WO2019130049A1 - Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur - Google Patents

Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur Download PDF

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Publication number
WO2019130049A1
WO2019130049A1 PCT/IB2017/058519 IB2017058519W WO2019130049A1 WO 2019130049 A1 WO2019130049 A1 WO 2019130049A1 IB 2017058519 W IB2017058519 W IB 2017058519W WO 2019130049 A1 WO2019130049 A1 WO 2019130049A1
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Prior art keywords
etoricoxib
release
formulation
pharmaceutical combination
solvents
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PCT/IB2017/058519
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English (en)
Inventor
Lizandra PATTARO MARCONDES
María Lastenia RODRIGUEZ FLORES
Mishel Estefanía OLEAS RECALDE
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Grünenthal GmbH
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Priority to PCT/IB2017/058519 priority Critical patent/WO2019130049A1/fr
Priority to MX2018013070A priority patent/MX2018013070A/es
Priority to ARP180103918A priority patent/AR114074A1/es
Priority to UY0001038043A priority patent/UY38043A/es
Publication of WO2019130049A1 publication Critical patent/WO2019130049A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K31/33—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention consists in a pharmaceutical combination comprising extended-release tramadol hydrochloride and immediate-release etoricoxib.
  • the present invention also refers to the use of the pharmaceutical combination for relieving and/or treating the pain manifestations in patients suffering them, due to the exposition to diverse types of pathologies.
  • the pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is considered as“unpleasant” to the set of feelings among which are suffering, anxiety, depression and despair. Therefore, a small amount of pain, regardless the cause, it can produce variations in the daily routine of an individual. It has been considered that the most severe pain is the one generated by a surgery - post-surgery pain - classified as acute pain, usually nociceptive, but it can also be neuropathic, which includes trauma.
  • the post-surgery pain, and an acute pain in general, can be treated with 2 classes of drugs: 1 ) non-steroidal anti-inflammatory drugs (NSAIDs) which act through prostaglandin synthesis to produce analgesic and anti-inflammatory effect, but are related to a low gastrointestinal and renal tolerance, and risks of interference in coagulation system ; 2) narcotic analgesics which act directly on the central nervous system opioid receptors, but could cause drug dependence, respiratory depression, constipation, nausea, vomiting and sedation (Manjunath Sh. et al. , J. Maxillofac. Oral Surg. 1 1 (3): 264-270, 2012).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the NSAIDs it is known that the therapeutic effect occurs in virtue of the biosynthesis blocking of a lipid mediators group to prostaglandins and thromboxanes (derived from arachidonic acid) by the inhibition of the cyclo-oxygenase enzyme (COX).
  • COX cyclo-oxygenase enzyme
  • the first step of the prostaglandin synthesis is catalyzed by COX which converts arachidonic acid (AA) in prostaglandin G2 (PGG2).
  • the cyclo-oxygenase system is composed by two homologous isoforms of the COX (Araujo et al., Arq. Bras. Cardiol. 85(3): 222-229, 2005):
  • COX-1 present in many types of cells, for example, kidneys, gastrointestinal mucosa, uterus and platelets, and it is expressed all the time, performing important roles, such as the maintenance of the function of the gastric mucosa and other cytoprotection factors of the gastric mucosa, the renal perfusion and aggregation.
  • COX-2 normally found in the brain and kidneys and, when it is induced by inflammatory
  • the prostaglandins are lipids which measure many biological responses, some of them are protection, and other potentially harmful. From discoveries indicating that COX-1 as physiologically constitutive, and which acts as gastric cytoprotector and maintainer of the renal and platelet homeostasis; and COX-2 or inductive, which arose only in situation of tissue trauma and inflammation, the idea arose that the COX-2 specific inhibitors would avoid the inflammatory process without undesirable side effects with the same efficiency, without causing the gastrointestinal effects derived from the inhibition of COX-1 (Araujo et al. , Arq. Bras. Cardiol. 85(3): 222- 229, 2005).
  • non-selective NSAIDs so-called traditional or conventional, aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, sulindac, diclofenac, piroxicam, beta piroxicam, meloxicam and ketoprofen are found.
  • selective NSAIDs or COX-2 rofecoxib, valdecoxib, parecoxib, celecoxib, etoricoxib and lumiracoxib are found (Baltouni M., Arq. Bras. Cardiol. 94(4): 538-546, 2010).
  • the compound etoricoxib (5-chloro-2[6-methyl pyridine-3-yl]-3-[4-methylsulfonylphenyl]pyridine), of chemical structure according to the Formula 1 , is a drug belonging to the non-steroidal anti-inflammatory drugs (NSAIDs) of the group of coxibs, classified as highly selective inhibitor of COX-2, which is competitively reversibly connected to COX-2.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Etoricoxib is a free-base anhydrous which exists in the form of 13 polymorphs, Forms l-V and IX-XVI of the free-base, and two hydrated forms: sesquihydrate and hemihydrate (WO0192230, WO0137833, W02005085199).
