FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"HIGH DRUG CONTENT TABLETS"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House, DO - Corporate Bldg,
Wing -A, B.D. Sawant Marg,
Chakala, Andheri (East),
Mumbai - 400 099

THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE
INVENTION

FIELD OF INVENTION:
The present invention relates to the high drug content tablets, particularly to the high drug content tablets comprising the crystalline drugs, more particularly to the linezolid.
BACKGROUND OF INVENTION:
Tablet dosage form is the preferred dosage form over the other dosage forms due to the several advantages, not limited to, the ease of administration by the patient, ease of manufacturing and the cost. In the pharmaceutical industry the Formulation of tablets, on a broader view, usually involves the mixing of the active pharmaceutical ingredient ("API") with excipient(s) with or without binder and finally compressing the blend into the tablets. The pharmaceutical tablet suitably accommodates mild or moderate dose of active ingredient or drug. The only disadvantage of tablet dosage form is the size of tablets, especially when the quantity of active ingredient to be presented in each tablet is high. Under such circumstances the swallowing of tablets becomes difficult due to the larger size of tablets.
While dealing with the tablets containing mild or moderate dose of drug, the excipient tends to be the predominant portion of tablets and compaction typically entails excipient selection, enhancing the excipients properties, or improving the process to mix or formulate the tablet. However, when a high drug load is desired selection and/or manipulation of the excipient its quantities or process may not be enough to sufficiently compact the tablet. Furthermore, because of the high drug load, the mechanical properties (such as compactibility) of the API predominate. The impact of insufficient compaction may lead to larger size tablets or the need for a patient to take more tablets then would be required if compaction were sufficient to obtain the desired drug load.
There are numerous drugs, not limited to certain NSAID'S or antibiotics or antivirals, wherein the dose is very high and the manufacturing the tablet with acceptable size and weight becomes difficult. The excessive addition of excipient(s) to a powder mixture does improve the
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performance of the powder mixture relative to that of the compactibility of the drug, however, such addition will lower the maximum drug load per tablet, thereby increasing the size of the tablet per unit dose. This is commercially undesirable.
However in the prior art, the tablets of high drug content are being developed using limited excipients, which are generally known as compaction aid. The prior art reveals that majority of excipients are unsuitable to address the issue of compactability of drug. The most preferred compaction aid is microcrystalline cellulose. Surprisingly the said compaction aids are susceptible to a reduction in their compactability due to pharmaceutical processes, such as granulation. Hence, for optimal performance, these compaction aids should be matched with the drugs based on its mechanical characteristics.
The oxazolidinones represent a novel chemical class of synthetic antimicrobial agents that possess promising activity against antibiotic-sensitive and MIC90-resistant gram-positive bacteria in vitro and in animal models of infection. In clinical trials, the first member of the class, linezolid, demonstrated 100% bioavailability after oral dosing and achieved blood levels well in excess of the MIC90 for staphylococci, enterococci, and streptococci. The oxazolidinones are not cross-resistant with other antimicrobial classes and act by inhibiting the formation of the initiation complex in bacterial protein synthesis.
Linezolid is sold under the trade name ZYVOX in United States of America. ZYVOX Tablets for oral administration contain 400 mg or 600 mg linezolid as film-coated compressed tablets. The drug appears to inhibit the initiation of protein synthesis at the ribosomal level in susceptible bacteria. Linezolid is primarily used for nosocomial infections caused by various gram-positive organisms with documented resistance to other antibiotics.
ZYVOX I.V. Injections are also available as a ready-to-use sterile isotonic solution for intravenous infusion. Linezolid can be administered both IV and orally every 12 hours, and must be used only when indicated to avoid the development of resistance against it. Potential side effects include thrombocytopenia, headache, nausea, and diarrhea. Other oxazolidinones are currently under investigation.
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Linezolid, also known as (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide, may be represented by Formula I.

