WO2004019901A2 - Composition pharmaceutique a liberation prolongee - Google Patents

Composition pharmaceutique a liberation prolongee Download PDF

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Publication number
WO2004019901A2
WO2004019901A2 PCT/IB2003/003602 IB0303602W WO2004019901A2 WO 2004019901 A2 WO2004019901 A2 WO 2004019901A2 IB 0303602 W IB0303602 W IB 0303602W WO 2004019901 A2 WO2004019901 A2 WO 2004019901A2
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composition according
composition
pharmaceutically acceptable
weight
esters
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WO2004019901A3 (fr
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Rajesh Suresh Kshirsagar
Sampath Kumar Devarajan
Kour Chand Jindal
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Orchid Pharma Ltd
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Orchid Chemicals and Pharmaceuticals Ltd
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Priority to AU2003260803A priority Critical patent/AU2003260803A1/en
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Publication of WO2004019901A3 publication Critical patent/WO2004019901A3/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • 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
    • A61K9/2072—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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • United States Patent No.5,128,142 discloses a controlled release formulation comprising an adsorbate of a mixture of a pharmaceutically useful active ingredient and an inactive substance adsorbed on a cross linked polymer.
  • the inactive substance is selected to modify the dissolution of active ingredients from the cross-linked polymer in vivo.
  • the inactive substance is preferably present in the adsorbate in an amount of 0.5 - 3 parts by weight relative to 1 part by weight of the active ingredients.
  • United States Patent No.4,968,508 discloses a sustained release matrix tablet comprising from about 0.1% to about 90% by weight of cefaclor, about 5% to about 29% by weight by hydrophihc polymer and about 0.5% to about 25% by weight of an acrylic polymer which dissolve at a pH in the range of about 5.0 to about 7.4, the total weight of polymers being less than 30% by weight of the formulation.
  • cefaclor a specific cefaclor formulation is claimed, the text suggests that the matrix formulation is suitable for weakly basic drugs and particularly suitable for cephalexin and cefaclor.
  • United States Patent No.5,948,440 discloses a controlled release tablet of an active ingredient comprising of cefaclor, cephalexin or their pharmaceutically acceptable hydrates, salts or esters as active ingredients and a mixture of hydrophihc polymers selected from the group consisting of at least one hydroxypropyl methylcellulose and at least one hydroxypropyl cellulose.
  • the composition optionally also contains one or more of a water soluble or water dispersible diluent, the quantities are such that the therapeutically effective active ingredient is released at a rate suitable for twice daily administration of the pharmaceutical composition.
  • WOOO/15198 teaches controlled delivery pharmaceutical composition having temporal and spatial control, comprising a drag, a gas generating component, a swelling agent, a viscolyzing agent and optionally a gel forming polymer.
  • the viscolyzing agent initially and the gel forming polymer thereafter form a hydrated gel matrix which entraps the gas, causing the tablet to float so that it is retained in the stomach thereby providing spatial control and at the same time resulting in sustained release of the drag providing temporal control.
  • the combination of gas generating component, swelling agent and viscolyzing agent results in the controlled drag delivery systems. Thus all these components are essential for achieving the temporal and spatial control.
  • a preferred once daily ciprofloxacin formulation comprising 69.9% ciprofloxacin base, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% cross linked polyvinyl pyrrolidone and optionally other excipients is disclosed.
  • WO 02/41876 discloses a pharmaceutical composition in the form of a tablet for controlled release of an active ingredient comprising a beta lactam antibiotic such as cephalexin, cefaclor or their pharmaceutically acceptable hydrates, salts or esters as active ingredients, and a mixture of hydrophihc polymers selected from the group consisting of at least one sodium alginate and at least one xanthan gum as controlled release matrix and optionally probenecid as an antibiotic adjuvant as either immediate release or controlled release part.
  • the composition may contain one or more of a water-soluble and/or water dispersible diluent. The quantity of the hydrophihc polymer matrix still provides the desired once a day drug release profile.
