EP3179987A1 - Pharmaceutical composition of etoricoxib - Google Patents

Pharmaceutical composition of etoricoxib

Info

Publication number
EP3179987A1
EP3179987A1 EP14748167.5A EP14748167A EP3179987A1 EP 3179987 A1 EP3179987 A1 EP 3179987A1 EP 14748167 A EP14748167 A EP 14748167A EP 3179987 A1 EP3179987 A1 EP 3179987A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
modifier
etoricoxib
calcium
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Withdrawn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
EP14748167.5A
Other languages
German (de)
French (fr)
Inventor
Miha Vrbinc
Blatnik Sandra UREK
Zupet ROK
Matej Stergar
Katarina Dobrovoljc
Franc Vrecer
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.)
KRKA dd
Original Assignee
KRKA dd
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 KRKA dd filed Critical KRKA dd
Publication of EP3179987A1 publication Critical patent/EP3179987A1/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Withdrawn legal-status Critical Current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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising etoricoxib and at least one excipient with impact on the pH of the final formulation.
  • Etoricoxib is a common name for 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'- bipyridine, a compound of formula (I):
  • Etoricoxib belongs to the class of COX-2 selective inhibitors and is particularly used for the treatment rheumatoid arthritis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Like other COX-2 inhibitors, its mechanism of action involves the reduction of the generation of prostaglandins (PGs) from arachidonic acid.
  • PGs prostaglandins
  • Etoricoxib is available in the market under trademark Arcoxia, as a film coated tablet in 30mg, 60mg, 90mg and 120mg strengths.
  • the core tablet comprises anhydrous calcium hydrogen phosphate, croscarmellose sodium, and magnesium stearate and microcrystalline cellulose.
  • the tablet is further coated by non-functional film coating.
  • Etoricoxib is a substance with pH dependent solubility. It has a high solubility in the gastric media at low pH, whereas its solubility decreases as pH increases. Reported pKa of etoricoxib is 4.6.
  • EP 912518 discloses etoricoxib, a process for the production thereof, its use and pharmaceutical compositions thereof.
  • the patent discloses inter alia a tablet comprising the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which may be e.g. inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate
  • granulating and disintegrating agents for example, corn starch, or alginic acid
  • binding agents for example, starch, gelatin or acacia
  • lubricating agents for
  • IN 691/MUM/2004 discloses a composition
  • a composition comprising at least one diluent in an amount of 20 to 70 %, at least one binder in an amount of 0.1 % to 20%, at least one glidant from 0.01 % to 3%, at least one lubricant from 0.3% to 3%, optionally solubilizer from 2% to 20% and at least one disintegrant from 0.6% to 8%.
  • the percentages given are calculated based on the total mass of the formulation.
  • Exemplified formulations comprise dibasic calcium phosphate, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate and sodium starch glycollate.
  • the composition may be prepared by direct compression or wet granulation. In case of wet granulation process also PVP is added to the composition.
  • etoricoxib comprising diluents selected from e.g. calcium hydrogen phosphate anhydrous, microcrystalline cellulose, mannitol and lactose.
  • the formulations further comprise binder, disintegrant, lubricant, and optionally glidant and antitacking agent. It is reported that formulations may be prepared by direct compression, dry granulation or wet granulation.
  • WO 2014/033526 describes pharmaceutical compositions of etoricoxib prepared by dry granulation, whereby etoricoxib retains its initial polymorphic form.
  • the particles of etoricoxib used for the preparation of the pharmaceutical composition of the invention can be needle shaped, despite the fact that needle shaped etoricoxib particles are known to be hardly formulated into the pharmaceutical composition due to the technological problems, such as sticking to the die walls during compression.
  • the needle shaped particles of etoricoxib can be incorporated into pharmaceutical composition of the present invention in the manner that the shape of the particles of etoricoxib does not have undesirable impact on technological performance, i.e. did not cause the die walls.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising etoricoxib or a pharmaceutically acceptable salt thereof, at least one pH modifying agent and optionally at least one additional pharmaceutically acceptable excipient.
  • Etoricoxib particles used in the composition according to the present invention are preferably in crystalline forms which are physically stable. More preferably, polymorphic form I is used.
  • Etoricoxib is freely soluble in acidic media, for example in 0.1 M HCI (pH 1 .1 ), 0.01 M HCI (pH 2.1 ) and artificial gastric juice (pH 2.0) with a solubility > 3 mg/mL at room temperature.
  • Etoricoxib is less soluble at higher pH values of the media, for example in acetate buffer (pH 4.5), FeSSIF (pH 5.0), FeSSIF with addition of bile salts and lecitine (pH 5.0), purified water (pH 5.6), FaSSIF (pH 6.5), FaSSIF with addition of bile salts and lecitine (pH 6.5) and phosphate buffer (pH 6.8), wherein the solubility is less than 1 mg/mL at room temperature.
  • pH modifier having a pH value of its 1 % (w/v) aqueous dispersion above 6.6, preferably above 7, increases the dissolution profile of etoricoxib from the pharmaceutical composition.
  • a pH modifier having a pH value of its 1 % (w/v) aqueous dispersion in the range of 7.0 to 8.5 is used in the composition according to the present invention.
  • the pH value of the pH modifier is defined by measuring a 1 % (w/v) aqueous dispersion, preferably suspension, of the pH modifier using pH meter, such as Radiometer PHM240.
  • pH meter such as Radiometer PHM240.
  • the detailed description of pH value determination of pH modifier is further disclosed in the illustrative examples of the present invention. If not disclosed in other manner, the pH value of pH modifier is according to the present invention defined by measuring the pH of a 1 % (w/v) aqueous suspension of the pH modifier
  • the pH modifier can be selected from excipients with different primary functions, e.g. diluents, binders, disintegrants, lubricants, glidants and antitacking agents, which are capable of modifying the pH of the microenvironment of etoricoxib particles (alone or in intimated junction, such as an intimate mixture, with at least one excipient) in the pharmaceutical composition and during its dissolution.
  • the pH modifier is selected from the group of diluents and disintegrants, which are capable of ionization when dispersed in liquid media, preferably in aqueous media.
  • the pH modifier is selected from the group of diluents.
  • the pH modifier can be selected from excipients, which are available in grades with different pH specifications, i.e. which are available in plurality of grades that exert different pH values when dispersed in media, preferably in aqueous media under the same test conditions, wherein the difference in pH among individual grades is preferably at least 0.5 pH units.
  • the pH modifier can be incorporated completely intragranularly or completely extragranularly, or can be divided in between intragranular and extragranular phase in any ratio.
  • the pharmaceutical composition of the invention comprises granules and an extragranular phase.
  • the granules or the extragranular phase or both, granules and extragranular phase can comprise the pH modifier.
  • the pharmaceutical composition of the present invention comprises etoricoxib having an average particle size between 1 and 200 ⁇ , preferably between 1 and 150 ⁇ and most preferably between 15 and 150 ⁇ .
  • the average particle size is determined by laser method using a Malvern Mastersizer.
  • the diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern Mastersizer Apparatus MS 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles.
  • the particles to be subjected to the particle size measurement are first suspended in appropriate non-polar dispersant and then subjected to a size determination in a Malvern
  • Mastersizer MS 2000 instrument Usually, 100-800 mg of substance is dispersed in 5-10 mL of dispersant. Average particle size of etoricoxib is determined by Malvern Mastersizer 2000
  • compositions of the present invention are solid pharmaceutical compositions.
  • the compositions can be in the form of tablets, minitablets, microtablets, coated tablets, coated minitablets, coated microtablets, pills, powders, lozenges, sachets, soft and hard gelatin capsules, suppositories etc.
  • the pharmaceutical composition of the present invention is preferably suitable for oral application.
  • the pharmaceutical composition is an oral dosage form such as a tablet or coated tablet.
  • the pharmaceutical composition of the present invention is preferably formulated in a unit dosage form, each dosage form containing about 10 to about 200 mg of etoricoxib, more preferably about 30 mg to about 120 mg of etoricoxib.
  • Etoricoxib in polymorphic form I may be prepared according to any process known in the art, such as the process disclosed in WO 2012/163839 or WO 2013/075732.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of etoricoxib calculated to produce the desired therapeutic effect, in association with at least one suitable excipient.
  • An immediate release composition of unit dosage form is preferred.
  • the pharmaceutically acceptable excipients used for the preparation of the pharmaceutical composition of the present invention particularly include excipients with different functions.
  • Excipients used for the preparation of pharmaceutical composition of the present invention are of pharmaceutical grade, i.e. their quality is appropriate for mammal use and intended for the preparation of solid pharmaceutical compositions.
  • the pharmaceutical compositions of the present invention can comprise at least one excipient selected from the groups of diluents, binders, disintegrants, lubricants, glidants and antitacking agents. In another embodiment of the present invention, more than one excipient is selected and comprised from the groups of diluents, binders, disintegrants, lubricants, glidants and antitacking agents.
  • excipients with different functions e.g. pH modifiers, antioxidants, surfactants etc.
  • excipients with different functions can be included in the pharmaceutical composition of the present invention and the opposite, one or more excipients with different functions can be excluded from the composition.
  • excipients can have multiple functions, i.e. one excipient can be used as diluent and/or pH modifier etc.
  • the pharmaceutical composition of the present invention can comprise one or more diluents.
  • Suitable diluents are selected from carbohydrates or its derivatives such as lactose, e.g. lactose monohydrate, anhydrous lactose, spray dried and/or granulated lactose, sucrose, fructose, dextrates, saccharose, raffinose, trehalose, fructose or mixtures thereof, dextrin, sugar alcohols such as xylitol, mannitol, maltitol, isomalt, sorbitol, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low moisture starch, corn starch, pregleatinised starch, low moisture pregelatinised starch, magnesium aluminometasilicate such as Neusilin, calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lac
  • the pharmaceutical composition comprises low moisture diluents, having loss on drying less than 3% w/w, preferably less than 2% w/w and most preferably less than 1 .5% w/w, measured by halogen dryer, such as Mettler Toledo HR73 or R 83 or equivalent equipment.