(I)
Linezolid disrupts bacterial growth by inhibiting the initiation process in protein synthesis. Linezolid is highly absorbed when administered orally, with a bioavailability of approximately 100 percent. This allows conversion from intravenous to oral therapy as soon as the patient is clinically stable; thus, it provides an advantage over comparative therapy that can be delivered only parenterally. Linezolid is metabolized via hepatic oxidation without any cytochrome P-450 pathways. Elimination occurs through nonrenal, renal, and fecal mechanisms accounting for 65, 30, and 5 percent, respectively. The half-life is approximately five hours. Generally, the dosing interval for an antibiotic is three times the half-life—the dosing interval for linezolid is every 12 hours.
US6514529 assigned to Pharmacia & Upjohn describes tablets of high drug content, wherein the linezolid is compressed into a tablet using excipients corn starch, microcrystalline cellulose, hydroxyl propyl cellulose, sodium starch glycolate and magnesium stearate. The tablets thus produced provide blood levels of linezolid, equivalent to the blood levels produced by IV administration of the linezolid. Crystalline form II is used preferably.
WO2003090720 assigned to Novartis AG deals with high drug load tablet pharmaceutical formulation comprising crystalline compound I, binder, disintegrant, glidant, lubricant. Inventor of said application uses microcrystalline cellulose to achieve high drug load in tablet.
US6558699 equivalent to W09925321 assigned to SmithKline Beecham Corporation deals with high drug loaded formulations wherein microcrystalline cellulose is used as a compression aid to
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attain higher drug content of tablet.
US5376382 assigned to Asta Medica Aktiengellschaft, Germany relates to a medicinal formulation in the form of tablets, granulates or pellets containing thioctic acid as active ingredient, and having an active ingredient content of more than 45% by weight, said granulate or the granulate used to produce said tablets being produced by intensive moistening of thioctic acid with more than 30 weight % water, relative to the amount of solid substance used ,the active ingredient being repeatedly moistened with maximum energy input in a granulator, and subsequently dried at temperature between 20°C and 50°C .
US4609675 assigned to The Upjohn Company deals with a pharmaceutical, high drug content ibuprofen dry granulation formulation composition comprising 85-99% w/w of ibuprofen, 1-15% of croscarmellose sodium NF and microcrystalline cellulose added extragranularly.
Almost all prior art reference restricts the selection of compression aid to the microcrystalline cellulose, wherever the high drug content is desired. The prior art doesn't reveal the use of water soluble excipient to achieve high drug content of in tablets. Hence the tablets consisting of high drug content are highly desired, wherein the water soluble excipients are used as compression aid.
OBJECTIVE OF THE INVENTION:
Objective of the present invention is to provide high drug content tablet.
Another objective of the present invention is to provide water soluble excipients based high drug content tablet.
Another objective of present invention is to provide water soluble excipients based high drug content tablet of an antibacterial oxazolidinone agent.
Another objective of present invention is to provide water soluble excipients based high drug content tablet of Linezolid.
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Another objective of present invention is to use select appropriate particle size of Linezolid to achieve maximum drug load.
DETAILED DESCRIPTION OF INVENTION:
For the purpose of present invention the term "high drug content tablets" represents the tablet wherein the quantity of drug is about, equal to or more than 50%" of total tablet weight.
For the purpose of present invention the term "high linezolid content tablets" represents the tablet wherein the quantity of linezolid is about, equal to or more than 50% of total tablet weight.
The terms drug, active agent, active ingredient or active pharmaceutical ingredient has same meaning for the purpose of this document and are used interchangeably. Linezolid includes the linezolid, its pharmaceutical^ acceptable salts and hydrates.
The water soluble excipients of the present invention are the excipients in tablet which acts as a filler and facilitate the compression of the tablet. The term is interchangeably used as compression aid.
The present invention is directed to water soluble excipient based high drug content tablet of an antibacterial oxazolidinone agent more preferably to the crystalline form of Linezolid. Since linezolid has a good aqueous solubility (3mg/ml) and hence despite a high dose of 600mg the active pharmaceutical ingredient particle size was did not play a major role with respect to dissolution and bioavailability of the dosage form but the active pharmaceutical ingredient's characteristics like crystalline nature greatly influenced the compressibility of the tablets. In accordance with the said invention different ranges of particle size of crystalline Linezolid were evaluated. For the purpose of present invention the linezolid having 90% particles not more than 250 microns, specifically 200 microns and more specifically 150 microns was found to be suitable. However the compression of linezolid tablets observes the severe drawback of capping while compression with the linezolid having particle size above the specified limit,
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In the present invention the crystalline linezolid can be compressed into a tablet, using water soluble excipient as a compression aid, having a sufficient hardness and without facing the problem of capping or lamination, provided the 90% particles of linezolid are not more than 250 microns, specifically 200 microns and more specifically 150 microns.
However in one of he embodiments of the invention the crystalline linezolid can be compressed into a tablet, using water soluble or water insoluble and/or water swellable compression aid, having a sufficient hardness and without facing the problem of capping or lamination, provided the 90% particles of linezolid are not more than 250 microns, specifically 200 microns and more specifically 150 microns.
The tablet of present invention essentially comprises Linezolid or its pharmaceutically acceptable salts and at least one diluent, additionally the tablet has one or more binder, disintegrating agent and a lubricant.
Water soluble excipients used in the present invention are selected from the group not limited to the, sugars or sugar derivatives. The said sugars and sugars alcohols include, without limitation, lactose, mannitol, dextrose, sucrose, sorbitol and combination thereof. The lactose and mannitol are preferred water soluble excipient in accordance with the present invention. The commercially available grades of lactose which are suitable for granulation are preferred wherein the Phamatose 200M is the more preferred grade of Lactose. Pharmatose 200M consist of 100% of particles less than 250 Microns. Mannitol is a naturally occurring sugar alcohol, 50% as sweet as sucrose. Mannitol is commercially available as Pearlitol SD 200. In preferred tablet of linezolid of present invention uses the combination of Lactose and mannitol as a water soluble excipients or a compression aid, wherein Phamatose 200M and Pearlitol SD 200 are combined. The water soluble excipients of present tablet can be added as intragranular and/or extragranular.
In one of the embodiment the water insoluble and/or water swellable excipients can act as a compression aid, wherein the 90% particles of linezolid are not more than 250 microns, specifically 200 microns and more specifically 150 microns. The said insoluble and/or water swellable excipient is microcrystalline cellulose.
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The tablets of present invention include binder to bind the active ingredient and other excipients together. Binders for solid pharmaceutical compositions include Polyvinyl pyrrolidone, acacia, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, pregelatinized starch, starch and mixtures thereof. The preferred binders are polyvinyl pyrrolidone, carboxymethylcellulose sodium.
Tablet of the present invention also consist disintegrant. Disintegrants include carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol , Primellose croscarmellose sodium, guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab.RTM.) and starch. When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. Accordingly, a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Suitable lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.
The tablets of the present invention can be optionally film coated, using the common film forming polymers not limited to class of celluloses or methacrylates.
The tablets of the present invention can be prepared using any process well-known in pharmaceutical art, but wet granulation approach is preferred one. Linezolid is mixed uniformly with water soluble excipients and disintegrant and optionally binder is added. The dry blend is
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further granulated using suitable aqueous or non aqueous solvents optionally consisting binder dissolved or dispersed. Wet mass thus obtained was dried and dried granules were subsequently milled or sieved to get appropriate granule size. The dried granules were further lubricated and compressed into tablets.
Based on the individual dose, the tablet of present invention consist of generally from 50 to 800 mg of linezolid, preferably from 100 to 600 mg, particularly preferably from 400 to 600 mg. The tablet of present invention comprises water soluble excipient, less than or equal to the 50% of total tablet weight.
EXAMPLE I:

Ingredients mg/tablet
Granulation
Linezolid 600
Lactose monohydrate (Pharmatose 200M) 58.4
Mannitol (Pearlitol SD 200) 68.6
Croscarmellose Sodium (Ac Di Sol) 29.4
Na CMC BINDER 16.8
Lubrication
Mannitol (Pearlitol SD 200) 50
Croscarmellose Sodium (Ac Di Sol) 12.6
Magnesium Stearate 4.2
Total 840
Coating
OpadryY-1-7000 16.8
Linezolid was mixed uniformly with PHARMATOSE 200 M and Pearlitol SD 200 and crosscarmallose sodium. The dry blend is further granulated using suitable aqueous or non aqueous solvents optionally consisting Sodium Carboxymethyl cellulose. Wet mass thus obtained was dried and dried granules were subsequently milled or sieved to get appropriate granule size. Finally dried granules were mixed with pearlitol SD 200 and crosscarmellose sodium and magnesium stearate. Finally the lubricated granules were compressed into tablets.
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Example II:

Ingredients mg/tablet
Granulation
Linezolid 600
Lactose monohydrate (Pharmatose 200M) 58.4
Mannitol (Pearlitol SD 200) 68.6
Croscarmellose Sodium (Ac Di Sol) 29.4
Polyvinyl pyrrolidone 16.8
Lubrication
Mannitol (Pearlitol SD 200) 50
Croscarmellose Sodium (Ac Di Sol) 12.6
Magnesium Stearate 4.2
Total 840
Coating
OpadryY-1-7000 16.8
Linezolid was mixed uniformly with PHARMATOSE 200 M and Pearlitol SD 200 and crosscarmallose sodium. The dry blend is further granulated using suitable aqueous or non aqueous solvents optionally consisting PVP. Wet mass thus obtained was dried and dried granules were subsequently milled or sieved to get appropriate granule size. Finally dried granules were mixed with pearlitol SD 200 and crosscarmellose sodium and magnesium stearate. Finally the lubricated granules were compressed into tablets.

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