  • United States Patent No.6,399.086 discloses a controlled release beta lactam antibiotic agent preferably amoxicillin trihydrate in a hydrophihc and/or hydrophobic polymer matrix such that at least 50% but not more than 67.61 + 5.78 % of the active agent is released within 3-4 hrs from oral administration and remainder is released at a controlled rate from the said composition.
  • the composition teaches the use of commonly used hydrophihc polymers such as hydrophihc cellulose derivatives, hydrophihc methacrylic acid derivatives, chitosan, and alginates.
  • hydrophihc cellulose derivative such as methylcellulose, hydroxypropyl methylcellulose, and hydroxyethyl cellulose, is disclosed.
  • the hydrophobic polymers used in the invention are acrylamides and polyamido derivatives and hydrophobic methacrylic acid derivatives.
  • the preferred hydrophobic polymer is ethyl cellulose.
  • the composition may not be suitable for once daily administration. Hence, it is necessary that the matrix formulation should release the drag over extended period of time.
  • WO 02/36126 discloses a fast disintegrating controlled release oral composition
  • a core material containing cefuroxime axetil present as controlled release form the cefuroxime axetil being provided with an outer coating of a copolymer selected from aqueous dispersions of enteric methacrylic acid and methacrylic acid esters anionic copolymers having carboxyl group as the functional group or mixture thereof and an inner coating of a sustained release copolymer selected from aqueous dispersions of acrylate or methacrylate pH independent copolymers having quaternary ammonium group as a functional group or mixture thereof.
  • the coating composition may contain plasticizers.
  • the composition is suitable for once daily administration.
  • the particles are less sensitive to the effect of gastric/stomach emptying time. As the particles are smaller, a portion of the particles gradually reaches the small intestine and passes small intestine relatively faster than the tablet dosage form even in the presence of food. Hence, there is a potential chance of drag dissolution/delivery in the non-absorbable gastro-intestinal tract site. Therefore, there are chances for failure of the mul ti-particula te control release system especially if the drag has narrow absorption window in the gastro- intestinal tract. Cefuroxime axetil and cefpodoxime proxetil are reported to be absorbed from the upper part of the gastrointestinal tract. Hence, developing and achieving once daily administration through the multi-particulate controlled release system for the said drags having absorption in upper part of GIT with short biological half-life, and the cumbersome process involved in developing such type of dosage form, makes it undesirable.
  • Cefpodoxime proxetil and cefuroxime axetil are broad spectrum antibiotics active against both gram positive and gram negative microorganisms. Cefpodoxime proxetil and cefuroxime axetil oral bioavailability is reported to be 50%, with a slight increase in the bioavailability in the presence of food, and they are orally administered twice daily. Cefpodoxime proxetil and cefuroxime axetil molecules tend to form gels, upon exposure to the environmental fluids. These drags form gel in contact with acidic media of the stomach, leading to reduction in dissolution and that, in turn, leads to poor bioavailability.
  • cefuroxime axetil and cefpodoxime proxetil have narrow absorption window, i.e., absorbed less from the upper part of gastrointestinal tract, and at the same time, have plasma half- lives of 1.2 and 2.1 to 2.9 hrs, respectively.
  • This gelling effect is temperature dependent but does occur at temperature of about 37 °C, i.e., at the physiological temperature at which the disintegration of orally administered tablets takes place.
  • the relatively slow permeation of moisture from the film coat to the core which occurs upon administration of the tablets provided with conventional film coats, leads to gelling of cefuroxime axetil present in the core.
  • the gel formation leads to poor disintegration of the tablet core and hence poor dissolution of cefuroxime axetil, thus the absorption from the GIT is greatly reduced. This occurs with both the crystalline and amorphous forms of cefuroxime axetil.
  • 6,323,193 discloses that addition of sodium citrate to the formulation containing amo ⁇ hous cefuroxime axetil, inhibits the tendency of amo ⁇ hous cefuroxime axetil to form a gel. This may be due to the presence of citrate ions, which prevents cefuroxime axetil molecules from bridging with each other to form a gel, thereby helping in the tablet dissolution.
