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WO2006018814A2 - Suspensions liquides orales de métaxalone - Google Patents

Suspensions liquides orales de métaxalone Download PDF

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Publication number
WO2006018814A2
WO2006018814A2 PCT/IB2005/052705 IB2005052705W WO2006018814A2 WO 2006018814 A2 WO2006018814 A2 WO 2006018814A2 IB 2005052705 W IB2005052705 W IB 2005052705W WO 2006018814 A2 WO2006018814 A2 WO 2006018814A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
form according
metaxalone
sorbitan
agents
Prior art date
Application number
PCT/IB2005/052705
Other languages
English (en)
Other versions
WO2006018814A3 (fr
Inventor
Ajay Kumar Singla
Malluru Subba Rao
Tausif Monif
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006018814A2 publication Critical patent/WO2006018814A2/fr
Publication of WO2006018814A3 publication Critical patent/WO2006018814A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—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
    • A61K9/141—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
    • A61K9/143—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 inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to liquid oral suspension dosage forms of metaxalone and processes for their preparation.
  • Metaxalone 5-[(3,5-dimethylphenoxy) methyl] -2-oxazolidinone, is a muscle relaxant indicated as an adjunct to rest, physical therapy and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions. It is marketed under the brand name SKELAXIN®, and is available in two strengths, 400 mg and 800 mg. The recommended dose of metaxalone for adults and children over 12 years of age is two 400 mg (or one 800 mg) tablets, taken three to four times daily.
  • Liquid pharmaceutical compositions offer many advantages over solid compositions. Liquid dosage forms generally have better bioavailability, are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Further, liquids provide a rapid onset of pharma ⁇ cological action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract.
  • Liquid dosage forms may be administered in the form of solutions, suspensions, elixirs and syrups.
  • the liquid preparation should have a pleasant flavor in order to ensure patient compliance.
  • the liquid preparation should preferably not contain any ethanol, since the possibility of ethanol having a harmful effect even in physiologically acceptable, non ⁇ toxic concentrations cannot be ruled out completely, particularly in children.
  • ethanol when ethanol is used, there is the risk of abuse or relapse in alcohol- dependent patients.
  • the suitability of the formulation for diabetic patients should also be taken into account. Therefore, elixirs and syrups are generally not the preferred dosage forms.
  • U.S. Patents Nos. 6,407,128 and 6,683,102 disclose methods of increasing the oral bioavailability of metaxalone by administration of an oral dosage form with food.
  • the administration with food results in an increase in the maximal drug concentration (C max )
  • WO 04/019937 discloses a pharmaceutical composition that includes metaxalone and pharmaceutically acceptable excipients, characterized in that the pharmaceutical composition has enhanced oral bioavailability.
  • the metaxalone used may be a micronized, a salt form of metaxalone, a high-energy crystalline form of metaxalone or an amorphous metaxalone.
  • the properties of a liquid oral suspension are greatly influenced by the particle size of the suspended active substance.
  • a small particle size ensures the fastest possible dissolution of the active substance in gastrointestinal tract.
  • the properties and pharmacokinetic parameters of the liquid suspension dosage form are independent of even particle size limitations.
  • the inventors have presently developed a liquid oral suspension dosage form that achieves rapid onset of action and a pharmacokinetic profile that is not affected by the fed or fasted state of a subject ingesting the dosage form.
  • a liquid oral suspension dosage form which includes a therapeutically effective amount of metaxalone, at least one thickening agent, at least one wetting agent, at least one sweetening agent and one or more phar- maceutically acceptable liquid carriers.
  • Embodiments of the liquid oral suspension dosage form include one or more of the following features.
  • the metaxalone may be milled to a D particle size of less than about 2000 nm and a D particle size of less than about 600 nm.
  • 50 r metaxalone particles may be milled in the presence of surface modifiers.
  • the surface modifier may be one or more of polymers, natural products and surface-active agents.
  • the polymers may be one or more of polyvinyl pyrrolidone, hy- droxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxy propyl cellulose and polyvinyl alcohol.
