WO2010046933A2 - Pharmaceutical compositions of taste-masked linezolid - Google Patents

Pharmaceutical compositions of taste-masked linezolid Download PDF

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Publication number
WO2010046933A2
WO2010046933A2 PCT/IN2009/000597 IN2009000597W WO2010046933A2 WO 2010046933 A2 WO2010046933 A2 WO 2010046933A2 IN 2009000597 W IN2009000597 W IN 2009000597W WO 2010046933 A2 WO2010046933 A2 WO 2010046933A2
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Prior art keywords
linezolid
taste
glyceryl
composition
masked
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PCT/IN2009/000597
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French (fr)
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WO2010046933A3 (en
Inventor
Pratibha Sudhir Pilgaonkar
Maharukh Tehmasp Rustomjee
Anilkumar Surendrakumar Gandhi
Atul A. Kelkar
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Rubicon Research Private Limited
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Publication of WO2010046933A2 publication Critical patent/WO2010046933A2/en
Publication of WO2010046933A3 publication Critical patent/WO2010046933A3/en

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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
    • A61K9/48—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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—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
    • 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
    • A61K9/2072—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
    • 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
    • A61K9/48—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
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions of taste-masked linezolid suitable for oral administration as suspension, powder for suspension, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets or the like.
  • the invention further relates to methods for masking the objectionable taste of linezolid by using at least one taste-masking agent and to its incorporation into such palatable formulations.
  • Oxazolidinones are gram positive anti -bacterial agents.
  • Linezolid is a synthetic antibacterial that belongs to this class of oxazolidinones. It has in-vitro activity against aerobic gram positive bacteria including those of the following genera: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumonias), Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria and anaerobic micro-organisms.
  • Staphylococcus e.g., Staphylococcus aureus, Staphylococcus epidermidis
  • Streptococcus e.g., Streptococcus viridans, Streptococcus pneumonias
  • Enterococcus Bacillus, Corynebacterium, Ch
  • Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 5OS subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process. It is orally effective and fairly soluble in water. It is mainly used for the treatment of infections caused by multi- resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). It is usually reserved for the treatment of serious bacterial infections where older antibiotics have failed due to antibiotic resistance. Conditions such as skin infections or nosocomial pneumonia where methicillin or penicillin resistance is found are indicators for linezolid use. It also offers a treatment option for patients who are intolerant of vancomycin as well as other antibacterial agents, or who have infections that are refractory.
  • MRSA methicillin-resistant Staphylococcus aureus
  • U.S. Patent No. 5,688,792 discloses (S)-N-[[3-[3-fiuoro-4-(4-morpholinyl) phenyl]-2-oxo-5 oxazolidinyl] methyl]acetamide, or linezolid.
  • US Patent No. 6,514,529 provides a compressed tablet of linezolid comprising starch, microcrystalline cellulose along with binder and disintegrant that provides high drug load and excellent bioavailability.
  • Linezolid is marketed by Pfizer under the trade name Zyvox (in the United States) or Zyvoxid (in Europe). It is commercially available in the form of injection, tablet and powder for suspension. With increasing prevalence of methicillin resistant S. aureus (MRSA) for nosocomial and community-acquired infections in children, linezolid was approved by the USFDA in December 2002 for the treatment of Gram-positive infections in children. It is considered safe and effective for the treatment of resistant infections in children as a suitable alternative to vancomycin for infections caused by MRSA. Linezolid has a very bitter taste and a major challenge for the development of pediatric formulations.
  • MRSA methicillin resistant S. aureus
  • U.S. Patent No. 6,451,345 provides taste-masked microcapsules wherein the bitter taste of linezolid is masked by a combination of microencapsulation by solvent coacervation and subsequent functional membrane coating on said microcapsules.
  • the taste-masked linezolid granules are optionally blended with other pharmaceutically acceptable excipients and filled into unit dose containers or compressed into fast-disintegrating/ effervescent/chewable tablets.
  • U.S. Patent Application 20040191326 discloses dry oxazolidinone formulations comprising mixture of sugars like sorbitol and sucrose for reconstitution.
  • the application relates to development of dry formulations with varying levels of sugars or viscosity enhancing substances for obtaining homogeneous suspensions.
  • Such suspension vehicles mask objectionable taste of linezolid by limiting transport of drug from microencapsulated linezolid particles.
  • Linezolid dry formulation for preparing substantially homogeneous suspensions of drug particles coated at least in part, with a hydrophobic polymer film has been disclosed in U.S. Patent Application 20040170686. Specifically, it is directed to a suspension vehicle which enables the maintenance of coated drug particles in suspension for an extended period of time, without sedimentation or floating, even after shaking in the presence of air.
  • the present invention addresses this need after rigorous experimentation and discloses taste- masked linezolid and formulations based on the same.
  • the taste-masked linezolid of the present invention provides palatable compositions with pleasant mouth feel wherein the bitter taste of linezolid is effectively masked using at least one taste-masking agent.
  • the present invention provides a pharmaceutical composition for oral administration, comprising a. taste-masked linezolid; and b. at least one pharmaceutically acceptable excipient, wherein the taste-masked linezolid comprises linezolid and at least one taste-masking agent.
  • the taste-masking agent used for linezolid comprises water insoluble polymeric excipient, water insoluble non-polymeric excipient, ion exchange resin, carbomer, adsorbent, cyclodextrin or its derivatives.
  • Such taste-masked linezolid is incorporated in compositions including, but not limited to, suspension, powder for suspension, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like.
  • Taste-masking technologies are known. However, not all taste- masking technologies can work with every drug. Taste-masking technologies can, in certain instances, interfere with disintegration, provide inadequate taste-masking for a given active or interfere with the bioavailability or pharmacokinetic properties of the drug relative to a swallow tablet. Therefore, it becomes important to develop taste-masking technology for an active agent that not only enhances the organoleptic properties of the dosage form containing the same, but also does not interfere with the bioavailability of the drug.
  • Linezolid may be present in crystalline, part crystalline or amorphous form.
  • the crystalline form may have different polymorphs.
  • Also included within the scope of the present invention are the salts, esters, amides, prodrugs, active metabolites, analogs and the like of linezolid.
  • linezolid is used in the form of a pharmaceutically acceptable salt thereof.
  • suitable salts include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid.
  • salts or “salts” also include addition salts of free acids or free bases. All such salts are acceptable provided that they are non-toxic and do not substantially interfere with the desired pharmacological activity. Additionally, polymorphs, hydrates and solvates as well as amorphous forms of linezolid can be utilized for the purpose of the present invention.
  • linezolid as used in the present invention relates to either the free base or pharmaceutically acceptable salts thereof.
  • Linezolid may be employed in an amount which is effective for the treatment of Vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonia, complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, community-acquired pneumonia and the like.
  • the concentration of linezolid in the formulation is from about 2% to about 85% by weight of the dosage form. In one embodiment of the present invention, the concentration of linezolid is about 5% to about 75% by weight of the dosage form.
  • the bitter taste of linezolid according to various embodiments of the present invention is masked by using at least one taste-masking agent such as water insoluble polymeric excipient, water insoluble non-polymeric excipient, ion exchange resin, carbomer, adsorbent, cyclodextrin or its derivative, and the like, or any combination thereof.
  • Linezolid in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like, is taste-masked using at least one taste-masking agent.
  • linezolid is taste-masked by using water insoluble excipients.
  • water insoluble excipient includes polymeric or non-polymeric excipients that are not completely soluble in water across a pH range of 1-8 commonly encountered in the gastrointestinal tract or are soluble only at a particular pH encountered in the gastrointestinal tract.
  • taste-masking using these water insoluble excipients can be achieved by coating.