  • United States Patent No. 4,865,851 discloses cefuroxime axetil composition
  • cefuroxime axetil composition comprising particulate cefuroxime axetil coated with an integral coating of a lipid or mixture of lipids which are insoluble in water and which serves to mask the bitter taste of cefuroxime axetil but disperses or dissolves on contact with gastro-intestinal fluid.
  • the resulting particles can be inco ⁇ orated into pharmaceutical compositions for oral administration, for example aqueous suspension, dry product for reconstitution with water or granules.
  • a sustained release dosage form should deliver the medicament at a constant rate throughout the GIT.
  • beta lactam antibiotics as they have a narrow abso ⁇ tion window, instability in higher pH and some of the beta lactam antibiotics also forms gel upon exposure to the GIT fluids.
  • a decline in the solubility due to gel formation in response to pH fluctuations within the body may result in a decreased release rate and thus poor bioavailability.
  • the sustained release matrix form may be retained in the stomach for a long time due to the size of the dosage form and delayed stomach emptying time in the presence of food. Stomach emptying is particularly important in the preparation of sustained release formulation for drags having narrow abso ⁇ tion window.
  • Sustained release preparations of drags are advantageous since the frequency of dosing can be reduced by maintaining a constant plasma concentration of drug over an extended period of time to ensure sustained effect of active ingredient.
  • Polymer blends in sustained release compositions are known and used in the pharmaceutical industry because of the blend versatility of being able to create different release properties.
  • Polysaccharides such as carrageenans are desirable biopolymers for use in sustained release compositions because they are derived from naturally occurring seaweeds.
  • the present invention is based on the observation that the release of active ingredient from the delivery system is controlled by the specific polymers present in the matrix and in specific concentrations, thus allowing blood levels above MIC over extended period of time such that the frequency of the dosage form can be reduced to twice daily or once daily dosing.
  • the copolymers and a release enhancer along with a biopolymer the gelling characteristics of the active ingredient was eliminated, and we could achieve a constant release of the drag in- vitro over a extended period of time both in acidic and alkaline pH.
  • the main objective of the present invention is to provide an oral sustained release formulation of a beta lactam antibiotic or their pharmaceutically acceptable salts, hydrates or esters.
  • Further objective of the present invention is to avoid gelling of beta lactam antibiotic on contact with the gastro-intestinal fluid, yet controlling the release of the beta lactam antibiotic or their pharmaceutically acceptable salts, hydrates or esters in a non disintegrating matrix such that it provides therapeutically effective blood levels of the medicaments for prolonged period suitable for twice or once daily administration.
  • the present invention provides a sustained release oral pharmaceutical composition
  • a beta lactam antibiotic or their pharmaceutically acceptable salts, hydrates or esters comprising a beta lactam antibiotic or their pharmaceutically acceptable salts, hydrates or esters; mixture of polymers comprising of a water soluble N-vinyl-2-pyrrolidone/vinyl acetate copolymer and polysaccharide(s); a release enhancer(s); and other pharmaceutically acceptable excipients.
  • the polysaccharide is selected from different grades of carrageenan, used either alone or in combination thereof.
  • the pharmaceutical composition comprises of a mixture of polymers from about 1 to 35% by weight of the composition.
  • the pharmaceutical composition comprises from about 1 to 30% of N-vinyl-2-pyrrolidone/vinyl acetate copolymer by weight of the composition. In an embodiment of the present invention the pharmaceutical composition comprises from about 0.5 to 20% of carrageenan(s) by weight of the composition.
  • the pharmaceutical composition comprises drug release enhancers from about 0.1 to 25% by weight of the total weight of the composition, used either alone or in combination.
  • the pharmaceutical composition comprises from about 0.1 to 10% of solubilizer by weight of the composition. In an embodiment of the present invention the pharmaceutical composition comprises of lubricant from about 0.2 % to about 5% by weight of the total weight of the composition, used either alone or in combination .
