WO2010026597A1 - Formes posologiques orales de linézolide et leurs procédés de préparation - Google Patents

Formes posologiques orales de linézolide et leurs procédés de préparation Download PDF

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Publication number
WO2010026597A1
WO2010026597A1 PCT/IN2008/000557 IN2008000557W WO2010026597A1 WO 2010026597 A1 WO2010026597 A1 WO 2010026597A1 IN 2008000557 W IN2008000557 W IN 2008000557W WO 2010026597 A1 WO2010026597 A1 WO 2010026597A1
Authority
WO
WIPO (PCT)
Prior art keywords
sodium
pharmaceutical composition
extrusion
linezolid
preferable
Prior art date
Application number
PCT/IN2008/000557
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Podili Khadgapathi
Kamala Venkata Rama Rao
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Priority to PCT/IN2008/000557 priority Critical patent/WO2010026597A1/fr
Publication of WO2010026597A1 publication Critical patent/WO2010026597A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to solid oral dosage form of Linezolid manufactured with extrusion and spheronization method, the dosage forms especially exhibits the reproducible dissolution.
  • Linezolid is a well-known synthetic antibacterial agent belonging to the class of oxazolidinone derivatives. Chemically, it is (S)- N— [[3-[3-Fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxa zolidinyl]methyl]-acetamide.
  • the empirical formula is Ci 6 H 20 FN 3 O 4 . Its molecular weight is 337.35.
  • Linezolid is sold under the brand name(s) of ZYVOX® LV. Injection, ZYVOX Tablets, and ZYVOX for Oral Suspension. Tablets were given two to three times a day. Linezolid exhibits polymorphism and the polymorphs of Linezolid are reported in Patent No. US 2007/0104785 and WO 2007/102082. It is difficult to formulate, because of gelling tendency of the drug. It is important that Linezolid for oral administration should produce reproducible dissolution, which provides high bioavailability, whereby absorption into the blood stream is maximized and the amount of Linezolid remaining in the gastrointestinal tract is minimized.
  • the WO 2007/102082 patent discloses the manufacturing of high drug content solid dosage form comprising about 50 mg to about 800 mg oxazolidinone or a pharmaceutically acceptable salt, hydrate or crystalline form.
  • the dosage form preferably contains the lactose-based water soluble excipient and the granules are manufactured with wet granulation.
  • This method of granulation is an expensive process because of labor, time, equipment, energy and cost. Loss of material may occur, during various stages of processing. Stability may be major concern for moisture sensitive or thermo labile drugs.
  • the present invention describes the extrusion and spheronization method suitable for manufacturing of Linezolid solid oral dosage forms.
  • the extrusion and spheronization method produces the pellets or beadlets of size range between 0.5 and 2 mm in mean diameter and have a narrow size distribution. Their reproducible higher particle surface area is ideal for manufacturing of different solid oral dosage forms (or) coating of pellets.
  • the extrusion and spheronization method involves forming the powder into a wet mass, which is forced through a restricted area (extrusion) to form strands of extrudate that are broken into short lengths and rounded by placement on a rotating plate within a cylinder. This method of granulation has following advantages compared to the other method present in the prior art.
  • This method requires less concentration of binder for producing granules
  • This process is capable of making uniform sized spherical particles and increases the surface area. 4.
  • the granules produced by extrusion and spheronization are useful for manufacturing of tablets, capsules and alternatively can be filled into sachets
  • This invention relates to an oral dosage form comprising of Linezolid containing in 60 to 90% by weight.
  • the present invention relates to manufacturing of solid oral dosage forms of Linezolid, using extrusion and spheroniozation.
  • the dosage forms shows reproducible dissolution.
  • the solid dosage form includes Linezolid and one or more of pharmaceutically acceptable excipients.
  • a pharmaceutical composition comprising a core in the form of beadlet or pellet, manufacture by extrusion and spheronization method, the core comprises:
  • Linezolid in 60 to 90% by weight of dosage form; one or more binders selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose, Pregelatinized cornstarch in 0.2 to 10% by weight; and, one or more disintegrants selected from the group consisting of Sodium starch glycolate, Cross-linked sodium, Carboxy methylcellulose and Cross-linked polyvinyl pyrrolidone in 1 to 10% by weight.
  • binders selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose, Pregelatinized cornstarch in 0.2 to 10% by weight
  • disintegrants selected from the group consisting of Sodium starch glycolate, Cross-linked sodium, Carboxy methylcellulose and Cross-linked polyvinyl pyrrolidone in 1 to 10% by weight.
  • the preferred binder for the present invention is Sodium Carboxy methylcellulose and the most preferably concentration is about in 0.2 to 5% by weight of the core.
  • the disintigrants suitable for the present invention is Sodium starch glycolate in about 2 % to 8% by weight.
  • the beadlet of the present invention prepared by mixing Linezolid, Carboxymethyl cellulose sodium and sodium starch glycolate with solvent and the wet mass is then extruded, using extruder. The extrudate is subsequently spheronized using spheronizer.
  • the wet beadlet or pellets were dried by suitable methods, such as by tray drying or by fluid bed drying, to form the dry spheronized beadlet of the present invention.
  • the pellets or beadlet are mixed with glidants and lubricants. Then the final blend is compressed into tablets (or) filled into capsules (or) filled into sachets.
  • the dosage form of the present invention provides a reproducible dissolution profile.
  • a pharmaceutical composition comprising a core in the form of beadlet or pellet, manufacture by extrusion and spheronization method, the core comprises: (a) Linezolid in 60 to 90% by weight of dosage form;
