generally, it is preferred to provide helical screws at the inlet portion to convey the material away from the inlet.
  • the material may be extruded in the extruder barrel with screws and/or with paddles. It is preferred to use more than one screw shaft, for example a twin-screw shaft, to maximise the extrusion effect on the material being extruded.
  • the use of paddles also maximises the shear effect on the material being- extruded, -
  • the paddles may be offset at any desired angle or combination of angles to generate internal heat within the drug as appropriate to melt the drug.
  • the configuration and/or size of the paddles will depend on factors such as the diameter and/or length of the extruder, the ratio of the length to the diameter, the extruder speed, the torque applied and the desired temperature to melt the Cox-2 drug.
  • the screws and/or the paddles may be in the forward and/or reverse direction to maximise the pressure within the mixing zone as desired.
  • a preferred arrangement comprises helical transfer screws at inlet portion of the extruder, a plurality of paddles which may have differing sizes and degrees to which they are offset and further helical transfer screws at the outlet portion to convey the extrudate out of the extruder. Further preferably the helical transfer screws at the outlet portion may comprise a reverse helix followed by a forward helix.
  • Cox-2 drug When the Cox-2 drug is substantially fully melted, a liquid is formed.
  • the Cox- 2 drug should be fully melted so that on cooling, a single continuous phase of the Cox-2 drug is formed.
  • additional components such as a disintegrant or an additional pharmaceutically active agent or any of the other excipients described above are combined with the Cox-2 drug, either prior to melting or after the melting process.
  • the additional components used are often insoluble in the Cox-2 drug melt and a dispersion of the solid additional component within the liquid melt is produced.
  • the dispersion is mixed so that the additional component is uniformly or homogeneously combined with the melted Cox-2 drug. A uniform mixture is thus produced.
  • the mixture is allowed to cool by methods hereinafter discussed until a solid is produced.
  • solidified melt granules means granules formed from the Cox-2 drug in fully molten form optionally with any additional component, cooling to a temperature below the melting point of the Cox-2 drug and forming the solid mass into granules.
  • the granular composition of the invention comprises a plurality of such granules.
  • the melt is allowed to solidify in any manner found convenient. This includes both rapid cooling and slow cooling.
  • the molten Cox-2 drug may be allowed to cool overnight at ordinary temperatures or in a cooled vessel.
  • the molten Cox-2 drug may be poured onto cooling trays which may be static or continuously moving. Static trays may be placed in cooling cabinets. Moving trays or belts may have additional cooling means, such as cooled water.
  • the cooled melt forms a solid and may be scraped off the belt or collected as it falls off one end of a continuously moving belt.
  • the Cox-2 drug is fully molten as it exits the extruder.
  • This extrudate may consist of the Cox-2 drug, without additional ingredients, wherein the Cox-2 drug is present as a single continuous phase.
  • the extrudate may contain additional components, for example one or more of a disintegrant, a surfactant and a diluent, which are blended within the molten Cox-2 drug.
  • the extrudate is formed into two or more thin ribbons. This is preferably achieved by passing the molten extrudate through channels at the outlet which form streams or ribbons of extrudate which may be directed onto the cooling means, preferably a cooling belt or a cooling drum.
  • the ribbons of molten extrudate are cooled rapidly by said cooling means, i.e. the ribbons solidify in thin ribbons, which solidify in 5 minutes or less, preferably 1 minute or less (e.g. 0-60 seconds), more preferably in 50 seconds or less (e.g. 1-50 seconds), more preferably 1-40 seconds and most preferably 1-30 seconds.
  • each ribbon of molten extrudate is greater than the depth of the ribbon so that cooling is optimised.
  • the width of each ribbon will, of course, depend, at least to some extent, on the viscosity of the molten material.
  • each ribbon of molten extrudate has a depth on the cooling means of up to thin ribbons, of 10 mm or less, preferably 0.1 to 6 mm, more preferably 0.5 to 5 mm, for example 3 to 4 mm and most preferably 1-3 mm, for example 2 mm.