  • the pharmaceutical composition comprises diluents selected from microcrystalline cellulose, calcium hydrogen phosphate, saccharides such as lactose and/or saccharose and polyols or mixtures thereof. More preferably, the pharmaceutical formulation of the present invention comprises at least one diluent selected from microcrystalline cellulose and calcium hydrogen phosphate or mixtures thereof.
  • the pharmaceutical composition of the present invention furthermore comprises one or more binders, selected from povidone (polyvinilpyrrolidone), copovidone (vinylpyrrolidone-vinyl acetate copolymer), powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose and hydroxypropyl methylcellulose or other cellulose ethers, corn or potato or rice starch, pregelatinised starch, a-starch or dextrin, gum arabic, pullulan, polymethacrylates or a mixture of binders.
  • povidone polyvinilpyrrolidone
  • copovidone vinylpyrrolidone-vinyl acetate copolymer
  • powdered cellulose crystalline cellulose
  • microcrystalline cellulose microcrystalline cellulose
  • silicified microcrystalline cellulose cellulose derivatives such as
  • the dry binders can be selected from copovidone, povidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, starch derivatives such as pregelatinised starch, low substituted hydroxypropylcellulose or mixtures thereof.
  • the pharmaceutical formulation of the present invention comprises at least one binder, selected from microcrystalline cellulose, povidone and hydroxypropylcellulose or mixtures thereof.
  • the pharmaceutical composition of the present invention furthermore comprises one or more disintegrants, selected from crospovidone, starch, pregelatinised starch, sodium starch glycollate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hydroxypropylcellulose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan, alginic acid or mixtures thereof.
  • disintegrants are selected from microcrystalline cellulose, croscarmellose sodium, low substituted hydroxypropylcellulose and crospovidone or mixtures thereof.
  • the pharmaceutical composition of the present invention can furthermore comprise one or more lubricants, selected from the group of metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium, calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, meads wax or spermaceti, boric acid, sodium stearyl fumarate, macrogols or mixtures thereof.
  • lubricants are selected from magnesium and/or calcium stearate, talc, sodium stearyl fumarate or mixtures thereof; most preferably sodium stearyl fumarate is used.
  • the pharmaceutical formulation of the present invention can furthermore comprise one or more glidants, selected from colloidal silica, talc and magnesium trisilicate.
  • the pharmaceutical formulation of the present invention can furthermore comprise one or more antitacking agents, selected from talc, glyceryl monostearate and stearic acid.
  • the pharmaceutical composition of the present invention is preferably in form of a solid dosage form such as a tablet and preferably comprises etoricoxib, at least one pH modifier and optionally at least one further excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant, glidant and antitacking agent.
  • compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one further excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant and/or glidant.
  • compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant and/or antitacking agent.
  • compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one excipient selected from excipients with the function as defined: diluent, binder, disintegrant and lubricant.
  • the pH modifier can be selected from excipients which are available for pharmaceutical use at one or different pH values as defined by manufacturers, independently of the method used.
  • the pH modifier can be preferably selected from the group of excipients comprising silicified microcrystalline cellulose, magnesium aluminometasilicate such as Neusilin ® , calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate, calcium lactate or mixtures thereof, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or calcium), polacrilin potassium, sodium and/or calcium alginate, docusate sodium, magnesium, calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, sodium stearyl fumarate and any mixtures thereof.
  • excipients comprising silicified microcrystalline cellulose, magnesium aluminometasilicate such as Neusilin ® , calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbon
  • the pH modifier can be selected from the group of excipients comprising calcium salts of phosphoric acid such as calcium hydrogen phosphate in anhydrous and/or hydrated form, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium) and/or sodium stearyl fumarate or a mixture thereof.
  • the pH modifier is calcium hydrogen phosphate anhydrous having pH value of its 1 % (w/v) aqueous dispersion, preferably suspension, above 6.6, preferably above 7.0, such as 7.0 to 8.5.
  • Solid dosage forms described above can be optionally coated with an aqueous soluble film coating, having an average thickness of at least 1 ⁇ , measured by scanning electron microscopy (SEM) of crossection of coated solid dosage form.
  • Optional film coating comprises one or more aqueous soluble polymers selected from cellulose ethers such as hydroxypropyl methylcellulose (hypromellose) having a viscosity (2% w/v aqueous solution) of less than 50 mPas, preferably less than 25 mPas and most preferably less than 20 mPas measured at 20 ⁇ by rotation viscometer according to USP 29 monograph for hypromellose.
  • cellulose ethers such as hydroxypropyl methylcellulose (hypromellose) having a viscosity (2% w/v aqueous solution) of less than 50 mPas, preferably less than 25 mPas and most preferably less than 20 mPas measured at 20 ⁇ by rotation viscometer according
  • polymers that can be used for coating are selected from polyvinyl alcohol, povidone, sodium carboxymethyl cellulose, waxy materials, acrylic polymers, block polymer of polyvinyl alcohol and polyethylene glycol commercially available under trade name Kollicoat ® IR and Kollicoat ® Protect.
  • excipients can be present in the film coating that are selected from antitacking agents, pigments, colourant and/or plasticizers.
  • Typical cellulose ethers used in film coatings are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose.
  • Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film.
  • plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
  • polyols glycol, propylene glycol, macrogols
  • organic esters phthalate esters, dibutyl sebacate, citrate esters, triacetin
  • oils/glycerides castor oil, acetylated monoglycerides, fractionated coconut oil.
  • Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials from each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.
  • Pigments can be selected from metal oxides such as iron or titanium oxides.
  • Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
  • composition of the coating suspension (calculated on dry material) and, therefore a composition of the film coating is particularly preferred which comprises:
  • plasticizer preferably 1 -40% of plasticizer
  • composition of the coating layer of the present invention preferably comprises at least one excipient selected from excipients with the function as defined of polymer and plasticizer. In another aspect of the present invention, the composition of the coating layer of the present invention preferably comprises at least one excipient selected from excipients with the function as defined polymer, plasticizer and colourant/opacifier.
  • the pharmaceutical composition of the present invention comprises etoricoxib in an amount of 15-60%, more preferably 20-50%, most preferably 20-40%.
  • the pharmaceutical composition of the present invention comprises: etoricoxib: 15-60%, more preferably 20-50%, most preferably 20-40%; diluent: 20-80%, more preferably 30-80%, most preferably 35-70%; binder: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; disintegrant: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; lubricant: 1 -20%, more preferably 1 -15%, most preferably 1 -10%; glidant: 0-20%, more preferably 0-15%, most preferably 0-10%; antitacking agent: 0-20%, more preferably 0-15%, most preferably 0-10%; wherein the pH modifiercan be selected from the group of diluent, binder, disintegrant, lubricant, glidant and/or antitacking agent.
  • the pH value of the pharmaceutical composition is determined by measuring the pH value of a 20% w/v suspension prepared by dispersing a powdered form of the pharmaceutical composition, preferably a powdered tablet core, in appropriate amount of purified water using pH Radiometer PHM240.
  • the detailed description of pH determination of pharmaceutical formulations is further disclosed in the examples section of the presentapplication.
  • the pH of the pharmaceutical composition according to the invention, such as a coated tablet according to the present invention determined by above mentioned method (20% w/v suspension) is preferably in the range of 6.9 to 9.0, more preferably in the range of 7.0 to 8.5, most preferably 7.0 to 8.0.
  • composition of the present invention can be prepared by any known technological procedures, e.g. direct compression or granulation, using well known and readily available excipients.
  • the composition is prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, suspending or lyophilizing processes.
  • the active ingredient will usually be mixed with at least one excipient or a mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or a mixture of excipients.
  • at least one excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the etoricoxib.
  • processes for the preparation of the pharmaceutical formulation of the present invention comprise steps, which are preferred to exclude the influence of water in each technological step.
  • the processes are preferably selected from direct compression, dry granulation or wet granulation.
  • water in the process i.e. in wet granulation or aqueous-based film coating, it should be evaporated during the process, e.g. by the means of drying.
  • etoricoxib can be granulated by state of the art hot melt processes such as hot melt extrusion or hot melt granulation, where at least one excipient, which function as a binder, has a melting or softening temperature below 170°C, preferably below 140°C and most preferably below 120 q C. Softening temperature of such binders can be decreased by using proper plasticizers such as polyethylene glycole 400, triethylcitrate, triacetin, dibutylsebacate in weight ratio of binder and plasticizer from 5 to 50%, preferably 10 to 30%.
  • hot melt processes such as hot melt extrusion or hot melt granulation, where at least one excipient, which function as a binder, has a melting or softening temperature below 170°C, preferably below 140°C and most preferably below 120 q C.
  • Softening temperature of such binders can be decreased by using proper plasticizers such as polyethylene glycole 400, triethylcitrate, triace
  • composition of the present invention can be prepared by direct compression by processes known in the art.
  • the "dry granulation” method is a method of formulation wherein the raw material powder is subjecting a compression moulding into a pellet or sheet, using granules produced by crushing and division by a suitable method. Such methods are described in "Theory and Practice of Industrial Pharmacy", 3 rd ed. (Lachmann L et al, Lea&Febiger, 1986) or “Pharmaceutical Dosage Forms: Tablets, Volume 1 ", 2 ed (Lieberman HA et al, Marcel Dekker, 1989).
  • Dry granulation can be performed by processes known in the art as slugging and/or roller compaction, the latter being preferred.
  • Etoricoxib optionally sieved to eliminate agglomerates, is usually mixed and dry-granulated with at least one excipient or a mixture of excipients into slugs/compacted material by using roller compactor or compression machine. The obtained slugs/compacted material is crushed and optionally sieved to obtain a uniform distribution of the granules of a dry granulate.