  • etoricoxib as monodrug, are available in approximately 55 countries in Europe, Latin America, Asia and the United States, and it is approved for use in rheumatoid arthritis, osteoarthritis, acute gout, chronic musculoskeletal pain and primary dysmenorrhea.
  • the half-life of etoricoxib is 20 hours (Takemoto J. et al., Clin. Pharmacokinet. 47 (1 1 ): 703-720, 2008).
  • etoricoxib will depend on the type of pain to be treated being only once a day, in doses of 30, 60, 90 and 120 mg.
  • the recommended dose is 120 mg once a day
  • tramadol hydrochloride As it is presented in the literature, hereinafter the common nomenclature of tramadol will be indistinctly used to refer to the tramadol hydrochloride. Its behavior is atypical compared to other morphine-type opioids, since despite of having a relatively weak agonist effect on m opioid receptors, its analgesic effect in large part is due to its action in the neurotransmitters system, since it releases serotonin and it inhibits the reuptake of norepinephrine Specifically the (+) enantiomer binds with m receptors and it inhibits the reuptake of norepinephrine, while the (-) enantiomer inhibits reuptake of norepinephrine and it stimulates the a-2 adrenergic receptors.
  • tramadol is indicated for the treatment of pain in the short or long term, with moderate to severe intensity.
  • the half-life of tramadol is 6.3 hours (https://www.accessdata.fda.goV/drugsatfda_docs/label/1 999/20281 S16LBL.PDF).
  • the recommended dose of immediate-release tramadol is from 50 mg to 200 mg per day, and it can be administered every 4- 6 hours. When it is about delayed-release tramadol, the recommended administration is a dose of 100 mg once a day.
  • the amount of tramadol to be administered will depend on the intensity of pain to be treated. (Https ://www. accessdata.fda.gov/drugsatfda_docs/label/2002/75986lbl. pdf,
  • tramadol presents less side effects in comparison with other opioid-type analgesics, such as dependence, tolerance and risk of addiction and abuse, it is suggested to not administer repeatedly in time or in high doses analgesics such as tramadol and opioids (Epstein et al., Biol. Psychol. 73(1 ): 90- 99, 2006). For this reason, it has been proposed in the prior art to combine them with other non-opioid drugs, in order to decrease the amount necessary to generate an equivalent level of analgesia, without the above-mentioned side effects.
  • the patent application WO2010043412 refers to co-crystals formed by tramadol and by a NSAID, wherein it is mentioned that the preferred embodiments are a co-crystal formed between (-)-tramadol and (S)-naproxen, (+)-tramadol and (R)-naproxen or (rac)-tramadol-HCI and celecoxib.
  • the preferred molecular ratio is 1 :2
  • the co-crystal (rac)- tramadol-HCI and celecoxib is 1 :1 . It is indicated that within the many preferred NSAIDs are the selective inhibitors of COX-2.
  • a co-crystal comprising a combination of tramadol and at least one coxib, mentioned among these latter compounds is etoricoxib.
  • etoricoxib a combination of tramadol and at least one coxib, mentioned among these latter compounds.
  • the patent application WO201 1015360 discloses a pharmaceutical composition comprising the combination between one of the main tramadol active metabolites, such as O-desmethyl- tramadol, and at least one inhibitor of COX, in order to decrease the dose of the opioid.
  • the low solubility of some COX such as naproxen, diclofenac and ibuprofen, indicating that a way to solve said inconvenient is disposing other pharmaceutical forms comprising both active pharmaceutical principles (APIs).
  • the preferred COX-2 inhibitors they include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib and cimicoxib.
  • the specific examples, as well as the set of claims of this document refer to O-desmethyl-tramadol co-crystals and one NSAID, among them a co-crystal with etoricoxib is not disclosed.
  • Patent application W00051685 describes a pharmaceutical combination -which can comprise the formulated APIs separately to be concomitantly administered, or they can be presented in the same pharmaceutical form, such as a pill-, comprising tramadol and a selective COX-2 inhibitor, such as the compound 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyl oxazole (tilmacoxib), useful for treating or preventing pain, inflammation and certain neurological disorders.
  • a pharmaceutical combination - which can comprise the formulated APIs separately to be concomitantly administered, or they can be presented in the same pharmaceutical form, such as a pill-, comprising tramadol and a selective COX-2 inhibitor, such as the compound 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyl oxazole (tilmacoxib), useful for treating or preventing pain, inflammation and certain neurological disorders.