  • the natural products may be one or more of dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates and pullulan.
  • the surface-active agents may be ben- zalkonium chloride, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, poloxamers, poloxamines, polyethylene glycol, vitamin E and polyethylene glycol-phospholipid.
  • the ratio of metaxalone to surface modifier ranges from about 1:2 to about 1:50.
  • the thickening agents may be xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof.
  • the thickening agents are present at a concentration range of from about 0.1% to about 5% w/w of the dosage form.
  • the wetting agents may be one or more of sodium lauryl sulphate, sorbitan esters of fatty acids, sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, ethylene oxide-propylene oxide block copolymers, lecithins, oleic acid and oleic acid salts, propylene glycol monostearate and monolaurate, glycerol monostearate and monooleate, fatty alcohol- polyethylene glycol ethers, fatty acid-polyethylene glycol esters, sodium dode- cylsulphate, dioctyl sodium sulphosuccinate, ethoxylated mono- and diglycerides, sucrose fatty acid esters, fatty acid salts, ethoxylated triglycerides , polyoxyethylated hydrogenated castor oil,
  • the sweetening agents may be sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
  • the liquid carriers may be purified water, liquid glucose, glycerol, and aqueous solutions of sugar alcohols.
  • the aqueous solutions of sugar alcohols may be sorbitol, mannitol and xylitol and mixtures thereof.
  • the liquid carrier may be present at a con ⁇ centration of from about 10% to about 30% w/w of the dosage form.
  • the dosage form may further include one or more pharmaceutically acceptable excipients.
  • the one or more pharmaceutically acceptable excipients may be sol- ubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
  • a process for the preparation of a liquid oral suspension dosage form of metaxalone includes dispersing metaxalone particles in a portion of the carrier comprising at least one wetting agent; dispersing at least one thickening or suspending agent in another portion of the carrier; mixing the two dispersions and adding sweeteners and one or more conventional phar ⁇ maceutically acceptable excipients; and adjusting to the required volume with the carrier.
  • a method of treating discomforts associated with acute, painful musculoskeletal conditions in a patient in need thereof includes administering a liquid oral suspension dosage form comprising a therapeutically effective amount of metaxalone, at least one thickening agent, at least one wetting agent, at least one sweetening agent and one or more pharmaceutically acceptable liquid carriers.
  • Embodiments of the method may include one or more of the following features.
  • the dosage form may further include a non steroidal anti-inflammatory drug.
  • the present invention provides a liquid suspension dosage form for oral admin ⁇ istration that includes a therapeutically effective amount of metaxalone in association with at least one thickening or suspending agent, at least one wetting agent, at least one sweetening agent and a pharmaceutically acceptable liquid carrier.
  • micronized and milled are interchangeable to mean a process of reducing the size of the particles.
  • Suitable surface modifiers include one or more of polymers, natural products and surfactants.
  • the surface modifiers may be polyvinylpyrrolidone, hy- droxypropyl methylcellulose, polyethylene glycols, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, hydroxypropyl cellulose, methylcellulose, and polyvinyl alcohol.
  • Suitable natural products may include dextran, xanthan, chitosan, pectin, dextrin, maltodextrin, starch, alginates, and pullulan.
  • the mechanical means applied to reduce the particle size of the drug substance may be carried out in a dispersion mill.
  • Suitable dispersion mills include ball mills, attrition mills, vibratory mills and media mills, such as bead mill and high-pressure ho- mogenizers.
  • a media mill is preferred due to the relatively shorter milling time required to provide the intended result.
  • the relative amount of metaxalone and surface modifier will vary with respect to the type of surface modifier.
  • the metaxalone and surface modifier may be present in a ratio ranging from about 1:2 to about 1:50.
  • Suitable thickening agents function as suspending agents and include hydrocolloids known for such purpose, for example xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth and starch.
  • hydrocolloids known for such purpose, for example xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth and starch.
  • synthetic suspending agents may be used.
  • carbopols, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone, hydroxy propylcellulose or mixtures thereof may be used.
  • the thickening agents of the present invention prevent rapid settling and caking of the suspension over time.
