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EP2968170A1 - Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof - Google Patents

Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof

Info

Publication number
EP2968170A1
EP2968170A1 EP14711148.8A EP14711148A EP2968170A1 EP 2968170 A1 EP2968170 A1 EP 2968170A1 EP 14711148 A EP14711148 A EP 14711148A EP 2968170 A1 EP2968170 A1 EP 2968170A1
Authority
EP
European Patent Office
Prior art keywords
linezolid
dosage form
pharmaceutical composition
ionic surfactant
formulation
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.)
Withdrawn
Application number
EP14711148.8A
Other languages
German (de)
English (en)
French (fr)
Inventor
Evangelos Karavas
Efthimios Koutris
Vasiliki SAMARA
Ioanna Koutri
Anastasia Kalaskani
Athina Iliopoulou
Christina KIZIRIDI
Morfis Abatzis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmathen SA
Original Assignee
Pharmathen SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmathen SA filed Critical Pharmathen SA
Publication of EP2968170A1 publication Critical patent/EP2968170A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the present invention relates to a stable pharmaceutical formulation for oral administration containing a therapeutically effective quantity of an oxazolidinone antibacterial agent such as Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof and a method for the preparation thereof.
  • an oxazolidinone antibacterial agent such as Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof
  • Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria such as streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to several other antibiotics.
  • Gram-positive bacteria such as streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to several other antibiotics.
  • VRE vancomycin-resistant enterococci
  • MRSA methicillin-resistant Staphylococcus aureus
  • Oxazolidinone antibiotics such as Linezolid
  • Oxazolidinone antibiotics have been known to contain the oxazolidinone ring in them structurally and hence their name. They are potent antibiotics which are saved as drugs of last resort against gram-positive bacteria. They are not to be used against bacteria which are sensitive to narrow spectrum antibiotics. Mechanistically oxazolidinone antibiotics show their action by inhibiting protein biosynthesis in the bacteria, which in turn causes cell death.
  • the oxazolidinones are protein synthesis inhibitors: they stop the growth and reproduction of bacteria by disrupting translation of messenger RNA (mRNA) into proteins in the ribosome.
  • mRNA messenger RNA
  • Linezolid appears to work on the first step of protein synthesis, initiation, unlike most other protein synthesis inhibitors, which inhibit elongation. It does so by preventing the formation of the initiation complex, composed of the 30S and 50S subunits of the ribosome, tRNA, and mRNA.
  • Linezolid binds to the 23S portion of the 50S subunit (the center of peptidyltransferase activity). Due to this unique mechanism of action, cross-resistance between Linezolid and other protein synthesis inhibitors is highly infrequent or nonexistent.
  • Linezolid is (S)-N-( ⁇ 3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo- l,3-oxazolidin-5-yl ⁇ methyl)acetamide.
  • the molecular formula is C 16 H 20 FN 3 O 4 corresponding to a molecular weight of 337.35. It is a white or almost white crystalline powder which is slightly soluble in water and freely soluble in methanol and methylene chloride.
  • Linezolid exhibits polymorphism and the main polymorphic forms that are known in the literature are form II and form III.
  • Form II is more stable at temperatures below 85°C and thus, form III has the tendency of converting to form II when exposed to conditions of elevated temperature and humidity.
  • EP-B- 1248616 discloses taste masked antibiotic composition in the form of microcapsules comprising particles of Linezolid coated with an inner polymeric coating prepared by solvent coacervation of a microencapsulation polymer and an outer plasticised enteric polymer.
  • WO-A-2010/026597 discloses a pharmaceutical composition comprising a core containing Linezolid in the form of beadlet or pellet, manufactured by extrusion and spheronization method.
  • an object of the present invention to provide an improved stable solid dosage formulation for oral administration containing an oxazolidinone antibacterial agent, and in particular Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof, as an active ingredient, which overcomes the deficiencies of the prior art and avoids polymorphic transformation of the active pharmaceutical ingredient resulting in longer shelf-life of the product.
  • Further object of the present invention is to provide a stable solid dosage formulation for oral administration containing Linezolid that overcomes the low water solubility of the active ingredient and has acceptable pharmacotechnical properties. It is another object of the present invention to provide an oral solid dosage formulation comprising Linezolid as an active ingredient, which is bioavailable and with sufficient self- life.
  • a further approach of the present invention is the selection of the appropriate active ingredient particle size distribution in order to obtain the optimum dissolution profile.
  • a major object of the present invention is the selection of the optimal combination of pharmaceutical acceptable excipients and method of preparation in order to achieve the appropriate dissolution profile and stability for the finished dosage form.
  • Said dosage form affords predictable and reproducible drug release rates in order to achieve better treatment to a patient.
  • Another aspect of the present invention is to provide an oral solid dosage formulation comprising Linezolid which is manufactured through a fast, simple and cost-effective process.
  • a pharmaceutical composition for oral administration comprising Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof, as an active ingredient, and an effective amount of the non- ionic surfactant Poloxamer to enhance the active ingredient's solubility.
  • a process for the preparation of a stable, solid dosage form for oral administration, containingan oxazolidinone antibacterial agent such as Linezolid comprises the following steps: -weighing of Linezolid and all excipients and sieving
  • composition of the present invention may be alternatively manufactured by a direct compression process.
  • Fig. 1 shows the dissolution profile of Formulation Trial 2.
  • Fig. 2 shows the dissolution profile of Formulation Trials 3 A-C.
  • Fig. 4 shows the dissolution profile of Formulation Trial 5.
  • Fig. 5 shows the dissolution profile of Formulation Trial 6.
  • Fig. 6 shows the dissolution profile of Formulation Trial 7.
  • a pharmaceutical composition comprising an active ingredient (e.g. Linezolid) is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions.
  • an active ingredient e.g. Linezolid
  • the main object of the present invention is to provide an immediate release composition of Linezolid or pharmaceutical acceptable salt, derivative or polymorph thereof that is simple to manufacture, bioavailable, cost effective, stable and possesses good pharmacothechnical properties.
  • Particle size is having a pronounced effect on the absorption of drugs with low aqueous solubility. Due to the poor solubility of Linezolid the influence of its particle size distribution on its dissolution was extensively studied in order to achieve the objects of the present invention.
  • the first step in that process is the disintegration of the dosage form followed by dissolution of the active ingredient.
  • One way to increase dissolution rate of poorly soluble drugs such as Linezolid is to increase the surface available for dissolution by reducing particle size.