  • composition has a synergistic effect when the pharmaceutical active principles are present in a ration based on a fraction of their respective EDso, and that said ration can variate from 1 :1 to 1 :300 or 1 :1 to 300:1 , depending on the desired result, but results which support the synergistic effect are not shown.
  • both APIs are administered in the form of suspension, dissolving them in an aqueous solution of hydroxypropyl methyl cellulose, but it is not mentioned the release or delivery form of each pharmaceutical active principle.
  • W00051685 does not describe a pharmaceutical combination comprising tramadol and etoricoxib.
  • the international filing W02008092219 describes that one of the problems of the prior art is to maintain unaltered the bioavailability of drugs every time that they are put in contact in the same pharmaceutical composition, as well as avoid physical-chemical interactions among them. It is described a composition for oral use which comprises a combination of tramadol, ketoprofen and optionally one or more excipients, wherein the tramadol and the ketoprofen would not be in contact and/or it would be preventing their interaction. It is disclosed -among others- an oral solid pharmaceutical form in form of trilayer tablets, wherein each active principle is disposed in one layer, separated by at least by one intermediate isolating layer.
  • compositions useful for treating pain comprising slow-release tapentadol hydrochloride and a second analgesic which can be tramadol, an analogue of GABA or an NSAID.
  • a bilayer tablet comprising tapentadol hydrochloride and naproxen. It is not mentioned a combination between tramadol and etoricoxib.
  • the pharmaceutically active ingredients are found in a form in which they can be properly handled and processed.
  • the convenient handling is important not only to obtain a product and commercially viable manufacturing processes, but also from the perspective of the design of the pharmaceutical formulations which comprise a combination of two APIs with particular characteristics.
  • One of the requirements is that no significant change exists that would be detrimental of physical-chemical characteristics of the active pharmaceutical ingredient, for example, its chemical composition, density, hygroscopicity and solubility.
  • the bipyridyl compounds -such as etoricoxib- are generally highly crystalline, having low solubility in water and hydrophobic, resulting in difficulties in the preparation of pharmaceutical formulations and problems associated with the bioavailability.
  • This document describes a pharmaceutical suspension comprising etoricoxib particles -wherein it has not been specified what is the form in which the etoricoxib is found- which has a particle average diameter of 0.2 to 14 pm at a concentration of 50 to 300 mg/ml, and an aqueous injection carrier, for intramuscular administration 1 time per day, useful for treating a disorder selected from the group consisting in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arth ritis, and pain associated with dental surgery. Therefore, for solving the low solubility in aqueous solution of etoricoxib, in this injectable composition, it is described the use of etoricoxib with a particle average diameter of 0.2-14 pm and an aqueous injection carrier.
  • a pharmaceutical composition in tablets or capsules form which comprises etoricoxib in the polymorphic form I, or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and which comprises at least one solubility enhancer selected among surfactants; hydrocolloids, such as cellulose derivatives (for example, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and hydroxyl methyl cellulose); polymers such as N-vinyl-2-pyrrolidone and polyvinyl pyrrolidone; copolymers such as vinylpyrrolidone copolymer and vinyl acetate, wherein the solubility enhancer preferentially used in the pharmaceutical composition of etoricoxib is sodium lauryl sulfate.
  • solubility enhancer preferentially used in the pharmaceutical composition of etoricoxib is sodium lauryl sulfate.
  • Document CN1 05343002 describes the preparation of an etoricoxib oral microemulsion, suitable for large-scale production, wherein the emulsion comprises 1 -3% of etoricoxib, 3-10% of oily phase, 3-10% of emulsifier, 3-10% of co-emulsifier, 0-0.2% of sweetener agent, 0-0.5% of essence, 0.1 -0.5% of preservative and 70-90% water.
  • the disclosed preparation method comprises adding the etoricoxib in the oily phase and dissolved it; add the emulsifier and the co-emulsifier in the oily phase to form a crude emulsion, and finally, transferring the crude emulsion to a high pressure homogenizer, adding water and homogenize it at high pressure to obtain the microemulsion preparation.
  • a high pressure homogenizer adding water and homogenize it at high pressure to obtain the microemulsion preparation.
  • document CN104586799 it is claimed dispersible tablets of etoricoxib and a preparation method thereof, wherein for obtaining a suitable solubility and speed of dissolution of the active principle, it is used a solid dispersion medium and lyophilization or spray drying.
  • both APIs have significantly different half-lives, 6 hours for tramadol and 20 hours for etoricoxib, for which there is no disclosed pharmaceutical combinations comprising both APIs that considers these relevant differences. This may be due to the drastic problems of solubility of the etoricoxib, the polymorphic instability of the etoricoxib, the possibility of interaction between the two APIs, among other factors.