  • Water insoluble polymeric excipients for taste-masking linezolid as employed in the present invention include, but are not limited to, polymethacrylic acid copolymers, other polymethylmethacrylates, dispersion of polyvinyl acetate with polyvinylpyrrolidone (Kollicoat SR 30 D), cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, dimethylaminoethyl methacrylate ' neutral methacrylate ester (Eudragit EPO), acrylic/methacrylic acid esters ' trimethyl ammonioethyl methacrylate copolymer (Eudragit RL and RS
  • Water insoluble non-polymeric excipients for taste-masking linezolid as employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, or combinations thereof.
  • Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids useful in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, for example, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof.
  • the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof.
  • Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof.
  • Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low-melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes.
  • natural waxes such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes.
  • spermaceti wax carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof. Mixtures of these waxes with the fatty acids may also be used.
  • Waxes are also monoglyceryl esters, di glyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol is substituted by a fatty acid.
  • Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate
  • the water insoluble non-polymeric excipient employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil), Croduret® (Hydrogenated castor oil), Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil), Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated cottonseed oil), Softtisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), EmulcireTM (Cetyl alcohol), Plurol® diisostearique (Pol
  • Coating of the active ingredient can be done by any of the techniques known in the art like hot melt granulation, fluid bed coating, wet granulation, dry granulation or spray drying. Coating by these techniques ensures close proximity of linezolid with water insoluble excipient and provides taste-masked linezolid.
  • the coating techniques ensure complete or partial covering of linezolid by the water insoluble excipient.
  • the coating may be partial or complete, yet sufficient to mask the bitter taste of linezolid.
  • the taste-masking coatings, based on lipids or waxes require that the melting point of the lipid should be sufficiently high to prevent melting in the mouth and should not be so high that active ingredient itself melts or is chemically degraded while preparation of the formulation.
  • Lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers. Coating can be carried out in the range from about 1% to about 150% weight gain. In one embodiment, coating is carried out in the range of from about preferably from about 2% to about 120% weight gain. In another embodiment, coating is carried out in the range of from about 5% to about 100% weight gain.
  • Ion exchange resins are solid and water insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium and are not absorbed by the body.
  • the resulting ion exchange is reversible and stoichiometric with the displacement of one ionic species by another.
  • the drug-resinates effectively mask the taste of a bitter or unpleasant tasting drug within the matrix of the ion exchange material.
  • the correct selection of ion exchange resin is important so that the drug is not released in the mouth leading to perception of the bitter taste of drug.
  • the invention provides a taste-masked linezolid wherein taste-masking is achieved by reversibly adsorbing the active compound on to an ion exchange resin wherein the polymeric matrix of the ion exchange resin can have functional groups including anionic groups, e.g., weakly acidic- carboxylic, esteric and phosphonic; strongly acidic-sulfonic and cationic groups, e.g., weakly basic- tertiary amine; strongly basic- quaternary amine.
  • anionic groups e.g., weakly acidic- carboxylic, esteric and phosphonic
  • strongly acidic-sulfonic and cationic groups e.g., weakly basic- tertiary amine
  • strongly basic- quaternary amine e.g., weakly basic- tertiary amine
  • suitable polymeric matrices include copolymers of acrylic and substituted acrylic acids; styrene and styrene derivatives; cellulose esters; vinyl and substituted vinyl esters; and polysulfonic acids and polysulfonic acid esters.
  • the ion exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin.
  • the mobile or exchangeable moieties depending on the type of resin can be but not limiting to sodium, hydrogen, potassium, chloride and the like.
  • Another embodiment of the present invention uses a cationic exchange resin to mask the bitter taste of linezolid not limiting to Amberlite ® IRP64 (porous copolymer of methacrylic acid and divinylbenzene), Amberlite ® IRP69 (sulfonated copolymer of styrene and divinylbenzene), Amberlite ® IRP88 (cross linked polymer of methacrylic acid and divinylbenzene), DOWEX ® RTM.
  • ion exchange resin can be used for complexation with linezolid in a ratio of linezolid to resin of about 1 :0.2 to about 1:10. In another embodiment, linezolid to resin ratio is of about 1 :8. In still another embodiment, this ratio is of about 1 :5.
  • Cyclodextrins are crystalline, cyclic oligosaccharides derived from starch.
  • Examples of cyclodextrin derivatives which can be employed for linezolid taste- masking include ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, trimethyl- ⁇ -cyclodextrin, 2-hydroxymethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, 3-hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfate, ⁇ -cyclodextrin sulfonate, or ⁇ - cyclodextrin sulfobutyl ether.
  • Cyclodextrin makes an inclusion complex with linezolid molecule by acting as a hydrophobic host cavity.
  • Such complexes for taste-masking purposes can be processed by mixing, grinding, solid dispersion, kneading, spray drying and melting method.
  • cyclodextrin derivative can be used for complexation in a ratio of linezolid to cyclodextrin derivative of about 1 :0.5 to about 1 :15.
  • linezolid to cyclodextrin ratio is of about 1:8. In still another embodiment, this ratio is of about 1:4.
  • Linezolid can be taste-masked by complexation with carbomers including, but not limited to, carbomer 934, carbomer 971, carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable compositions.
  • carbomers including, but not limited to, carbomer 934, carbomer 971, carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable compositions.
  • These complexes can be prepared by mixing, blending or slurrying linezolid and carbomer together to allow the desired complex formation.
  • carbomer can be used for complexation with linezolid in a ratio of linezolid to carbomer of about 1:0.5 to about 1:15.
  • linezolid to carbomer ratio is of about 1:10. In still another embodiment, this ratio is of about 1 :5.
  • the bitter taste of linezolid can also be masked by formation of adsorbates, by adsorbing or partially or significantly blending linezolid with an adsorbent selected from, but not limited to, bentonite, kaolite, zeolite, sodium alginate, magnesium aluminium silicate, silica gel, or activated charcoal, or mixtures thereof.
  • adsorbent materials can surround the drug particles by forming a physical bond, by Van der Waals interactions, and hydrogen bonding force of attraction, so that the bitter taste of the drug is not perceived.
  • the adsorbate of linezolid can be formed by mixing or blending the active with the adsorbent in high or moderate shear mixers like planetary mixer or rapid mixer granulator.
  • adsorbate can be formed by wet granulation involving the adsorbent and linezolid in any conventional granulation equipment.
  • adsorbent can be used for taste- masking linezolid in a ratio of linezolid to adsorbent of about 1 :1 to about 1 :50.
  • linezolid to adsorbent ratio is of about 1 :20. In another embodiment, this ratio is of about 1 :10.
  • the taste-masked linezolid of the present invention in the form of, but not limited to, powder, granules, pellets, beads or the like is suitable for incorporation into various oral dosage forms including, but not limited to, suspensions, powder for suspensions, orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, sprinkle granules, quick melt wafers, lozenge, chewing gum or the like.
  • These oral formulations may contain from about 5% to about 95% of taste-masked linezolid.
  • the linezolid may be so taste-masked that its bioavailability is preferably not compromised.
  • Dispersible tablet refers to a tablet which disperses in aqueous phase, e.g. in water before administration.
  • a water-dispersible tablet according to the British Pharmacopoeia and European Pharmacopoeia, should meet the requirements of the test for dispersible tablets as regards dispersion time ( ⁇ 3 minutes) and dispersion quality (i.e. to pass through a 710 ⁇ m sieve).
  • the dispersible tablet compositions comprising taste-masked linezolid can further comprise pharmaceutically acceptable excipients such as , but not limited to, one or more viscolizers, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, glidants or lubricants, solubilizers, wetting agents or stabilizers.
  • pharmaceutically acceptable excipients such as , but not limited to, one or more viscolizers, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, glidants or lubricants, solubilizers, wetting agents or stabilizers.
  • viscolizers include, but are not limited to, polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, microcrystalline cellulose; gums such as gum arabic alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, karaya, whelan; polyols such as dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; carbopol, starch and starch-based polymers such as pre-
  • viscolizers are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene oxide, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof.
