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WO2010026597A1 - Oral dosage forms of linezolid and processes for their preparation - Google Patents

Oral dosage forms of linezolid and processes for their preparation 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
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WO
WIPO (PCT)
Prior art keywords
sodium
pharmaceutical composition
extrusion
linezolid
preferable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2008/000557
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Podili Khadgapathi
Kamala Venkata Rama Rao
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Hetero Research Foundation
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Hetero Research Foundation
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Publication date
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Priority to PCT/IN2008/000557 priority Critical patent/WO2010026597A1/en
Publication of WO2010026597A1 publication Critical patent/WO2010026597A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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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  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

A high drug load spheronized beadlet is provided wherein, a 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. The pharmaceutical beadlet or pellet is manufacture by extrusion and spheronization method. The beadlet or pellet is manufactured, for example using Linezolid, Sodium Carboxy methylcellulose, sodium starch glycolate and magnesium stearate. The spheronized pellets or beadlet are manufactured into different pharmaceutically acceptable dosage forms.

Description

ORAL DOSAGE FORMS OF LINEZOLID AND PROCESSES FOR THEIR
PREPARATION
FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
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 Ci6H20FN3O4. Its molecular weight is 337.35.
It is used in the treatment of vancomycin-resistant Enterococcus faecium infections; nosocomial pneumonia; complicated skin and skin structure infections including diabetic foot infections, without concomitant osteomyelitis; uncomplicated skin and skin structure infections and community acquired pneumonia.
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. Any active pharmaceutical ingredient, which is not absorbed will be therapeutically ineffective and by remaining in the gastrointestinal tract may cause side effects. In order get reproducible dissolution, it is important to prevent the gelling tendency of the Linezolid. U.S. Patent No. US 2007/0104785 discloses the manufacturing of the solid oral dosage forms of Linezolid polymorphic Form III with reproducible dissolution profile. The reproducible dissolution was achieved "by reducing gelling tendency of the Linezolid" in dosage forms. The gelling tendency was reduced using effervescent couple (or) by incorporating water insoluble polymers (or) by adding clays in the dosage form (or) these combinations and the granules are manufactured with dry granulation. This method of granulation has limitations like, it requires a specialized heavy duty tablet press to form slug. It does not permit uniform colour distribution. The process tends to create more dust than wet granulation and increasing the potential contamination.
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. After studying all above disadvantages of wet granulation and dry granulation process present in the prior art for manufacturing of solid oral dosage forms of Linezolid, the gelling tendency has been reduced with new approach of manufacturing in the present invention. 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.
1. Its ability to incorporate higher levels of active components without producing excessively larger particles.
2. This method requires less concentration of binder for producing granules
3. 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
5. Applicable to both immediate and controlled release dosage form 6. Improvement of bioavailability, reduction of the risk of dose dumping, and decrease local irritation in the gastrointestinal tract. It is desirable to develop solid dosage forms containing Linezolid, which provide reproducible dissolution profiles. We hereby disclose solid dosage forms comprising Linezolid that provide reproducible dissolution profiles in an aqueous media and processes for the preparation of these solid dosage forms.
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.
SUMMARY OF THE INVENTION
According to one embodiment of the present invention Linezolid, 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.
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.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, 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;
(b) One or more binders selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose, Pregelatinized cornstarch in 0.2 to 10% by weight; and,
(c) 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. Linezolid in any polymorphic form 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%.
The beadlet of the present invention prepared as mentioned in this section. 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. During spherinization, 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. In one embodiment, 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.
The process of the present invention also resulted in a high (>90%) yield of beads of narrow particle size cut. The non-agglomerating beadlet are then dried by suitable methods, such as by tray drying or by fluid bed drying, to form the dry spheronized beadlet of the present invention. 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. Typically, 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.
Preferably, 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 (anti-agglomerate) 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.
Various dosage forms of Linezolid are manufactured using the formula and process described in the following examples.
Examples Example 1
Figure imgf000007_0001
Process: 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.
Example 2
Figure imgf000008_0001
Process: The extrusion and spheronization was done with the procedure described in the example 1.The lubricated blend was compressed into tablets using appropriate tooling.
Example 3
Figure imgf000008_0002
Process: The extrusion and spheronization was done with the procedure described in the example IThe lubricated blend was compressed into tablets using appropriate tooling.
Example 4
Figure imgf000009_0001
Process: The extrusion and spheronization was done with the procedure described in the example IThe lubricated blend was compressed into tablets using appropriate tooling.
Example 5
Figure imgf000009_0002
Process: The extrusion and spheronization was done with the procedure described in the example 1 The lubricated blend was filled into capsules (or) into sachets.
Example 6
Figure imgf000010_0001
Process: The extrusion and spheronization was done with the procedure described in the example 1 The lubricated blend was filled into capsules (or) into sachets (or) compressed into tablets.
Example 7
Figure imgf000010_0002
Process: The extrusion and spheronization was done with the procedure described in the example 1.The lubricated blend was compressed into tablets using appropriate tooling.