  • bioavailability of poorly soluble drugs may be increased by using specific excipients able to enhance the active ingredient's solubility.
  • Poloxamer is the excipient of choice for dissolution problems with solid oral dosage forms.
  • Poloxamers are non-ionic polyoxyethylene-polyoxypropylene copolymers. When the concentration of the poloxamers in the system increases, this results in the formation of multimolecular aggregates. Polypropylene oxide usually forms central hydrophobic cores wherein methyl groups interact via Van der Waals forces with the substance undergoing solubilisation. However, water solubility is believed to be due to the polyethylene oxide block by hydrogen bonding interactions of ether oxygen with water molecules.
  • the non-ionic surfactant poloxamer is present in the preferred composition of the present invention in an amount of more than 1% (w/w) and less than 10% (w/w). Most preferably, poloxamer is present in an amount of more than 1% (w/w) and less than 5% (w/w).
  • Sodium starch glycolate as disintegrant provides the necessary force to rapture and eventually disintegrate the tablets. Specifically, due to its extremely large swelling capacity in aqueous solution it enhances the forces needed to push particles apart within tablet pores exerted by the water, resulting in rapid tablet disintegration. The disintegrant efficiency of sodium starch glycolate is unimpaired in the presence of hydrophobic excipients, such as lubricants unlike many other disintegrants. Increasing the tablet compression pressure also appears to have no effect on disintegration time. Moreover, tablets prepared with sodium starch glycolate have good storage properties. Sodium starch glycolate is present in the preferred composition of the present invention in an amount of more than 1% (w/w) and less than 10% (w/w).
  • sodium starch glycolate is present in an amount of more than 5% (w/w) and less than 10% (w/w). It has been surprisingly found that the objects of the present invention are achieved when the formulation is prepared using Linezolid with specific particle size, in particular wherein ⁇ 90 ⁇ 75 ⁇ , as measured using laser light scattering techniques such as with a Malvern Mastersizer machine.
  • the small particle size of the active ingredient in combination with the use of the surfactant Poloxamer enhances Linezolid' s solubility and improves the dissolution properties of the tablets. Tableting is preferred production method because is faster, easier, adds fewer steps to the process, is the most economical and ensures a high production yield.
  • the excipients in the formulation were chosen carefully to give appropriate dissolution rate and stability of the finished dosage form.
  • the tablets of the present invention were tested for dissolution of Linezolid in 1000ml of buffer as dissolution media in USP II apparatus and rotated at 50rpm.
  • the preferred composition of the present invention releases at least 80% of Linezolid in 45 minutes. Most preferably at least 80% of Linezolid is released in 30 minutes.
  • a composition for tableting may be prepared by wet granulation. In wet granulation, the active ingredient and the excipients in powder form are blended and then further mixed in the presence of a liquid that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray-dried lactose and colloidal silica.
  • compositions of the present invention may also contain one or more additional formulation excipients such as diluents, disintegrants, binders, lubricants, glidants, colorants and flavouring agents, provided that they are compatible with the active ingredient of the composition, so that they do not interfere with it in the composition and in order to increase the stability of the drug and the self-life of the pharmaceutical product.
  • additional formulation excipients such as diluents, disintegrants, binders, lubricants, glidants, colorants and flavouring agents
  • Diluents may be added to the formulations of the present invention. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose, dextrates, dextrose, fructose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, xylitol, maltose, maltodextrin, maltitol, lactose.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose function include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include alginic acid, carbomer, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, methylcellulose, polydextrose, polyethylene oxide, polyvinylpyrroline.
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include sodium starch glycolate, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmelose sodium, guar gum, methylcellulose, polacrilin potassium, sodium alginate, crospovidone.
  • Glidants can be added to improve the ftowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, calcium silicate, calcium phosphate tribasic.
  • 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 surface irregularities to the product.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include talc, magnesium stearate, calcium stearate, glycerylbehenate, hydrogenated castor oil, stearic acid, sodium lauryl sulfate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers are, for example, mint powder, menthol, cherry flavour, xylitol, vanillin, aspartame, acesulfame potassium, saccharin.
  • Solid compositions may optionally be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • Tablets may be coated with coating compositions such as Opadry® to impart aesthetic appeal.
  • coating compositions such as Opadry® to impart aesthetic appeal.
  • Such a coating may comprise about 3% by weight of the tablet.
  • Linezolid immediate release tablets of Example 1 were prepared according to the following manufacturing process: Linezolid was mixed with the excipients of the internal phase. The granulation liquid, water, was added to the mixture. The wetted mass was dried. The external phase was added to the obtained granule. The powder mixture was compressed into tablets.
  • the amount of Sodium starch glycolate was increased to 6%.
  • the non-ionic surfactant Poloxamer was used in an amount of 2%.
  • Linezolid immediate release tablets of Example 3 were prepared according to the following manufacturing process: Poloxamer was dissolved in water. Linezolid was mixed with the excipients of the internal phase. The poloxamer solution was added to the mixture. The wetted mass was dried. The external phase was added to the obtained granule. The powder mixture was compressed into tablets.
  • Formulation trial 4 was also studied regarding its chemical stability. After storage of tablets in chambers under normal (25°C/ 60 % RH), intermediate (30°C/ 65 % RH) and accelerated conditions (40°C/ 75 % RH), for 3 months, no raise of impurities was observed (Table 9).
  • Linezolid immediate release tablets of Example 5 were prepared according to the following manufacturing process: Linezolid was mixed with the excipients of the internal phase. The external phase was added to the obtained mixture. The powder mixture was compressed into tablets.
  • the amount of Poloxamer was increased to 3% and Polyvinylpyrrolidone (PVP) was added in the formulation as a binder.
  • PVP Polyvinylpyrrolidone
  • Lactose monohydrate was substituted by Lactose spray-dried in order to improve the flow properties of the bulk mixture since it is more suitable for direct compression or dry granulation.
  • the tablets were prepared with the same manufacturing process as in example 5.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP14711148.8A 2013-03-11 2014-03-10 Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof Withdrawn EP2968170A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20130100147A GR1008143B (el) 2013-03-11 2013-03-11 Φαρμακευτικο σκευασμα περιεχον ενα οξαζολιδινονικο αντιβακτηριακο παραγοντα και μεθοδος για την παρασκευη αυτου
PCT/EP2014/000605 WO2014139657A1 (en) 2013-03-11 2014-03-10 Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof

Publications (1)

Publication Number Publication Date
EP2968170A1 true EP2968170A1 (en) 2016-01-20

Family

ID=50336255

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14711148.8A Withdrawn EP2968170A1 (en) 2013-03-11 2014-03-10 Pharmaceutical composition containing an oxazolidinone antibacterial agent and method for the preparation thereof

Country Status (3)

Country Link
EP (1) EP2968170A1 (el)
GR (1) GR1008143B (el)
WO (1) WO2014139657A1 (el)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6451345B1 (en) 2000-01-20 2002-09-17 Eurand Pharmaceuticals Ltd. Functional coating of linezolid microcapsules for taste-masking and associated formulation for oral administration
AR031135A1 (es) * 2000-10-10 2003-09-10 Upjohn Co Composiciones de antibiotico topico para el tratamiento de infecciones oculares
WO2006008640A1 (en) * 2004-07-15 2006-01-26 Pharmacia & Upjohn Company Llc Non-aqueous suspension containing a drug having an unpleasant taste
WO2007102082A1 (en) * 2006-03-09 2007-09-13 Glenmark Pharmaceuticals Limited High oxazolidinone content solid dosage forms
WO2010026597A1 (en) 2008-09-02 2010-03-11 Hetero Research Foundation Oral dosage forms of linezolid and processes for their preparation
CN102885788B (zh) * 2011-07-22 2016-06-29 重庆华邦制药有限公司 一种晶型稳定的利奈唑胺片及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2014139657A1 *

Also Published As

Publication number Publication date
WO2014139657A1 (en) 2014-09-18
GR1008143B (el) 2014-03-14

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