WO2014118809A1 - Pharmaceutical composition with linezolid - Google Patents

Pharmaceutical composition with linezolid Download PDF

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Publication number
WO2014118809A1
WO2014118809A1 PCT/IS2014/050001 IS2014050001W WO2014118809A1 WO 2014118809 A1 WO2014118809 A1 WO 2014118809A1 IS 2014050001 W IS2014050001 W IS 2014050001W WO 2014118809 A1 WO2014118809 A1 WO 2014118809A1
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WIPO (PCT)
Prior art keywords
pharmaceutical formulation
range
linezolid
sodium
tablet
Prior art date
Application number
PCT/IS2014/050001
Other languages
French (fr)
Inventor
Torfi E. Kristjansson
Original Assignee
Actavis Group Ptc Ehf.
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Application filed by Actavis Group Ptc Ehf. filed Critical Actavis Group Ptc Ehf.
Publication of WO2014118809A1 publication Critical patent/WO2014118809A1/en

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    • 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
    • A61K9/2009—Inorganic compounds
    • 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

Definitions

  • the present invention is within the field of pharmaceuticals and pertains to particular formulations of the antibiotic linezolid or a salt thereof.
  • Linezolid is a synthetic antibiotic of the oxazolidinone class type. The preparation thereof is described in WO 95/07271.
  • the chemical formula of the compound is (S)-/V-( ⁇ 3-[3-fluoro-4 (morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methyl)acetamide, with the structure being shown in Formula I.
  • Staphylococcus aureus including hospital-acquired pneumonia, infections of the skin etc.
  • Linezolid was first approved for use in 2000 and was the first commercially available oxazolidinone, though others are in development.
  • Linezolid exists in different polymorphic forms, at least the forms I, II, III, and IV.
  • the current commercially available product, (Zyvox, Zyvoxid; by Pfizer) uses form II, which is described in US patent No. 6,559,305.
  • Form IV is described in US 2006/0142283, this form is also claimed by WO 2005/035530 but referred to as Form III.
  • the recognised Form III is disclosed in US patent No. 7,714, 128, and is characterised by XRD peaks expressed as 2 ⁇ at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9, and 29.9 degrees.
  • 2006/0111350 also discloses the different polymorphic forms, and the amorphous form is disclosed in WO 2007/026369.
  • a proposed dosage form in this prior art document is of the effervescent type, making use of an effervescent couple which can produce gas bubbles when in contact with water, which helps disrupting the gel layer that forms around Form III crystals.
  • the disclosed dosage forms comprise sodium hydrogen carbonate and citric acid as an effervescent couple.
  • 2010/026597 discloses multiparticulate compositions, which requires forming a core in the form of a beadlet or pellet, obtained by extrusion and spheronization, where the core comprises linezolid form III. These processes however require special material or equipment or both.
  • the present invention provides stable formulations with linezolid or a salt thereof that can be successfully used with different polymorphic forms of the compound, overcoming existing problems with gelling properties and challenges due to bulk properties.
  • the invention provides in a first aspect a pharmaceutical tablet formulation comprising linezolid or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium hydrogen carbonate as disintegrant.
  • Salts of the active compound in accordance with the present invention include but are not limited to the tartrate salt, mesylate salt, succinate salt, maleate salt, esylate salt, acetate salt, sulphate salt, phosphate salt, hydrobromide salt, hydrochloride salt, tosylate salt, benzoate salt, hexanoate salt, octanoate salt, gluconate salt, aspartate salt, and citrate salt.
  • the formulation is suitable for any polymorphic forms, and in particular the polymorphic forms other than Form II, that have proven difficult to successfully formulate commercially.
  • the linezolid in the formulation of the invention is in some embodiments of form I, form II, form III, form IV, amorphous form, or in certain embodiments a mixture of any two or more of these forms.
  • Sodium hydrogen carbonate is the monosodium salt of carbonic acid, also referred to as sodium bicarbonate, with the formula NaHC0 3 .
  • linezolid is susceptible to alkaline degradation, compatability with sodium hydrogen carbonate was tested and found fully acceptable.
  • the invention is suitable for conventional (non- effervescent) tablet dosage forms.
  • Conventional tablet forms can be described in the context herein as those tablet forms that disintegrate in less than 60 minutes and preferably less than 30 minutes, but typically in more than 2 minutes or 5 minutes (when tested with conventional disintegration protocols. Tablet dosage form with such characteristics are comprised as embodiments of the present invention.