  • the thickening agents may be present in a concentration ranging from about 0.1% to about 5% w/w of the dosage form.
  • wetting agents are surfactants which are capable of lowering the contact angle between a liquid and the solid surface over which it spreads. This helps remove air at the solid surface and replaces it with the liquid. They hinder caking of the particles in suspensions during storage and facilitate rapid dispersion of the solid throughout the aqueous phase.
  • Suitable wetting agents may include one or more of nonionic, cationic, anionic, and zwitterionic surfactants.
  • the wetting agents which may be employed include sodium lauryl sulphate, sorbitan esters of fatty acids, such as sorbitan monolaurate, sorbitan monooleate, sorbitan trioleate, sorbitan monopalmitate, sorbitan monostearate, and sorbitan tristearate (available under the trade name polysorbate 20, 40, 60, 80, 65, 61, 85 and 21), ethylene oxide-propylene oxide block copolymers (available under the trade name poloxamers), lecithins, oleic acid and oleic acid salts, propylene glycol monostearate and monolaurate, glycerol monostearate and monooleate, fatty alcohol- polyethylene glycol ethers (for example PEG 10 cetyl ether, PEG 20 oleyl ether etc.), fatty acid
  • Suitable sweetening agents or sweeteners may include sugars, cyclamates, aspartame, potassium acesulfame, sodium saccharine, neohesperidine, dihy- drochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
  • Suitable pharmaceutically acceptable liquid carriers may include purified water, liquid glucose, glycerol, aqueous solutions of sugar alcohols, such as sorbitol, mannitol and xylitol, and mixtures thereof.
  • a mixture of sorbitol solution and purified water is used as the pharmaceutically acceptable liquid carrier.
  • the sorbitol solution is used to aid in forming and maintaining the particle size and shape of the solids in the suspension. It provides a smooth texture and sweet taste to the suspension. In addition, it acts as a cryoprotectant, protecting the suspension from freezing.
  • the sorbitol solution is present at a concentration from about 10% to about 30% w/w of the dosage form.
  • the liquid oral suspension dosage form of metaxalone may additionally include one or more conventional pharmaceutically acceptable excipients.
  • Suitable pharma ⁇ ceutically acceptable excipients include one or more solubilizers, anti-foaming agents, flavouring agents, opacifiers, colouring agents, buffers and preservatives.
  • Suitable solubilizers include alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methyl- cellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols; 2-pyrrolidone, 2-piperidone, caprolactam, N- alkylpyrrolidone, N-hydroxyalkylpyrrolidone and polyvinylpyrrolidone. Solubilizers may be present in the dosage form at a concentration of about 0.5% to about 1.5% w/w of the dosage form.
  • the suspension dosage form may also contain an antifoaming agent, such as any commercially available agent useful for such purpose including simethicone emulsion.
  • the antifoaming agent is present in sufficient concentration to allow control of the foam, which forms on dilution with water.
  • the antifoaming agent is present at concentration of from about 0.2% by weight to about 1% w/w.
  • the buffer systems suitable for the suspension dosage form of the present invention are those which maintain the pH of the liquid suspension in the range of about 4 to about 6.
  • Suitable buffers may include citric acid or its corresponding salts and acetic acid or its salts.
  • Suitable preservatives include sodium benzoate, methyl and propyl parabens, sodium citrate and benzalkonium chloride as well as other pharmaceutical acceptable preservatives.
  • sodium benzoate may be used.
  • Suitable opacifiers include pharmaceutically acceptable metal oxides, for example, titanium dioxide.
  • Suitable flavoring agents include those that are approved by the FDA for use in sweetened pharmaceuticals, foods, candies, beverages and the like; these materials impart flavors, such as grape, cherry, citrus, peach, strawberry, bubble gum, peppermint and wintergreen.
  • EXAMPLE 1 Preparation of an oral suspension of metaxalone (milled) [49]
  • Test Drug (A) Metaxalone Oral Suspension prepared according to Example 1 given above (containing milled metaxalone).
  • Test Drug (B) Metaxalone Oral Suspension prepared according to Example 2 given above (containing unmilled metaxalone).
  • Reference Drug (R) Commercially available metaxalone tablets (SKELAXIN® 400 mg).
  • Table 4 Represents the time taken to achieve maximum concentration (t ).
  • Table 5 provides in vitro dissolution data for metaxalone suspensions prepared according to Examples 1 and 2 and for SKELAXIN® tablets carried out at 50 rpm in USP Apparatus II using 900 mL water containing 1% sodium lauryl sulphate as the medium.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