  • binders selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose, Pregelatinized cornstarch in 0.2 to 10% by weight; and,
  • One or more disintegrants selected from the group consisting of Sodium starch glycolate, Cross-linked sodium, Carboxy methylcellulose and
  • Cross-linked polyvinyl pyrrolidone in 1 to 10% by weight may be used in pharmaceutical process of present invention.
  • Binders suitable for the present invention, are those, which when utilized in small proportions, support formation of beadlets during extrusion and spheronization.
  • the preferred binder for the present invention is Sodium
  • Carboxy methylcellulose The amount of binder required for the production of core is in the range of about 0.2% to 10% by weight of core. The most preferably concentration is in the range about 0.2 to 5% by weight of the core.
  • the disintigrants suitable for the present invention are Sodium starch glycolate, Cross-linked sodium, Carboxy methylcellulose and Cross-linked polyvinyl pyrrolidone. The most preferable disintigrant is Sodium starch glycolate and required concentration is in the concentration range is in the range of 1% to 10% by weight of the beadlet or pellet. The most preferable concentration is in the range of 2 % to 8%.
  • a granulation solvent the preferred granulation solvents are water, isopropyl alcohol and ethanol (or) its mixers, is mixed with a) Linezolid b) a binder and (c) a disintegrant, to form a wet mass.
  • the wet mass is then extruded, for example by employing Umang or other type extruder, to form an extrudate.
  • the extrudate is subsequently spheronized using a spheronized such as Umang or other type, to form beadlets.
  • These threads or noodles are then spun on a high-speed rotating plate, which breaks them into small pieces and rounds the ends to make spherical particles by a process known as spheronization.
  • This spheronization generates centrifugal force. Under these forces, if the particles do not have enough moisture absorbent, the moisture will be extracted out of the particles (drawn to the surface during spheronization), which will cause agglomeration.
  • a dry mixture containing the same proportions of medicament, optional binder and optional disintegrant, as are present in the wet mass is dusted onto the extrudate and onto the forming beadlets to absorb granulation solvent at the surface of the extrudate and beadlets and, thus, reduce the surface tackiness of the beadlets, thereby forming non- agglomerating beadlets.
  • the dry mixture is prepared and then separated into two parts, a first part, containing about 4% to about 15% by weight of the dry mixture, is set aside for use in dusting during spheronization, while the second part is mixed with the granulation solvent to form the wet mass which is subsequently extruded and spheronized.
  • a pharmaceutical composition of the present invention comprises a core, which is the dry spheronized beadlet, and one or more pharmaceutically acceptable excipients and solid oral dosage form may surround by coating.
  • the core employed in the pharmaceutical composition of the present invention may be formed of a beadlet or pellet having a diameter of about 0.5 to 2 mm, and preferably from about 0.5 to about 1.2 mm.
  • the core of the present invention provides a predictable dissolution profile, corresponding to the intestine transit time of about and permit reproducible release therein.
  • the pharmaceutical composition of the present invention further comprises disintigrant, an anti-adherent and lubricant disposed on the exterior of the beadlets.
  • the beads or particles are prepared for oral delivery of the drugs in tablet or suspension dosage form. Upon oral ingestion the dosage form dissolves allowing the contents in the tablet or suspension to be exposed to the gastric contents.
  • the anti-adherent is typically a hydrophobic material such as talc, magnesium stearate or fumed silica. Talc is the preferred anti- adherent.
  • the tablets are coated with film coating, which provides good appearance and the film coating is non functional.
  • Linezolid Various dosage forms of Linezolid are manufactured using the formula and process described in the following examples.
  • Linezolid, Sodium starch glycolate, Sodium carboxy methylcellulose and microcrystalline cellulose are sifted through suitable mesh and blended.
  • the dry mix is granulated by aqueous solution of Sodium lauryl sulphate in rapid mixer granulator.
  • the wet mass was extruded and spheronized.
  • the beadlets are dried and mixed with microcrystalline cellulose and Sodium starch glycolate.
  • the blend is lubricated with Magnesium stearate and compressed into a tablet using appropriate tooling or the granules are filled into sachets.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention porte sur un granule sphéronisé à charge de médicament élevée, dans lequel un noyau comprend du linézolide de 60 à 90 % en poids sous forme posologique; un ou plusieurs liants choisis dans le groupe constitué par du sodium de carboxyméthylcellulose, de l’hydroxypropylméthylcellulose, de l'amidon de maïs pré-gélatiné en 0,2 à 10 % en poids; et un ou plusieurs désintégrants choisis dans le groupe constitué par du glycolate d'amidon de sodium, du sodium réticulé, de la carboxyméthylcellulose et du polyvinylpyrrolidone réticulé en 1 à 10 % en poids. Le granule ou la pastille pharmaceutique sont fabriqués par un procédé d'extrusion et de sphéronisation. Le granule ou la pastille sont fabriqués, par exemple, à l'aide de linézolide, de carboxyméthylcellulose de sodium, de glycolate d'amidon de sodium et de stéarate de magnésium. Les granules ou pastilles sphéronisés sont fabriqués sous différentes formes posologiques pharmaceutiquement acceptables.
PCT/IN2008/000557 2008-09-02 2008-09-02 Formes posologiques orales de linézolide et leurs procédés de préparation WO2010026597A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000557 WO2010026597A1 (fr) 2008-09-02 2008-09-02 Formes posologiques orales de linézolide et leurs procédés de préparation