Claims

We claim:
1. A pharmaceutical composition comprising core in the form of beadlet or pellet, manufactured by extrusion and spheronization method, the core comprises: a) Linezolid 60 to 90% by weight of dosage form; b) One or more binders selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose and Pregelatinized cornstarch, in 0.2 to 10% by weight; and, c) 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.
2. The pharmaceutical composition of claim 1 wherein said binder is selected from the group consisting of Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose and pregelatinized corn starch.
3. Preferable binder according to claim 2 is Sodium Carboxy methylcellulose.
4. The pharmaceutical composition of claim 1 wherein, the binder is present in the concentration range of from about 1 % to about 10% by weight.
5. The preferable concentration of binder according to claim 4 is about 0.2% to about 3% by weight.
6. The pharmaceutical composition of claim 1 wherein said disintigrant is selected from the group consisting Sodium starch glycolate, Cross-linked sodium, Carboxy methylcellulose and Cross-linked polyvinyl pyrrolidone.
7. The preferable disintigrant according to claim 7 is Sodium starch glycolate.
8. The pharmaceutical composition of claim 1 wherein, the disintigrant is present in the concentration range of about 1 to 10% by weight.
9. The most preferable concentration range of the disintigrant according to claim 9 is 1 to 8% by weight.
10. The pharmaceutical composition of claim 1, where Linezolid used is Form I, Form II, Form III or Form IV.
11. The preferable form of Linezolid according to claim 10 is Linezolid form III.
12. The pharmaceutical composition of claim 1 contains a diluent selected from the group consisting of Mannitol, Sorbitol, Xylitol, Lactose, Microcrystalline cellulose, Magnesium carbonate, Calcium carbonate, Dicalcium phosphate and tribasic calcium phosphate.
13. The pharmaceutical composition of claim 11 wherein the preferable diluent is microcrystalline cellulose.
14. The pharmaceutical composition of claim 1 contains glidant, the preferable glidants are Talc and Colloidal silicondioxide.
15. The pharmaceutical composition of claim 1 further comprising an anti- adherent coating disposed on the exterior of said core.
16. The pharmaceutical composition of claim 1 contains a lubricant, selected from the group consisting of magnesium stearate, calcium stearate, stearic acid and sodium stearyl fumarate.
17. The most preferable lubricant according to claim 15 is magnesium stearate.
18. The pharmaceutical composition of claim 1 wherein said composition is compressed into tablets, encapsulated in a capsule or suspended in solvent for oral administration.
19. The pharmaceutical composition of claim 1 wherein the solid pharmaceutical composition comprises the pellets (or) beadlet of size range between 0.5 and 2 mm in mean diameter and have a narrow size distribution.
20. The process of manufacturing according to claim 1 is extrusion and spherinization, comprising the Linezolid, Sodium Carboxymethyl cellulose, Sodium starch glycolate, Microcrystalline cellulose, Talc and Magnesium stearate.
21. The process of manufacturing according to claim 1 is extrusion and spherinization, the manufacturing steps involved are forcing wet mass through suitable mesh and drying, mixing and compression/filling.
22. The process of manufacturing according to claim 1 is extrusion and spherinization, comprising a binder selected from the group consisting of