  • Weight granulation can be performed by using granulation liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water.
  • Organic solvents used in granulation for the preparation of the pharmaceutical formulation of the present invention are selected from alcohols with 1 to 4 carbon atoms like absolute ethanol, concentrated alcohol (96 vol%), methanol, isopropropanol, ketons such as acetone or esters such as ethylacetate or mixtures thereof as solvents or as organic/water dispersions, containing less that 50% of water.
  • Excipients selected from diluents, binders, disintegrants, lubricants, glidants and antitacking agents can optionally be dissolved, suspended, emulsified or dispersed into the granulation liquid which is sprayed onto the powder mixture comprising etoricoxib and at least one excipient or a mixture of excipients.
  • Granulation could be performed using state of the art granulators such as high shear granulator, low shear granulator, or a fluid bed granulator.
  • etoricoxib and pH modifier preferably selected from diluents and disintegrators
  • etoricoxib and pH modifier preferably selected from diluents and disintegrators
  • etoricoxib and pH modifier preferably selected from diluents and disintegrators
  • at least one excipient or a mixture of excipients can be used partially intragranularly and partially extragranularly.
  • the mixing of etoricoxib and at least one excipient or a mixture of excipients may be effected in conventional devices used for mixing of powder, e.g. motionless (passive) mixers, fluidized bed, diffusion, biconic diffusion, biconic, tubular, cubic, planetary, Y-, V-shaped or high-shear mixers.
  • the same mixing equipment may be used also in the preparation of the compression mixture in direct compression.
  • the same equipment may be used in the preparation of compression mixture with the prior step of a granulate preparation by a granulation as described by the terms "dry granulation" and "wet granulation".
  • drying devices such as a fluid-bed dryer or drying chambers can be used.
  • the compression in particular to tablet or tablet cores, can be effected using an automatic rotary compressing machine from different manufacturers of equipment for use in pharmaceutical industry.
  • etoricoxib is first prepared according to a suitable synthetic process and then purified, e.g. by crystallization or other means. Then, the size of etoricoxib particles is determined and if it is found that there are particles having a suitable particle size, then this etoricoxib is milled or crunched to a smaller size, i.e. that the average particle size of etoricoxib is between 1 and 200 ⁇ , preferably 1 -150 ⁇ and most preferably 15-150 ⁇ .
  • the average particle size is determined by a laser method using a Malvern Mastersizer.
  • a direct compression process comprises:
  • the dry granulation process comprises:
  • the dry granulation process comprises:
  • the dry granulation process comprises:
  • the wet granulating process comprises:
  • the wet granulation process comprises: granulating optionally sieved etoricoxib and at least one excipient or a mixture of excipients using granulating liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water;
  • the wet granulation process comprises:
  • the pH modifier can be added as excipient or mixtures of excipients in the granulating step or in the subsequent step of adding additives to the granulate.
  • an excipient of the same chemical structure e.g. microcrystalline cellulose and/or calcium hydrogen phosphate anhydrous
  • granulate i.e. intragranular phase
  • extragranular additive i.e. as extragranular additive
  • the use of different particle size of the excipient is preferred for each phase.
  • smaller average particle size of the excipient is preferred in comparison to the extragranular phase.
  • the particle size of an excipient is evaluated by scanning electron microscopy (SEM).
  • SEM scanning electron microscopy
  • the average particle size is determined according to the publicly available data of the manufacturers of excipients.
  • the pharmaceutical composition according to the present invention comprises the ratios of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40.
  • the pharmaceutical composition of the present invention comprises different excipients which are divided between granulate (i.e. intragranular phase) and as additive to the granulate (i.e. as extragranular additive), the ratios are defined for each excipient of the same chemical structure individually. It has been observed that use of a combination of calcium hydrogen phosphate anhydrous and microcrystalline cellulose in extragranular phase significantly increases flowability of the compression mixture. Use of small average particle size of calcium hydrogen phosphate anhydrous in extragranular phase is not the best choice because of inappropriate flowability, which effect can be minimized by addition of the excipient with larger average particle size in extragranular phase by selection of the same excipient, i.e.
  • magnesium stearate is more hydrophilic than magnesium stearate, which means that the compression mixture which comprises sodium stearyl fumarate is less subjected to over-mixing which can affect dissolution rate of etoricoxib from the formulation.
  • a preferred composition according to the present invention comprises calcium hydrogen phosphate as a pH modifier, microcrystalline cellulose and sodium stearyl fumarate. More preferred is a composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase.
  • composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly.
  • composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein both of the listed excipients are divided between intragranular phase and extragranular phase.
  • composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein both of the listed excipients are divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly, and wherein the w/w ratio of at least one of the listed excipients incorporated intragranulary and extragranulary is in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40.
  • the composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase.
  • the intragranular phase and the extragranular phase comprise the pH modifier, with the pH modifier preferably being a diluents as defined above, and more preferably being calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous.
  • the weight ratio of the pH modifier of the intragranular phase to the pH modifier of the extragranular phase is ranging from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40.
  • the intragranular phase comprises calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, and/or microcrystalline cellulose, in particular both calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous, and microcrystalline cellulose.
  • the extragranular phase comprises calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, and/or microcrystalline cellulose, in particular both calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous, and microcrystalline cellulose.
  • the weight ratio of calcium hydrogen phosphate of the intragranular phase to calcium hydrogen phosphate of the extragranular phase is ranging 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40. It is also preferred that the weight ratio of microcrystalline cellulose of the intragranular phase to microcrystalline cellulose of the extragranular phase is ranging from95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 75:25 to about 65:35.
  • the etoricoxib is preferably comprised in the intragranular phase. Moreover, it is preferred that the average particle size of the calcium hydrogen phosphate and/or microcrystalline cellulose of the extragranular phase is higher than the average particle size of these excipients of the intragranular phase. More preferably, the average particle size of calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, of the extragranular phase is equal to or more than 60 ⁇ . Furthermore, the average particle size of microcrystalline cellulose of the extragranular phase is equal to or more than 100 ⁇ .
  • composition according to the invention comprises sodium stearyl fumarate in the extragranular phase of the composition.
  • the respective solid components shown in the table below were homogenized in a containermixer.
  • the homogenized mixture was compacted using a roller compactor Fitzpatrick IR220A by applying a compaction pressure of 4.2 MPa and a roller speed up to 7 rpm.
  • the compacted material was crushed and sieved to prepare a granulate.
  • Average particle size of etoricoxib used for preparation of the pharmaceutical compositions according to Examples 1 , 3 and 4 was 89 ⁇ and 105 ⁇ for Example 2, determined as described in the present application. pH value of etoricoxib was as follows:
  • pH of etoricoxib suspension was determined as follows: Homogenized etoricoxib was weighed in an amount corresponding to etoricoxib content in a tablet powder that was used for preparing 20% (w/v) suspension of a tablet powder for particular dose. Etoricoxib suspension was prepared in freshly boiled and cooled water by adding the same volume of water that was used for preparation of 20% (w/v) suspension of a tablet powder of the same dose. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ⁇ and 25 ⁇ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 . pH values of the calcium hydrogen phosphate anhydrous used in the granulate preparation in Examples 1 -4 were as follows:
  • pH of 1 % (w/v) of calcium hydrogen phosphate anhydrous was determined as follows: A 1 % (w/v) calcium hydrogen phosphate suspension was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ⁇ and 25 ⁇ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 .
  • pH of 1 % (w/v) of calcium hydrogen phosphate anhydrous was determined as follows: A 1 % (w/v) calcium hydrogen phosphate suspension was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ⁇ and 25 ⁇ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 . Preparation of tablet cores
  • Example 1 b-4b The compression mixtures of Examples 1 b-4b were compressed into round tablets having a theoretical weight of 400 mg.
  • the disintegration time of tablet cores was measured on an Erweka dissolution tester according to Ph. Eur. in purified water at 37 ⁇ ⁇ . Average hardness of tablet cores measurement was performed on an Erweka hardness tester using 20 tablet cores. Data for disintegration time and hardness of tablet cores are shown in the table below.
  • Tablet cores of Examples 1 -4 were coated in an automatic coating pan with water-based film coating suspension, prepared by suspending of ready-to-use mixture, commercially available as Opadry 85F28751 II HP white by addition of ferric oxide.
  • the theoretical weight of the film coated tablets was 412 mg.
  • pH values of the film coated tablets of Examples 1 -4 were as follows: Arcoxia 120 mg
  • Example 1 Example 2 Example 3 Example 4
  • pH of film coated tablets (20% (w/v) suspension) was determined as follows: Tablets were finely powdered in a mortar and a 20% (w/v) suspension of tablet powder was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ⁇ and 25°C on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 .
  • Dissolution profiles of film coated tablets of Examples 1 -4 in comparison to the reference Arcoxia 120 mg film coated tablets, Batch No. H016730 were determined in acetate buffer solution pH 4.5 and are shown in Figure 1 .
  • the tablets prepared in accordance with Example 1 and Example 2 do not exhibit a dissolution profile comparable to dissolution profile of the reference tablet.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition comprising etoricoxib, at least one pH modifier and optionally at least one additional pharmaceutically acceptable excipient. In particular, the pH modifier is selected from the group of excipients having a pH value of a 1 % (w/v) aqueous dispersion, preferably suspension, above 6.6, preferably above 7.0.