  • Cooling will normally occur first on the side of the ribbon proximate the cooling means. Accordingly, usually the lower surface of the ribbons solidifies while the upper surface of the ribbon is still molten. As the ribbon is further cooled, the extrudate solidifies throughout its depth.
  • a plurality of ribbons are provided extending parallel to each other, for example on a cooling belt.
  • there are more than two ribbons for example three, four, five, six, seven, eight, nine or ten or more ribbons according to the size of the extruder.
  • the number of ribbons may be limited by the width of the ribbon formed and the whole width of the cooling means which provides for a maximum number of ribbons. It has been found that the ribbons of molten Cox-2 drug do not spread on the cooling means, accordingly there requires only a small space between the ribbons.
  • a significant temperature difference between the molten extrudate as it comes into contact with the cooling means for example at least 25 0 C, preferably at least 35 0 C, more preferably at least 45 0 C and most preferably at least 55 0 C.
  • the upper end of the above ranges is limited by the melting point of the drug, but it is not desired to heat the extruded material to too high a temperature as the extra energy costs will not be balanced by any processing advantage. Accordingly, a practical upper limit to each of the above ranges is 100 0 C, more usually 8O 0 C.
  • the molten mixture will be cooled to a temperature below the melting point of the drug before being formed into granules.
  • the molten drug mixture may be cooled by passing the molten mixture onto a moving cooling belt, preferably a continuously rotating cooling belt.
  • the belt is cooled by water.
  • the water may be applied to the underside of the belt along its length or partially along its length as desired and according to the length of the belt, the quantity of molten drug mixture and the speed of the belt. It is especially preferred to cool the molten drug mixture at least initially by cooling means, for example until it has started to solidify.
  • the belt is water-cooled along substantially the whole of its length and it is of minimum length required (e.g. 3-7m) to allow it to cool to the solid state.
  • the solidified melt may be formed into granules by a plurality of methods. For example, it may be pulverised into granules. It may be milled and/or sieved. It may also be passed through a spray device such as a spray tower or spray granulator in which the molten material is sprayed from an orifice into a stream of cooled air, allowed to congeal/solidify and then collected. If the molten Cox- 2 drug is extruded, the extrudate may be cooled and then broken into conveniently sized pieces, followed by milling and or sieving. Alternatively, the extrudate may be extruded through holes and chopped into suitably sized granules for tabletting. If it is cooled on a moving belt or drum, the cooled melt may be broken into conveniently sized pieces, followed by milling and or sieving.
  • a spray tower or spray granulator in which the molten material is sprayed from an orifice into a stream of cooled air
  • the granular composition may be sieved to ensure that the melt granules are of the appropriate size for efficient tabletting.
  • the granules produced on cooling the molten drug are preferably of a suitable size for tabletting, preferably in a standard large scale tabletting machine.
  • the melt granules in the granular composition preferably have a mean particle size in the range 10- 2000 ⁇ m, more preferably 50-1000 ⁇ m and most preferably 100-400 ⁇ m. Valuable results are achieved when the bulk density of the melt granules is in the range 0.1-igml '1 , more preferably 0.3-0.6gml "1 .
  • the tapped density may be in the range 0.3-0.7gml ⁇ 1 (more preferably 0.4-0.6 gml '1 ).
  • the melt granules may have a porosity of 0.5-2.0 g/ml.
  • the Cox-2 drug preferably forms a continuous phase in the granule. That is to say the crystalline structure of the Cox-2 drug is not interrupted by another crystalline structure. This may occur, for example, if the Cox-2 drug is only partially melted where the crystalline structure of the melted Cox-2 drug is interrupted by the non-melted Cox-2 drug, thus providing that the Cox-2 drug does not have a single crystalline structure.
