EP4188337A1 - Préparation contenant du dexkétoprofène et du tramadol et procédé de fabrication associé - Google Patents

Préparation contenant du dexkétoprofène et du tramadol et procédé de fabrication associé

Info

Publication number
EP4188337A1
EP4188337A1 EP21749158.8A EP21749158A EP4188337A1 EP 4188337 A1 EP4188337 A1 EP 4188337A1 EP 21749158 A EP21749158 A EP 21749158A EP 4188337 A1 EP4188337 A1 EP 4188337A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
oral dosage
solid oral
mixtures
intragranular
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.)
Pending
Application number
EP21749158.8A
Other languages
German (de)
English (en)
Inventor
Katja SKRLEC
Klemen KORASA
Katja PISANEC
Elena Smirnova
Radivoje RASKOVIC
Grega Hudovornik
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 EP4188337A1 publication Critical patent/EP4188337A1/fr
Pending legal-status Critical Current

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a pharmaceutical composition comprising a combination of dexketoprofen and tramadol in a solid oral dosage form.
  • the invention further relates to a process for the preparation of the composition of the invention comprising the combination of dexketoprofen and tramadol.
  • compositions comprising dexketoprofen and tramadol are known in the art.
  • WO 2008/092219 states that dexketoprofen and tramadol are not compatible and thus teaches separation of the two actives e.g. by providing them as separate unit dosage forms or by providing a multilayer tablet with the two actives being placed in separate layers with at least one intermediate barrier layer.
  • Such products have the disadvantage that they are inconvenient in manufacture and/or use. No commercial product has been developed on this basis.
  • the solid oral dosage form Skudexa ® is commercially available. This product is described in example 4 of EP 2956 129 A.
  • the tablet core comprises microcrystalline cellulose, pregelatinised maize starch, croscarmellose sodium, sodium stearyl fumarate and silica colloidal, anhydrous.
  • the tablet is further coated by film coating comprisingpolyvinyl alcohol, titanium dioxide, macrogol/PEG 3350, and talc.
  • film coating comprisingpolyvinyl alcohol, titanium dioxide, macrogol/PEG 3350, and talc.
  • a further object is to provide a method for manufacturing such solid oral dosage forms, which is simple and convenient and is optimized in respect to energy consumption and has so minimal environmental footprint.
  • Solid oral dosage form comprising dexketoprofen trometamol, tramadol hydrochloride and optional excipients, wherein the solid oral dosage form includes an intragranular phase and an extragranular phase, wherein either
  • dexketoprofen trometamol is present in the extragranular phase and tramadol hydrochloride is present in the intragranular phase; and wherein any binder belonging to the group consisting of maize starch, pregelatinised maize starch, hypromellose and mixture thereof, is absent from the optional excipients.
  • Solid oral dosage form according to item 1 which is a tablet and preferably a film- coated tablet.
  • Solid oral dosage form according to anyone of item 1 to 3, wherein the intragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof or wherein the extragranular phase contains a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein both intragranular and extragranular phase contain a diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose, and mixtures thereof, or wherein no lactose is contained in the solid oral dosage form.
  • Solid oral dosage form according to anyone of item 1 to 4, wherein the intragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof or wherein the extragranular phase contains a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof, or wherein both intragranular and extragranular phase contain a disintegrant selected from croscarmellose sodium, carmellose sodium, carmellose calcium, carmellose, crospovidone, and mixtures thereof.
  • Solid oral dosage form according to anyone of item 1 to 6, wherein the intragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof or wherein the extragranular phase contains a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof, or wherein both intragranular and extragranular phase contain a glidant selected from talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, and mixtures thereof.
  • step (d) converting the resulting mixture into the solid oral dosage form.
  • the method of item 9 or 10 wherein the mixture of step (a) and/or the mixture of step (c) is sieved before it is further processed.
  • Figure 1 shows the initial value of the dissolution profiles of tramadol hydrochloride comprised in the film-coated tablets of Example 3 and of the Reference Example in Ph. Eur buffer pH 6.8 with baskets, at 100 rpm of stirring speed and 900 ml of buffer volume.
  • Figure 2 shows the initial value of the dissolution profiles of dexketoprofen comprised in the film-coated tablets of Example 3 and of the Reference Example in Ph. Eur buffer pH 6.8 with baskets, at 100 rpm of stirring speed and 900 ml of buffer volume.