  • the weight percent of the viscolizer in the dosage form is about 2 to about 75 weight percent. In one embodiment, the weight percent of the viscolizer in the dosage form is about 10 to about 70 weight percent. In another embodiment, the weight percent of the viscolizer in the dosage form is about 5 to about 50 weight percent.
  • Viscolizers act to control the sedimentation rate of dispersed linezolid, thereby producing homogeneous dispersions when the dispersible tablets are dispersed in water before administration thus ensuring substantially uniform dosing. They rapidly generate viscosity when the dispersible tablets come in contact with water, and a homogenous suspension is formed, which can be easily swallowed by children and the elderly, with minimal effect on the release properties of the biologically active ingredient.
  • the disintegrants that ensure rapid dispersibility of the formulation include, but are not limited to, starch, sodium starch glycolate, pregelatinised starch, crosslinked polyvinyl pyrrolidone, cross linked calcium or sodium carboxy methyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacrylic acid, alginates, colloidal magnesium-aluminum silicate, calcium silicate and the like.
  • the disintegrant is cross-linked polyvinyl pyrrolidone.
  • the disintegrant is calcium silicate.
  • Superdisintegrants include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems.
  • the disintegrant is crospovidone.
  • the disintegrant is starch.
  • binders include, but are not limited to, starch, pregelatinized starch, polyvinyl pyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.
  • suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol, dicalcium phosphate, and the like.
  • lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate.
  • the tablet compositions of the invention may also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • compositions may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.
  • salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.
  • solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof.
  • compositions of the present invention may also include stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like.
  • stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like.
  • the wetting agent may be chosen from the broad classes of surfactants, including nonionic, cationic, anionic, and zwitterionic surfactants known in the art.
  • sorbitan fatty acid esters can include, for example, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (T ween®), sodium lauryl sulfate, sorbic acid, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene fatty acid esters, mono- and diglycerides, medium chain glyceride (Capmul) glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate and glyceryl caprylate (Capmul MCM), polyoxyethylene-polyoxypropylene copolymers and block copolymers and mixtures thereof.
  • Souring agents include, but are not limited to, monosodium fumarate and/or citric acid.
  • compositions of the present invention comprising taste-masked linezolid include one sweetening agent such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and one or more flavors, e.g., mint flavor, orange flavor, lemon flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 51 1815, and fruit extracts.
  • sweetening agent such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate
  • flavors e.g., mint flavor, orange flavor, lemon flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor,
  • taste-masked linezolid is incorporated in an orally disintegrating tablet.
  • Orally disintegrating tablets disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation.
  • the orally disintegrating tablets comprising taste-masked linezolid can further comprise directly compressible coprocessed excipient.
  • PCT Application WO2007052289 describes directly compressible coprocessed excipient comprising at least one water soluble excipient and water insoluble inorganic excipient such as calcium silicate.
  • the water soluble carbohydrate can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide.
  • carbohydrates include, but are not limited to, monosaccharides such as sorbitol, glucose, dextrose, fructose, maltose or xylitol, disaccharides such as sucrose, trehalose, lactose, glucose, galactose or mannitol, and oligosaccharides and polysaccharides such as dextrates and maltodextrins.
  • the water soluble and water insoluble excipients in the directly compressible coprocessed excipient can be in a ratio of water-soluble excipient to water insoluble excipient of from about 50:1 to about 1 :50. In one embodiment of the present invention, this ratio is about 30:1 to about 1 :30.
  • this ratio is from about 20:1 to about 1 :20.
  • the amount of directly compressible coprocessed excipient employed in the orally disintegrating tablet compositions comprising taste-masked linezolid is about 5% to about 95 % by weight of the said dosage form.
  • the orally disintegrating tablet compositions of taste-masked linezolid can further comprise pharmaceutically acceptable excipients as disclosed above under dispersible tablets.
  • the orally disintegrating tablet compositions based on taste-masked linezolid dissolve or disintegrate in the oral cavity, preferably within about 60 seconds.
  • the orally disintegrating tablet compositions comprising taste-masked linezolid can be prepared by any of the known nonlimiting techniques such as freeze-drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like.
  • the taste-masked linezolid can be incorporated in chewable tablets or effervescent tablets.
  • Chewable tablets are taken slowly by chewing or sucking in the mouth, and enable taste-masked linezolid contained therein to be orally administered without water.
  • Effervescent tablets are intended to be dissolved or dispersed in water before administration and generally contain acid substances and carbonates or bicarbonates, which react rapidly in the presence of water releasing carbon dioxide. These tablets comprise various pharmaceutically acceptable excipients as have been discussed under dispersible tablets and orally disintegrating tablets.
  • the effervescent tablets can comprise effervescent couples selected from, but not limited to, thermolabile gas generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.
  • thermolabile gas generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.
  • tablette and “tablet composition” are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/ melt granulation. In one embodiment, the process is direct compression which involves compression of taste- masked drug-excipient blend after mixing them for a definite time period.
  • the taste-masked linezolid can be incorporated in suspensions, syrups or dry suspensions for administration.
  • compositions of the present invention comprising taste-masked linezolid release linezolid in a controlled manner over a period of time, for example, from about 2 to about 24 hours.
  • taste-masked linezolid is further coated with a combination of water soluble and water insoluble excipients, as discussed above. The amount of coating not only ensures the taste-masking but also controls the release of taste-masked linezolid. Any of the taste-masking approaches described above can be used in combination with coating for the purpose of achieving a controlled release dosage form of taste-masked linezolid.
  • pellets or granules or the like of linezolid are prepared comprising at least one release retardant in combination with one or more pharmaceutically acceptable excipients.
  • Suitable release retardants include, but are not limited to, cellulose ethers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose and carboxymethylcellulose sodium; polysaccharides, such as carageenan, guar gum, xanthan gum, tragacanth and ceratonia; polymethacrylates, such as copolymers of acrylic and methacrylic acid esters containing quarternary ammonium groups; cellulose esters, such as cellulose acetate; acrylic acid polymers, such as carbomers; waxes, such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax; alginates, such as alginic acid and sodium alginate; and fatty acid derivatives, such as glyceryl monostea
  • the taste-masked linezolid compositions of the present invention may be adapted to deliver one more active agent in addition to linezolid.
  • the additional active agent may be selected from, but not limited to, penicillin, ciprofloxacin, rifampicin, clindamycin, gentamycin, vancomycin, isoniazid, dextrometho ⁇ han, quinupristin, dalfopristin, rifalazil or fusidic acid or the like.
  • process for preparing a pharmaceutical composition of the present invention for oral administration comprises; a. coating linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is a water insoluble polymeric excipient or a water insoluble non-polymeric excipient, or a combination thereof .
  • process for preparing a pharmaceutical composition of the present invention for oral administration comprises; a. complexing linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is an ion exchange resin, a carbomer, a cyclodextrin or a derivative thereof.
  • at least one taste-masking agent is an ion exchange resin, a carbomer, a cyclodextrin or a derivative thereof.
  • process for preparing a pharmaceutical composition of the present invention for oral administration comprises; a. adsorbing linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is an adsorbent.
  • Another embodiment the present invention discloses a method of treating bacterial infections comprising administering to a subject in need thereof compositions comprising taste-masked linezolid and at least one pharmaceutically acceptable excipient.
  • Example 1 Dispersible tablet formulation of taste-masked linezolid by coating with wax dispersion
  • Lubritab was melted at around 80 0 C and Capmul MCM was added to it. Part of water was heated to same temperature and added to molten wax with homogenization to get an emulsion. Hydroxypropyl methyl cellulose was then added to remaining amount of water along with sucralose. This solution was then added to above emulsion under homogenization. Talc was added to the mixture and homogenized well. The coating dispersion was sprayed on linezolid pellets to weight gain of 50%.