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2008/000557 WO2010026597A1 (fr) 2008-09-02 2008-09-02 Formes posologiques orales de linézolide et leurs procédés de préparation

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WO2010026597A1 true WO2010026597A1 (fr) 2010-03-11

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103099792A (zh) * 2012-12-10 2013-05-15 成都欣捷高新技术开发有限公司 一种高载药量、体外快速溶出的iv晶型利奈唑胺片的制备方法
WO2014033744A2 (fr) 2012-08-10 2014-03-06 Indoco Remedies Limited Nouvelle composition pharmaceutique de linézolide
WO2014118809A1 (fr) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Composition pharmaceutique comprenant du linézolide
WO2014139657A1 (fr) 2013-03-11 2014-09-18 Pharmathen S.A. Composition pharmaceutique contenant un agent antibactérien de type oxazolidinone et son procédé de préparation
US9132132B2 (en) 2010-09-02 2015-09-15 Hetero Research Foundation Pharmaceutical compositions of linezolid
RU2690491C2 (ru) * 2017-07-19 2019-06-04 Общество с ограниченной ответственностью "МБА-групп" Твердофазный линезолидсодержащий препарат

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070225A2 (fr) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Formulation de tablette a base d'oxazolidinone
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2008008120A1 (fr) * 2006-07-14 2008-01-17 Fmc Corporation Forme solide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070225A2 (fr) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Formulation de tablette a base d'oxazolidinone
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2008008120A1 (fr) * 2006-07-14 2008-01-17 Fmc Corporation Forme solide

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9132132B2 (en) 2010-09-02 2015-09-15 Hetero Research Foundation Pharmaceutical compositions of linezolid
WO2014033744A2 (fr) 2012-08-10 2014-03-06 Indoco Remedies Limited Nouvelle composition pharmaceutique de linézolide
US9492459B2 (en) 2012-08-10 2016-11-15 Indoco Remedies Limited Pharmaceutical composition of linezolid
CN103099792A (zh) * 2012-12-10 2013-05-15 成都欣捷高新技术开发有限公司 一种高载药量、体外快速溶出的iv晶型利奈唑胺片的制备方法
WO2014118809A1 (fr) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Composition pharmaceutique comprenant du linézolide
WO2014139657A1 (fr) 2013-03-11 2014-09-18 Pharmathen S.A. Composition pharmaceutique contenant un agent antibactérien de type oxazolidinone et son procédé de préparation
RU2690491C2 (ru) * 2017-07-19 2019-06-04 Общество с ограниченной ответственностью "МБА-групп" Твердофазный линезолидсодержащий препарат

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