Formes galéniques de suspensions liquides orales de métaxalone et procédés de préparation desdites formes galéniques.
PCT/IB2005/052705 2004-08-16 2005-08-16 Suspensions liquides orales de métaxalone WO2006018814A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1509DE2004 2004-08-16
IN1509/DEL/2004 2004-08-16

Publications (2)

Publication Number Publication Date
WO2006018814A2 true WO2006018814A2 (fr) 2006-02-23
WO2006018814A3 WO2006018814A3 (fr) 2006-08-24

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMC20100077A1 (it) * 2010-07-19 2012-01-20 Farmalip S R L Dolcificante.
US20130040939A1 (en) * 2009-09-10 2013-02-14 Bial - Portela & Ca, S.A. Oral Suspension Formulations of Esclicarbazepine Acetate
ITUB20155193A1 (it) * 2015-11-03 2017-05-03 Italfarmaco Spa Sospensioni orali di Givinostat fisicamente e chimicamente stabili
WO2018049184A1 (fr) * 2016-09-09 2018-03-15 Cutispharma, Inc. Suspensions et diluants pour le métronidazole et le baclofène
US10568839B2 (en) 2011-01-11 2020-02-25 Capsugel Belgium Nv Hard capsules
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993767A (en) * 1975-11-18 1976-11-23 A. H. Robins Company, Incorporated Compositions to suppress gastric bleeding in indomethacin and phenylbutazone therapy
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
US20050163839A1 (en) * 2003-01-29 2005-07-28 Sun Pharmaceutical Industries Limited Oral controlled release pharmaceutical composition containing metaxalone as active agent
CA2534924A1 (fr) * 2003-08-08 2005-02-24 Elan Pharma International Ltd. Nouvelles compositions de metaxalone

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130040939A1 (en) * 2009-09-10 2013-02-14 Bial - Portela & Ca, S.A. Oral Suspension Formulations of Esclicarbazepine Acetate
ITMC20100077A1 (it) * 2010-07-19 2012-01-20 Farmalip S R L Dolcificante.
US10568839B2 (en) 2011-01-11 2020-02-25 Capsugel Belgium Nv Hard capsules
KR102603894B1 (ko) 2015-11-03 2023-11-20 이탈파마코 에스.피.에이. 기비노스타트(givinostat)의 물리적 및 화학적으로 안정한 경구 현탁액
ITUB20155193A1 (it) * 2015-11-03 2017-05-03 Italfarmaco Spa Sospensioni orali di Givinostat fisicamente e chimicamente stabili
WO2017077436A1 (fr) * 2015-11-03 2017-05-11 Italfarmaco Spa Suspensions orales de givinostat physiquement et chimiquement stables
IL258608A (en) * 2015-11-03 2018-06-28 Italfarmaco Spa Gibinostat oral suspensions are physically and chemically stable
KR20180082468A (ko) * 2015-11-03 2018-07-18 이탈파마코 에스.피.에이. 기비노스타트(givinostat)의 물리적 및 화학적으로 안정한 경구 현탁액
US10688047B2 (en) 2015-11-03 2020-06-23 Italfarmaco Spa Physically and chemically stable oral suspensions of givinostat
AU2016349169B2 (en) * 2015-11-03 2021-11-11 Italfarmaco Spa Physically and chemically stable oral suspensions of Givinostat
WO2018049184A1 (fr) * 2016-09-09 2018-03-15 Cutispharma, Inc. Suspensions et diluants pour le métronidazole et le baclofène
US11324696B2 (en) 2016-09-09 2022-05-10 Azurity Pharmaceuticals, Inc. Suspensions and diluents for metronidazole and baclofen
US11446246B2 (en) 2016-09-09 2022-09-20 Azurity Pharmaceuticals, Inc. Suspensions and diluents for metronidazole and baclofen
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11878079B2 (en) 2017-04-14 2024-01-23 Capsugel Belgium Nv Pullulan capsules

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