  • Linezolid was treated with cationic exchange resin Amberlite IRP 69 (1 :2.5 ratio) in 0.1 N HCl to get a taste-masked linezolid resin complex.
  • the complex was blended with other excipients like spray dried mannitol, microcrystalline cellulose, sodium starch glycolate, citric acid, aspartame, colloidal silicon dioxide, talc and flavor and finally lubricated using magnesium stearate.
  • the blend was compressed to get a chewable tablet. The tablets imparted good mouth feel without sense of undesirable taste of linezolid.
  • Example 4 Dispersible tablets of taste-masked Linezolid using glyceryl behenate Table 6 Taste-masking using glyceryl behenate and linezolid formulation
  • Linezolid granules were prepared by melt granulating linezolid with glyceryl behenate. These taste-masked linezolid granules were further mixed with other ingredients. The blend lubricated with sodium stearyl fumarate was directly compressed into dispersible tablets. Tablets with desired taste, disintegration time and dispersibility were obtained.
  • Linezolid was blended well with colloidal silicon dioxide as per following composition:
  • Eudragit EPO along with other ingredients was dispersed in water.
  • Eudragit NE 30 D was added towards the end in the coating system. This was sprayed on the blend of linezolid and colloidal silicon dioxide using a fluidized bed coater to 30% weight gain.
  • Table 9 Dispersible tablets of taste-masked linezolid
  • Example 6 Dispersible tablets of taste-masked linezolid using glyceryl behenate
  • Linezolid granules were prepared by melt granulation with glyceryl behenate. These granules were sized and blended with remaining excipients except magnesium stearate. The blend was lubricated and compressed to get dispersible tablets. The tablets were characterized and the properties are tabulated below:
  • the dispersible tablets had excellent palatability in comparison to marketed formulation Zyvox (granules/powder for suspension) and passed the disintegration and dispersibility tests as per Ph. Eur. (4 th Edition).
  • Dissolution study of dispersible tablets was carried out using USP apparatus II in pH 6.8 phosphate buffer at 50 rpm. The drug release was compared with Zyvox.
  • the drug release from dispersible tablets was comparable with marketed formulation Zyvox.

Abstract

The present invention relates to a pharmaceutical composition of linezolid for oral administration, comprising taste-masked linezolid and at least one pharmaceutically acceptable excipient. The taste-masked linezolid comprises linezolid and at least one taste-masking agent. The invention further relates to methods for masking the objectionable taste of linezolid by using at least one taste-masking agent and its incorporation into such palatable formulations. The pharmaceutical compositions of taste-masked linezolid are suitable for oral administration as suspensions, powders for suspensions, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like.

Description

PHARMACEUTICAL COMPOSITIONS OF TASTE-MASKED LINEZOLID
Field of the Invention
The present invention relates to pharmaceutical compositions of taste-masked linezolid suitable for oral administration as suspension, powder for suspension, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets or the like. The invention further relates to methods for masking the objectionable taste of linezolid by using at least one taste-masking agent and to its incorporation into such palatable formulations.
Background of the Invention Oxazolidinones are gram positive anti -bacterial agents. Linezolid is a synthetic antibacterial that belongs to this class of oxazolidinones. It has in-vitro activity against aerobic gram positive bacteria including those of the following genera: Staphylococcus (e.g., Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumonias), Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria and anaerobic micro-organisms. Linezolid selectively inhibits bacterial protein synthesis via a unique mechanism of action. Specifically, it binds to a site on the bacterial ribosome (23S of the 5OS subunit) and prevents the formation of a functional 70S initiation complex which is an essential component of the translation process. It is orally effective and fairly soluble in water. It is mainly used for the treatment of infections caused by multi- resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). It is usually reserved for the treatment of serious bacterial infections where older antibiotics have failed due to antibiotic resistance. Conditions such as skin infections or nosocomial pneumonia where methicillin or penicillin resistance is found are indicators for linezolid use. It also offers a treatment option for patients who are intolerant of vancomycin as well as other antibacterial agents, or who have infections that are refractory.
U.S. Patent No. 5,688,792 discloses (S)-N-[[3-[3-fiuoro-4-(4-morpholinyl) phenyl]-2-oxo-5 oxazolidinyl] methyl]acetamide, or linezolid. US Patent No. 6,514,529 provides a compressed tablet of linezolid comprising starch, microcrystalline cellulose along with binder and disintegrant that provides high drug load and excellent bioavailability.
Linezolid is marketed by Pfizer under the trade name Zyvox (in the United States) or Zyvoxid (in Europe). It is commercially available in the form of injection, tablet and powder for suspension. With increasing prevalence of methicillin resistant S. aureus (MRSA) for nosocomial and community-acquired infections in children, linezolid was approved by the USFDA in December 2002 for the treatment of Gram-positive infections in children. It is considered safe and effective for the treatment of resistant infections in children as a suitable alternative to vancomycin for infections caused by MRSA. Linezolid has a very bitter taste and a major challenge for the development of pediatric formulations. Commercially available pediatric formulation is an orange flavored powder for reconstitution into a suspension having a concentration of 100 mg of linezolid per 5ml. Even with its orange flavoring, sweeteners and other inactive ingredients, the objectionable taste of the drug is not completely masked. This explains need for development of pleasant tasting and taste-masked linezolid formulations.
U.S. Patent No. 6,451,345 provides taste-masked microcapsules wherein the bitter taste of linezolid is masked by a combination of microencapsulation by solvent coacervation and subsequent functional membrane coating on said microcapsules. The taste-masked linezolid granules are optionally blended with other pharmaceutically acceptable excipients and filled into unit dose containers or compressed into fast-disintegrating/ effervescent/chewable tablets. U.S. Patent Application 20040191326 discloses dry oxazolidinone formulations comprising mixture of sugars like sorbitol and sucrose for reconstitution. Specifically, the application relates to development of dry formulations with varying levels of sugars or viscosity enhancing substances for obtaining homogeneous suspensions. Such suspension vehicles mask objectionable taste of linezolid by limiting transport of drug from microencapsulated linezolid particles. Linezolid dry formulation for preparing substantially homogeneous suspensions of drug particles coated at least in part, with a hydrophobic polymer film has been disclosed in U.S. Patent Application 20040170686. Specifically, it is directed to a suspension vehicle which enables the maintenance of coated drug particles in suspension for an extended period of time, without sedimentation or floating, even after shaking in the presence of air.
Thus there have been some attempts in the prior art to provide taste-masked linezolid. Microencapsulation attempted for masking the bitter taste however involves complex and cumbersome methods and the process is not environmentally friendly as it employs organic solvents. Further in a liquid formulation linezolid can tend to leak out of the microcapsules, leaving a bitter taste in the mouth.
Bitter taste of linezolid poses major issue of drug compliance, particularly with pediatric population. It is hence required for this age group that taste- masked linezolid is preferably presented in dosage forms that are easy to carry and administer which increase patient compliance. There, thus, exists an urgent need for improved taste-masked linezolid composition which is palatable and does not impart bitter after-taste following administration.
The present invention addresses this need after rigorous experimentation and discloses taste- masked linezolid and formulations based on the same. The taste-masked linezolid of the present invention provides palatable compositions with pleasant mouth feel wherein the bitter taste of linezolid is effectively masked using at least one taste-masking agent.
Summary of the Invention The present invention provides a pharmaceutical composition for oral administration, comprising a. taste-masked linezolid; and b. at least one pharmaceutically acceptable excipient, wherein the taste-masked linezolid comprises linezolid and at least one taste-masking agent. The taste-masking agent used for linezolid comprises water insoluble polymeric excipient, water insoluble non-polymeric excipient, ion exchange resin, carbomer, adsorbent, cyclodextrin or its derivatives. Such taste-masked linezolid is incorporated in compositions including, but not limited to, suspension, powder for suspension, dispersible tablets, orally disintegrating tablets, chewable tablets, effervescent tablets and the like.