  • intragranular phase is meant to characterize the phase of the pharmaceutical composition of the present invention, which is obtained by granulation, more specifically by dry granulation.
  • extragranular phase is meant to characterize the phase of the pharmaceutical composition of the present invention, which is formed by the components that are admixed to the granulated components, i.e. the components that are added after granulation.
  • the present invention relates to pharmaceutical compositions containing dexketoprofen trometamol and tramadol hydrochloride as the active ingredients.
  • dexketoprofen should be understood as references to dexketoprofen trometamol and all references to tramadol should be understood as references to tramadol hydrochloride.
  • the "intragranular phase” and “extragranular phase” can be distinguished from each other by means of the following methods of analysis: Fourier transform infrared (FT-IR) microspectroscopy, Energy-dispersive X-ray spectroscopy (EDS) and Scanning electron microscopy (SEM).
  • FT-IR Fourier transform infrared
  • EDS Energy-dispersive X-ray spectroscopy
  • SEM Scanning electron microscopy
  • mass % Unless specified otherwise or unless the context dictates otherwise, relative amount indications are given as mass %. The basis for mass % indications regarding the extragranular phase components is the total of the pharmaceutical composition (excluding coating, if present) being 100 mass %.
  • average particle size 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 Aparatus. 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 instrument.
  • excipients are to be classified according to information provided in Handbook of Pharmaceutical Excipients (The Royal Pharmaceutical Society, 2020).
  • the substance may exercise one, two or more of these functions in the composition of the present invention.
  • the composition is in accordance with amount indications of the present invention as long as there is at least one (mental) way of splitting the total amount of the substance into separate fractions for the applicable excipient types such that each of these fractions complies with the amount specifications for the respective excipient type.
  • the expression "excipient of the same chemical structure” is meant to require identity in terms of the structural formula. In case of polymeric substances, it means identity in terms of the structural formula of the repeating units. Hence, two polymeric excipients may be seen as "excipient of the same chemical structure” if they are characterized by the same chemical structure of the repeating units. By contrast, differences in physical parameters such as particle size or average molecular weight are not relevant for the assessment whether excipients have the same chemical structure in the sense of these embodiments of the present invention.
  • Indications of tablet hardness are based on a determination of tablet hardness by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.8).
  • Indications of tablet disintegration time are based on a determination of tablet disintegration time by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.1).
  • Indications of tablet dissolution times are based on a determination of tablet dissolution times by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.3).
  • Indications of compression mixture properties are based on a determination of compression mixture flowability by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.36 Powder flow; Ph.Eur 10.0, 2.9.34 Measurement of bulk density and tapped density).
  • Indication of uniformity of dosage units are based on determination of content uniformity with calculation of acceptance value (AV) by means of Pharmacopoeia (Ph.Eur 10.0, 2.9.40)
  • the term “comprising” is used to characterize a group of elements such that further unmentioned elements may additionally be present.
  • the term comprising is intended to characterize a group of elements, which does not include further unmentioned elements.
  • disclosures with the term “comprising” are to be understood in one aspect as disclosures using the term “consisting of'.
  • Indications of values are to be understood in one aspect as indications of the specified value ⁇ 10% permitted variation, in another aspect as the indicated value with a permitted variation as determined by conventional rounding rules, and in yet another aspect as the precise specified value without permitted variation.
  • the present invention relates to a pharmaceutical composition comprising a combination of dexketoprofen and tramadol, both as salts.
  • the pharmaceutical composition of the present invention is provided as a solid oral dosage form. This may include coated or uncoated tablets, capsules filled with uncompressed powder/granules, capsules filled with compressed minitablets, microtablets or pellets, sachet comprising loose powder/granules.
  • the preferred solid oral dosage form of the present invention is a film-coated tablet.
  • composition is characterized by the absence of certain binders.
  • the solid oral dosage form of present invention is characterized by distribution of one active ingredient in the intragranular phase and the other active ingredient in the extragranular phase.
  • dexketoprofen is distributed intragranularly and tramadol is distributed extragranularly.
  • dexketoprofen is distributed extragranularly and tramadol is distributed intragranularly.