  • Conventional tablets include tablets that are intended for swallowing and the dosage forms of the present invention are preferably of such type.
  • a tablet of the tablet formulation of the present invention may comprise in certain embodiments in the range of about 400 mg to about 1000 mg linezolid, such as 400, 500, 600 or 750 mg. 600 mg is the presently preferred dosage size.
  • a tablet with a high weight proportion of the active ingredient such as in the range of about 40-80%, such as in the range of about 60%-80% such as in the range of about 65-75 wt%, for example about 60%, 65%, 70% or 75%.
  • a tablet of the present formulation can in some embodiments have a total core weight (excluding optional coating) in the range of 700-1200 mg and typically in the range 800-1000 mg.
  • the tablets are coated; when the tablet is coated, the coating generally adds about 2-4 wt% to the weight of the core.
  • a coated tablet with a core weight of about 840 mg will have total weight of about 860-875 mg.
  • any suitable coating may be applied in the present invention.
  • Preferred coating materials include mixtures of hydroxypropyl methylcellulose (HPMC; hypromellose) and copovidone (copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in the mass proportion 3:2), suitably together with polyethylene glycol as plasticiser.
  • HPMC hydroxypropyl methylcellulose
  • copovidone copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in the mass proportion 3:2
  • Aquarius Preferred HSP218011 is an example of such material.
  • the formulation comprises in preferred embodiments a filler or diluent, which can be selected from several alternatives well known in the art.
  • Suitable diluents or fillers include one or more of lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, starch, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof.
  • MMC microcrystalline cellulose
  • microcrystalline cellulose is selected as the most preferred filler.
  • the tablets of the invention will generally contain a large relative amount of the active ingredient, there is accordingly relatively little filler used when filler is incorporated.
  • microcrystalline cellulose is used as filler, in the range of about 5-20 wt% of the tablet core, preferably in the range of about 7-15 wt%, such as in the range of about 8-12 wt%, or about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt% or about 12 wt%.
  • a binder is preferably comprised in the formulation, which can be selected from e.g. methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), and polyvinylalcohol. Hydroxypropyl cellulose is preferred as binder.
  • the tablet formulation comprises as mentioned sodium hydrogen carbonate as disintegrant.
  • the amount of sodium hydrogen carbonate can be suitably in the range of 5-15 wt%, such as in the range of 5-10 wt%, such as about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt%. The amount used may depend on whether further disintegrant substances are used.
  • the composition comprises in certain embodiments a further disintegrant, in particular this further disintegrant can in be some embodiments carboxymethyl cellulose, sodium starch glycolate or a combination of both.
  • Carboxymethyl cellulose is preferably used in the range of about 3-8 wt% of the core weight, such as in the range of about 4-6 wt%, such as about 3 wt%, about 4 wt% or about 5 wt%.
  • Sodium starch glycolate is preferably included in the composition in the range of about 2-5 wt%, such as in the range of about 2-4 wt%, such as about 3 wt%, 4 wt% or about 5 wt%.
  • both substances can preferably be used in a weight ratio in the range of about 3 : 1 to about 1 : 1, such as more preferably in a ratio in the range from about 2: 1 to 1 : 1, such as in the ration of about 2: 1, about 5 :3 (1.67: 1), or about 3:2 (1.5: 1).
  • the tablet formulation of the invention is suitably formulated with wet granulation. Water or an aqueous solution is preferred as granulation liquid. In one embodiment, a portion of binder is dissolved in water and this solution is used as granulation liquid.
  • 20-50 wt% of the binder such as 25 wt% or 33 wt%, can be dissolved in the granulation liquid (e.g. regular grind grain size material, suitably hydroxypropyl cellulose such as Klucel EF, or the like) and the remainder, which is preferably fine grind grain size material (e.g. Klucel EXF hydroxypropyl cellulose or the like) is added as dry ingredient to the granulation blend.
  • the granulation liquid e.g. regular grind grain size material, suitably hydroxypropyl cellulose such as Klucel EF, or the like
  • fine grind grain size material e.g. Klucel EXF hydroxypropyl cellulose or the like
  • the active ingredient linezolid is contained within the granules.
  • At least a portion of the filler and binder are included in the granulation blend.
  • a portion of the filler material may be used in the granule blend and the remaining portion in the extragranular matrix.