  • the crystalline structure of the solidified melted Cox-2 drug is different from the crystalline structure of unmelted Cox-2 drug, for example in terms of particle size.
  • the solidified melt granules may be formulated directly or they may be combined with an extra-granular composition and formulated into a unit dose.
  • the melt granules are combined thoroughly with extra-granular composition so as to form a uniform mixture of ingredients. This may be achieved by conventional mixing and blending techniques. Examples of apparatus that may be used to facilitate this process are: Ribbon Blender, IBC Blender, V- Bender and Plough Benders. Examples include filling of the loose powder mixture into a sachet or a capsule or compressing it into a tablet. Tablets are the preferred unit dosage form according to the invention. They may be swallowed or they may be chewed. It has unexpectedly been found that the taste of the Cox-2 drug has been substantially masked which allows the dosage form to be maintained in the oral cavity for a period of time whilst the formulation is swallowed.
  • the compressed tablet composition of the present invention may optionally be coated with a film coat, for example based on a conventional cellulose polymer such as hydroxypropylmethylcellulose, or a conventional sugar coat, for example based on sucrose or lactose.
  • a film coat for example based on a conventional cellulose polymer such as hydroxypropylmethylcellulose, or a conventional sugar coat, for example based on sucrose or lactose.
  • the granular composition may if desired be combined with a flow acid such as silicon dioxide and filled into capsules.
  • a flow acid such as silicon dioxide
  • a preferred tablet composition according to the present invention may be prepared by incorporating silicon dioxide and optionally other excipients within the composition to be tabletted, preferably to form a powder blend, followed by compression into tablets.
  • a process to prepare a granular composition comprising melting a Cox-2 drug (preferably Celecoxib, Etodolac, Nimesulide, Rofecoxib or Meloxicam), incorporating a disintegrating agent uniformly within the melted Cox-2 drug, allowing said Cox- 2 drug to cool to form a solid and comminuting said melt to form a granular composition.
  • the disintegrating agent is thus generally combined with the Cox-2 drug to form a uniform mixture of solid disintegrating agent in the liquid Cox-2 drug melt prior to cooling.
  • the Cox-2 drugs are available from their manufacturers or suppliers mentioned hereinabove; colloidal silicon dioxide (also known as colloidal silica) is available from Degussa, Frankfurt, DE under the trade name Aerosil 200; Croscarmellose sodium is available from the FMC Corporation, Brussels, BE under the tradename Ac-Di-SoI; and sodium starch glycolate is available from Edward Mendell, Reigate, GB under the tradename Explotab; Poloxamer is available from BASF, DE under the trade name Pluronic F68; dicalcium phosphate is available under the trade name Emcompress from Univar Limited UK; hydrogenated castor oil is available from BASF, DE under the trade name Cremophor RH40; microcrystalline cellulose is available from the FMC Corporation, Brussels, BE under the trade name Avicel PH 101 ; magnesium stearate and stearic acid is available from Hays Chemicals UK.
  • the extruder is an APV MPC40 twin screw extruder available
  • the dissolution was measured using the dissolution method described in the US Pharmacopoeia Vol. 23, page 1791 , Apparatus 2 using paddles at 50 rpm and a phosphate buffer (selected at pH 7.2 and/or pH 6.0 and/or pH 5.8).
  • the process for all illustrative examples involves the melting of the Cox-2 NSAID drug and adding other materials to the molten material.
  • the values in normal text indicate that the components which form part of the melt granular composition and values in bold text indicate that the components which form part of the extra-granular composition.
  • the Cox-2 NSAID drug is first melted by heating in a stainless steal vessel until fully molten.
  • the disintegrating agent is first melted by heating in a stainless steal vessel until fully molten.
  • croscarmellose sodium and/or sodium starch glycolate is then added to the molten drug and mixed for 5-10 minutes until uniformly dispersed.
  • the molten mixture was poured onto a stainless steel tray and cooled over a period of up to 60 minutes, while stirring to ensure that the suspension was maintained.