  • the present invention is further characterized by a manufacturing of the solid oral dosage form of the invention using granulation methods without using solvents, such as dry granulation methods such as roller compaction or slugging.
  • the invention further relates to a process for the preparation of the composition of the invention comprising the combination of dexketoprofen and tramadol.
  • the desired distribution of dexketoprofen in the intragranular phase and tramadol in the extragranular phase is achieved by preparing a first mixture comprising dexketoprofen, granulating it by dry granulation, followed by mixing with the components of the extragranular phase.
  • the desired distribution of tramadol in the intragranular phase and dexketoprofen in the extragranular phase is achieved by preparing a first mixture comprising tramadol, granulating it by dry granulation, followed by mixing with the components of the extragranular phase.
  • the solid oral dosage form of the present invention exhibits excellent performance characteristics, including the desired dissolution properties as well as superior stability. Moreover, advantageous handling performance can be accomplished during manufacture: the materials to be processed exhibit advantageous flowability and compressibility.
  • the manufacturing process of the present invention is furthermore characterized by its simplicity.
  • Dexketoprofen is the active S-(+) enantiomer of ketoprofen. It belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs) and acts by reversible inhibition of cyclooxygenase to block or reduce prostaglandin formation. It has the following chemical structure:
  • Dexketoprofen is mainly used for the treatment of mild-to-moderate pain.
  • Dexketoprofen is commercially available in the form of the tromethamine salt (2-amino-2-hydroxymethyl-l,3- propanediol, TRIS or trometamol salt).
  • the tromethamine salt of Dexketoprofen is available on the markets in form of 12.5 mg and 25 mg film-coated immediate release oral tablets in which the dose is calculated on the weight of free dexketoprofen form, i.e. acid form.
  • the present invention is, however, limited to the use of the specific tromethamine salt form of dexketoprofen.
  • the pharmaceutical composition of the present invention can comprise dexketoprofen tromethamine having an average particle size between 2.5 and 110 pm, optionally between 20 and 60 pm.
  • the average particle size is determined by laser method using a Malvern Mastersizer.
  • the solid oral dosage form of the invention may contain from 8 to 75 mg, preferably from 10 to 55 mg, more preferably 12.5 mg or 25 mg dexketoprofen (expressed as the free acid amounts; the 12.5 mg and 25 mg amounts being equivalent to 18.4 and 36.9 mg dexketoprofen tromethamine) per unit dosage form.
  • dexketoprofen is present only in the intragranular phase (when tramadol is in the extragranular phase). In another embodiment, dexketoprofen is present only in the extragranular phase (when tramadol is in the intragranular phase).
  • Tramadol is an opioid that is used as an analgesic to treat moderate to severe pain. It is a 1:1 mixture of the (1R,2R) and (lS,2S)-stereoisomers and it is characterized by the following chemical structure:
  • Tramadol is commercially available in the form of its hydrochloride salt.
  • tramadol is used in the form of the hydrochloric acid salt.
  • polymorphs, hydrates or solvates of tramadol are also no particular restriction regarding the possible use of polymorphs, hydrates or solvates of tramadol.
  • the pharmaceutical composition of the present invention can comprise tramadol hydrochloride having an average particle size between 10 and 300 pm, optionally between 60 and 150 pm.
  • the average particle size is determined by laser method using a Malvern Mastersizer.
  • the above-mentioned commercial product Skudexa ® comprises a combination of 75 mg of tramadol hydrochloride (together with 25 mg of dexketoprofen).
  • the solid oral dosage form of the present invention may contain from 17.6 to 105.4 mg, preferably from 26.3 to 87.8 mg, more preferably 32.9 mg or 65.9 mg tramadol (expressed as the free base; the values 32.9 mg and 65.9 mg tramadol being equivalent to 37.5 mg and 75 mg tramadol hydrochloride, respectively) per unit dosage form.
  • the pharmaceutical composition according to the present invention may, in addition to the active ingredients, comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients used for the preparation of the pharmaceutical composition of the present invention preferably include two or more excipients with different functions. Excipients used for the preparation of pharmaceutical composition of the present invention are typically of pharmaceutical grade, i.e. their quality is appropriate for human 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, disintegrants, lubricants, glidants and antitacking agents.
  • the pharmaceutical compositions are characterized by the absence of any binder belonging to the group consisting of maize starch, pregelatinised maize starch, hypromellose and mixture thereof as disclosed in EP2956129.