  • the inventors of the present invention have surprisingly found, that it is possible to formulate a fixed-dose oral combination which comprises tramadol and etoricoxib in the same dosage unit, which solves the problems caused by the prolonged half-life of the etoricoxib in contrast with the short half-life of tramadol, as well as the difficult solubility of etoricoxib, the different solubility of both APIs, and possible interactions between them.
  • the separated formulation of each API allowed them solving the problem of technique related to substantially different half-lives of the APIs, given that the etoricoxib is an API which has a half-life of 20 hours and the tramadol of 6 hours, so their release profiles in the same dosage unit were able to adjust them.
  • the inventors surprisingly found a formulation for the immediate-release of the etoricoxib with specific excipients, and on the other hand, a distinctive formulation for tramadol in order to obtain the extended-release of it, making possible that the pharmaceutical combination of the present invention can be administered once a day.
  • the pharmaceutical combination of the present invention comprises two formulations, each one containing an API, and which were independently formulated by means of a manufacturing process which was surprisingly found by the inventors, and which allowed them to use specific excipients for etoricoxib overcoming the problems of technique described above.
  • the inventors found that the solubilization of etoricoxib with a specific surfactant agent and a particular mixture of solvents or carriers, would allow its wet granulation without the formation of needles or another agglomerates which decreased its solubility and stability, contrary to what is described in the prior art. Additionally, during the manufacturing process of this invention a stable and soluble specie of etoricoxib was obtained, contrary also to what is described in the prior art which indicates that during the manufacture of the product in aqueous medium, it is produced a polymorphic interconversion leading to the reduction of the solubility and stability of said API.
  • the present invention relates to a pharmaceutical combination comprising tramadol and etoricoxib in two separate formulations, being the tramadol formulation of extended-release and the etoricoxib formulation of immediate-release.
  • the present invention relates to a pharmaceutical combination in the form of a solid oral dosage unit formed by a first extended-release formulation containing tramadol and a second immediate-release formulation containing etoricoxib.
  • the pharmaceutical combination of the present invention is in the same solid dosage unit such as capsule, tablet, bilayer tablet, granulate or sachet forms.
  • the pharmaceutical combination of the present invention relates to a bilayer tablet comprising extended-release tramadol, immediate-release etoricoxib, and distinctive pharmaceutically acceptable excipients for each formulation, in the appropriate proportions for each one of the APIs.
  • the present invention refers to a pharmaceutical combination formed by: A) A first formulation of extended-release tramadol hydrochloride containing from 2.0% to 12.0% w/w of as the first pharmaceutically active ingredient, and from 30% to 40% w/w of pharmaceutically acceptable excipients; and B) a second formulation of immediate-release etoricoxib containing from 6.0% to 18.0% w/w of etoricoxib as the second pharmaceutically active ingredient, and from 40% to 52% w/w of pharmaceutically acceptable excipients, along with pharmaceutically acceptable solvents or carriers; wherein the “% w/w” of each one of the ingredients is referred regarding to the total weight of the pharmaceutical combination, and wherein the solvents or carriers are not included within the total weight thereof.
  • the present invention relates to a pharmaceutical combination formed by: A) A first formulation of extended-release tramadol hydrochloride containing from 2.0% to 12.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, and containing the following pharmaceutically acceptable excipients:
  • solvents or carriers being the“% w/w” of each one of the referred ingredients regarding to the total weight of the pharmaceutical combination, wherein the solvents or carriers are not considered within the total weight thereof.
  • the present invention consists of a pharmaceutical combination comprising:
  • etoricoxib as pharmaceutically active ingredient, and containing the following pharmaceutically acceptable excipients:
  • solvents or carriers being the“% w/w” of each one of the referred ingredients regarding to the total weight of the pharmaceutical combination, wherein the solvents or carriers are not considered within the total weight thereof.
  • the present invention refers to a pharmaceutical formulation of immediate-release etoricoxib.
  • This formulation comprises from, in w/w referred to the total weight of the pharmaceutical formulation: 10.3% to 31 .0% w/w of etoricoxib,
  • solvents or carriers are not included within the total weight of the pharmaceutical formulation.
  • the present invention refers to a manufacturing process to prepare the pharmaceutical combination which includes the process to prepare the first formulation of extended-release tramadol hydrochloride and the second formulation of immediate-release etoricoxib.
  • the present invention refers to a manufacturing process to prepare the pharmaceutical formulation of immediate-release etoricoxib.
  • the etoricoxib polymorph I was preferably used, which corresponds to the raw material used for the exemplified embodiments, but which do not limit the present invention.
  • the racemic mixture of tramadol hydrochloride was used, which corresponds to the raw material used for the exemplified embodiments, but which do not limit the present invention.
  • pharmaceutically active ingredient or “API”, as it is used in the present invention, it refers to a substance having a therapeutic effect.