Detailed Description of the Invention
Palatability and mouth feel are extremely important factors for achieving total compliance of patients who are being administered the unpleasant, disagreeable or objectionable tasting active pharmaceutical agent. Taste-masking technologies are known. However, not all taste- masking technologies can work with every drug. Taste-masking technologies can, in certain instances, interfere with disintegration, provide inadequate taste-masking for a given active or interfere with the bioavailability or pharmacokinetic properties of the drug relative to a swallow tablet. Therefore, it becomes important to develop taste-masking technology for an active agent that not only enhances the organoleptic properties of the dosage form containing the same, but also does not interfere with the bioavailability of the drug.
The present inventors, through thorough research have developed taste-masked linezolid wherein the bitter, unpleasant and otherwise undesirable taste of linezolid is masked. Linezolid may be present in crystalline, part crystalline or amorphous form. The crystalline form may have different polymorphs. Also included within the scope of the present invention are the salts, esters, amides, prodrugs, active metabolites, analogs and the like of linezolid.
In one embodiment of the present invention, linezolid is used in the form of a pharmaceutically acceptable salt thereof. Suitable salts include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid. The term "salt" or "salts" also include addition salts of free acids or free bases. All such salts are acceptable provided that they are non-toxic and do not substantially interfere with the desired pharmacological activity. Additionally, polymorphs, hydrates and solvates as well as amorphous forms of linezolid can be utilized for the purpose of the present invention. The term "linezolid" as used in the present invention relates to either the free base or pharmaceutically acceptable salts thereof.
Linezolid may be employed in an amount which is effective for the treatment of Vancomycin-resistant Enterococcus faecium infections, nosocomial pneumonia, complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis, community-acquired pneumonia and the like. The concentration of linezolid in the formulation is from about 2% to about 85% by weight of the dosage form. In one embodiment of the present invention, the concentration of linezolid is about 5% to about 75% by weight of the dosage form.
The bitter taste of linezolid according to various embodiments of the present invention is masked by using at least one taste-masking agent such as water insoluble polymeric excipient, water insoluble non-polymeric excipient, ion exchange resin, carbomer, adsorbent, cyclodextrin or its derivative, and the like, or any combination thereof. Linezolid in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like, is taste-masked using at least one taste-masking agent.
In one embodiment of the present invention, linezolid is taste-masked by using water insoluble excipients. The term "water insoluble excipient" as used herein includes polymeric or non-polymeric excipients that are not completely soluble in water across a pH range of 1-8 commonly encountered in the gastrointestinal tract or are soluble only at a particular pH encountered in the gastrointestinal tract. In one embodiment taste-masking using these water insoluble excipients can be achieved by coating.
Water insoluble polymeric excipients for taste-masking linezolid as employed in the present invention include, but are not limited to, polymethacrylic acid copolymers, other polymethylmethacrylates, dispersion of polyvinyl acetate with polyvinylpyrrolidone (Kollicoat SR 30 D), cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, ethylhydroxy ethylcellulose phthalate, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, dimethylaminoethyl methacrylate'neutral methacrylate ester (Eudragit EPO), acrylic/methacrylic acid esters' trimethyl ammonioethyl methacrylate copolymer (Eudragit RL and RS), ethyl acrylate' methyl methacrylate neutral copolymer (Eudragit NE30D and Eudragit NE40D), or any combinations thereof.
Water insoluble non-polymeric excipients for taste-masking linezolid as employed in the present invention include, but are not limited to, fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids, or combinations thereof.
Fatty acids are carboxylic acids derived from or contained in an animal or vegetable fat or oil. Fatty acids are composed of a chain of alkyl groups containing from 4 to 22 carbon atoms and are characterized by a terminal carboxyl group. Fatty acids useful in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. Other fatty acids include, for example, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof. In one embodiment the fatty acids employed include, but are not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof. Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof.
Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons. Waxes are low-melting organic mixtures or compounds having a high molecular weight and are solid at room temperature. Waxes may be hydrocarbons or esters of fatty acids and alcohols. Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. Specific examples include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof. Mixtures of these waxes with the fatty acids may also be used.
Waxes are also monoglyceryl esters, di glyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol is substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate polyglyceryl diisostearate, Iauroyl macrogolglycerides, oleyl macrogolglycerides, stearoyl macrogolglycerides, and the like, and mixtures thereof. In one embodiment the water insoluble non-polymeric excipient employed includes, but is not limited to, Cutina® (Hydrogenated castor oil), Hydrobase® (Hydrogenated soybean oil), Castorwax® (Hydrogenated castor oil), Croduret® (Hydrogenated castor oil), Carbowax®, Compritol® (Glyceryl behenate), Sterotex® (Hydrogenated cottonseed oil), Lubritab® (Hydrogenated cottonseed oil), Apifil® (Wax yellow), Akofine® (Hydrogenated cottonseed oil), Softtisan® (Hydrogenated palm oil), Hydrocote® (Hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Emulcire™ (Cetyl alcohol), Plurol® diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures thereof. In a further embodiment the non-polymeric release retardant employed includes, but is not limited to, Compritol®, Sterotex®, Lubritab®, stearic acid, cetyl alcohol, and mixture thereof.
Coating of the active ingredient can be done by any of the techniques known in the art like hot melt granulation, fluid bed coating, wet granulation, dry granulation or spray drying. Coating by these techniques ensures close proximity of linezolid with water insoluble excipient and provides taste-masked linezolid. The coating techniques ensure complete or partial covering of linezolid by the water insoluble excipient. The coating may be partial or complete, yet sufficient to mask the bitter taste of linezolid. Further, the taste-masking coatings, based on lipids or waxes require that the melting point of the lipid should be sufficiently high to prevent melting in the mouth and should not be so high that active ingredient itself melts or is chemically degraded while preparation of the formulation. Lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers. Coating can be carried out in the range from about 1% to about 150% weight gain. In one embodiment, coating is carried out in the range of from about preferably from about 2% to about 120% weight gain. In another embodiment, coating is carried out in the range of from about 5% to about 100% weight gain.
Ion exchange resins are solid and water insoluble high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium and are not absorbed by the body. The resulting ion exchange is reversible and stoichiometric with the displacement of one ionic species by another. The drug-resinates effectively mask the taste of a bitter or unpleasant tasting drug within the matrix of the ion exchange material. The correct selection of ion exchange resin is important so that the drug is not released in the mouth leading to perception of the bitter taste of drug.
The invention provides a taste-masked linezolid wherein taste-masking is achieved by reversibly adsorbing the active compound on to an ion exchange resin wherein the polymeric matrix of the ion exchange resin can have functional groups including anionic groups, e.g., weakly acidic- carboxylic, esteric and phosphonic; strongly acidic-sulfonic and cationic groups, e.g., weakly basic- tertiary amine; strongly basic- quaternary amine. Additionally, suitable polymeric matrices include copolymers of acrylic and substituted acrylic acids; styrene and styrene derivatives; cellulose esters; vinyl and substituted vinyl esters; and polysulfonic acids and polysulfonic acid esters. The ion exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin. The mobile or exchangeable moieties depending on the type of resin can be but not limiting to sodium, hydrogen, potassium, chloride and the like.
Another embodiment of the present invention uses a cationic exchange resin to mask the bitter taste of linezolid not limiting to Amberlite® IRP64 (porous copolymer of methacrylic acid and divinylbenzene), Amberlite® IRP69 (sulfonated copolymer of styrene and divinylbenzene), Amberlite® IRP88 (cross linked polymer of methacrylic acid and divinylbenzene), DOWEX® RTM. resins (strong cationic exchangers based upon polystyrenesulphonic acid with variable crosslinking (1-12% divinylbenzene)), Tulsion® 335 - (Polacrilex/{Potacirilex S), Tulsion® 339 (Polacrilin potassium USP), Tulsion® 344 (Sodium polystyrene sulfonate BP), Indion® 204 (crosslinked polyacrylic acid), Indion® 214 (crosslinked polyacrylic acid), Indion® 234 (crosslinked polyacrylic acid), Indion® 234S (crosslinked polyacrylic acid), Indion® 294 (crosslinked polyacrylic acid), Purolite® Cl 15 HMR (carboxylic acid functional group), Purolite® Cl 15 E (carboxylic acid functional group), Purolite® ClOO HMR (sulfonic acid functional group), Purolite® 100 MR (sulfonic acid functional group) or cation exchange resins having phosphonic functional groups.