  • 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 (sometimes referred to as polyols) such as xylitol, mannitol, maltitol, isomalt, and sorbitol, cellulosic materials such as powdered cellulose, microcrystalline cellulose, and 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 and calcium lactate or mixtures thereof.
  • sugar alcohols sometimes referred to as polyols
  • cellulosic materials such as powdered cellulose, microcrystalline cellulose, and silicified microcrystalline cellulose
  • the pharmaceutical composition comprises diluents selected from microcrystalline cellulose, silicified microcrystalline cellulose and sugar alcohols (polyols) or mixtures thereof. More preferably, the pharmaceutical formulation of the present invention comprises at least one diluent selected from microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof. In some embodiments, no lactose is used. The absence of lactose from the pharmaceutical composition of the present invention is of course fully consistent with the preferred use of one of microcrystalline cellulose, silicified microcrystalline cellulose and sugar alcohols (polyols) or mixtures thereof and it is also consistent with the more preferred use of microcrystalline cellulose, silicified microcrystalline cellulose or mixtures thereof.
  • the diluent is preferably contained in the solid oral dosage form in a relative amount of from 40% to 75% w/w of the total amount, preferably from 50% to 65% by the total weight of the composition.
  • the pharmaceutical composition of the present invention comprises one or more disintegrants.
  • Suitable disintegrants may be selected from crospovidone, sodium starch glycolate, sodium and/or calcium salts of carboxymethyl cellulose, cross- linked carboxymethylcell ulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potassium, low substituted hyd roxy p ro py I ce 11 u I ose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guargum, chitosan, alginic acid or mixtures thereof.
  • disintegrants are selected from croscarmellose sodium and carmellose calcium, and mixtures thereof.
  • the disintegrant is preferably present in the solid oral dosage form of the invention in amounts from 1% to 15% of the total composition weight, preferably from 3% to 10% of the total weight of the composition.
  • the pharmaceutical composition of the present invention can comprise one or more lubricants.
  • Suitable lubricants may be 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 and mixtures thereof; most preferably magnesium stearate is used.
  • the lubricant is preferably present in the solid oral dosage form of the invention in amounts from 0.1 % to 5 % by the total composition weight, preferably from 0.5 % to 3 % by the total weight of the composition.
  • the glidant can be selected from various useful glidants or antisticking agents including talc, silica derivates, anhydrous colloidal silica, hydrated colloidal silica, or mixtures thereof.
  • the preferred glidant is anhydrous colloidal silica.
  • the glidant is preferably present in the solid oral dosage form of the invention in amounts from 0.1 % to 2 % by the total composition weight, preferably from 0.5 % to 1.5 % by the total weight of the composition.
  • the pharmaceutical composition of the present invention comprises dexketoprofen in an amount of 5-30%, more preferably 7.5-25%, most preferably 10-20% and tramadol in an amount of 5-40%, more preferably 10-35%, most preferably 15-30%. More preferably, the pharmaceutical composition of the present invention comprises dexketoprofen trometamol in an amount of 5-30%, more preferably 7.5-25%, most preferably 10-20% and tramadol hydrochloride in an amount of 5-40%, more preferably 10-35%, most preferably 15-30%.
  • the pharmaceutical composition of the present invention comprises: dexketoprofen: 5-30%, more preferably 7.5-25%, most preferably 10-20%; tramadol: 5-40%, more preferably 10-35%, most preferably 15-30%; diluent: 20-80%, more preferably 40-75%, most preferably 50-65%; disintegrant: 1 -20%, more preferably 1 -15%, most preferably 3 -10%; lubricant: 0 -10%, more preferably 0.1 -5%, most preferably 0.5 -3%; glidant: 0-10%, more preferably 0-6%, most preferably 0.1-4%.
  • the pharmaceutical composition of the present invention comprises: dexketoprofen tromethamol: 5-30%, more preferably 7.5-25%, most preferably 10- 20%; tramadol hydrochloride: 5-40%, more preferably 10-35%, most preferably 15-30%; diluent: 20-80%, more preferably 40-75%, most preferably 50-65%; disintegrant: 1 -20%, more preferably 1 -15%, most preferably 3 -10%; lubricant: 0 -10%, more preferably 0.1 -5%, most preferably 0.5 -3%; glidant: 0-10%, more preferably 0.1-2%, most preferably 0.5-1.5%.