Description

PHARMACEUTICAL COMPOSITION OF ETORICOXIB
Field of the invention
The present invention relates to a pharmaceutical composition comprising etoricoxib and at least one excipient with impact on the pH of the final formulation.
Background of the invention
Etoricoxib is a common name for 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl]-2,3'- bipyridine, a compound of formula (I):
Etoricoxib belongs to the class of COX-2 selective inhibitors and is particularly used for the treatment rheumatoid arthritis, psoriatic arthritis, osteoarthritis, ankylosing spondylitis, chronic low back pain, acute pain and gout. Like other COX-2 inhibitors, its mechanism of action involves the reduction of the generation of prostaglandins (PGs) from arachidonic acid.
Etoricoxib is available in the market under trademark Arcoxia, as a film coated tablet in 30mg, 60mg, 90mg and 120mg strengths. The core tablet comprises anhydrous calcium hydrogen phosphate, croscarmellose sodium, and magnesium stearate and microcrystalline cellulose. The tablet is further coated by non-functional film coating.
Etoricoxib is a substance with pH dependent solubility. It has a high solubility in the gastric media at low pH, whereas its solubility decreases as pH increases. Reported pKa of etoricoxib is 4.6.
EP 912518 discloses etoricoxib, a process for the production thereof, its use and pharmaceutical compositions thereof. The patent discloses inter alia a tablet comprising the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which may be e.g. inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
IN 691/MUM/2004 discloses a composition comprising at least one diluent in an amount of 20 to 70 %, at least one binder in an amount of 0.1 % to 20%, at least one glidant from 0.01 % to 3%, at least one lubricant from 0.3% to 3%, optionally solubilizer from 2% to 20% and at least one disintegrant from 0.6% to 8%. The percentages given are calculated based on the total mass of the formulation. Exemplified formulations comprise dibasic calcium phosphate, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate and sodium starch glycollate. The composition may be prepared by direct compression or wet granulation. In case of wet granulation process also PVP is added to the composition.
In WO 2012/163839 several formulations of etoricoxib have been disclosed comprising diluents selected from e.g. calcium hydrogen phosphate anhydrous, microcrystalline cellulose, mannitol and lactose. The formulations further comprise binder, disintegrant, lubricant, and optionally glidant and antitacking agent. It is reported that formulations may be prepared by direct compression, dry granulation or wet granulation.
WO 2014/033526 describes pharmaceutical compositions of etoricoxib prepared by dry granulation, whereby etoricoxib retains its initial polymorphic form.
It has been observed that by using excipients commonly used in the pharmaceutical industry a desired in vitro release profile of etoricoxib cannot be achieved. Moreover, the use of needle shaped particles of etoricoxib usually has the drawback that etoricoxib particles stick to the equipment used during manufacture of the pharmaceutical composition, such as the walls of a compression die. Thus, there is still a need for a pharmaceutical composition of etoricoxib having a desired in vitro dissolution profile which can easily be prepared and processed, even when using needle shaped etoricoxib staring material.
These problems have been solved by the pharmaceutical composition according to the invention. The inventors have found out that desired in-vitro dissolution and processability of etoricoxib pharmaceutical composition is highly dependent on properties of excipients and on technological processes used. In particular, it has been unexpectedly found out that only by using excipients with specific physical properties and using specific manufacturing process target dissolution profile similar to that obtained for marketed product Arcoxia can be achieved.
Furthermore, the particles of etoricoxib used for the preparation of the pharmaceutical composition of the invention can be needle shaped, despite the fact that needle shaped etoricoxib particles are known to be hardly formulated into the pharmaceutical composition due to the technological problems, such as sticking to the die walls during compression. However, the needle shaped particles of etoricoxib can be incorporated into pharmaceutical composition of the present invention in the manner that the shape of the particles of etoricoxib does not have undesirable impact on technological performance, i.e. did not cause the die walls.
Detailed description of the invention
The present invention relates to a pharmaceutical composition comprising etoricoxib or a pharmaceutically acceptable salt thereof, at least one pH modifying agent and optionally at least one additional pharmaceutically acceptable excipient.
Etoricoxib particles used in the composition according to the present invention are preferably in crystalline forms which are physically stable. More preferably, polymorphic form I is used.
Etoricoxib is freely soluble in acidic media, for example in 0.1 M HCI (pH 1 .1 ), 0.01 M HCI (pH 2.1 ) and artificial gastric juice (pH 2.0) with a solubility > 3 mg/mL at room temperature. Etoricoxib is less soluble at higher pH values of the media, for example in acetate buffer (pH 4.5), FeSSIF (pH 5.0), FeSSIF with addition of bile salts and lecitine (pH 5.0), purified water (pH 5.6), FaSSIF (pH 6.5), FaSSIF with addition of bile salts and lecitine (pH 6.5) and phosphate buffer (pH 6.8), wherein the solubility is less than 1 mg/mL at room temperature. According to the present invention it has been surprisingly found out that the use of a pH modifying agent, hereinafter denoted as pH modifier, having a pH value of its 1 % (w/v) aqueous dispersion above 6.6, preferably above 7, increases the dissolution profile of etoricoxib from the pharmaceutical composition. Most preferably, a pH modifier having a pH value of its 1 % (w/v) aqueous dispersion in the range of 7.0 to 8.5 is used in the composition according to the present invention.
The pH value of the pH modifier is defined by measuring a 1 % (w/v) aqueous dispersion, preferably suspension, of the pH modifier using pH meter, such as Radiometer PHM240. The detailed description of pH value determination of pH modifier is further disclosed in the illustrative examples of the present invention. If not disclosed in other manner, the pH value of pH modifier is according to the present invention defined by measuring the pH of a 1 % (w/v) aqueous suspension of the pH modifier
The pH modifier can be selected from excipients with different primary functions, e.g. diluents, binders, disintegrants, lubricants, glidants and antitacking agents, which are capable of modifying the pH of the microenvironment of etoricoxib particles (alone or in intimated junction, such as an intimate mixture, with at least one excipient) in the pharmaceutical composition and during its dissolution. Preferably, the pH modifier is selected from the group of diluents and disintegrants, which are capable of ionization when dispersed in liquid media, preferably in aqueous media. Most preferably, the pH modifier is selected from the group of diluents.
Preferably, the pH modifier can be selected from excipients, which are available in grades with different pH specifications, i.e. which are available in plurality of grades that exert different pH values when dispersed in media, preferably in aqueous media under the same test conditions, wherein the difference in pH among individual grades is preferably at least 0.5 pH units.
In yet another embodiment of the present invention, the pH modifier can be incorporated completely intragranularly or completely extragranularly, or can be divided in between intragranular and extragranular phase in any ratio.
The term »intragranularly« refers to an intragranular phase, such as granules,, wherein etoricoxib is granulated with an excipient or a mixture of excipients or wherein an excipient or a mixture of excipients is granulated without etoricoxib. The term »extragranularly« relates to the additives added to the granulate, i.e. added to the intragranular phase. Hence, according to this embodiment, the pharmaceutical composition of the invention comprises granules and an extragranular phase. The granules or the extragranular phase or both, granules and extragranular phase, can comprise the pH modifier.
In another embodiment, the pharmaceutical composition of the present invention comprises etoricoxib having an average particle size between 1 and 200 μηι, preferably between 1 and 150 μηι and most preferably between 15 and 150 μηι. The average particle size is determined by laser method using a Malvern Mastersizer.
The term »average particle size« as used herein refers to volume mean diameter of particles.
The diameter and volume mean diameter can be determined by laser light scattering using e.g. a Malvern Mastersizer Apparatus MS 2000. Particle sizes are determined by measuring the angular distribution of laser light scattered by a homogeneous suspension of particles.
The particles to be subjected to the particle size measurement are first suspended in appropriate non-polar dispersant and then subjected to a size determination in a Malvern
Mastersizer MS 2000 instrument. Usually, 100-800 mg of substance is dispersed in 5-10 mL of dispersant. Average particle size of etoricoxib is determined by Malvern Mastersizer 2000
Hydro F using Silicone Fluid F10 as the dispersion medium.
The preferred pharmaceutical compositions of the present invention are solid pharmaceutical compositions. The compositions can be in the form of tablets, minitablets, microtablets, coated tablets, coated minitablets, coated microtablets, pills, powders, lozenges, sachets, soft and hard gelatin capsules, suppositories etc. The pharmaceutical composition of the present invention is preferably suitable for oral application. Thus, it is preferred that the pharmaceutical composition is an oral dosage form such as a tablet or coated tablet.
The pharmaceutical composition of the present invention is preferably formulated in a unit dosage form, each dosage form containing about 10 to about 200 mg of etoricoxib, more preferably about 30 mg to about 120 mg of etoricoxib. The term »etoricoxib« relates to etoricoxib in any crystalline form or amorphous form, preferably in crystalline form and most preferably in polymorphic form I. Etoricoxib in polymorphic form I may be prepared according to any process known in the art, such as the process disclosed in WO 2012/163839 or WO 2013/075732.
The term »unit dosage form« refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of etoricoxib calculated to produce the desired therapeutic effect, in association with at least one suitable excipient. An immediate release composition of unit dosage form is preferred.