  • hydroxypropyl cellulose is used as binder, and is mixed in the granule blend.
  • Microcrystalline cellulose is suitably filler in the embodiment, a portion of which is in the granule blend and the remainder in the extragranular matrix.
  • Suitable lubricants include but are not limited to, one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, calcium stearate, talc, hydrogenated castor oil, and mixtures thereof.
  • Lubricant is typically added in an amounts varying in the range from about 0.1% to about 4% by weight, preferably from about 0.5 % to about 2% by weight may be used, relative to the net weight of the formulation (core weight). According to the most preferred embodiments, sodium stearyl fumarate is selected as the lubricant.
  • particle size of the active ingredient or excipients is not a critical factor.
  • relatively fine particle size of the active ingredient such as but not limited to Form III linezolid
  • the linezolid substance has a particle size (D90 by volume) which is less than 120 ⁇ , and preferably less than 100 ⁇ , and more preferably less than 80 ⁇ , such as less than 75 ⁇ or less than 60 ⁇ .
  • the D50 vale (limit which 50% of particles fall below) is preferably less than 90 ⁇ , and more preferably less than 70 ⁇ , and even more preferably less than 50 ⁇ .
  • antioxidants can also be incorporated in the formulations in order to reduce or prevent oxidation of the drug compound, they may be suitably selected from one or more of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium metabisulfate, malic acid, citric acid and ascorbic acid.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • sodium metabisulfate malic acid
  • citric acid citric acid
  • ascorbic acid sodium metabisulfate
  • Example 1 Tablet Formulation A
  • Microcrystalline cellulose (Avicel PH 102) 32.85 3.91 Hydroxypropyl cellulose (Klucel EXF) 12.6 1.5
  • Microcrystalline cellulose (Avicel PH 102) 47.55 5.66
  • the tablets were manufactured with wet granulation process in high shear mixer.
  • Hydroxypropyl cellulose (Klucel EF) was dissolved in water and this liquid was added to linezolid, microcrystalline cellulose (intragranular portion) and hydroxypropyl cellulose (Klucel EXF) in the high shear mixer.
  • the resulting granules were wet screened and dried in fluid bed drier to LOD ⁇ l% (loss on drying). Dried granules were screened and blended with extragranular materials in two steps without/with lubricant (sodium stearyl fumarate). Tablets were compressed in rotary tablet machine.
  • Microcrystalline cellulose (Avicel PH 1( D2) 47.55 5.66
  • Example 3 Stability test, tablets A and B
  • the table shows results of the stability tests at 40°C / 75% RH (relative humidity). Stability results are all within limits.
  • Example 5 Pilot scale batch A pilot scale batch was prepared, composition was the same as for the above formulations A and B. Manufacture was conducted under low humidity conditions (30% ⁇ 5% RH).
  • Hydroxypropyl cellulose (Klucel EF) was dissolved in purified water by stirring. Linezolid, hydroxypropyl cellulose (Klucel EXF) and microcrystalline cellulose were added to high speed granulator, mixed and screened and re-blended. The active blend was granulated with HPC solution and the granules wet screened and dried in fluid bed drier until LOD (moisture scale, 5 g, 105°C) was ⁇ 1%.
  • LOD moisture scale, 5 g, 105°C
  • Dry granules were blended with pre-screened sodium hydrogen carbonate, microcrystalline cellulose, croscarmellose sodium and sodium starch glycolate in IPC Blender.
  • the blend was lubricated with pre-screened sodium stearyl fumarate.
  • Tablets were compressed on rotary tablet machine.
  • Tooling used was 9.3 x 19 mm oval normal concave with embossing L and 600.
  • Tablets were packed in al/al blisters and HDPE (Duma) containers with two desiccant canisters.

Abstract

A pharmaceutical tablet formulation with linezolid or a salt thereof as an active ingredient is provided. The formulation comprises, a filler which is preferably microcrystalline cellulose, and sodium hydrogen carbonate as disintegrant. In some embodiments the disintegrant is a mixture of carboxymethylcellulose and sodium starch glycolate.

Description

Pharmaceutical composition with linezolid
FIELD OF INVENTION
The present invention is within the field of pharmaceuticals and pertains to particular formulations of the antibiotic linezolid or a salt thereof.