  • the pharmaceutical composition according to the present invention may optionally comprise 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 ratio of each excipient of the same chemical structure may optionally be in the range of from 70:30 to 20:80, preferably from 65:35 to 25:75, more preferably from 60:40 to 30:70.
  • 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.
  • a preferred composition according to the present invention comprises microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate. More preferred is a composition, wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase. More preferred is a composition, 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 microcrystalline cellulose and croscarmellose sodium, wherein both of the listed excipients are divided between intragranular phase and extragranular phase. Hence, it is particularly preferred that the composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase.
  • the dexketoprofen trometamol is comprised in the intragranular phase and the tramadol hydrochloride in the extragranular phase.
  • the average particle size of 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 microcrystalline cellulose of the extragranular phase is equal to or more than 100 pm.
  • the solid dosage forms described above can be optionally coated with an aqueous soluble film coating, typically having an average thickness of at least 1 pm, measured by scanning electron microscopy (SEM) of crossection of coated solid dosage form.
  • the optional film coating comprises one or more aqueous soluble polymers.
  • the film coating can optionally be functional having reduced permeability for water and/or moisture. Suitable methods for applying film coatings to tablet cores are generally known in the art, such as coating of tablet cores in perforated coating drums like Manesty, Ace I a cota, GS or Glatt coating drums.
  • Polymers that can be used for film coating can be selected from cellulose ethers such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose; polyvinyl alcohol, povidone, sodium carboxymethyl cellulose, waxy materials, acrylic polymers cuch as Eudragit ® L or E types , block polymer of polyvinyl alcohol and polyethylene glycol.
  • Film coating can optionally comprise other excipients from the functional groups of lubricants, antitacking agents, pigments, colourant and/or plasticizers.
  • Film coatings characterized by low permeability for gases such as water vapor and/or oxygen may be based on polymers such as polyvinyl alcohol (e.g. Opadry AMB), low viscosity hypromellose types, sodium carboxymethyl cellulose, aminoalkyl methycrylate copolymers (e.g. Eudragit E PO or Eudragit E 12,5).
  • polyvinyl alcohol e.g. Opadry AMB
  • low viscosity hypromellose types e.g. Opadry AMB
  • sodium carboxymethyl cellulose e.g. Eudragit E PO or Eudragit E 12,5
  • aminoalkyl methycrylate copolymers e.g. Eudragit E PO or Eudragit E 12,5
  • plasticizers which can be used for coating the pharmaceutical compositions of the present invention
  • plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols having average molecular weight in the range from 200 to 10,000, preferably B00 to 8,000), organic esters (phthalate esters, dibutyl sebacate, citrate esters, triacetin), oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
  • Commonly used lubricants and/or antitacking agents can be selected from the group of metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium stearate, calcium stearate, aluminium stearate or zinc stearate, magnesium palmitate and magnesium oleate, fatty acids with 12 to 20 carbon atoms such as stearic acid, palmitic acid and oleic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, meads wax or spermaceti, boric acid, sodium stearyl fumarate, and mixtures thereof.
  • metal salts of fatty acids with 12 to 20 carbon atoms such as magnesium stearate, calcium stearate, aluminium stearate or zinc stearate, magnesium palmitate and magnesium oleate
  • fatty acids with 12 to 20 carbon atoms such as stearic acid, palmitic acid and oleic acid
  • hydrogenated vegetable oil hydrogenated castor oil
  • talc meads
  • Colourants/opacifiers which can be used for coating the pharmaceutical compositions of the present invention are classified into several groups: organic dyes and their lakes, inorganic colours, natural colours. Pigments can be selected from metal oxides such as iron or titanium oxides.
  • Film coating suspensions can be used as ready-to-make preparations which are available on the market.
  • Film coating dispersion can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), preferably water.
  • composition of film-coating suspension (calculated on dry material) which comprises:
  • polymer 1-98.8% by weight of polymer, preferably 1-95% of polymer
  • plasticizer 1-50% by weight of plasticizer, preferably 1-40% of plasticizer,
  • lubricant 0.1-20% by weight of lubricant, preferably 1-10% of lubricant,
  • colourant/opacifier and/or pigment 0.1-20% by weight of colourant/opacifier and/or pigment, preferably 0.1-10% of colourant/opacifier and or/pigment. All weight% indications are based on the total of the film coating being 100 weight%.