In one embodiment, ion exchange resin can be used for complexation with linezolid in a ratio of linezolid to resin of about 1 :0.2 to about 1:10. In another embodiment, linezolid to resin ratio is of about 1 :8. In still another embodiment, this ratio is of about 1 :5.
Several cyclodextrin derivatives are also employed for complexation and hence taste- masking of active agents. Cyclodextrins are crystalline, cyclic oligosaccharides derived from starch. Examples of cyclodextrin derivatives which can be employed for linezolid taste- masking include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2-hydroxymethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, or β- cyclodextrin sulfobutyl ether. Cyclodextrin makes an inclusion complex with linezolid molecule by acting as a hydrophobic host cavity. Such complexes for taste-masking purposes can be processed by mixing, grinding, solid dispersion, kneading, spray drying and melting method. In one embodiment, cyclodextrin derivative can be used for complexation in a ratio of linezolid to cyclodextrin derivative of about 1 :0.5 to about 1 :15. In another embodiment, linezolid to cyclodextrin ratio is of about 1:8. In still another embodiment, this ratio is of about 1:4.
Linezolid can be taste-masked by complexation with carbomers including, but not limited to, carbomer 934, carbomer 971, carbomer 974 or the like wherein the complex is held together by ionic bonding and gel properties of the carbomer, providing stable and palatable compositions. These complexes can be prepared by mixing, blending or slurrying linezolid and carbomer together to allow the desired complex formation. In one embodiment, carbomer can be used for complexation with linezolid in a ratio of linezolid to carbomer of about 1:0.5 to about 1:15. In another embodiment, linezolid to carbomer ratio is of about 1:10. In still another embodiment, this ratio is of about 1 :5.
Further, the bitter taste of linezolid can also be masked by formation of adsorbates, by adsorbing or partially or significantly blending linezolid with an adsorbent selected from, but not limited to, bentonite, kaolite, zeolite, sodium alginate, magnesium aluminium silicate, silica gel, or activated charcoal, or mixtures thereof. These adsorbent materials can surround the drug particles by forming a physical bond, by Van der Waals interactions, and hydrogen bonding force of attraction, so that the bitter taste of the drug is not perceived. The adsorbate of linezolid can be formed by mixing or blending the active with the adsorbent in high or moderate shear mixers like planetary mixer or rapid mixer granulator. Alternatively, adsorbate can be formed by wet granulation involving the adsorbent and linezolid in any conventional granulation equipment. In one embodiment, adsorbent can be used for taste- masking linezolid in a ratio of linezolid to adsorbent of about 1 :1 to about 1 :50. In another embodiment, linezolid to adsorbent ratio is of about 1 :20. In another embodiment, this ratio is of about 1 :10.
The taste-masked linezolid of the present invention in the form of, but not limited to, powder, granules, pellets, beads or the like is suitable for incorporation into various oral dosage forms including, but not limited to, suspensions, powder for suspensions, orally disintegrating tablets, dispersible tablets, chewable tablets, effervescent tablets, sprinkle granules, quick melt wafers, lozenge, chewing gum or the like. These oral formulations may contain from about 5% to about 95% of taste-masked linezolid. The linezolid may be so taste-masked that its bioavailability is preferably not compromised.
Dispersible tablet refers to a tablet which disperses in aqueous phase, e.g. in water before administration. A water-dispersible tablet, according to the British Pharmacopoeia and European Pharmacopoeia, should meet the requirements of the test for dispersible tablets as regards dispersion time (< 3 minutes) and dispersion quality (i.e. to pass through a 710 μm sieve).
The dispersible tablet compositions comprising taste-masked linezolid can further comprise pharmaceutically acceptable excipients such as , but not limited to, one or more viscolizers, binders, disintegrants, superdisintegrants, diluents, salivating agents, surfactants, flavors, sweeteners, colorants, diluents, souring agents, glidants or lubricants, solubilizers, wetting agents or stabilizers.
Examples of viscolizers include, but are not limited to, polyalkylene oxides such as polyethylene oxide; cellulose ethers such as hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, sodium carboxy methylcellulose, calcium carboxymethyl cellulose, microcrystalline cellulose; gums such as gum arabic alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, karaya, whelan; polyols such as dipropylene glycol, polypropylene glycol, propylene glycol, polyethylene glycol (PEG), sorbitol and glycerol; carbopol, starch and starch-based polymers such as pregelatinized starch, acrylic acid and methacrylic acid polymers, and esters thereof, maleic anhydride polymers; polymaleic acid; poly(acrylamides); poly(olefinic alcohol)s; poly(N-vinyI lactams); polyoxyethylated saccharides; polyoxazolines; polyvinylamines; polyvinylacetates; polyimines; povidone vinylpyrrolidone/vinyl acetate copolymer and polyvinyl acetate, polyvinyl acetate, chitin, cyclodextrin, gelatin, chitosan, and combinations thereof.
In one embodiment of the present invention, viscolizers are hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyethylene oxide, sodium carboxy methylcellulose, microcrystalline cellulose, guar gum, xanthan gum, alginates and combinations thereof. The weight percent of the viscolizer in the dosage form is about 2 to about 75 weight percent. In one embodiment, the weight percent of the viscolizer in the dosage form is about 10 to about 70 weight percent. In another embodiment, the weight percent of the viscolizer in the dosage form is about 5 to about 50 weight percent.
Viscolizers act to control the sedimentation rate of dispersed linezolid, thereby producing homogeneous dispersions when the dispersible tablets are dispersed in water before administration thus ensuring substantially uniform dosing. They rapidly generate viscosity when the dispersible tablets come in contact with water, and a homogenous suspension is formed, which can be easily swallowed by children and the elderly, with minimal effect on the release properties of the biologically active ingredient.
The disintegrants that ensure rapid dispersibility of the formulation include, but are not limited to, starch, sodium starch glycolate, pregelatinised starch, crosslinked polyvinyl pyrrolidone, cross linked calcium or sodium carboxy methyl cellulose, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacrylic acid, alginates, colloidal magnesium-aluminum silicate, calcium silicate and the like. In one embodiment, the disintegrant is cross-linked polyvinyl pyrrolidone. In another embodiment, the disintegrant is calcium silicate.
Superdisintegrants include, but are not limited to, natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose as well as effervescent disintegrating systems. In one embodiment, the disintegrant is crospovidone. In another embodiment, the disintegrant is starch.
Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, polyvinyl pyrrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts. Examples of suitable diluents include, but are not limited to, starch, microcrystalline cellulose, lactose, xylitol, mannitol, dicalcium phosphate, and the like. Examples of lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, talc, and sodium stearyl fumarate. The tablet compositions of the invention may also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
The said compositions may also include salivating agents such as, but not limited to, micronised polyethylene glycol, sodium chloride or precipitated micronised silica to improve the disintegration properties of the said compositions.
Examples of solubilizers include, but are not limited to cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof. The compositions of the present invention may also include stabilizers such as, but not limited to, benzoic acid, sodium benzoate, citric acid, and the like. The wetting agent may be chosen from the broad classes of surfactants, including nonionic, cationic, anionic, and zwitterionic surfactants known in the art. These can include, for example, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters (T ween®), sodium lauryl sulfate, sorbic acid, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene fatty acid esters, mono- and diglycerides, medium chain glyceride (Capmul) glyceryl monooleate (Peceol), glyceryl ricinoleate, glyceryl laurate and glyceryl caprylate (Capmul MCM), polyoxyethylene-polyoxypropylene copolymers and block copolymers and mixtures thereof.. Souring agents include, but are not limited to, monosodium fumarate and/or citric acid.