TECHNICAL BACKGROUND AND PRIOR ART
Linezolid is a synthetic antibiotic of the oxazolidinone class type. The preparation thereof is described in WO 95/07271. The chemical formula of the compound is (S)-/V-({3-[3-fluoro-4 (morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide, with the structure being shown in Formula I.
Figure imgf000002_0001
Formula I
It is used in particular against serious infections caused by Gram-positive bacteria, such as streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant
Staphylococcus aureus (MRSA) including hospital-acquired pneumonia, infections of the skin etc. Linezolid was first approved for use in 2000 and was the first commercially available oxazolidinone, though others are in development.
Bulk properties of linezolid create formulation challenges, the substance is light and fluffy and difficult to granulate. A typical tablet dose is 600 mg which adds to the formulation challenges as this limits the relative amount of inert excipients that can be added.
Linezolid exists in different polymorphic forms, at least the forms I, II, III, and IV. The current commercially available product, (Zyvox, Zyvoxid; by Pfizer) uses form II, which is described in US patent No. 6,559,305. Form IV is described in US 2006/0142283, this form is also claimed by WO 2005/035530 but referred to as Form III. The recognised Form III is disclosed in US patent No. 7,714, 128, and is characterised by XRD peaks expressed as 2Θ at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9, and 29.9 degrees. US
2006/0111350 also discloses the different polymorphic forms, and the amorphous form is disclosed in WO 2007/026369.
Some of the forms (e.g. Form I and III) cause additional difficulties in formulating because of gelling tendencies. When these crystalline forms come in contact with water, the surface of the crystals dissolve and the dissolved linezolid tends to stick to the crystal surface instead of spreading in water, forming a gel layer around the crystal. The gel formation around the crystal acts as a barrier impeding further contact with water, which in turn retards the solubilisation of linezolid. The gelling potential of linezolid Form III is described in US
2007/0104785, which suggests certain dosage forms addressing these problems. A proposed dosage form in this prior art document is of the effervescent type, making use of an effervescent couple which can produce gas bubbles when in contact with water, which helps disrupting the gel layer that forms around Form III crystals. The disclosed dosage forms comprise sodium hydrogen carbonate and citric acid as an effervescent couple. WO
2010/026597 discloses multiparticulate compositions, which requires forming a core in the form of a beadlet or pellet, obtained by extrusion and spheronization, where the core comprises linezolid form III. These processes however require special material or equipment or both.
It would be advantageous and appreciated in the field if alternative formulations were available that would suit different polymorphic forms and allow economic production. This would make possible producing formulations at much lower cost than the available formulations of the dominant commercial polymorph.
SUMMARY OF INVENTION
The present invention provides stable formulations with linezolid or a salt thereof that can be successfully used with different polymorphic forms of the compound, overcoming existing problems with gelling properties and challenges due to bulk properties.
DETAILED DESCRIPTION The invention provides in a first aspect a pharmaceutical tablet formulation comprising linezolid or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium hydrogen carbonate as disintegrant.
Salts of the active compound in accordance with the present invention include but are not limited to the tartrate salt, mesylate salt, succinate salt, maleate salt, esylate salt, acetate salt, sulphate salt, phosphate salt, hydrobromide salt, hydrochloride salt, tosylate salt, benzoate salt, hexanoate salt, octanoate salt, gluconate salt, aspartate salt, and citrate salt.
It will be appreciated that the formulation is suitable for any polymorphic forms, and in particular the polymorphic forms other than Form II, that have proven difficult to successfully formulate commercially. Accordingly, the linezolid in the formulation of the invention is in some embodiments of form I, form II, form III, form IV, amorphous form, or in certain embodiments a mixture of any two or more of these forms.
Sodium hydrogen carbonate is the monosodium salt of carbonic acid, also referred to as sodium bicarbonate, with the formula NaHC03. As linezolid is susceptible to alkaline degradation, compatability with sodium hydrogen carbonate was tested and found fully acceptable.
As illustrated in the examples herein, the invention is suitable for conventional (non- effervescent) tablet dosage forms. Conventional tablet forms can be described in the context herein as those tablet forms that disintegrate in less than 60 minutes and preferably less than 30 minutes, but typically in more than 2 minutes or 5 minutes (when tested with conventional disintegration protocols. Tablet dosage form with such characteristics are comprised as embodiments of the present invention. Conventional tablets include tablets that are intended for swallowing and the dosage forms of the present invention are preferably of such type.