  • pharmaceutically acceptable excipient means that it is an acceptable excipient from the point of view of its toxicity to humans.
  • disintegrant refers to an agent which accelerates the disintegration of the contents of the pill and the dispersion of the active ingredient in water or in the gastrointestinal fluids.
  • the disintegrant may be present in the pharmaceutical combination as a single compound or as a mixture of compounds.
  • examples of disintegrants are sodium starch glycollate, crospovidone, croscarmellose, microcrystalline cellulose, sodium carboxymethyl starch, sodium carboxymethyl cellulose and corn starch, or mixtures thereof.
  • lubricant refers to an agent capable of reducing the adhesion of powder to the used dispensers of the machine and the friction between the particles.
  • the lubricant can be present in the pharmaceutical combination as a single compound or as a mixture of compounds.
  • examples of lubricants are talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, such as colloidal silicon dioxide 130, colloidal silicon dioxide 200, colloidal silicon dioxide 300, colloidal silicon dioxide 380, or mixtures thereof.
  • extended-release matrix refers to pharmaceutically acceptable excipients which are used in order to release the API in an extended period of time from its administration.
  • hydrophilic matrix Within the matrix of extended-release hydrophilic matrix are found which are formed by excipients such as sodium alginate, various grades of hydrophilic polymers, such as hypromellose or hydroxyl-propyl methylcellulose (HPMC) K15M, HPMC K1 00M and HPMC K200M, and polyacrylate polymers, such as Eudragit RL100 and Eudragit RS100, or a mixture thereof.
  • excipients such as sodium alginate, various grades of hydrophilic polymers, such as hypromellose or hydroxyl-propyl methylcellulose (HPMC) K15M, HPMC K1 00M and HPMC K200M, and polyacrylate polymers, such as Eudragit RL100 and Eudragit RS100, or a mixture thereof.
  • surfactant refers to those agents which allow to reduce the surface tension between two phases achieving its homogeneous mixture.
  • examples of surfactants are phospholipids, polyethylene glycols, meglumine, sorbitol esters, Brij®58, polysorbates such as Tweens, polyoxyethylene ethers, or mixtures thereof.
  • binder refers to those agents which maintain bound the combined products, thus maintaining the granulation.
  • binders are compounds of the group of the polyvinylpyrrolidone (PVP), such as diverse types of povidones, povidone 25, povidone 30 or povidone 90, vinyl pyrrolidones copolymers with other derivatives of vinyl, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pregelatinized starch, or mixtures thereof.
  • PVP polyvinylpyrrolidone
  • solvent refers to those inert substances of liquid nature which allow the incorporation of the remaining elements of the formulation, in order to obtain an homogeneous and uniform mixture.
  • solvent it can be mentioned water, ethanol, polyethylene glycols, glycerin, or mixtures thereof.
  • the solvent or carrier is not considered within the final weight of the formulation.
  • compositions comprised by the present invention include flavoring agents, load agents, adhesives, dyes, and sweetening agents.
  • FIG. 1 X-Ray powder diffraction (XRPD) pattern of etoricoxib polymorph I.
  • XRPD X-Ray powder diffraction
  • the diffraction pattern showed a crystalline structure and comprised distinctive reflections, expressed as values of 20°, in 7.5; 9.73; 1 1 .8; 12.42; 13.01 ; 15.51 ; 16.58; 18.14; 1 9.19; 19.4; 20.07; 21 .18; 21 .51 ; 21 .89; 22.56; 22.77; 23.32; 23.7; 24.19; 25.12; 26.40; 26.95; 27.67; 28.44; 29.32; 29.93; 30.75; 31 .28; 34.78; 35.83 and 39.27.
  • Figure 2 X-Ray powder diffraction (XRPD) pattern of the etoricoxib hemihydrate.
  • the diffraction pattern showed a crystalline structure and comprised distinctive reflections, expressed as values of 20°, in 3.49; 3.55; 3.62; 3.79; 3.94; 4.04; 4.14; 4.43; 4.50; 4.54; 4.94; 5.03; 5.12; 5.26; 5.53; 5.73; 6.13; 7.10; 9.07; 9.85; 10.83; 13.46; 16.41 ; 24.54 and 35.95.
  • Figure 3 X-Ray powder diffraction
  • Dissolution profile of etoricoxib at pH 1.2 from fixed dose combinations comprising tramadol and etoricoxib.
  • the etoricoxib dissolution percentage at pH 1 .2 over time is shown for a fixed dose combination, from bilayer tablets prepared according to the present invention.
  • the results shown correspond to the average (X) independently obtained for 6 samples, measured in time 0, 10, 15, 20, 25 and 30 minutes. In addition it is shown, with vertical bars, the standard deviation at each measured point of time.