The pharmaceutical compositions of the present invention comprising taste-masked linezolid include one sweetening agent such as, but not limited to, aspartame, stevia extract, glycyrrhiza, saccharine, saccharine sodium, acesulfame, sucralose and dipotassium glycyrrhizinate; and one or more flavors, e.g., mint flavor, orange flavor, lemon flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 51 1815, and fruit extracts.
In one embodiment, taste-masked linezolid is incorporated in an orally disintegrating tablet. Orally disintegrating tablets (ODTs) disintegrate/dissolve in the mouth rapidly without administering extra water, providing the convenience of a tablet formulation while allowing the ease of swallowing provided by a liquid formulation.
The orally disintegrating tablets comprising taste-masked linezolid can further comprise directly compressible coprocessed excipient. PCT Application WO2007052289 describes directly compressible coprocessed excipient comprising at least one water soluble excipient and water insoluble inorganic excipient such as calcium silicate. The water soluble carbohydrate can be a monosaccharide, disaccharide, oligosaccharide or polysaccharide. Examples of carbohydrates include, but are not limited to, monosaccharides such as sorbitol, glucose, dextrose, fructose, maltose or xylitol, disaccharides such as sucrose, trehalose, lactose, glucose, galactose or mannitol, and oligosaccharides and polysaccharides such as dextrates and maltodextrins. The water soluble and water insoluble excipients in the directly compressible coprocessed excipient can be in a ratio of water-soluble excipient to water insoluble excipient of from about 50:1 to about 1 :50. In one embodiment of the present invention, this ratio is about 30:1 to about 1 :30. In a further embodiment of the present invention, this ratio is from about 20:1 to about 1 :20. The amount of directly compressible coprocessed excipient employed in the orally disintegrating tablet compositions comprising taste-masked linezolid is about 5% to about 95 % by weight of the said dosage form.
The orally disintegrating tablet compositions of taste-masked linezolid can further comprise pharmaceutically acceptable excipients as disclosed above under dispersible tablets. The orally disintegrating tablet compositions based on taste-masked linezolid dissolve or disintegrate in the oral cavity, preferably within about 60 seconds.
The orally disintegrating tablet compositions comprising taste-masked linezolid can be prepared by any of the known nonlimiting techniques such as freeze-drying, molding and sublimation, compression, cotton candy process, mass extrusion, etc or use of specialized excipients such as effervescent couple, highly micronized agents, coprocessed excipients or the like.
In another embodiment of the present invention, the taste-masked linezolid can be incorporated in chewable tablets or effervescent tablets. Chewable tablets are taken slowly by chewing or sucking in the mouth, and enable taste-masked linezolid contained therein to be orally administered without water. Effervescent tablets are intended to be dissolved or dispersed in water before administration and generally contain acid substances and carbonates or bicarbonates, which react rapidly in the presence of water releasing carbon dioxide. These tablets comprise various pharmaceutically acceptable excipients as have been discussed under dispersible tablets and orally disintegrating tablets. The effervescent tablets can comprise effervescent couples selected from, but not limited to, thermolabile gas generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.
The terms "tablet" and "tablet composition" are used synonymously within the context of the present invention. These terms should be construed to include a compacted or compressed powder composition obtained by compressing or otherwise forming the composition to form a solid having a defined shape. Tablets in accordance with the invention may be manufactured using conventional techniques of common tableting methods known in the art such as direct compression, wet granulation, dry granulation and extrusion/ melt granulation. In one embodiment, the process is direct compression which involves compression of taste- masked drug-excipient blend after mixing them for a definite time period.
In a still another embodiment of the present invention, the taste-masked linezolid can be incorporated in suspensions, syrups or dry suspensions for administration.
The various dosage forms as described in the present invention comprising taste-masked linezolid are immediate release dosage forms that release the taste-masked linezolid instantly upon reaching either stomach or intestine. In one embodiment of the present invention, compositions of the present invention comprising taste-masked linezolid release linezolid in a controlled manner over a period of time, for example, from about 2 to about 24 hours. In such a formulation, taste-masked linezolid is further coated with a combination of water soluble and water insoluble excipients, as discussed above. The amount of coating not only ensures the taste-masking but also controls the release of taste-masked linezolid. Any of the taste-masking approaches described above can be used in combination with coating for the purpose of achieving a controlled release dosage form of taste-masked linezolid.
In another embodiment of the present invention, pellets or granules or the like of linezolid are prepared comprising at least one release retardant in combination with one or more pharmaceutically acceptable excipients. Suitable release retardants include, but are not limited to, cellulose ethers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose and carboxymethylcellulose sodium; polysaccharides, such as carageenan, guar gum, xanthan gum, tragacanth and ceratonia; polymethacrylates, such as copolymers of acrylic and methacrylic acid esters containing quarternary ammonium groups; cellulose esters, such as cellulose acetate; acrylic acid polymers, such as carbomers; waxes, such as hydrogenated castor oil, hydrogenated vegetable oil, carnauba wax and microcrystalline wax; alginates, such as alginic acid and sodium alginate; and fatty acid derivatives, such as glyceryl monostearate and glyceryl palmitostearate. These pellets or granules or the like are further coated using excipients described above in order to achieve taste-masking of linezolid.
In a still further embodiment of the present invention the taste-masked linezolid compositions of the present invention may be adapted to deliver one more active agent in addition to linezolid. The additional active agent may be selected from, but not limited to, penicillin, ciprofloxacin, rifampicin, clindamycin, gentamycin, vancomycin, isoniazid, dextromethoφhan, quinupristin, dalfopristin, rifalazil or fusidic acid or the like.
In one embodiment process for preparing a pharmaceutical composition of the present invention for oral administration is disclosed that comprises; a. coating linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is a water insoluble polymeric excipient or a water insoluble non-polymeric excipient, or a combination thereof .
In another embodiment process for preparing a pharmaceutical composition of the present invention for oral administration is disclosed that comprises; a. complexing linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is an ion exchange resin, a carbomer, a cyclodextrin or a derivative thereof. In still another embodiment process for preparing a pharmaceutical composition of the present invention for oral administration is disclosed that comprises; a. adsorbing linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is an adsorbent.
Another embodiment the present invention discloses a method of treating bacterial infections comprising administering to a subject in need thereof compositions comprising taste-masked linezolid and at least one pharmaceutically acceptable excipient.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. Details of the present invention, including its objects and advantages, are provided in the non-limiting exemplary illustrations below.
Examples
Example 1: Dispersible tablet formulation of taste-masked linezolid by coating with wax dispersion
Table 1 Pelletization of linezolid
Figure imgf000021_0001
Procedure: All the ingredients were blended and Kollidon VA 64 solution in water was added to the blend to get wet mass. The mass was passed through cone sieve to get extrudates which were then spheronized and dried. These pellets were then coated using wax coating dispersion as follows:
Table 2 Composition of coating dispersion
Figure imgf000021_0002
Lubritab was melted at around 800C and Capmul MCM was added to it. Part of water was heated to same temperature and added to molten wax with homogenization to get an emulsion. Hydroxypropyl methyl cellulose was then added to remaining amount of water along with sucralose. This solution was then added to above emulsion under homogenization. Talc was added to the mixture and homogenized well. The coating dispersion was sprayed on linezolid pellets to weight gain of 50%.
