(
(51) International Patent Classification: Declarations under Rule 4.17: A61K9/24 (2006.01) A61K 31/135 (2006.01) — as to applicant's entitlement to apply for and be granted a A61K9/50 (2006.01) A61K 31/444 (2006.01) patent (Rule 4.17(H)) A61K 45/06 (2006.01) A61P 43/00 (2006.01) Published: (21) International Application Number: — with international search report (Art. 21(3)) PCT/IB20 17/0585 19 — with amended claims (Art. 19(1)) (22) International Filing Date: — in black and white; the international application as filed 29 December 2017 (29. 12.2017) contained color or greyscale and is available for download from PATENTSCOPE (25) Filing Language: English (26) Publication Language: English (71) Applicant: GRLTNENTHAL GMBH [DE/DE]; Ziegler- stralte 6, 52078 Aachen (DE). (72) Inventors: PATTARO MARCONDES, Lizandra; 1001 SW 21st Ave, Boca Raton, Florida, FL 33486 (US). RO¬ DRIGUEZ FLORES, Maria Lastenia; St. Moises Lu¬ na Andrade and OE3A, Quito (EC). OLEAS RECALDE, Mishel Estefania; Nicolas Lopez and Jaime Chiriboga OE3-138, Quito (EC). (74) Agent: ROMERO ROSALES, Margarita; Av. La Coruna E25-58 & Av. 12 de Octubre, Edif. Altana Plaza, 3rd Floor, Office 304, Quito EC170523 (EC). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available) : ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG).
(54) Title: PHARMACEUTICAL COMBINATION COMPRISING EXTENDED-RELEASE TRAMADOL HYDROCHLORIDE AND IMMEDIATE-RELEASE ETORICOXIB, AND ITS USE FOR THE TREATMENT OF PAIN (57) Abstract: A pharmaceutical combination comprising: i) a first formulation of extended- release tramadol hydrochloride containing from 2.0% to 12.0% w/w of tramadol hydrochloride, and ii) a second formulation of immediate-release etoricoxib containing from 6.0% to 18% w/w of etoricoxib, solvents or carrier; manufacturing process to prepare the pharmaceutical combination and the individual formulations, wherein the combination is presented in a single dosage form such as, capsules, tablets, bilayer tablets, granulates and sachets. The present invention provides methods of preventing and treating pain, such as acute pain, and the use of the pharmaceutical combination for the prevention and treatment of pain, such as acute pain. PHARMACEUTICAL COMBINATION COMPRISING EXTENDED-RELEASE TRAMADOL HYDROCHLORIDE AND IMMEDIATE-RELEASE ETORICOXIB, AND ITS USE FOR THE TREATMENT OF PAIN
SPECIFICATION
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.
PRIOR ART
According to the definition given by the International Association for the Study of Pain (https://www.iasp-pain.org/Taxonomy), 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 (NSAI Ds) 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. 11(3) : 264-270, 201 2).
For the first mentioned classes of drugs, the NSAI Ds, 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). The first step of the prostaglandin synthesis is catalyzed by COX which converts arachidonic acid (AA) in prostaglandin G2 (PGG2). However, 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
mediators, it can be found in the macrophages, gastric epithelium , vascular and synovial endothelium (particularly in the renal vascular system). 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).
Among the non-selective NSAIDs, so-called traditional or conventional, aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, sulindac, diclofenac, piroxicam , beta piroxicam , meloxicam and ketoprofen are found. Within the selective NSAI Ds or COX-2, rofecoxib, valdecoxib, parecoxib, celecoxib, etoricoxib and lumiracoxib are found (Baltouni M., Arq. Bras. Cardiol. 94(4) : 538-546, 201 0).