The pharmaceutically acceptable excipients used for the preparation of the pharmaceutical composition of the present invention particularly include excipients with different functions. Excipients used for the preparation of pharmaceutical composition of the present invention are of pharmaceutical grade, i.e. their quality is appropriate for mammal use and intended for the preparation of solid pharmaceutical compositions. The pharmaceutical compositions of the present invention can comprise at least one excipient selected from the groups of diluents, binders, disintegrants, lubricants, glidants and antitacking agents. In another embodiment of the present invention, more than one excipient is selected and comprised from the groups of diluents, binders, disintegrants, lubricants, glidants and antitacking agents. Other and further excipients with different functions, e.g. pH modifiers, antioxidants, surfactants etc. can be included in the pharmaceutical composition of the present invention and the opposite, one or more excipients with different functions can be excluded from the composition. Furthermore, excipients can have multiple functions, i.e. one excipient can be used as diluent and/or pH modifier etc.
The pharmaceutical composition of the present invention can comprise one or more diluents. Suitable diluents are selected from carbohydrates or its derivatives such as lactose, e.g. lactose monohydrate, anhydrous lactose, spray dried and/or granulated lactose, sucrose, fructose, dextrates, saccharose, raffinose, trehalose, fructose or mixtures thereof, dextrin, sugar alcohols such as xylitol, mannitol, maltitol, isomalt, sorbitol, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low moisture starch, corn starch, pregleatinised starch, low moisture pregelatinised starch, magnesium aluminometasilicate such as Neusilin, calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lactate or mixtures thereof. Preferably, the pharmaceutical composition comprises low moisture diluents, having loss on drying less than 3% w/w, preferably less than 2% w/w and most preferably less than 1 .5% w/w, measured by halogen dryer, such as Mettler Toledo HR73 or R 83 or equivalent equipment. In another preferred embodiment of the present invention, the pharmaceutical composition comprises diluents selected from microcrystalline cellulose, calcium hydrogen phosphate, saccharides such as lactose and/or saccharose and polyols or mixtures thereof. More preferably, the pharmaceutical formulation of the present invention comprises at least one diluent selected from microcrystalline cellulose and calcium hydrogen phosphate or mixtures thereof. Preferably, the pharmaceutical composition of the present invention furthermore comprises one or more binders, selected from povidone (polyvinilpyrrolidone), copovidone (vinylpyrrolidone-vinyl acetate copolymer), powdered cellulose, crystalline cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose and hydroxypropyl methylcellulose or other cellulose ethers, corn or potato or rice starch, pregelatinised starch, a-starch or dextrin, gum arabic, pullulan, polymethacrylates or a mixture of binders. Preferably, the dry binders can be selected from copovidone, povidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, starch derivatives such as pregelatinised starch, low substituted hydroxypropylcelulose or mixtures thereof. More preferably, the pharmaceutical formulation of the present invention comprises at least one binder, selected from microcrystalline cellulose, povidone and hydroxypropylcellulose or mixtures thereof.
It is also preferred that the pharmaceutical composition of the present invention furthermore comprises one or more disintegrants, selected from crospovidone, starch, pregelatinised starch, sodium starch glycollate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hydroxypropylcellulose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan, alginic acid or mixtures thereof. Preferably, disintegrants are selected from microcrystalline cellulose, croscarmellose sodium, low substituted hydroxypropylcellulose and crospovidone or mixtures thereof.
The pharmaceutical composition of the present invention can furthermore comprise one or more lubricants, selected from the group of metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium, calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talc, meads wax or spermaceti, boric acid, sodium stearyl fumarate, macrogols or mixtures thereof. Preferably, lubricants are selected from magnesium and/or calcium stearate, talc, sodium stearyl fumarate or mixtures thereof; most preferably sodium stearyl fumarate is used. The pharmaceutical formulation of the present invention can furthermore comprise one or more glidants, selected from colloidal silica, talc and magnesium trisilicate.
The pharmaceutical formulation of the present invention can furthermore comprise one or more antitacking agents, selected from talc, glyceryl monostearate and stearic acid. The pharmaceutical composition of the present invention is preferably in form of a solid dosage form such as a tablet and preferably comprises etoricoxib, at least one pH modifier and optionally at least one further excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant, glidant and antitacking agent. In another aspect of the present invention, the compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one further excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant and/or glidant. In yet another aspect of the present invention, the compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one excipient selected from excipients with the function as defined: diluent, binder, disintegrant, lubricant and/or antitacking agent. In yet another aspect of the present invention, the compositions in the solid dosage forms of the present invention preferably comprise etoricoxib, at least one pH modifier and at least one excipient selected from excipients with the function as defined: diluent, binder, disintegrant and lubricant. The pH modifier can be selected from excipients which are available for pharmaceutical use at one or different pH values as defined by manufacturers, independently of the method used. The pH modifier can be preferably selected from the group of excipients comprising silicified microcrystalline cellulose, magnesium aluminometasilicate such as Neusilin®, calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate, calcium lactate or mixtures thereof, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or calcium), polacrilin potassium, sodium and/or calcium alginate, docusate sodium, magnesium, calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, sodium stearyl fumarate and any mixtures thereof. More preferably, the pH modifier can be selected from the group of excipients comprising calcium salts of phosphoric acid such as calcium hydrogen phosphate in anhydrous and/or hydrated form, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium) and/or sodium stearyl fumarate or a mixture thereof. Most preferably, the pH modifier is calcium hydrogen phosphate anhydrous having pH value of its 1 % (w/v) aqueous dispersion, preferably suspension, above 6.6, preferably above 7.0, such as 7.0 to 8.5.
Solid dosage forms described above can be optionally coated with an aqueous soluble film coating, having an average thickness of at least 1 μηι, measured by scanning electron microscopy (SEM) of crossection of coated solid dosage form. Optional film coating comprises one or more aqueous soluble polymers selected from cellulose ethers such as hydroxypropyl methylcellulose (hypromellose) having a viscosity (2% w/v aqueous solution) of less than 50 mPas, preferably less than 25 mPas and most preferably less than 20 mPas measured at 20 ^ by rotation viscometer according to USP 29 monograph for hypromellose. Other polymers that can be used for coating are selected from polyvinyl alcohol, povidone, sodium carboxymethyl cellulose, waxy materials, acrylic polymers, block polymer of polyvinyl alcohol and polyethylene glycol commercially available under trade name Kollicoat® IR and Kollicoat® Protect. Optionally, other excipients can be present in the film coating that are selected from antitacking agents, pigments, colourant and/or plasticizers.
Typical cellulose ethers used in film coatings are hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose. Acrylic polymers comprise a group of synthetic polymers with diverse functionalities. Some of them can be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure complete disintegration/dissolution of the film. Commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
Colourants/opacifiers are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Combination of different materials from each group can be combined in defined ratios. Film coating suspensions can be used as ready-to-make preparations which are available on the market.
Pigments can be selected from metal oxides such as iron or titanium oxides.
Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
A composition of the coating suspension (calculated on dry material) and, therefore a composition of the film coating is particularly preferred which comprises:
- 1 -99% by weight of polymer, preferably 1 -95% of polymer,
- 1 -50% by weight of plasticizer, preferably 1 -40% of plasticizer,
- 0.1 -20% by weight of colourant/opacifier and/or pigment, preferably 0.1 -10% of colourant/opacifier and or/pigment. The composition of the coating layer of the present invention preferably comprises at least one excipient selected from excipients with the function as defined of polymer and plasticizer. In another aspect of the present invention, the composition of the coating layer of the present invention preferably comprises at least one excipient selected from excipients with the function as defined polymer, plasticizer and colourant/opacifier.
If not indicated otherwise, all percentages ("%") given herein are wt. % (w/w), based on the total weight of the tablet core without film coating layer. Preferably, the pharmaceutical composition of the present invention comprises etoricoxib in an amount of 15-60%, more preferably 20-50%, most preferably 20-40%. According to a more preferred embodiment, the pharmaceutical composition of the present invention comprises: etoricoxib: 15-60%, more preferably 20-50%, most preferably 20-40%; diluent: 20-80%, more preferably 30-80%, most preferably 35-70%; binder: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; disintegrant: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; lubricant: 1 -20%, more preferably 1 -15%, most preferably 1 -10%; glidant: 0-20%, more preferably 0-15%, most preferably 0-10%; antitacking agent: 0-20%, more preferably 0-15%, most preferably 0-10%; wherein the pH modifiercan be selected from the group of diluent, binder, disintegrant, lubricant, glidant and/or antitacking agent.
