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 Ci ₆ H ₂₀ FN ₃ O ₄ . 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

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

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

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

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

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

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

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.