  • FIG. 4 Dissolution profile of tramadol between pH 1.2 and pH 7.2 from fixed dose combinations comprising tramadol and etoricoxib.
  • the tramadol dissolution percentage over time is shown for a fixed- dose combination, from bilayer tablets prepared according to the present invention.
  • the results shown correspond to the average (X) independently obtained for 6 samples, measured in time 0, 30, 240 and 480 minutes. In addition it is shown, with vertical bars, the standard deviation at each measured point of time.
  • composition comprising a first formulation of extended-release tramadol hydrochloride and a second formulation of immediate-release etoricoxib and which contains the following ingredients:
  • composition comprising a first formulation of extended-release tramadol and a second formulation of immediate-release etoricoxib and which contains the following ingredients:
  • the solvents or carriers are not included within the total weight of the pharmaceutical combination.
  • the formulations comprising separately extended-release tramadol and immediate-release etoricoxib and the pharmaceutical combination which comprise them are prepared according to the manufacturing process examples described below, wherein the pharmaceutical combination may be conveniently presented in any appropriate oral dosage form such as, for example, tablets, capsules, granules, sachets, bilayer tablets, or other solid administration forms.
  • composition in the bilayer tablet form comprising a first layer of extended-release tramadol hydrochloride and a second layer of immediate-release etoricoxib and which contains the following ingredients:
  • the solvents or carriers are not included within the total weight of the pharmaceutical combination.
  • the tramadol and etoricoxib layers are compressed to obtain bilayer tablets, as detailed below in the manufacturing process examples.
  • manufacture of a pharmaceutical combination comprising two formulations in accordance with the present invention comprises, at least, the following steps:
  • step 1 The mixture of step 1 is pre-compressed and then it is granulated to finally add the second fraction of lubricants.
  • a sieved mixture of solids is prepared which comprises the surfactant, two disintegrants and etoricoxib;
  • step 5 To the mixture obtained in step 4, the mixture obtained in step 3 is added, to perform the wet granulation with the addition of a second part of the first solvent along with a second solvent;
  • step 5 The granulate obtained in step 5 it is placed in the fluid bed and it is dried;
  • step 6 The granulate obtained in step 6 is sieved and lubricant is added.
  • the first and second granulates obtained in steps 2 and 7 are encapsulated in hard capsules, according to procedures widely described in the prior art.
  • the granulates obtained in steps 2 and 7 are mixed and compressed in a suitable tabletting press, to obtain the specifications indicated in Tables 1 and 2.
  • Example of Manufacturing Process 2 The manufacture of a pharmaceutical combination comprising two formulations in accordance with the present invention comprises, at least, the following steps:
  • composition for the first formulation of extended-release tramadol hydrochloride by the following steps:
  • the mixing time is 10 to 20 minutes;
  • step 2 Over the mixture obtained in step 1 , it is added 50% of a mixture which contains lubricants and it is mixed during 1 to 5 minutes;
  • step 3 A pre-compression of the mixture obtained in step 2 is performed and it is re-granulated by 0.7 to 2.0 mm mesh, preferably by 1 .0 mm mesh;
  • step 3 Finally, over the granulate obtained in step 3, the remaining 50% of the mixture which contains lubricants is added and it is mixed during 1 to 5 minutes.
  • composition for the second formulation of immediate-release etoricoxib by the following steps:
  • step 7 A wet granulation is performed by adding the solution prepared in step 5 to the mixture of solids obtained in step 6. The remaining 50% of ethanol and the water are also added;
  • step 7 The granulate obtained in step 7 it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C, preferably 30°C;
  • step 8 Finally the granulate obtained in step 8 is sieved by 0.7 to 2.0 mm mesh, preferably by 1 .0 mm mesh, and over it, the lubricant is sieved by 0.3 to 1 .0 mm mesh, preferably by 0.5 mm mesh, and it is mixed during 1 to 5 minutes.
  • the granulates obtained in steps 4 and 9 are encapsulated in hard capsules, procedure widely known and used in the pharmaceutical industry.
  • the granulates obtained in steps 4 and 9 are mixed and they are compressed in a suitable tabletting press, for obtaining the specifications indicated in Tables 1 and 2.
  • a pre-compression of the granulates obtained in step 4 is performed. Over it, the formulation obtained in step 9 is added and both are compressed together in a suitable tabletting press, obtaining the bilayer tablets. Finally the weight of the bilayer tablets, along with the other parameters specified in Tables 1 and 2 are determined.
  • the manufacture of a pharmaceutical formulation comprising immediate-release etoricoxib in accordance with the present invention comprises, at least, the following steps:
  • step 3 Perform a wet granulation by adding the solution prepared in step 1 to the mixing of solids obtained in step 2 and add water and the remaining 50% of ethanol;
  • step 3 The granulate obtained in step 3 it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C;
  • step 4 The granulate obtained in step 4 is sieved by 0.7 to 2.0 mm mesh, and over it, magnesium stearate is sieved by 0.3 to 1 .0 mm mesh, and it is mixed during 1 to 5 minutes;
  • step 6 Compress the granulate obtained in step 5 or fill hard capsules with it.