As mentioned above, linezolid is typically administered in relatively large dose, accordingly a tablet of the tablet formulation of the present invention may comprise in certain embodiments in the range of about 400 mg to about 1000 mg linezolid, such as 400, 500, 600 or 750 mg. 600 mg is the presently preferred dosage size. This results in tablets with a high weight proportion of the active ingredient (as too large tablets are inconvenient), such as in the range of about 40-80%, such as in the range of about 60%-80% such as in the range of about 65-75 wt%, for example about 60%, 65%, 70% or 75%. Accordingly, a tablet of the present formulation can in some embodiments have a total core weight (excluding optional coating) in the range of 700-1200 mg and typically in the range 800-1000 mg.
In preferred embodiments, the tablets are coated; when the tablet is coated, the coating generally adds about 2-4 wt% to the weight of the core. Thus a coated tablet with a core weight of about 840 mg will have total weight of about 860-875 mg.
Any suitable coating may be applied in the present invention. Preferred coating materials include mixtures of hydroxypropyl methylcellulose (HPMC; hypromellose) and copovidone (copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in the mass proportion 3:2), suitably together with polyethylene glycol as plasticiser. Aquarius Preferred HSP218011 is an example of such material.
The formulation comprises in preferred embodiments a filler or diluent, which can be selected from several alternatives well known in the art. Suitable diluents or fillers include one or more of lactose, sucrose, glucose, sorbitol, dextrates, dextrins, dextrose, fructose, mannitol, sorbitol, starch, carboxymethylcellulose calcium, microcrystalline cellulose (MCC), powdered cellulose, sodium chloride and mixtures thereof. According to preferred embodiments microcrystalline cellulose is selected as the most preferred filler. As the tablets of the invention will generally contain a large relative amount of the active ingredient, there is accordingly relatively little filler used when filler is incorporated. In some embodiments, microcrystalline cellulose is used as filler, in the range of about 5-20 wt% of the tablet core, preferably in the range of about 7-15 wt%, such as in the range of about 8-12 wt%, or about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt% or about 12 wt%.
A binder is preferably comprised in the formulation, which can be selected from e.g. methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone (povidone), and polyvinylalcohol. Hydroxypropyl cellulose is preferred as binder. The tablet formulation comprises as mentioned sodium hydrogen carbonate as disintegrant. The amount of sodium hydrogen carbonate can be suitably in the range of 5-15 wt%, such as in the range of 5-10 wt%, such as about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt%. The amount used may depend on whether further disintegrant substances are used. The composition comprises in certain embodiments a further disintegrant, in particular this further disintegrant can in be some embodiments carboxymethyl cellulose, sodium starch glycolate or a combination of both. Carboxymethyl cellulose is preferably used in the range of about 3-8 wt% of the core weight, such as in the range of about 4-6 wt%, such as about 3 wt%, about 4 wt% or about 5 wt%. Sodium starch glycolate is preferably included in the composition in the range of about 2-5 wt%, such as in the range of about 2-4 wt%, such as about 3 wt%, 4 wt% or about 5 wt%. Thus when both substances are included, they can preferably be used in a weight ratio in the range of about 3 : 1 to about 1 : 1, such as more preferably in a ratio in the range from about 2: 1 to 1 : 1, such as in the ration of about 2: 1, about 5 :3 (1.67: 1), or about 3:2 (1.5: 1). As illustrated with certain non-limiting examples shown herein below, the tablet formulation of the invention is suitably formulated with wet granulation. Water or an aqueous solution is preferred as granulation liquid. In one embodiment, a portion of binder is dissolved in water and this solution is used as granulation liquid.
For example, 20-50 wt% of the binder, such as 25 wt% or 33 wt%, can be dissolved in the granulation liquid (e.g. regular grind grain size material, suitably hydroxypropyl cellulose such as Klucel EF, or the like) and the remainder, which is preferably fine grind grain size material (e.g. Klucel EXF hydroxypropyl cellulose or the like) is added as dry ingredient to the granulation blend.
In granulation formulations of the invention, the active ingredient linezolid is contained within the granules. At least a portion of the filler and binder are included in the granulation blend. For example, a portion of the filler material may be used in the granule blend and the remaining portion in the extragranular matrix. In a preferred embodiment, hydroxypropyl cellulose is used as binder, and is mixed in the granule blend. Microcrystalline cellulose is suitably filler in the embodiment, a portion of which is in the granule blend and the remainder in the extragranular matrix.