  • the solid mass thus formed is milled by passing through a cone mill having a screen with a round hole size of 1 mm. The resulting granules were collected.
  • the Cox-2 drug was dry blended with other optional excipients which may be present in the granular component, and the mixture heated in an extruder to melt the Cox-2 drug fully and thereby mix the molten Cox-2 drug with the other optional expicients.
  • the molten mass is poured onto cooled stainless steel trays or a cooled moving belt at 1O 0 C and allowed to cool.
  • the molten mixture typically solidifies within 60 to 90 seconds; the mixture may be agitated during cooling.
  • the solid mass thus formed is milled by passing through a core mill having a screen with a round hole of 1 mm. The resulting granules are collected.
  • Example Kc Preparation of a tablet
  • the extra-granular components (shown in bold in Table 1), namely silicon dioxide, talc and stearic acid were blended simultaneously with the granular composition formed from Example 1(a) or 1 (b) above for approximately 15 minutes in a blender (V-Blender - Erweka all purpose).
  • the blended material was fed to a tabletting machine (Erweka tablet compression machine) and compressed into tablets containing a therapeutic dose of Cox-2 drug.
  • Tablets were prepared from the components indicated in Table 1 in the same manner as described for Example 1. The compressing weight of each formulation is adjusted to give a tablet containing the desired therapeutic level of the Cox-2 drug. Table 1
  • Examples 21 to 40 are indicated in Table 2. These are similar to the formulations of Examples 1 to 20, except that these examples do not include a silicon dioxide (Aerosil) wicking agent in the extra-granular composition.
  • An alternative wicking agent such as talc is used in place of the silicon dioxide or a further lubricant such as calcium or magnesium stearate is included in the composition.
  • Tablets were prepared in the same manner as described for Example 1. The compressing weight of each formulation is adjusted to give a tablet containing the desired therapeutic level of the Cox-2 drug.
  • Example 41 to 46 are indicated in Table 3. These formulations were formed into effervescent tablets in a manner similar to that of Example 1. The compressing weight of each formulation is adjusted to give tablets containing the desired therapeutic level of the Cox-2 drug.
  • Example 47 to 52 are also indicated in table 3. These formulations were formed into chewable tablets in a manner similar to that described for Example 1. The compressing weight of each formulation is adjusted to give tablets containing the desired therapeutic level of the Cox-2 drug.
  • Example 53-66 The formulations of Example 53-66 are indicated in Table 4. These formulations include additional pharmaceutically active components as part of the extra-granular composition. They are formed into tablets in a manner similar to that described for Example 1. The compressing weight of each formulation is adjusted to give tablets containing the desired level of the Cox-2 drug.
  • Examples 53 to 66 could be repeated with the additional pharmaceutically active component forming part of the melt-granular composition by adding the further active to the melt of the Cox-2 drug.
  • Tablets comprising 200 mg of Etodolac (Examples 67 and 68) were formed from the formulation as outlined in Table 5.
  • Example 67 The tablets of Example 67 were formed by a melt extrusion process in accordance with Examples 1(b) and 1 (c). The Etodolac was fully melted during the melt extrusion process.
  • Example 68 The tablets of Example 68 were formed from a dry blend of the components as listed in Table 5.
  • the Etodolac and microcrystalline cellulose were sieved through a 30 mesh screen, croscarmellose sodium, sodium lauryl sulphate and colloidal silicon dioxide sieved through a 40 mesh screen, and stearic acid passed through a 60 mesh screen.
  • the Etodolac, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate and colloidal silicon dioxide were combined and mixed with a V-blender. Stearic acid was added to the resulting mixture and blending continued for a further 2 minutes.