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable diluents in an amount from about 1 to about 40% by weight of the composition.
  • the pharmaceutical composition comprises from about 0.1 to 20% of binder by weight of the composition.
  • the pharmaceutical composition in the form of tablets are coated using conventional coating agents.
  • the pharmaceutical composition may be prepared by dry granulation using the following procedure. (i) blending the beta lactam antibiotic or its pharmaceutically acceptable salts, hydrates or esters, diluent(s) and copolymer; polysaccharide(s), disintegrant(s) and lubricant(s) either whole or in part; release enhancer(s), optionally integrity enhancer(s) and solubilizer(s) together, (ii) passing the blended mixture through a suitable sieve, (iii) compacting the blend using a roller compactor,
  • the process for the preparation of the sustained release pharmaceutical composition comprises the steps of: (i) blending the beta lactam antibiotic or their pharmaceutically acceptable salts, hydrates or esters, diluent(s), copolymer and polysaccharide(s); disintegrant(s) and lubricant(s) either whole or in part; release enhancer(s), optionally integrity enhancer(s) and solubilizer(s) together, (ii) passing the blended mixture through a suitable sieve, (iii) compacting the blend using a roller compactor, (iv) sizing the compacted material using an suitable mill, (v) resultant granules coated with ethyl cellulose in a suitable fluid bed processor, (vi) optionally sizing the coated granules by passing through a suitable sieve,
  • the beta lactam antibiotic include amoxycillin, ampicillin, cephalexin, cefprozil, cefadroxil, cefaclor, cefamandole, cefoxitin, cephalothin, cephapirin, ceftizoxime, cefonicid, cefpodoxime proxetil, cefuroxime axetil, cefotiam, hexetil, cefteram pivoxil, cefditoren pivoxil, cefcapene pivoxil, cefetamet pivoxil or their pharmaceutically acceptable salts, hydrates or esters.
  • the beta lactam antibiotic is in the form of a prodrag ester such as cefpodoxime proxetil, cefuroxime axetil, cefotiam hexetil, cefteram pivoxil, cefditoren pivoxil, cefcapene pivoxil or cefetamet pivoxil. More preferably, the beta lactam antibiotic is selected from cefpodoxime proxetil or cefuroxime axetil.
  • Carrageenan is a naturally occurring family of polysaccharides extracted from red seaweed. It is a high molecular weight polysaccharide made up of repeating galactose and 3,6 anhydrogalactose (3,6-AG) units, both sulfated and nonsulfated. The units are joined by alternating alpha 1-3 and beta 1-4 glycosidic linkages.
  • Three types of carrageenan are commercially available. They are iota, kappa and lambda. The primary differences which influence the properties of kappa, iota and lambda carrageenan are the number and position of the ester sulfate groups on the repeating galactose units.
  • carrageenan used is selected from Viscarin GP328, Niscarin GP 209, and Gelcarin GP911 (FMC).
  • ⁇ -vinyl-2-pyrrolidone and vinyl acetate is a synthetic water-soluble copolymer in a random 60:40 ratio (copolyvidonum).
  • Copolyvidonum is a highly effective film forming adhesive, the k-value for which is specified between 25.4 and 34.2.
  • the copolymer that may be used in the present invention include Plasdone S-630 (ISP) or Kollidon VA64 (BASF).
  • the pharmaceutical composition comprises release enhancer such as sodium chloride, potassium chloride; sulfates of sodium, potassium, calcium, magnesium; lactose or the like, used either alone or in combinations thereof.
  • the pharmaceutical composition comprises integrity enhancerss such as polyacrylic acid derivatives e.g. Carbopol 971P, Carbopol 974P, Novenon AA1, or the like, used either alone or in combinations thereof.
  • the pharmaceutical composition comprises of water soluble or water dispersible diluents.
  • the water soluble diluents are selected from mannitol, glucose, sorbitol, maltose, dextrates, dextrans, dextrins and the like, used either alone or in combinations thereof.