When the pH modifier of the present invention is comprised in the pharmaceutical composition of the present invention, the pH value of the pharmaceutical composition is determined by measuring the pH value of a 20% w/v suspension prepared by dispersing a powdered form of the pharmaceutical composition, preferably a powdered tablet core, in appropriate amount of purified water using pH Radiometer PHM240. The detailed description of pH determination of pharmaceutical formulations is further disclosed in the examples section of the presentapplication. The pH of the pharmaceutical composition according to the invention, such as a coated tablet according to the present invention determined by above mentioned method (20% w/v suspension) is preferably in the range of 6.9 to 9.0, more preferably in the range of 7.0 to 8.5, most preferably 7.0 to 8.0.
The composition of the present invention can be prepared by any known technological procedures, e.g. direct compression or granulation, using well known and readily available excipients. In another embodiment of the present invention, the composition is prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, suspending or lyophilizing processes. In the preparation of the pharmaceutical formulation of the present invention, the active ingredient will usually be mixed with at least one excipient or a mixture of excipients, or diluted by an excipient or mixture of excipients, or enclosed within an excipient or a mixture of excipients. When at least one excipient serves as a diluent, it may be a solid, semisolid or liquid material which acts as a vehicle or medium for the etoricoxib.
Based on the knowledge of the properties and stability of etoricoxib, it is a moisture sensitive drug. Therefore, processes for the preparation of the pharmaceutical formulation of the present invention comprise steps, which are preferred to exclude the influence of water in each technological step. This means that the processes are preferably selected from direct compression, dry granulation or wet granulation. When using water in the process, i.e. in wet granulation or aqueous-based film coating, it should be evaporated during the process, e.g. by the means of drying. In a special embodiment of the present invention etoricoxib can be granulated by state of the art hot melt processes such as hot melt extrusion or hot melt granulation, where at least one excipient, which function as a binder, has a melting or softening temperature below 170°C, preferably below 140°C and most preferably below 120 qC. Softening temperature of such binders can be decreased by using proper plasticizers such as polyethylene glycole 400, triethylcitrate, triacetin, dibutylsebacate in weight ratio of binder and plasticizer from 5 to 50%, preferably 10 to 30%.
The composition of the present invention can be prepared by direct compression by processes known in the art.
The "dry granulation" method is a method of formulation wherein the raw material powder is subjecting a compression moulding into a pellet or sheet, using granules produced by crushing and division by a suitable method. Such methods are described in "Theory and Practice of Industrial Pharmacy", 3rd ed. (Lachmann L et al, Lea&Febiger, 1986) or "Pharmaceutical Dosage Forms: Tablets, Volume 1 ", 2 ed (Lieberman HA et al, Marcel Dekker, 1989).
Dry granulation can be performed by processes known in the art as slugging and/or roller compaction, the latter being preferred. Etoricoxib, optionally sieved to eliminate agglomerates, is usually mixed and dry-granulated with at least one excipient or a mixture of excipients into slugs/compacted material by using roller compactor or compression machine. The obtained slugs/compacted material is crushed and optionally sieved to obtain a uniform distribution of the granules of a dry granulate.
"Wet granulation" can be performed by using granulation liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water. Organic solvents used in granulation for the preparation of the pharmaceutical formulation of the present invention are selected from alcohols with 1 to 4 carbon atoms like absolute ethanol, concentrated alcohol (96 vol%), methanol, isopropropanol, ketons such as acetone or esters such as ethylacetate or mixtures thereof as solvents or as organic/water dispersions, containing less that 50% of water. Excipients selected from diluents, binders, disintegrants, lubricants, glidants and antitacking agents can optionally be dissolved, suspended, emulsified or dispersed into the granulation liquid which is sprayed onto the powder mixture comprising etoricoxib and at least one excipient or a mixture of excipients. Granulation could be performed using state of the art granulators such as high shear granulator, low shear granulator, or a fluid bed granulator.
In the preparation of granulate, either by wet granulation, melt granulation or dry granulation, etoricoxib and pH modifier, preferably selected from diluents and disintegrators, can be incorporated partially intragranularly and partially extragranularly, alone or in combination with at least one excipient or a mixture of excipients. In another embodiment of the present invention, at least one excipient or a mixture of excipients can be used partially intragranularly and partially extragranularly.
The mixing of etoricoxib and at least one excipient or a mixture of excipients may be effected in conventional devices used for mixing of powder, e.g. motionless (passive) mixers, fluidized bed, diffusion, biconic diffusion, biconic, tubular, cubic, planetary, Y-, V-shaped or high-shear mixers. The same mixing equipment may be used also in the preparation of the compression mixture in direct compression. In another embodiment of the present invention, the same equipment may be used in the preparation of compression mixture with the prior step of a granulate preparation by a granulation as described by the terms "dry granulation" and "wet granulation".
For drying of granulate, prepared by wet granulation, conventional drying devices such as a fluid-bed dryer or drying chambers can be used. In the processes according to the invention, the compression, in particular to tablet or tablet cores, can be effected using an automatic rotary compressing machine from different manufacturers of equipment for use in pharmaceutical industry.
Conventional equipment can be used for applying a film coating, such as a Wurster coating system or conventional coating pans for use in pharmaceutical industry. The process for preparing the pharmaceutical composition according to the invention can be carried out as a granulation process or direct compression process. In each case, etoricoxib is first prepared according to a suitable synthetic process and then purified, e.g. by crystallization or other means. Then, the size of etoricoxib particles is determined and if it is found that there are particles having a suitable particle size, then this etoricoxib is milled or crunched to a smaller size, i.e. that the average particle size of etoricoxib is between 1 and 200 μηι, preferably 1 -150 μηι and most preferably 15-150 μηι. The average particle size is determined by a laser method using a Malvern Mastersizer.
In a preferred embodiment of the present invention, a direct compression process comprises:
- mixing etoricoxib and at least one excipient or a mixture of excipients, preferably at least one pH modifier and at least one additional pharmaceutically acceptable excipient, which can be optionally sieved before mixing to give a compression mixture;
- compressing the compression mixture to desired solid dosage form;
- optionally, applying a film coating. In another embodiment of the present invention, the dry granulation process comprises:
- granulating an optionally sieved at least one excipient or a mixture of excipients using process known in the art as slugging and/or roller compaction;
- addition of etoricoxib and excipient or a mixture of excipients to the granulate to give a compression mixture; - compressing the compression mixture to the desired solid dosage form;
- optionally, applying a film coating.
In another embodiment of the present invention, the dry granulation process comprises:
- granulating optionally sieved etoricoxib and at least one excipient or a mixture of excipients using processes known in the art as slugging and/or roller compaction;
- addition of excipient or a mixture of excipients to the granulate to give a compression mixture;
- compressing the compression mixture to the desired solid dosage form;
- optionally, applying a film coating. In a preferred embodiment of the present invention, the dry granulation process comprises:
- granulating a portion of optionally sieved etoricoxib and at least one excipient or a mixture of excipients using processes known in the art as slugging and/or roller compaction;
- addition of the rest of the etoricoxib and excipient or a mixture of excipients to the granulate to give a compression mixture;
- compressing the compression mixture to the desired solid dosage form;
- optionally, applying a film coating.
In another embodiment of the present invention, the wet granulating process comprises:
- granulating an optionally sieved at least one excipient or a mixture of excipients using granulating liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water;
- addition of etoricoxib and excipient or a mixture of excipients to the granulate to give a compression mixture;
- compressing the compression mixture to the desired solid dosage form; - optionally, applying a film coating.
In another embodiment of the present invention, the wet granulation process comprises: granulating optionally sieved etoricoxib and at least one excipient or a mixture of excipients using granulating liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water;
- addition of excipient or a mixture of excipients to the granulate to give a compression mixture;
- compressing the compression mixture to the desired solid dosage form;
- optionally, applying a film coating.
In another embodiment of the present invention, the wet granulation process comprises:
- granulating a portion of optionally sieved etoricoxib and at least one excipient or a mixture of excipients using granulating liquids, based on water, organic solvents or organic/water liquid solvents, which contain less that 50% of water;
- addition of the resting etoricoxib and excipient or a mixture of excipients to the granulate to give compression mixture;
- compressing the compression mixture to the desired solid dosage form; - optionally, applying a film coating.
In the above described dry granulation and wet granulation processes, the pH modifier can be added as excipient or mixtures of excipients in the granulating step or in the subsequent step of adding additives to the granulate.
When an excipient of the same chemical structure, e.g. microcrystalline cellulose and/or calcium hydrogen phosphate anhydrous, is divided between granulate (i.e. intragranular phase) and as an additive to the granulate (i.e. as extragranular additive), the use of different particle size of the excipient is preferred for each phase. For incorporation into the granulate smaller average particle size of the excipient is preferred in comparison to the extragranular phase. The particle size of an excipient is evaluated by scanning electron microscopy (SEM). For the microcrystalline cellulose, the term »smaller particle size« means average particle size less than 100 μηι, and the term »larger average particle size« means average particle size equal or more than 100 μηι. For the calcium hydrogen phosphate anhydrous, the term »smaller average particle size« means average particle size less than 60 μηι, and the term »larger average particle size« means average particle size equal or more than 60 μηι. The average particle size is determined according to the publicly available data of the manufacturers of excipients.