  • the resulting blend was compressed using 10.5 mm round sugar coated curative punches (Erweka tablet compression machine). During compression of the dry blend the following problems were observed:
  • Example 68 The tablets formed from Example 68 were milled to form granules, and the granules subjected to a secondary compression process. This is known as slugging. Although the resulting granules exhibited improved flowability and compressibility, such a process is laborious and time consuming.
  • Example 67 melt extrusion
  • excellent flow characteristics i.e. non-sticky
  • Satisfactory tablets were produced and the melt extrusion process offered significant manufacturing advantages over the dry blend process.
  • the tablets formed by the melt extrusion process had a disintegration time of 29 seconds, whereas the tablets formed from the dry blend after slugging had a disintegration time of 36 seconds.
  • Example 69 The tablets of Example 69 were formed by a melt extrusion process in accordance with Examples 1 (b) and 1(c). The Celecoxib was fully melted during the melt extrusion process.
  • Example 70 The tablets of Example 70 were formed from a dry blend of the components as listed in Table 7.
  • the Celecoxib and microcrystalline cellulose were sieved through a 30 mesh screen, the croscarmellose sodium, sodium lauryl sulphate and colloidal silicon dioxide sieved through a 40 mesh screen, and stearic acid passed through a 60 mesh screen.
  • the Celecoxib, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate and colloidal silicon dioxide were combined and mixed with a V-blender.
  • Stearic acid was added to the resulting mixture and blending continued for a further 2 minutes.
  • the resulting blend was compressed using 10.5 mm round sugar coated curative punches (Erweka tablet compression machine). During compression of the dry blend the following problems were observed: (1) The mixture exhibited a sticky consistency and showed high levels of sticking to the tablet punches and the die wall. The tablets were therefore difficult to eject from the tabletting machine. (2) There was significant tablet capping.
  • Example 70 The tablets formed from Example 70 were milled to form granules, and the granules subjected to a secondary compression process (compression force 60 N). This is known as slugging. Although the resulting granules exhibited improved flowability and compressibility, such a process is laborious and time consuming.
  • Example 69 melt extrusion
  • excellent flow characteristics i.e. non-sticky
  • Satisfactory tablets were produced and the melt extrusion process offered significant manufacturing advantages over the dry blend process.
  • the tablets had a hardness of 140 N.
  • Example 69 melting extrusion
  • disintegration time of 40 seconds compared with the tablets formed from the dry blend after slugging (disintegration time of 1 minute 20 seconds).

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Abstract

La présente invention concerne une composition granulaire comprenant une pluralité de granulés de fusion solidifiés incluant un inhibiteur sélectif de Cox-2.
PCT/GB2005/003863 2004-10-19 2005-10-07 Compositions granulaires comprenant des granules de fusion solidifies d’un inhibiteur selectif de cox-2 Ceased WO2006043025A1 (fr)

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WO2007034135A1 (fr) * 2005-09-22 2007-03-29 Reckitt Benckiser Healthcare (Uk) Limited Composition comprenant un ains et du paracetamol
WO2009071219A3 (fr) * 2007-12-08 2009-09-11 Bayer Schering Pharma Aktiengesellschaft Comprimé dispersible oral
WO2011050944A1 (fr) * 2009-10-28 2011-05-05 Ratiopharm Gmbh Formulations contenant du célécoxib