  • the water dispersible diluents are selected from carboxymethyl cellulose, calcium carboxymethyl cellulose, microcrystalline cellulose, pregelatinized starch, and the like, used either alone or in combinations thereof.
  • the pharmaceutical composition comprises of the lubricant such as talc, stearic acid, magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, hydrogenated vegetable oil, and the like, used either alone or in combinations thereof.
  • the pharmaceutical composition comprises of disintegrant such as croscarmellose sodium (Acdisol), crospovidone, calcium carboxymethyl cellulose, sodium starch glycolate, and the like, used either alone or in combinations thereof.
  • disintegrant such as croscarmellose sodium (Acdisol), crospovidone, calcium carboxymethyl cellulose, sodium starch glycolate, and the like, used either alone or in combinations thereof.
  • the pharmaceutical composition comprises of solubilizer such as cationic surfactants like cetrimide, benzalkonium chloride, benzethonium chloride; anionic surfactants like sodium lauryl sulphate, docusate sodium; and non-ionic surfactants like glyceryl monooleate, polyoxyethylene sorbitan fatty acid, polyoxyethylene sorbitan fatty esters, polyvinyl alcohol or sorbitan esters, used either alone or in combinations thereof.
  • solubilizer such as cationic surfactants like cetrimide, benzalkonium chloride, benzethonium chloride; anionic surfactants like sodium lauryl sulphate, docusate sodium; and non-ionic surfactants like glyceryl monooleate, polyoxyethylene sorbitan fatty acid, polyoxyethylene sorbitan fatty esters, polyvinyl alcohol or sorbitan esters, used either alone or in combinations thereof.
  • the pharmaceutical composition in the form of tablets are
  • Cefpodoxime proxetil calcium carboxymethyl cellulose, croscarmellose sodium, sodium lauryl sulfate, lactose anhydrous, Plasdone S-630, Viscarin
  • GP328, and Carbopol 97 IP were screened through 40 mesh sieve and roll compacted. The compacts were crushed and passed through 20 mesh to get granules. The granules were blended with magnesium stearate. The lubricated granules were then compressed into the tablets using a tablet press. The tablets were coated.
  • Cefpodoxime proxetil calcium carboxymethyl cellulose, croscarmellose sodium, sodium lauryl sulfate, lactose anhydrous, Plasdone S-630, and
  • Viscarin GP209 were screened through 40 mesh sieve and roll compacted.
  • the compacts were crashed and passed through 20 mesh to get granules.
  • the granules were blended with Gelcarin GP911, Carbopol 97 IP, and magnesium stearate.
  • the lubricated granules were then compressed into the tablets using a tablet press. The tablets were coated.
  • Cefpodoxime proxetil, lactose anhydrous, Plasdone S-630, Gelcarin GP911, and, magnesium stearate were screened through 40 mesh sieve and roll compacted. The compacts were crashed and passed through 20 mesh to get granules. The resultant granules were coated with ethyl cellulose aqueous dispersion in a fluid bed processor. The resultant dried granules were screened and blended with calcium carboxymethyl cellulose, croscarmellose sodium, and magnesium stearate. The lubricated granules were then compressed into the tablets using a tablet press. The tablets were coated. Dissolution profile
  • Cefpodoxime proxetil, lactose anhydrous, Plasdone S-630, Gelcarin GP911, and, magnesium stearate were screened through 40 mesh sieve and roll compacted. The compacts were crashed and passed through 20 mesh to get granules. The resultant granules were coated with ethyl cellulose aqueous dispersion in a fluid bed processor. The resultant dried granules were screened and blended with croscarmellose sodium, and magnesium stearate. The lubricated granules were then compressed into the tablets using a tablet press.
  • the tablets were coated.
  • Cefpodoxime proxetil, lactose anhydrous, croscarmellose sodium, Plasdone S- 630, Gelcarin GP911, and, magnesium stearate were screened through 40 mesh sieve and roll compacted. The compacts were crashed and passed through 20 mesh to get granules. The resultant granules were coated with ethyl cellulose aqueous dispersion in a fluid bed processor. The resultant dried granules were screened and blended with calcium carboxymethyl cellulose, croscarmellose sodium, and magnesium stearate. The lubricated granules were then compressed into the tablets using a tablet press. The tablets were coated.