Carboxymethylcellulose sodium, Hydroxypropyl methylcellulose and Pregelatinized cornstarch.
23. The process of manufacturing according to claim 1 is extrusion and spherinization, preferable binder for this process is Sodium Carboxymethylcellulose.
24. The process of manufacturing according to claim 1 is extrusion and spherinization, comprising a disintegrant selected from the group consisting of Sodium starch glycolate, Cross-linked sodium, Carboxy methyl cellulose, Cornstarch, and Cross-linked polyvinyl pyrrolidone.
25. The process of manufacturing according to claim 1 is extrusion and spherinization, preferable disintegrant for this process is Sodium starch glycolate.
26. The process of manufacturing according to claim 1 is extrusion and spherinization, comprising the diluents selected for this process are
Mannitol, Sorbitol, Xylitol, Lactose, Microcrystalline cellulose, Magnesium carbonate, Calcium carbonate, Dicalcium phosphate, Tribasic calcium phosphate, and Calcium sulphate.
27. The process of manufacturing according to claim 1 is extrusion and spherinization; the preferable diluent for this process is microcrystalline cellulose.
28. The process of manufacturing according to claim 1 is extrusion and spherinization, the glidants suitable for this process are Talc and Colloidal silicondioxide.
PCT/IN2008/000557 2008-09-02 2008-09-02 Oral dosage forms of linezolid and processes for their preparation Ceased WO2010026597A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103099792A (en) * 2012-12-10 2013-05-15 成都欣捷高新技术开发有限公司 Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving
WO2014033744A2 (en) 2012-08-10 2014-03-06 Indoco Remedies Limited A novel pharmaceutical composition of linezolid
WO2014118809A1 (en) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Pharmaceutical composition with linezolid
WO2014139657A1 (en) 2013-03-11 2014-09-18 Pharmathen S.A. Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof
US9132132B2 (en) 2010-09-02 2015-09-15 Hetero Research Foundation Pharmaceutical compositions of linezolid
RU2690491C2 (en) * 2017-07-19 2019-06-04 Общество с ограниченной ответственностью "МБА-групп" Solid-phase linezolid-containing preparation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070225A2 (en) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Oxazolidinone tablet formulation
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2008008120A1 (en) * 2006-07-14 2008-01-17 Fmc Corporation Solid form

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001070225A2 (en) * 2000-03-22 2001-09-27 Pharmacia & Upjohn Company Oxazolidinone tablet formulation
US20070104785A1 (en) * 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2008008120A1 (en) * 2006-07-14 2008-01-17 Fmc Corporation Solid form

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 (en) 2012-08-10 2014-03-06 Indoco Remedies Limited A novel pharmaceutical composition of linezolid
US9492459B2 (en) 2012-08-10 2016-11-15 Indoco Remedies Limited Pharmaceutical composition of linezolid
CN103099792A (en) * 2012-12-10 2013-05-15 成都欣捷高新技术开发有限公司 Preparation method of IV crystal linezolid tablets having high drug loading capacity and capable of quickly dissolving
WO2014118809A1 (en) 2013-01-29 2014-08-07 Actavis Group Ptc Ehf. Pharmaceutical composition with linezolid
WO2014139657A1 (en) 2013-03-11 2014-09-18 Pharmathen S.A. Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof
RU2690491C2 (en) * 2017-07-19 2019-06-04 Общество с ограниченной ответственностью "МБА-групп" Solid-phase linezolid-containing preparation

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