  • composition of the film-coating layer of the pharmaceutical composition of the present invention preferably comprises at least one excipient selected from excipients with the function as defined of polymer and plasticizer.
  • 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, lubricant, antitacking agent and colourant/opacifier.
  • composition of the present invention can be prepared by any known technological procedures which are absent of solvents, e.g., dry granulation.
  • the composition is prepared in a manner known per se, for example by means of conventional mixing, granulating, or coating processes.
  • the active ingredients 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.
  • processes for the preparation of the pharmaceutical formulation of the present invention comprise steps, which exclude solvents and especially water from all technological steps of incorporation of dexketoprofen into tablet cores. This means that the processes are preferably selected from dry granulation.
  • the "dry granulation” method is a method of formulation wherein the raw material powder is subjected to a compression molding into a pellet or sheet, using granules produced by crushing.
  • Dry granulation can be performed by processes known in the art as slugging and/or roller compaction, the latter being preferred.
  • Dexketoprofen or tramadol optionally sieved to eliminate agglomerates, are 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.
  • active ingredients and excipients preferably selected from diluents, disintegrants, glidants and lubricants can be incorporated partially intragranularly and partially extragranularly, alone or in combination with at least one excipient or a mixture of excipients.
  • at least one excipient or a mixture of excipients can be used partially intragranularly and partially extragranularly.
  • dexketoprofen or tramadol 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.
  • motionless (passive) mixers fluidized bed
  • diffusion biconic diffusion, biconic, tubular, cubic, planetary, Y-, V-shaped or high-shear mixers.
  • 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".
  • the compression in particular to tablet ortablet 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 dry granulation process comprises:
  • the dry granulation process comprises:
  • an excipient of the same chemical structure e.g. microcrystalline cellulose
  • granulate i.e. intragranular phase
  • extragranular additive the use of different particle size and/or particle morphology of the excipient is preferred for each phase.
  • particle size and/or particle morphology of the excipient is preferred 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 sieve analysis already by its manufacturer.
  • the term «smaller particle size» means average particle size less than 100 pm
  • 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 may optionally comprise 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 ratio of each excipient of the same chemical structure may optionally be in the range of from 70:30 to 20:80, preferably from 65:35 to 25:75, more preferably from 60:40 to 30:70.
  • 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.
  • microcrystalline cellulose with larger particle size significantly increases flowability of the compression mixture. It is therefore preferred to use excipients and/or active ingredient for the extragranular phase with larger average particle size.
  • microcrystalline cellulose and/or active ingredient with larger average particle size may be used for the extragranular phase.
  • the terms «smaller average particle size « and «larger average particle size « of specific excipients are as described hereinabove.
  • a preferred composition according to the present invention comprises microcrystalline cellulose, croscarmellose sodium, silica and magnesium stearate.
  • composition wherein at least one of the listed excipients is divided between intragranular phase and extragranular phase.
  • composition 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 microcrystalline cellulose and croscarmellose sodium, wherein both of the listed excipients are divided between intragranular phase and extragranular phase.
  • composition according to the invention comprises granules (i.e. an intragranular phase) and an extragranular phase.
  • the dexketoprofen trometamol is preferably comprised in the intragranular phase and the tramadol hydrochloride in the extragranular phase.
  • the average particle size of 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 microcrystalline cellulose of the extragranular phase is equal to or more than 100 pm.
  • the solid oral dosage form of the present invention is suitable for the treatment of pain.
  • it is suitable for the treatment of acute, chronic and postoperative pain of moderate to severe intensity originating from any cause and/or disease comprising especially those selected from the group of headache, toothache, inflammations, cancer, orthopaedic pain and migraine.
  • the fixed combination of both compounds is intended to allow optimised pain control with fewer side effects than observed for both compounds alone.
  • the solid oral dosage form of the present invention is to be administered orally. It may be administered by means of 1, 2, 3 or 4 unit dosage forms per day.
  • the total daily dosage of dexketoprofen should be in the range of from more than 0 to 100 mg, preferably 25 to 75 mg.