Suitable lubricants include but are not limited to, one or more of magnesium stearate, sodium stearyl fumarate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, calcium stearate, talc, hydrogenated castor oil, and mixtures thereof. Lubricant is typically added in an amounts varying in the range from about 0.1% to about 4% by weight, preferably from about 0.5 % to about 2% by weight may be used, relative to the net weight of the formulation (core weight). According to the most preferred embodiments, sodium stearyl fumarate is selected as the lubricant.
It is an advantage of the present invention that particle size of the active ingredient or excipients is not a critical factor. In some embodiments however, relatively fine particle size of the active ingredient (such as but not limited to Form III linezolid) is used, to further prevent gelling. Accordingly, in some embodiments, the linezolid substance has a particle size (D90 by volume) which is less than 120 μπι, and preferably less than 100 μπι, and more preferably less than 80 μιη, such as less than 75 μιη or less than 60 μιη. (The term D90 indicating that more than 90% of the particles by volume have a particle size below the stated limit.) Accordingly, the D50 vale (limit which 50% of particles fall below) is preferably less than 90 μιη, and more preferably less than 70 μηι, and even more preferably less than 50 μπη.
In certain embodiments, antioxidants can also be incorporated in the formulations in order to reduce or prevent oxidation of the drug compound, they may be suitably selected from one or more of butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium metabisulfate, malic acid, citric acid and ascorbic acid.
EXAMPLES
Example 1 : Tablet Formulation A
Lab batch A
API mg / tablet 600 mg
Batch scale 700 g / 833 tablets
Manufacturing method Wet granulation
Ingredient mg/tablet %
Intragranular material
Linezolid (form III) 600.0 71.43
Microcrystalline cellulose (Avicel PH 102) 32.85 3.91 Hydroxypropyl cellulose (Klucel EXF) 12.6 1.5
Hydroxypropyl cellulose (Klucel EF) 4.2 0.5
Total intragranulation ingredients 649.65 77.34
Water (g/batch) 113.2
Extragranular material
Microcrystalline cellulose (Avicel PH 102) 47.55 5.66
Sodium starch glycolate 25.2 3.0
Sodium hydrogen carbonate 67.2 8.0
Croscarmellose sodium 42.0 5.0
Sodium stearyl fumarate 8.4 1.0
Total extragranular ingredients 190.35 22.66
Net total (tablet core) 840 mg
Coating
- 0 0
Total tablet weight 840 mg
IPC, granules
LOD (loss on drying) after drying 105°C, % 0.22
Bulk density g/ml 0.52
IPC, core tablets 9.3 x 19 mm elliptical
convex with Logo L/750
Weight (mg) 841.4
Weight variation (%) 0.62
Resistance to crushing (N)* 103 - 128
Avg. 118
Disintegration (min:sec) 2:0
Friability % 4 min (25rpm) 0.24
Tab thickness mm) 6.0
The tablets were manufactured with wet granulation process in high shear mixer.
Hydroxypropyl cellulose (Klucel EF) was dissolved in water and this liquid was added to linezolid, microcrystalline cellulose (intragranular portion) and hydroxypropyl cellulose (Klucel EXF) in the high shear mixer. The resulting granules were wet screened and dried in fluid bed drier to LOD< l% (loss on drying). Dried granules were screened and blended with extragranular materials in two steps without/with lubricant (sodium stearyl fumarate). Tablets were compressed in rotary tablet machine.
Resulting tablets were packed into alu/alu blister and samples tested for stability for 3 months at 30°C / 65% RH and 40°C / 75% RH. Example 2: Formulation B
Lab batch B
mg / tablet 600 mg
Batch scale 700 g / 833 tablets
Manufacturing method Wet granulation
Ingredient mg/tablet %
Intragranular material
Linezolid (form III) 600.0 71.43
Microcrystalline cellulose (Avicel PH 1( D2) 32.85 3.91
Hydroxypropyl cellulose (Klucel EXF) 12.6 1.5
Hydroxypropyl cellulose (Klucel EF) 4.2 0.5
Total intragranulation ingr Bdients 649.65 77.34
Water (g/batch) 106.5
Extragranular material
Microcrystalline cellulose (Avicel PH 1( D2) 47.55 5.66
Sodium starch glycolate 25.2 3.0
Sodium hydrogen carbonate 67.2 8.0
Croscarmellose sodium 42.0 5.0
Sodium stearyl fu ma rate 8.4 1.0
Total extragranular ingr Bdients 190.35 22.66
Net total (tablet core) 840 mg
Coating
Aquarius Preferred HSP BPP218011 25.2 3.0
Total tablet weight 865.2 mg
IPC, granules
LOD after drying 105°C, % 0.19
Bulk density g/ml 0.52
IPC, core tablets 9.3 x 19 mm eW'n )tical
convex with logo
Net weight (core) (mg) 838.4
Weight variation (%) 0.59
Resistance to crushing (N)* 102 - 117
Avg. 110
Disintegration (min:sec) 2:05
Friability % 4 min (25 rpm) 0.24
Tab thickness (mm) 6.07
The tablets were manufactured as described for Formulation A, adding a coating step, batch coating in perforated coating pan. Samples were tested for stability. Example 3: Stability test, tablets A and B
The table shows results of the stability tests at 40°C / 75% RH (relative humidity). Stability results are all within limits.