When an excipient of the same chemical structure, such as diluent or disintegrant e.g. microcrystalline cellulose and/or calcium hydrogen phosphate anhydrous, is divided between granulate (i.e. intragranular phase) and as an additive to the granulate (i.e. as extragranular additive), the pharmaceutical composition according to the present invention comprises the ratios of each excipient of the same chemical structure, defined as w/w ratio of excipient in intragranular phase to excipient in extragranular phase, in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40. Wherein the pharmaceutical composition of the present invention comprises different excipients which are divided between granulate (i.e. intragranular phase) and as additive to the granulate (i.e. as extragranular additive), the ratios are defined for each excipient of the same chemical structure individually. It has been observed that use of a combination of calcium hydrogen phosphate anhydrous and microcrystalline cellulose in extragranular phase significantly increases flowability of the compression mixture. Use of small average particle size of calcium hydrogen phosphate anhydrous in extragranular phase is not the best choice because of inappropriate flowability, which effect can be minimized by addition of the excipient with larger average particle size in extragranular phase by selection of the same excipient, i.e. calcium hydrogen phosphate anhydrous with larger average particle size or different excipient, i.e. microcrystalline cellulose with larger average particle size. The terms »smaller average particle size« and »larger average particle size« of specific excipients are described by the present invention.
Furthermore, sticking to the punches can also be prevented by substitution of magnesium stearate with sodium stearyl fumarate. According to the literature, sodium stearyl fumarate is more hydrophilic than magnesium stearate, which means that the compression mixture which comprises sodium stearyl fumarate is less subjected to over-mixing which can affect dissolution rate of etoricoxib from the formulation.
A preferred composition according to the present invention comprises calcium hydrogen phosphate as a pH modifier, microcrystalline cellulose and sodium stearyl fumarate. More preferred is a composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase.
More preferred is a composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly.
Even more preferred is a composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein both of the listed excipients are divided between intragranular phase and extragranular phase.
Most preferred is a composition which comprises calcium hydrogen phosphate as pH modifier and microcrystalline cellulose, wherein both of the listed excipients are divided between intragranular phase and extragranular phase, and wherein at least one of the listed excipients having a larger average particle size is incorporated extragranularly, and wherein the w/w ratio of at least one of the listed excipients incorporated intragranulary and extragranulary is in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40.
Hence, it is particularly preferred that the composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase. Preferably, the intragranular phase and the extragranular phase comprise the pH modifier, with the pH modifier preferably being a diluents as defined above, and more preferably being calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous. Moreover, it is preferred that the weight ratio of the pH modifier of the intragranular phase to the pH modifier of the extragranular phase is ranging from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40.
More preferably, the intragranular phase comprises calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, and/or microcrystalline cellulose, in particular both calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous, and microcrystalline cellulose. Preferably, the extragranular phase comprises calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, and/or microcrystalline cellulose, in particular both calcium hydrogen phosphate, such as calcium hydrogen phosphate anhydrous, and microcrystalline cellulose. Moreover, it is preferred that the weight ratio of calcium hydrogen phosphate of the intragranular phase to calcium hydrogen phosphate of the extragranular phase is ranging 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 70:30 to about 60:40. It is also preferred that the weight ratio of microcrystalline cellulose of the intragranular phase to microcrystalline cellulose of the extragranular phase is ranging from95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50:, even more preferably from about 75:25 to about 65:35.
The etoricoxib is preferably comprised in the intragranular phase. Moreover, it is preferred that the average particle size of the calcium hydrogen phosphate and/or microcrystalline cellulose of the extragranular phase is higher than the average particle size of these excipients of the intragranular phase. More preferably, the average particle size of calcium hydrogen phosphate, in particular calcium hydrogen phosphate anhydrous, of the extragranular phase is equal to or more than 60 μηι. Furthermore, the average particle size of microcrystalline cellulose of the extragranular phase is equal to or more than 100 μηι.
In addition, it is particularly preferred that the composition according to the invention comprises sodium stearyl fumarate in the extragranular phase of the composition.
The following examples illustrate the invention and are not intended to restrict the scope of the invention in any way.
Examples 1-4
Preparation of granulate
The respective solid components shown in the table below were homogenized in a containermixer. The homogenized mixture was compacted using a roller compactor Fitzpatrick IR220A by applying a compaction pressure of 4.2 MPa and a roller speed up to 7 rpm. The compacted material was crushed and sieved to prepare a granulate. Table: Composition of granulate (in mg/1 tablet core).
Average particle size of etoricoxib used for preparation of the pharmaceutical compositions according to Examples 1 , 3 and 4 was 89 μηι and 105 μηι for Example 2, determined as described in the present application. pH value of etoricoxib was as follows:
pH of etoricoxib suspension was determined as follows: Homogenized etoricoxib was weighed in an amount corresponding to etoricoxib content in a tablet powder that was used for preparing 20% (w/v) suspension of a tablet powder for particular dose. Etoricoxib suspension was prepared in freshly boiled and cooled water by adding the same volume of water that was used for preparation of 20% (w/v) suspension of a tablet powder of the same dose. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ^ and 25^ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 . pH values of the calcium hydrogen phosphate anhydrous used in the granulate preparation in Examples 1 -4 were as follows:
pH of 1 % (w/v) of calcium hydrogen phosphate anhydrous was determined as follows: A 1 % (w/v) calcium hydrogen phosphate suspension was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ^ and 25^ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 .
Preparation of compression mixture
The components shown in table below were added to the granulates of Examples 1 a-3a obtained above and mixed in a high-shear mixer or conic mixer to obtain compression mixture.
Table: Composition of compression mixture (in mg/1 tablet core).
The pH values of the different types of calcium hydrogen phosphate anhydrous used compression mixture preparation in Examples 1 -4 were as follows:
pH of 1 % (w/v) of calcium hydrogen phosphate anhydrous was determined as follows: A 1 % (w/v) calcium hydrogen phosphate suspension was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ^ and 25^ on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 . Preparation of tablet cores
The compression mixtures of Examples 1 b-4b were compressed into round tablets having a theoretical weight of 400 mg. The disintegration time of tablet cores was measured on an Erweka dissolution tester according to Ph. Eur. in purified water at 37 <Ό. Average hardness of tablet cores measurement was performed on an Erweka hardness tester using 20 tablet cores. Data for disintegration time and hardness of tablet cores are shown in the table below.
It has been observed that during preparation of tablets cores according to Examples 1 and 2, sticking to the punches occurred. The sticking to the punches was connected to the needle like particle shape of etoricoxib which is hard to formulate. The incorporation of excipients as extragranular additives having larger average particle size to the granulate, prevented crushed needles of etoricoxib to be sticked to the punches. It is assumed that the contact surface of needles of etoricoxib and punches is minimized. It has further been surprisingly found that the use of sodium stearyl fumarate, yet alone or in combination with divided incorporation of calcium hydrogen phosphate and microcrystalline cellulose between intragranular and extragranular phase, prevent the compression mixture to stick to the die walls during compression process. Higher average hardness was achieved in Examples 1 , 3 and 4, which additionally prevent sticking to the punches.
Film coating
Tablet cores of Examples 1 -4 were coated in an automatic coating pan with water-based film coating suspension, prepared by suspending of ready-to-use mixture, commercially available as Opadry 85F28751 II HP white by addition of ferric oxide. The theoretical weight of the film coated tablets was 412 mg. pH values of the film coated tablets of Examples 1 -4 were as follows: Arcoxia 120 mg
Example 1 Example 2 Example 3 Example 4
H016730 pH of 20% (w/v)
6.43 6.29 7.09 7.12 6.79 suspension
pH of film coated tablets (20% (w/v) suspension) was determined as follows: Tablets were finely powdered in a mortar and a 20% (w/v) suspension of tablet powder was prepared in freshly boiled and cooled water. After stirring the suspension for 15 minutes the pH value of the sample suspension was measured at a temperature of between 20 ^ and 25°C on a suitable, calibrated pH meter Radiometer PHM240 using combined glass electrode XC161 .
Dissolution profiles of film coated tablets of Examples 1 -4 in comparison to the reference Arcoxia 120 mg film coated tablets, Batch No. H016730 were determined in acetate buffer solution pH 4.5 and are shown in Figure 1 . As evident from the Figure 1 , the tablets prepared in accordance with Example 1 and Example 2 do not exhibit a dissolution profile comparable to dissolution profile of the reference tablet.