  • the total daily dosage of tramadol should be in the range of from more than 0 to 250 mg, preferably 75 to 225 mg.
  • the solid oral dosage form of the present invention does not require combination with further agents to accomplish the desired therapeutic, i.e. analgesic effect. However, combination with further active agents may nevertheless be helpful or even advantageous. For instance, it may be advantageous to combine therapy with the solid oral dosage of the present invention with administration of an agent that may reduce the side effects of the opioid tramadol, such as an agent against opioid induced constipation.
  • agents may include but are not limited to lactulose or naloxone.
  • a packaged pharmaceutical product which comprises the solid oral dosage form of the present invention within a primary packaging.
  • Typical primary packagings are blisters or larger containers with a screw cap.
  • the packaged pharmaceutical product uses a primary packaging with a packaging material containing polyvinylidene chloride (PVDC).
  • PVDC polyvinylidene chloride
  • the primary packaging is a blister, wherein one or both of the foils forming the blister is made from the PVDC-containing material.
  • the packaged pharmaceutical product according to the present invention may be a blister, wherein the upper foil with cavities is made from a PVDC- containing material, which is laminated to a lower foil made from aluminium material, and wherein the solid oral dosage form of the invention is contained in the cavities.
  • the PVDC-containing material is PVC/PVDC/PVC primary packaging or PVC/PE/PVDC/PE/PVC primary packaging, more preferably the amount of PVDC is 120 g/m 2 in PVC/PVDC/PVC primary packaging or 180 g/m 2 in PVC/PE/PVDC/PE/PVC primary packaging.
  • the reference product, Skudexa ® tablets was used as commercially available.
  • the qualitative and quantitative composition of commercially available Skudexa ® tablets is as disclosed in Example 4 of EP2956129.
  • Compaction was performed applying standard procedures in roller compaction technology, employing Hosokawa C250 equipment. Afterwards, the compacts were sieved through 1.0 mm mesh size and mixed with the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate in the amounts specified in table 1. The components were mixed in the container mixer to obtain the compression mixture.
  • the compression mixture was compressed on a standard rotary tablet press to tablet cores with the following properties:
  • the resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol, which was prepared according to the manufacturer's recommendation (Colorcon).
  • the film-coating was performed in a standard film-coater.
  • Tramadol hydrochloride was sieved together with the intragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate through 1.0 mm mesh size to prepare a blend for roller compaction.
  • the compaction was performed applying standard procedures in a roller compaction technology. Afterwards, the compacts were sieved and mixed with dexketoprofen trometamol and the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate. The components were mixed in the container mixer to obtain the compression mixture.
  • the compression mixture was compressed on a standard rotary tablet press to obtain tablet cores. Compression force from 8 to 20 kN was applied during the process and tablet cores with hardness between 70 and 150 N were obtained.
  • the resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol, which is prepared according to the manufacturer's recommendation (Colorcon).
  • the film-coating was performed in a standard film-coater.
  • Dexketoprofen trometamol was sieved together with the intragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate through 1.0 mm mesh size to prepare a blend for roller compaction.
  • Table 1 specifies the amounts of active substances and excipients that were used.
  • the compaction was performed applying standard procedures in roller compaction technology. Afterwards, the compacts were sieved and mixed with tramadol hydrochloride and the extragranular part of microcrystalline cellulose, croscarmellose sodium, silica, colloidal anhydrous and magnesium stearate in amounts as specified in table 1 below. The components were mixed in the container mixer to obtain the compression mixture.
  • Example 3 The compression mixture of Example 3 was compressed on a standard rotary tablet press to tablet cores with the same properties as specified above for the Comparative Example.
  • the resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol (Opadry II), which is prepared according to the manufacturer's recommendation (Colorcon).
  • the film-coating is performed in a standard film-coater.
  • Dexketoprofen trometamol was sieved together with the intragranular excipients through 1.0 mm mesh size to prepare a blend for roller compaction. Amounts were employed as specified in table 1 below.
  • the compaction was performed applying standard procedures in roller compaction technology. Afterwards, the compacts were sieved and mixed with tramadol hydrochloride and the extragranular excipients. The components were mixed in the container mixer to obtain the compression mixture. The compression mixture was compressed on a standard rotary tablet press to obtain a tablet core. A compression force from 8 to 20 kN was applied during the process and tablet cores with hardness between 70 and 150 N were obtained.