  • the critical points of the manufacturing processes that must be considered are at least the following: i) mixing times: these times must be carefully evaluated to ensure the correct dispersion of the active ingredients, as well as the mixing time of the final mixture must be considered to avoid the lack of lubrication of the mixture, which can be evidenced by the adherence of the mixture to the punches; ii) the ratio of solvents: as indicated below in‘Results,’ the appropriate selection and ratio of the solvents will allow the complete dissolution of the etoricoxib; iii) the sequence of addition of the ingredients must be as indicated in the steps of the Examples of manufacturing processes, and; iv) controlled temperature in each step where specified.
  • the size of the sieves could change when different lot sizes are used. Therefore, the person skilled in the art will identify the appropriate size to obtain the products with the required parameters according to the present invention. The same will happen with the mixing times and temperatures in each stage that requires it.
  • To calculate the potency of the active in each of the obtained mixtures of etoricoxib and tramadol a sampling of 3 points of each one of the mixtures is performed, in the center, left side and right side, at two different depths. Between 0.5 to 1 .0 g are taken for each point and they are valued.
  • Each of the final mixes obtained are measured, independently, the following parameters: bulk density, tapped density, fluidity coefficient, Carr index.
  • the compression step As a norm, it is adjusted the hardness of the tablet varying the main compression force. Before performing the compression, the parameters of each layer in terms of average weight, thickness, diameter, hardness, disintegration and friability are adjusted. Finalizing the compression the hardness, friability, average weight, thickness and disintegration are measured.
  • tests to evaluate the solubility of etoricoxib in different media were performed. Between 1 to 2 g of etoricoxib were dissolved in each medium: water, ethanol, isopropanol, meglumine, Tween 80, Polyglycol 600, Polyglycol 400. Also, assays with mixtures in different proportions between the mentioned solvents were performed, and when it was suitable estimated, the heating was applied in order to benefit, and subsequently, evaluate, the etoricoxib solubilization in that conditions. Assays of Dissolution Profiles
  • the dissolution was quantified by two different pH: 1 .2 and 7.2.
  • the dissolution mediums used were: artificial gastric juice pH 1 .2; and phosphate tampon pH 7.2.
  • the patterns of XRPD were collected in a Fa. Stoe & Cie GmbH, STADI P diffractometer, Mythen detector, using the CuKa line as the source of radiation.
  • the data were collected between 2 and 50 °20, with a step size of 0.5 °20 and a re-counting time per step of 30 seconds.
  • Table 4 shows the experimental data obtained evaluating the solubility of etoricoxib in different solvents or carriers, which are typically used when it is necessary solubilizing and/or improving the solubility of diverse APIs with pharmaceutical purposes. It was found that in water, in a water/ethanol mixture, as well as in isopropanol, the etoricoxib was insoluble, wherein also it was observed the generation of a white precipitate. Probably in aqueous solution, this precipitate corresponds to the product of the polymorphic interconversion of etoricoxib, according to what is reported in the publication WO2014033526.
  • meglumine in combination with indicated solvents in the described conditions, to prepare a formulation comprising immediate-release etoricoxib.
  • meglumine -commonly used as an agent to adjust the pH and also as a surfactant agent and/or solubilizing- has been used as antibodies stabilizer, suppressing the formation of aggregates in solution and in the lyophilized preparations comprising them (US20091 17097).
  • document US4748174 describes that the formation of acid addition salts between meglumine and NSAIDs which are not soluble in aqueous solution or which present low solubility, improve the solubility of the respective NSAID, without adversely affecting the original pharmacological activity of the NSAID.
  • this document claims acid addition salts which are soluble in water, of meglumine with acetylsalicylic acid, bucoxico acid, flufenamic acid, mefenamic acid, niflumic acid, tiaprofenic acid, tolfenamic acid, bendazac, carprofen, ketoprofen, diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, fentiazac, flurbiprofen, isoxicam, naproxen, pirprofen, piroxicam, sulindac, suprofen, tenoxicam, tolmetin and zomepirac, and pharmaceutical compositions composed by the same ones for parental, oral, rectal and topical administration.
  • meglumine has been used to solubilize active principles other than etoricoxib, it has even been applied to solubilize many NSAIDs, which are different to etoricoxib, and on the other hand have been used diverse techniques, previously indicated, for improving the solubility of etoricoxib; nothing made it to predict that the meglumine could be useful to dissolve etoricoxib in aqueous solution, in such a way that it was also possible to use a wet granulation process for preparing a pharmaceutical combination comprising it.