Claims

Claims
1 . A pharmaceutical composition comprising etoricoxib or a pharmaceutically acceptable salt thereof, at least one pH modifier and optionally at least one additional pharmaceutically acceptable excipient.
2. The pharmaceutical composition according to claim 1 wherein the pH modifier is selected from the group of excipients having a pH value of a 1 % (w/v) aqueous dispersion, preferably suspension, above 6.6, preferably above 7.0.
3. The pharmaceutical composition according to claim 1 or 2 wherein the pH modifier is selected from the group of excipients having a pH value of a 1 % (w/v) aqueous dispersion, preferably suspension, in the range of 7.0 to 8.5.
4. The pharmaceutical composition according to any of the preceding claims comprising etoricoxib: 15-60%, more preferably 20-50%, most preferably 20-40%; diluent: 20-80%, more preferably 30-80%, most preferably 35-70%; binder: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; disintegrant: 1 -80%, more preferably 1 -60%, most preferably 1 -50%; lubricant: 1 -20%, more preferably 1 -15%, most preferably 1 -10%; glidant: 0-20%, more preferably 0-15%, most preferably 0-10%; antitacking agent: 0-20%, more preferably 0-15%, most preferably 0-10%; wherein the pH modifier is selected from the group of diluent, binder, disintegrant, lubricant, glidant and/or antitacking agent
5. The pharmaceutical composition according to any of the preceding claims, wherein the pH modifier is selected from the group of diluents and/or disintegrants.
6. The pharmaceutical composition according to any of the preceding claims, wherein the pH modifier is selected from the group consisting of silicified microcrystalline cellulose, magnesium aluminometasilicate (Neusilin®), calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous or hydrate, calcium, sodium or potassium carbonate or hydrogencarbonate and calcium lactate or mixtures thereof, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or calcium), polacrilin potassium, sodium and or/calcium alginate, docusate sodium, magnesium calcium, aluminium or zinc stearate, magnesium palmitate and magnesium oleate, sodium stearyl fumarate and any mixtures thereof.
7. The pharmaceutical composition according to any of the preceding claims, wherein the pH modifier is selected from the group consisting of calcium salts of phosphoric acid such as calcium hydrogen phosphate anhydrous and/or hydrate, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium) and sodium stearyl fumarate.
8. The pharmaceutical composition according to any of the preceding claims, wherein the pH modifier is calcium hydrogen phosphate anhydrous having a pH value of a 1 % (w/v) aqueous dispersion, preferably suspension, above 6.6, preferably above 7.0.
9. The pharmaceutical composition according to claim 1 , wherein the pH value of the composition determined by measuring the pH of a 20% w/v suspension of the pharmaceutical composition in powder form is in the range of 6.9 to 9.0, more preferably in the range of 7.0 to 8.5, most preferably 7.0 to 8.0.
10. The pharmaceutical composition according to claim 8 or 9 further comprising sodium stearyl fumarate.
1 1 . The pharmaceutical composition according to claim 8 or 9 further comprising microcrystalline cellulose and sodium stearyl fumarate.
12. The pharmaceutical composition according to claim 1 1 , wherein at least one of calcium hydrogen phosphate and microcrystalline cellulose is divided between an intragranular phase and extragranular phase of the pharmaceutical composition.
13. The pharmaceutical composition according to claim 12, wherein at least one of calcium hydrogen phosphate and microcrystalline cellulose is divided between intragranular phase and extragranular phase, and wherein at least one of said excipients having a larger average particle size is incorporated extragranularly.
14. The pharmaceutical composition according to claim 13, wherein the w/w ratio of at least one of calcium hydrogen phosphate and microcrystalline cellulose incorporated intragranulary to extragranulary is in the range of from 95:5 to 40:60, preferably from 90:10 to 50:50, more preferably from 80:20 to 50:50, even more preferably from about 70:30 to about 60:40.
EP14748167.5A 2014-07-31 2014-07-31 Pharmaceutical composition of etoricoxib Withdrawn EP3179987A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2014/066560 WO2016015776A1 (en) 2014-07-31 2014-07-31 Pharmaceutical composition of etoricoxib

Publications (1)

Publication Number Publication Date
EP3179987A1 true EP3179987A1 (en) 2017-06-21

Family

ID=51298732

Family Applications (1)

Application Number Title Priority Date Filing Date
EP14748167.5A Withdrawn EP3179987A1 (en) 2014-07-31 2014-07-31 Pharmaceutical composition of etoricoxib

Country Status (2)

Country Link
EP (1) EP3179987A1 (en)
WO (1) WO2016015776A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107898787B (en) * 2017-12-15 2018-11-30 扬子江药业集团上海海尼药业有限公司 A kind of pharmaceutical composition and its preparation and preparation method
MX2018013070A (en) 2017-12-29 2019-10-15 Gruenenthal Gmbh Pharmaceutical combination comprising extended-release tramadol hydrochloride and immediate-release etoricoxib, and its use for the treatment of pain.

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050100594A1 (en) * 2003-11-12 2005-05-12 Nilendu Sen Pharmaceutical formulation containing muscle relaxant and COX-II inhibitor
EA023286B1 (en) * 2011-05-27 2016-05-31 ФАРМА ДжРС, Д.О.О. Process for the preparation of polymorphic form i of etoricoxib
PL2887924T3 (en) * 2012-08-27 2017-09-29 Cadila Healthcare Limited Pharmaceutical compositions of etoricoxib

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Exciepients", 1 January 2006, article ROWE: "Croscarmellose sodium", XP055472858 *
"Handbook of Pharmaceutical Excipients", 1 January 2006, article ROWE: "Povidone", XP055472856 *
"Handbook of Pharmaceutical Excipients", 1 January 2009, article ROWE: "Calcium Phosphate, Dibasic Anhydrous", XP055472866 *
ANONYMOUS: "Dicalcium phosphate, Innophos", 1 January 2013 (2013-01-01), XP055472861, Retrieved from the Internet <URL:www.innophos.com> [retrieved on 20180504] *
EYJOLFSSON: "Why are aqueous suspensions of the coarse grades of anhydrous calcium hydrogen phosphate acidic?", PHARMAZIE, vol. 65, 1 January 2010 (2010-01-01), pages 527, XP055472865 *
FMC: "Avicel PH-102", 1 January 2015 (2015-01-01), XP055472852, Retrieved from the Internet <URL:www.fmchealthandnutrition.com> [retrieved on 20180504] *
FMC: "Avicel PH-112", 1 January 2015 (2015-01-01), fmchealthandnutrition.com, pages 1 - 2, XP055472849, Retrieved from the Internet <URL:www.fmchealthandnutrition.com> [retrieved on 20180504] *
See also references of WO2016015776A1 *

Also Published As

Publication number Publication date
WO2016015776A1 (en) 2016-02-04

Similar Documents

Publication Publication Date Title
KR101156916B1 (en) Pharmaceutical compositions comprising imatinib and a release retardant
KR20160101720A (en) Pharmaceutical compositions comprising azd9291
CA2873949A1 (en) Dosage forms comprising apixaban and matrix former
WO2008001201A2 (en) Pharmaceutical compositions of clopidogrel
EP2714676B1 (en) A process for the preparation of polymorphic form i of etoricoxib
WO2018185175A1 (en) Pharmaceutical composition comprising lenvatinib mesylate
EP3897586A2 (en) Pharmaceutical composition comprising apixaban
EP3419603A1 (en) A unique high-shear granulation process for improved bioavailability of rivaroxaban
EP2701689B1 (en) Pharmaceutical compositions of raltegravir, methods of preparation and use thereof
EP3179987A1 (en) Pharmaceutical composition of etoricoxib
WO2020021110A1 (en) Pharmaceutical composition of ticagrelor
EP3860606A1 (en) Pharmaceutical composition comprising lenvatinib esylate or tosylate
TW201206502A (en) Controlled release nucleated tablet
WO2016012898A1 (en) Oral pharmaceutical composition of lurasidone
ETORICOXIE Etoricoxib belongs to the class of COX-2 selective inhibitors and is particularly used for the
WO2019170244A1 (en) Ticagrelor—containing tablet formulation
CA3187241A1 (en) Pharmaceutical compositions comprising ribociclib
JP2018030810A (en) Method for producing pharmaceutical tablet comprising gefitinib as active ingredient
WO2022162687A1 (en) Pharmaceutical compositions comprising nilotinib
JP2022113343A (en) Pharmaceutical tablet containing axitinib as active ingredient
EP3272348A1 (en) Pharmaceutical composition comprising idelalisib
KR20240055103A (en) Pharmaceutical compositions of bempedoic acid
JP2009084236A (en) Bicalutamide-containing formulation
WO2012016707A2 (en) Oral dosage form for the modified release of dimebolin
WO2022238563A1 (en) Pharmaceutical formulation of valsartan and sacubitril

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20170220

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20180514

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20211027