Figure imgf000009_0001
Three month samples showed no polymorphic change in XRD tests. Initial form III is intact and no conversion to form II is seen. (Data not shown.)
Example 4: Dissolution
Dissolution at different pH was tested. Results are shown in Figures 1-3. The dissolution profiles are similar at the different pH values tested (6.8, 4.5, 1.2) with no difference between the coated and uncoated tablets. The tablets compare favourably with reference tablets (Zyvoxid® 600 mg), with about 85% released after 15 minutes.
Example 5: Pilot scale batch A pilot scale batch was prepared, composition was the same as for the above formulations A and B. Manufacture was conducted under low humidity conditions (30% ±5% RH).
Hydroxypropyl cellulose (Klucel EF) was dissolved in purified water by stirring. Linezolid, hydroxypropyl cellulose (Klucel EXF) and microcrystalline cellulose were added to high speed granulator, mixed and screened and re-blended. The active blend was granulated with HPC solution and the granules wet screened and dried in fluid bed drier until LOD (moisture scale, 5 g, 105°C) was < 1%.
Dry granules were blended with pre-screened sodium hydrogen carbonate, microcrystalline cellulose, croscarmellose sodium and sodium starch glycolate in IPC Blender. The blend was lubricated with pre-screened sodium stearyl fumarate.
Tablets were compressed on rotary tablet machine. Tooling used was 9.3 x 19 mm oval normal concave with embossing L and 600.
Tablets were coated with Aquarius Preferred HSP BPP218011 White water solution in a perforated coating pan to a weight gain of 3% (2 - 4%).
Tablets were packed in al/al blisters and HDPE (Duma) containers with two desiccant canisters.

Claims

1. A pharmaceutical tablet formulation comprising linezolid or a pharmaceutically acceptable salt thereof as an active ingredient, and sodium hydrogen carbonate as disintegrant.
2. The pharmaceutical formulation of claim 1, comprising microcrystalline cellulose as filler.
The pharmaceutical formulation of claim 1 or 2, comprising a further disintegrant selected from carboxymethylcellulose, sodium starch glycolate and a combination of both.
The pharmaceutical formulation of any of the preceding claims, comprising a tablet core which is coated with a coating.
5. The pharmaceutical formulation of any of the preceding claims, comprising a non- effervescent tablet.
6. The pharmaceutical formulation of claim 1, comprising in the range of 5-15 wt%
sodium hydrogen carbonate, of the weight of the tablet core.
7. The pharmaceutical formulation of claim 3, comprising in the range of 3-10 wt%
carboxymethylcellulose of the weight of the tablet core.
8. The pharmaceutical formulation of any of the preceding claims, comprising in the range of 50-85 wt% linezolid of the weight of the tablet core, and preferably in the range of 60-80 wt% linezolid.
9. The pharmaceutical formulation of any of the preceding claims, comprising in the range of 5-20 wt% microcrystalline cellulose, and preferably in the range 7-15 wt%.
10. The pharmaceutical formulation of any of the preceding claims, wherein said linezolid or salt thereof is in a polymorphic form selected from Form I and Form III.
11. The pharmaceutical formulation of any of the preceding claims, comprising a lubricant selected from sodium stearyl fumarate, zinc stearate, magnesium stearate, calcium stearate, stearic acid, colloidal anhydrous silica, synthetic aluminum silicate, magnesium oxide, glyceryl behenate, hydrogenated castor oil, and mixtures thereof.