  • Figure 1 of the present invention shows the X-ray powder diffraction (XRPD) of the etoricoxib polymorph I used in the present invention as the raw material for the manufacture of the pharmaceutical combinations
  • Figure 2 shows the XRPD performed to 6 independent samples taken from the etoricoxib layers of the pharmaceutical combination prepared according to the Example 3 of the present invention.
  • XRPD X-ray powder diffraction
  • Tables 5 and 6 show the experimental data obtained by quantifying the amount of the dissolved active ingredient, from bilayer tablets prepared according to the present invention, specifically from the Example 3 of Formulation. Considering that the release of the etoricoxib must be immediate once the formulation is orally ingested, dissolution assays to pH 1 .2 were performed in order to mimetic the gastric pH; expected place of dissolution of the formulation containing etoricoxib. Table 5 shows the obtained values for six independent samples, from bilayer tablets prepared according to the present invention. It was observed that the dissolution reached in 10 minutes with an average value (X) of 86% and a standard deviation (S) of 3.2.
  • the dissolved amount of the etoricoxib in 1 0 minutes is found within the required dissolution for immediate-release products, which must be greater than 85% in 15 minutes (https://www.fda.gov/downloads/drugs/guidances/ucm070237.pdf).
  • the full dissolution profile between 0 and 30 minutes is shown in Figure 3, wherein it is clearly observed that from the 15 minutes the dissolution of etoricoxib reached the maximum.
  • dissolution assays were performed at times of 30 minutes, 6 hours (240 minutes) and 8 hours (480 minutes), between pH values of pH 1 .2 and pH 7.2 for simulating the conditions of physiological pH.
  • the samples were dissolved in the dissolution medium 1 (see Table 3) at pH 1 .2, they were stirred and samples were taken at the 30 minutes; then it was adding the dissolution medium 2 (see Table 3) until reaching a pH of 7.2, and samples were taken at 240 and 480 minutes (https://www.fda.gov/downloads/drugs/guidancecomplianceregulatory
  • Table 6 shows the obtained values for the release of tramadol for 6 independent samples, from bilayer tablets prepared according to the present invention. It was observed that at the 30 minutes it was reached an average dissolution (X) of 32% with a standard deviation (S) of the data of 0.5, reaching a partial dissolution at the 240 minutes and achieving the full dissolution at the 480 minutes.
  • Figure 4 shows the full dissolution profile obtained for the release of tramadol, wherein it is clearly observed that at the 480 minutes (8 hours) the dissolution of tramadol reaches the maximum.

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Abstract

La présente invention concerne une combinaison pharmaceutique comprenant : i) une première formulation de chlorhydrate de tramadol à libération prolongée contenant de 2,0 % à 12,0 % p/p de chlorhydrate de tramadol, et ii) une seconde formulation d'étoricoxib à libération immédiate contenant de 6,0 % à 18 % p/p d'étoricoxib, des solvants ou un support; un procédé de fabrication pour préparer la combinaison pharmaceutique et les formulations individuelles, la combinaison étant présentée sous une forme posologique unique telle que, des capsules, des comprimés, des comprimés bicouches, des granulés et des sachets. La présente invention concerne également des méthodes de prévention et de traitement de la douleur, telle qu'une douleur aiguë, et l'utilisation de la combinaison pharmaceutique pour la prévention et le traitement de la douleur, telle qu'une douleur aiguë.
PCT/IB2017/058519 2017-12-29 2017-12-29 Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur WO2019130049A1 (fr)

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PCT/IB2017/058519 WO2019130049A1 (fr) 2017-12-29 2017-12-29 Combinaison pharmaceutique comprenant du chlorhydrate de tramadol à libération prolongée et de l'étoricoxib à libération immédiate, et son utilisation pour le traitement de la douleur
MX2018013070A MX2018013070A (es) 2017-12-29 2017-12-29 Combinación farmacéutica que comprende clorhidrato de tramadol de liberación extendida y etoricoxib de liberación inmediata, y su uso para el tratamiento del dolor.
ARP180103918A AR114074A1 (es) 2017-12-29 2018-12-28 Combinación farmacéutica que comprende tramadol clorhidrato de liberación extendida y etoricoxib de liberación inmediata, y su uso para el tratamiento del dolor
UY0001038043A UY38043A (es) 2017-12-29 2018-12-28 Combinación farmacéutica que comprende tramadol clorhidrato de liberación extendida y etoricoxib de liberación inmediata, y su uso para el tratamiento del dolor

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CN113521292A (zh) * 2020-04-15 2021-10-22 江苏恒瑞医药股份有限公司 一种cox-2抑制剂和曲马多的复方制剂

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