  • Cefpodoxime proxetil, lactose anhydrous, Plasdone S-630, Gelcarin GP911, and, magnesium stearate were screened through 40 mesh sieve and roll compacted. The compacts were crashed and passed through 20 mesh to get granules. The resultant granules were coated with ethyl cellulose aqueous dispersion in a fluid bed processor. The resultant dried granules were screened and blended with calcium carboxymethyl cellulose, croscarmellose sodium, and magnesium stearate. The lubricated granules were then compressed into the tablets using a tablet press. The tablets were coated. Examples 12
  • Cefuroxime axetil calcium carboxymethyl cellulose, sodium lauryl sulfate, sodium chloride, Plasdone S-630, and Viscarin GP328, were screened through
  • Bioavailability study was done using the composition of Example 1 in normal healthy human volunteers. The study was conducted for comparison between conventional Cefpodoxime tablets 200mg and sustained release Cefpodoxime tablets 400mg.
  • Figure 1 Plot of comparative plasma profile of Cefpodoxime OD tablets 400mg (Test) v/s Cefpodoxime conventional tablets 200mg (Ref)

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Cephalosporin Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique orale à libération prolongée contenant une bêta-lactamine ou ses sels, hydrates ou esters pharmaceutiquement acceptables dans un mélange polymérique, la bêta-lactamine étant libérée pendant une période prolongée. Cette composition peut être administrée par voie orale une à deux fois par jour. De préférence, l'invention concerne une composition pharmaceutique à libération prolongée d'une bêta-lactamine présentant une tendance à se gélifier lorsqu'elle entre en contact avec les liquides gastro-intestinaux. De préférence encore, l'invention concerne une composition pharmaceutique à libération prolongée de promédicaments de cefpodoxime et de céfuroxime, tels que le cefpodoxime proxétil et le céfuroxime axétil.
PCT/IB2003/003602 2002-08-30 2003-08-29 Composition pharmaceutique a liberation prolongee Ceased WO2004019901A2 (fr)

Priority Applications (1)

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AU2003260803A AU2003260803A1 (en) 2002-08-30 2003-08-29 Sustained release pharmaceutical composition

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IN640/MAS/2002 2002-08-30
IN640CH2002 2002-08-30

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004105728A3 (fr) * 2003-05-27 2005-01-27 Ranbaxy Lab Ltd Dispersions solides de cefpodoxime-proxetil et leurs procedes de preparation
WO2005030178A1 (fr) * 2003-09-30 2005-04-07 Lupin Ltd. Formulation de liberation etendue d'antibiotiques de type beta-lactame
WO2005067895A1 (fr) * 2004-01-16 2005-07-28 Sandoz Ag Compositions pharmaceutiques a liberation controlee
WO2005065641A3 (fr) * 2004-01-06 2006-04-27 Panacea Biotec Ltd Compositions pharmaceutiques a liberation controlee
EP1681050A1 (fr) * 2005-01-13 2006-07-19 Strides Arcolab Limited Composition pharmaceutique dispersible avec libération prolongée
WO2006114277A3 (fr) * 2005-04-25 2007-05-24 Gruenenthal Gmbh Forme galenique a liberation amelioree du cefuroxime axetil