12. The pharmaceutical formulation of claim 11, comprising a lubricant selected from sodium stearyl fumarate and magnesium stearate.
13. The pharmaceutical formulation of any of the preceding claims prepared by wet granulation using water as granulation liquid.
14. The pharmaceutical formulation of any of the preceding claims, comprising linezolid granulated with at least a portion of the filler, and hydroxypropyl cellulose, and comprising said sodium hydrogen carbonate and a further disintegrant selected from carboxymethylcellulose, sodium starch glycolate and a combination of both, as extragranular ingredients.
15. The pharmaceutical formulation of any of the preceding claims comprising :
in the range of about 60-80 wt% linezolid,
in the range of about 8-12 wt% microcrystalline cellulose,
in the range of 1-3 wt% hydroxypropyl cellulose,
in the range of about 2-4 wt% sodium starch glycolate,
in the range of about 5-10 wt% sodium hydrogen carbonate, and
in the range of about 4-7 wt% carboxymethyl cellulose sodium.
16. The pharmaceutical formulation of claim 15, comprising :
about 71 wt% linezolid Form III,
about 9.6 wt% microcrystalline cellulose,
about 2.0 wt% hydroxypropyl cellulose,
about 3.0 wt% sodium starch glycolate,
about 8.0 wt% sodium hydrogen carbonate,
about 5.0 wt% carboxymethyl cellulose sodium, and about 1.0 wt% sodium stearyl fumarate.
17. A process for preparing a tablet formulation with linezolid active ingredient, comprising granulating linezolid, hydroxypropyl cellulose and microcrystalline cellulose with wet granulation, using water or aqueous solution as granulation liquid,
screening and drying the obtained granules,
blending granules with sodium hydrogen carbonate, a further portion of
microcrystalline cellulose and a disintegrant,
blending in a lubricant,
compressing tablets from the blend.
18. The process of claim 17, wherein said disintegrant is a mixture of carboxymethylcellulose and sodium starch glycolate.
PCT/IS2014/050001 2013-01-29 2014-01-29 Pharmaceutical composition with linezolid WO2014118809A1 (en)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (en) 1993-09-09 1995-03-16 The Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US6559305B1 (en) 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
WO2005035530A1 (en) 2003-10-16 2005-04-21 Symed Labs Limited A novel crystalline form of linezolid
US20060111350A1 (en) 2004-06-29 2006-05-25 Judith Aronhime Solid forms of linezolid and processes for preparation thereof
US20060142283A1 (en) 2004-06-29 2006-06-29 Judith Aronhime Crystalline form IV of linezolid
WO2007026369A1 (en) 2005-08-29 2007-03-08 Symed Labs Limited A novel amorphous form of linezolid
US20070104785A1 (en) 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2010026597A1 (en) 2008-09-02 2010-03-11 Hetero Research Foundation Oral dosage forms of linezolid and processes for their preparation
WO2010046933A2 (en) * 2008-10-22 2010-04-29 Rubicon Research Private Limited Pharmaceutical compositions of taste-masked linezolid

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995007271A1 (en) 1993-09-09 1995-03-16 The Upjohn Company Substituted oxazine and thiazine oxazolidinone antimicrobials
US6559305B1 (en) 2000-02-02 2003-05-06 Pharmacia & Upjohn Company Linezolid—crystal form II
WO2005035530A1 (en) 2003-10-16 2005-04-21 Symed Labs Limited A novel crystalline form of linezolid
US7714128B2 (en) 2003-10-16 2010-05-11 Symed Labs Limited Crystalline form of linezolid
US20060111350A1 (en) 2004-06-29 2006-05-25 Judith Aronhime Solid forms of linezolid and processes for preparation thereof
US20060142283A1 (en) 2004-06-29 2006-06-29 Judith Aronhime Crystalline form IV of linezolid
US20070104785A1 (en) 2005-07-29 2007-05-10 Navale Suryakant V Tablets of linezolid form iii and processes for their preparation
WO2007026369A1 (en) 2005-08-29 2007-03-08 Symed Labs Limited A novel amorphous form of linezolid
WO2010026597A1 (en) 2008-09-02 2010-03-11 Hetero Research Foundation Oral dosage forms of linezolid and processes for their preparation
WO2010046933A2 (en) * 2008-10-22 2010-04-29 Rubicon Research Private Limited Pharmaceutical compositions of taste-masked linezolid

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