  • the resulting tablet cores were subsequently coated with an aqueous film coating system based on polyvinyl alcohol, which was prepared according to the manufacturer's recommendation (Colorcon).
  • the film-coating was performed in a standard film-coater.
  • Table 2 Physical characteristics and sieve analysis of compression mixtures of Comparative example and Example 3.
  • the improvement in the flowabillity of the compression mixture is also reflected in the lower fluctuation of the uniformity of the content in the film-coated tablets.
  • FIG. 1 presents the dissolution profile of tramadol hydrochloride at initial value and Figure 2 presents the dissolution profile of dexketoprofen at initial value.
  • Table 4 shows the results of the stability tests of the film-coated tablets according to Reference Example (Skudexa), Comparative Example and Example 3 at 40 °C/75 % RH at 3 and 6 months, packed in PVC/PVDC/PVC forming film and sealing paper/aluminium foil. Stability was assessed by determining the relative amounts of dexketoprofen tromethamine amide as a degradation product.
  • Table 5 shows the results of stability tests of the film-coated tablets according to the Reference Example (Skudexa) and Example 3, at 40 °C/75 % RH at 3 and 6 months, packed in PVC/PVDC/PVC forming film and sealing paper/aluminium foil (120 g/m 2 of PVDC) and a special type of blisters with a higher amount of PVDC (180 g/m 2 ) - PVC/PE/PVDC/PE/PVC forming film and sealing paper/aluminium foil. Stability was assessed by determining the relative amounts of the degradation product dexketoprofen tromethamine amide.
  • the amount of the amide impurity of dexketoprofen - dexketoprofen tromethamine amide present in the compositions was measured by HPLC (XBridge column with C18 stationary phase, mobile phase: mixture of water/acetonitrile/potassium hydrogencarbonate, UV detection at 270 nm).
  • Table 6 Hardness of film-coated tablets after accelerated conditions in different primary packaging.

Abstract

La présente invention concerne des compositions pharmaceutiques comportant du dexkétoprofène et du tramadol, qui sont stables et faciles à fabriquer. Les compositions pharmaceutiques de la présente invention sont caractérisées par le dexkétoprofène présent dans une phase intra-granulaire et le tramadol présent dans une phase extra-granulaire ou vice versa. De plus, la présente invention concerne un procédé simple de fabrication de telles compositions pharmaceutiques. L'aspect clé du procédé de fabrication selon la présente invention est la préparation d'un granulé contenant du dexkétoprofène ou, dans un autre mode de réalisation, du tramadol au moyen d'une granulation à sec, avant le mélange du tramadol, ou dans l'autre mode de réalisation, du dexkétoprofène, et éventuellement d'autres excipients. La présente invention concerne également des utilisations médicales des compositions pharmaceutiques.
EP21749158.8A 2020-07-31 2021-07-23 Préparation contenant du dexkétoprofène et du tramadol et procédé de fabrication associé Pending EP4188337A1 (fr)

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SI202000143 2020-08-21
PCT/EP2021/070694 WO2022023211A1 (fr) 2020-07-31 2021-07-23 Préparation contenant du dexkétoprofène et du tramadol et procédé de fabrication associé

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WO2006077492A1 (fr) * 2005-01-24 2006-07-27 Ranbaxy Laboratories Limited Formes dosifiées orales à libération prolongée de gabapentine
BRPI0700133A (pt) 2007-01-29 2008-09-16 Incrementha P D & I Pesquisa D composição farmacêutica compreendendo tramadol e cetoprofeno em combinação
US20120276199A1 (en) * 2011-04-01 2012-11-01 Dr. Reddy's Laboratories Limited Taste masked pharmaceutical formulations
ES2432222B1 (es) * 2012-04-30 2014-06-10 Farmalider S.A. Composición farmacéutica inyectable de dexketoprofeno y tramadol
ITMI20130210A1 (it) 2013-02-14 2014-08-15 Menarini Lab Composizioni farmaceutiche contenenti dexketoprofene e tramadolo
EP3395331B1 (fr) * 2017-04-26 2019-08-21 Alfred E. Tiefenbacher (GmbH & Co. KG) Composition de comprimé pharmaceutique comprenant eltrombopag olamine

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