WO2008057058A1 (fr) * 2006-11-10 2008-05-15 Nobel Ilac Sanayii Ve Ticaret As Compositions pharmaceutiques orales
WO2008058848A1 (fr) * 2006-11-13 2008-05-22 Basf Se Utilisation de copolymères séquencés à base de vinyllactames et d'acétate de vinyle en tant que solubilisants
CN102028669A (zh) * 2010-10-27 2011-04-27 北京华禧联合科技发展有限公司 盐酸头孢卡品酯的缓释剂型及其制备方法
US8119163B2 (en) * 1998-11-02 2012-02-21 Alkermes Pharma Ireland Limited Nanoparticulate and controlled release compositions comprising cefditoren
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
WO2013109205A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Formulations pharmaceutiques en comprimés comprenant du céfétamet
CN104434875A (zh) * 2014-12-26 2015-03-25 华北制药河北华民药业有限责任公司 一种头孢克洛胶囊及其制备方法
WO2016088041A1 (fr) * 2014-12-01 2016-06-09 Sun Pharmaceutical Industries Limited Composition de cefpodoxime proxétil à libération prolongée
CN107569466A (zh) * 2017-09-17 2018-01-12 石家庄四药有限公司 一种直接压片法制备的头孢呋辛酯药物组合物
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
CN112023032A (zh) * 2020-09-14 2020-12-04 广东鼎信医药科技有限公司 一种含有消化酶的药物组合物及其制备方法
CN113908133A (zh) * 2021-11-29 2022-01-11 河南省儿童医院郑州儿童医院 一种头孢克肟缓释片及其制备方法
CN117243913A (zh) * 2023-10-24 2023-12-19 国药集团致君（深圳）制药有限公司 一种头孢克洛缓释组合物及其制备方法
WO2025046044A1 (fr) * 2023-09-01 2025-03-06 F. Hoffmann-La Roche Ag Nouveaux procédés de préparation de compositions semi-solides et leurs utilisations
CN120732800A (zh) * 2025-08-19 2025-10-03 湖南恒昌医药集团股份有限公司 头孢托仑匹酯缓释片及其制备方法
CN120938952A (zh) * 2025-09-22 2025-11-14 国药集团致君（深圳）制药有限公司 头孢克洛缓释片的组合物及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2742989B1 (fr) * 1995-12-29 1998-01-23 Adir Composition pharmaceutique bioadhesive pour la liberation controlee de principes actifs
AT413647B (de) * 1998-11-26 2006-04-15 Sandoz Ag Verwendung eines copolymerisats aus 1-vinyl-2-pyrrolidon und vinylacetat zur herstellung von cefuroximaxetil-hältigen tabletten
AU5241200A (en) * 1999-06-29 2001-01-31 Miciopharma Chemical Aktiengesellschaft Retard formulation of amoxicillin for oral administration

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8119163B2 (en) * 1998-11-02 2012-02-21 Alkermes Pharma Ireland Limited Nanoparticulate and controlled release compositions comprising cefditoren
WO2004105728A3 (fr) * 2003-05-27 2005-01-27 Ranbaxy Lab Ltd Dispersions solides de cefpodoxime-proxetil et leurs procedes de preparation
WO2005030178A1 (fr) * 2003-09-30 2005-04-07 Lupin Ltd. Formulation de liberation etendue d'antibiotiques de type beta-lactame
WO2005065641A3 (fr) * 2004-01-06 2006-04-27 Panacea Biotec Ltd Compositions pharmaceutiques a liberation controlee
AU2005204016B2 (en) * 2004-01-06 2008-05-22 Panacea Biotec Ltd. Non-disintegrating oral solid composition of high dose of water soluble drugs
EA011374B1 (ru) * 2004-01-06 2009-02-27 Панацея Биотек Лимитед Нераспадающаяся твёрдая композиция для перорального применения с высокой дозой растворимых в воде лекарственных средств
WO2005067895A1 (fr) * 2004-01-16 2005-07-28 Sandoz Ag Compositions pharmaceutiques a liberation controlee
EP1681050A1 (fr) * 2005-01-13 2006-07-19 Strides Arcolab Limited Composition pharmaceutique dispersible avec libération prolongée