Table 3 Compression of taste-masked linezolid dispersible tablets
All the ingredients were sifted and blended with taste-masked linezolid pellets. The blend was lubricated with magnesium stearate. The mixture was compressed as dispersible tablets. The dispersible tablets had excellent palatability and passed the disintegration and dispersibility tests as per Ph. Eur. (4th Edition). Example 2: Orally disintegrating tablet formulation of taste-masked linezolid
Table 4 Taste-masking by complexation with cyclodextrin
Figure imgf000023_0001
Procedure:
Linezolid and hydroxylpropyl β-Cyclodextrin were mixed physically and further milled in ball mill for about 12 hours. The complex formed was further blended with other excipients as shown in above table, followed by lubrication using magnesium stearate. The formulation was found to be palatable with good mouth feel and acceptable wicking time. Example 3: Chewable tablets of taste-masked linezolid by resin complexation
Table 5 Taste-masking of linezolid and compression of chewable tablets
Figure imgf000024_0001
Procedure:
Linezolid was treated with cationic exchange resin Amberlite IRP 69 (1 :2.5 ratio) in 0.1 N HCl to get a taste-masked linezolid resin complex. The complex was blended with other excipients like spray dried mannitol, microcrystalline cellulose, sodium starch glycolate, citric acid, aspartame, colloidal silicon dioxide, talc and flavor and finally lubricated using magnesium stearate. The blend was compressed to get a chewable tablet. The tablets imparted good mouth feel without sense of undesirable taste of linezolid.
Example 4: Dispersible tablets of taste-masked Linezolid using glyceryl behenate Table 6 Taste-masking using glyceryl behenate and linezolid formulation
Figure imgf000025_0001
Linezolid granules were prepared by melt granulating linezolid with glyceryl behenate. These taste-masked linezolid granules were further mixed with other ingredients. The blend lubricated with sodium stearyl fumarate was directly compressed into dispersible tablets. Tablets with desired taste, disintegration time and dispersibility were obtained.
Example 5: Dispersible tablets of taste-masked coated Linezolid
Table 7 Preparation of linezolid blend
Linezolid was blended well with colloidal silicon dioxide as per following composition:
Figure imgf000026_0001
Table 8 Taste-masking of linezolid using Eudragit EPO coating solution
Figure imgf000026_0002
Eudragit EPO along with other ingredients was dispersed in water. Eudragit NE 30 D was added towards the end in the coating system. This was sprayed on the blend of linezolid and colloidal silicon dioxide using a fluidized bed coater to 30% weight gain. Table 9 Dispersible tablets of taste-masked linezolid
Figure imgf000027_0001
Taste-masked linezolid granules were blended with other excipients as shown in table 9. The blend was lubricated using magnesium stearate and the tablets were compressed with optimum hardness.
Example 6: Dispersible tablets of taste-masked linezolid using glyceryl behenate
Table 10 Taste-masking using glyceryl behenate and formulation
Figure imgf000027_0002
Figure imgf000028_0001
Linezolid granules were prepared by melt granulation with glyceryl behenate. These granules were sized and blended with remaining excipients except magnesium stearate. The blend was lubricated and compressed to get dispersible tablets. The tablets were characterized and the properties are tabulated below:
Hardness (N) 71 - 78
Disintegration time (seconds) 21 - 24
Friability (%) 0.08
The dispersible tablets had excellent palatability in comparison to marketed formulation Zyvox (granules/powder for suspension) and passed the disintegration and dispersibility tests as per Ph. Eur. (4th Edition).
Dissolution study of dispersible tablets was carried out using USP apparatus II in pH 6.8 phosphate buffer at 50 rpm. The drug release was compared with Zyvox.
Table 11 Comparative Drug release profile from taste-masked linezolid formulation and Zyvox
Figure imgf000029_0001
The drug release from dispersible tablets was comparable with marketed formulation Zyvox.

Claims

1. A pharmaceutical composition for oral administration comprising: a. taste-masked linezolid; and b. at least one pharmaceutically acceptable excipient, wherein said taste-masked linezolid comprises linezolid and at least one taste- masking agent.
2. The composition of claim 1 wherein said taste-masking agent is a water insoluble polymeric excipient, water insoluble non-polymeric excipient, adsorbent, ion exchange resin, carbomer, cyclodextrin or a derivative thereof.
3. The composition of claim 2 wherein said water insoluble polymeric excipient is carboxymethylethylcellulose, ethylhydroxy ethylcellulose phthalate, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, polyvinyl acetate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, polymethacrylic acid copolymer, polymethylmethacrylates, dimethylaminoethyl methacrylate'neutral methacrylate ester, acrylic-methacrylic acid esters'trimethyl ammonioethyl methacrylate copolymer, ethyl acrylate'methyl methacrylate neutral copolymer, or any combination thereof.
4. The composition of claim 3 wherein said water insoluble polymeric excipient is polyvinyl acetate, dimethylaminoethyl methacrylate'neutral methacrylate ester, ethyl acrylate'methyl methacrylate neutral copolymer, or any combination thereof.
5. The composition of claim 2 wherein said water insoluble non-polymeric excipient is spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, mineral waxes, glyceryl monostearate, glyceryl distearate, glyceryl tristearate; glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate, polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides, stearoyl macrogolglycerides, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, cetyl alcohol, or stearyl alcohol, or a mixture thereof.
6. The composition of claim 5 wherein said water insoluble non-polymeric excipient is glyceryl behenate, hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated palm oil, or hydrogenated castor seed oil, or a mixture thereof.
7. The composition of claim 2 wherein said adsorbent is bentonite, kaolite, zeolite, sodium alginate, magnesium aluminium silicate, silica gel, or activated charcoal, or a mixture thereof.
8. The composition of claim 2 wherein said ion exchange resin is a cationic ion exchange resin.
9. The composition of claim 2 wherein said carbomer is carbomer 934, carbomer 971 or carbomer 974, or a mixture thereof.
10. The composition of claim 2 wherein said cyclodextrin derivative is α-cyclodextrin, β- cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin, trimethyl-β-cyclodextrin, 2- hydroxymethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β- cyclodextrin, β-cyclodextrin sulfate, β-cyclodextrin sulfonate, or β-cyclodextrin sulfobutyl ether.
11. The composition of claim 1 wherein said at least one pharmaceutically acceptable excipient is a viscolizer, binder, disintegrant, superdisintegrant, diluent, salivating agent, flavor, sweetener, souring agent, solubilizer, surfactant, stabilizer, colorant, glidant or lubricant.
12. The composition of claim 1 wherein said taste-masked linezolid is in the form of powder, granules, pellets or beads.
13. The composition of claim 1 wherein said composition is in the form of a suspension, powder for suspension, dispersible tablet, orally disintegrating tablet, chewable tablet, effervescent tablet, sprinkle granules, quick melt wafers, lozenge, or chewing gum.
14. The composition of claim 13 wherein said composition is in the form of a dispersible tablet.
15. A dispersible tablet composition for oral administration comprising: a. taste-masked linezolid; and b. at least one pharmaceutically acceptable excipient, wherein said taste-masked linezolid comprises linezolid and glyceryl behenate.
16. The composition of claim 13 wherein said composition is in the form of a powder for suspension.
17. The composition of claim 1 further comprising an additional active agent, said additional active agent being penicillin, ciprofloxacin, rifampicin, clindamycin, gentamycin, vancomycin, isoniazid, dextromethorphan, quinupristin, dalfopristin, rifalazil or fusidic acid.
18. A process for preparing a pharmaceutical composition for oral administration comprising a. coating linezolid with at least one taste-masking agent to form taste-masked linezolid; b. blending taste-masked linezolid of step (a) with other excipients, except lubricant, to form a uniform powder mix; c. lubricating the powder mix of step (b); and d. compressing the powder mix of step (c) into a dispersible tablet composition, wherein at least one taste-masking agent is a water insoluble polymeric excipient or a water insoluble non-polymeric excipient, or a combination thereof.
PCT/IN2009/000597 2008-10-22 2009-10-22 Pharmaceutical compositions of taste-masked linezolid WO2010046933A2 (en)

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