WO2011141490A1 (fr) * 2010-05-10 2011-11-17 Euro-Celtique S.A. Combinaison de granules chargés de principe actif et de principes actifs supplémentaires
WO2014033526A1 (fr) 2012-08-27 2014-03-06 Cadila Healthcare Limited Compositions pharmaceutiques d'étoricoxib
WO2015004505A1 (fr) * 2013-07-11 2015-01-15 More Pharma Corporation, S. De R.L. De C.V. Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire
US9700508B2 (en) 2010-05-10 2017-07-11 Euro-Celtique S.A. Pharmaceutical compositions comprising hydromorphone and naloxone
US9814710B2 (en) 2013-11-13 2017-11-14 Euro-Celtique S.A. Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome
CN108057025A (zh) * 2017-12-08 2018-05-22 佛山市弘泰药物研发有限公司 一种依托考昔口崩片及其制备方法
US9993433B2 (en) 2010-05-10 2018-06-12 Euro-Celtique S.A. Manufacturing of active-free granules and tablets comprising the same
CN112055591A (zh) * 2018-02-21 2020-12-08 日本新药株式会社 粒状组合物、粒状组合物的制造方法及粒状组合物的溶出性改善方法
EP4534076A1 (fr) 2023-10-05 2025-04-09 Laboratorios Silanes, S.A. de C.V. Combinaison de célécoxib-acétaminophène à stabilité améliorée et procédé pour sa préparation

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2851068A3 (fr) * 2005-09-22 2015-05-27 Reckitt Benckiser Healthcare (UK) Limited Composition comprenant un ains et du paracetamol
AU2006293798B2 (en) * 2005-09-22 2012-08-16 Reckitt Benckiser Healthcare (Uk) Limited Composition comprising a NSAID and paracetamol
WO2007034135A1 (fr) * 2005-09-22 2007-03-29 Reckitt Benckiser Healthcare (Uk) Limited Composition comprenant un ains et du paracetamol
WO2009071219A3 (fr) * 2007-12-08 2009-09-11 Bayer Schering Pharma Aktiengesellschaft Comprimé dispersible oral
JP2011506279A (ja) * 2007-12-08 2011-03-03 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト 経口で分散可能な錠剤
JP2015038123A (ja) * 2007-12-08 2015-02-26 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ 経口で分散可能な錠剤
WO2011050944A1 (fr) * 2009-10-28 2011-05-05 Ratiopharm Gmbh Formulations contenant du célécoxib
US9993433B2 (en) 2010-05-10 2018-06-12 Euro-Celtique S.A. Manufacturing of active-free granules and tablets comprising the same
WO2011141490A1 (fr) * 2010-05-10 2011-11-17 Euro-Celtique S.A. Combinaison de granules chargés de principe actif et de principes actifs supplémentaires
US9901540B2 (en) 2010-05-10 2018-02-27 Euro-Celtique S.A. Combination of active loaded granules with additional actives
US9700508B2 (en) 2010-05-10 2017-07-11 Euro-Celtique S.A. Pharmaceutical compositions comprising hydromorphone and naloxone
WO2014033526A1 (fr) 2012-08-27 2014-03-06 Cadila Healthcare Limited Compositions pharmaceutiques d'étoricoxib
WO2015004634A3 (fr) * 2013-07-11 2015-04-09 More Pharma Corporation, S. De R.L. De C.V. Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire
WO2015004505A1 (fr) * 2013-07-11 2015-01-15 More Pharma Corporation, S. De R.L. De C.V. Combinaison synergique de paracétamol/célécoxib pour le traitement de douleur inflammatoire
US9814710B2 (en) 2013-11-13 2017-11-14 Euro-Celtique S.A. Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome
US10258616B2 (en) 2013-11-13 2019-04-16 Euro-Celtique S.A. Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome
CN108057025A (zh) * 2017-12-08 2018-05-22 佛山市弘泰药物研发有限公司 一种依托考昔口崩片及其制备方法
CN112055591A (zh) * 2018-02-21 2020-12-08 日本新药株式会社 粒状组合物、粒状组合物的制造方法及粒状组合物的溶出性改善方法
EP3756670A4 (fr) * 2018-02-21 2021-11-03 Nippon Shinyaku Co., Ltd. Composition granulaire, procédé de production d'une composition granulaire et procédé d'amélioration de la propriété d'élution d'une composition granulaire
EP4534076A1 (fr) 2023-10-05 2025-04-09 Laboratorios Silanes, S.A. de C.V. Combinaison de célécoxib-acétaminophène à stabilité améliorée et procédé pour sa préparation

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