WO2006114277A3 (fr) * 2005-04-25 2007-05-24 Gruenenthal Gmbh Forme galenique a liberation amelioree du cefuroxime axetil
US8747900B2 (en) 2005-04-25 2014-06-10 Gruenenthal Gmbh Dosage form with improved release of cefuroximaxetil
WO2008057058A1 (fr) * 2006-11-10 2008-05-15 Nobel Ilac Sanayii Ve Ticaret As Compositions pharmaceutiques orales
EA019366B1 (ru) * 2006-11-13 2014-03-31 Басф Се Применение блок-сополимеров на основе виниллактамов и винилацетата в качестве ингибиторов кристаллизации, препарат агрохимических компонентов, включающий поливиниллактам-поливинилацетатный блок-сополимер, способ борьбы с нежелательным нападением насекомых или клещей и/или борьбы с фитопатогенными грибами и способ борьбы с нежелательным ростом растений
AU2007321357B2 (en) * 2006-11-13 2012-06-14 Basf Se Application of block copolymers based on vinyl lactams and vinyl acetate as solubilizers
US8211469B2 (en) 2006-11-13 2012-07-03 Basf Se Use of block copolymers based on vinyllactams and vinyl acetate as solubilizers
WO2008058848A1 (fr) * 2006-11-13 2008-05-22 Basf Se Utilisation de copolymères séquencés à base de vinyllactames et d'acétate de vinyle en tant que solubilisants
CN102028669A (zh) * 2010-10-27 2011-04-27 北京华禧联合科技发展有限公司 盐酸头孢卡品酯的缓释剂型及其制备方法
WO2013109205A1 (fr) * 2012-01-18 2013-07-25 Mahmut Bilgic Formulations pharmaceutiques en comprimés comprenant du céfétamet
US8476425B1 (en) 2012-09-27 2013-07-02 Cubist Pharmaceuticals, Inc. Tazobactam arginine compositions
US9925196B2 (en) 2013-03-15 2018-03-27 Merck Sharp & Dohme Corp. Ceftolozane-tazobactam pharmaceutical compositions
US11278622B2 (en) 2013-03-15 2022-03-22 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US9872906B2 (en) 2013-03-15 2018-01-23 Merck Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10420841B2 (en) 2013-03-15 2019-09-24 Merck, Sharp & Dohme Corp. Ceftolozane antibiotic compositions
US10376496B2 (en) 2013-09-09 2019-08-13 Merck, Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
US10933053B2 (en) 2013-09-09 2021-03-02 Merck Sharp & Dohme Corp. Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
WO2016088041A1 (fr) * 2014-12-01 2016-06-09 Sun Pharmaceutical Industries Limited Composition de cefpodoxime proxétil à libération prolongée
CN104434875A (zh) * 2014-12-26 2015-03-25 华北制药河北华民药业有限责任公司 一种头孢克洛胶囊及其制备方法
CN107569466A (zh) * 2017-09-17 2018-01-12 石家庄四药有限公司 一种直接压片法制备的头孢呋辛酯药物组合物
CN112023032A (zh) * 2020-09-14 2020-12-04 广东鼎信医药科技有限公司 一种含有消化酶的药物组合物及其制备方法
CN112023032B (zh) * 2020-09-14 2022-03-18 广东鼎信医药科技有限公司 一种含有消化酶的药物组合物及其制备方法
CN113908133A (zh) * 2021-11-29 2022-01-11 河南省儿童医院郑州儿童医院 一种头孢克肟缓释片及其制备方法
CN113908133B (zh) * 2021-11-29 2023-11-03 河南省儿童医院郑州儿童医院 一种头孢克肟缓释片及其制备方法
WO2025046044A1 (fr) * 2023-09-01 2025-03-06 F. Hoffmann-La Roche Ag Nouveaux procédés de préparation de compositions semi-solides et leurs utilisations
CN117243913A (zh) * 2023-10-24 2023-12-19 国药集团致君（深圳）制药有限公司 一种头孢克洛缓释组合物及其制备方法
CN120732800A (zh) * 2025-08-19 2025-10-03 湖南恒昌医药集团股份有限公司 头孢托仑匹酯缓释片及其制备方法
CN120938952A (zh) * 2025-09-22 2025-11-14 国药集团致君（深圳）制药有限公司 头孢克洛缓释片的组合物及其制备方法

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