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. 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 (WO01 92230, WO01 37833, W020050851 99). It has a limited water solubility, the relative solubility in equilibrium of the hemihydrate is 0.07 mg/mL, and its pKa is 4.6 due to the pyridine functio nality that it presents, and, consequently, the aqueous solubility is strongly dependent of the pH. Pharmaceutical products containing 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). The recommended administration of 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. Thus, for relieving the symptoms caused by osteoarthritis is 30 to 60 mg once a day, for rheumatoid arthritis is 90 mg once a day, and for pain and signs of inflammation associated with arthritis of acute gout, the recommended dose is 120 mg once a day (http://www.ema.europa.eu/ema/index.jsp7curkpages/medicines/human/referrals/Arcoxia/human_referral _0001 29.jsp&mid=WC0b01 ac05805c51 6f).
Formula 1. Chemical structure of the etoricoxib For the second group of drugs used in the treatment of acute pain, as defined by Manjunath Sh. et al in J. Maxillofac 11(3) :264-270, 201 2 , opioid analgesics are found and among them it is distinguished the tramadol for its safety profile. Specifically the tramadol hydrochloride, of chemical name hydrochloride of
( 1 RS, 2RS)-2-[(dimethylamino) methyl] - 1 - (3-methoxyphenyl) cyclohexanol , of chemical structure according to the Formula 2 , it is an analgesic which relieves pain by acting on specific nerve cells of the spinal cord and brain . 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 µ 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 µ receptors and it inhibits the reuptake of norepinephrine, while the (-) enantiomer inhibits reuptake of norepinephrine and it stimulates the a-2 adrenergic receptors. The use of 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 S 16LBL. 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, https://www.accessdata.fda.gov/drugsatfda_docs/label/201 5/204421 Origl s000lbl.pdf)
Formula 2. Chemical structure of the tramadol hydrochloride (racemate).
Even though 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. Thus, the association between NSAIDs and opioids is a common practice for the treatment of the acute post-surgery pain due to the increased analgesic effect and the decrease of the occurrence of adverse reactions (Na H.S. et al. , Korean J. Anesthesiol. 60(1 ): 30-35, 201 1) . The multimodal analgesia or balanced analgesia, intends to respond to this need through the rational use of combinations among analgesics. The combination of different analgesics has as objective to achieve an additive or synergistic therapeutic effect with a lower incidence of undesirable side effects, what it achieved specially when drug doses is lower than the conventional dose (Rodrigues-Silveiro J. et al., Drug Development Research. 72(5) :
391 -396, 201 1). In the literature, diverse pharmaceutical forms are described which comprise inhibitors of COX-2 and opioids such as pharmaceutically active ingredients, which are detailed below.
In publication W003070251 it is indicated that the combination of a COX-2 inhibitor with an opioid, would produce a greater analgesic effect. In this document, a composition comprising a COX -2 inhibitor and an opioid is claimed, indicating that the COX-2 inhibitors which could be used are meloxicam , celecoxib and rofecoxib, and among the opiates codeine, morphine, tramadol and fentanyl are included. In order to dispose comparative data, in this document, a triple liquid combination of meloxicam , codeine and paracetamol is exemplified, orally administered to rats, finding that there is an important antihyperalgesic activity, wherein the required meloxicam dose is 10 times less compared to the administration of meloxicam alone. Disposing a combination of meloxicam and codeine (without paracetamol), it was found that it is generated a significant opioid-type analgesia, but a greater codeine dose was required. It is indicated that the tramadol is another opioid having a greater analgesic efficacy than codeine, and it does not lead to perceptions of causing constipation and the abuse potential that codeine has. Therefore, it is indicated that it seems reasonable that a combination of meloxicam with tramadol would produce a better analgesia, and with lower doses when comparing with meloxicam and codeine, even though results for this pharmaceutical combination are not shown. However, this document does not mention the possibility of a combination between tramadol and etoricoxib, as well as it is not either mentioned the required release or delivery form for each one of the active ingredients.
The patent application WO201 004341 2 refers to co-crystals formed by tramadol and by a NSAI D, 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. For the tramadol and naproxen co-crystal it is indicated that the preferred molecular ratio is 1:2, while for 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. It is also mentioned that the association of two active principles in the form of a co crystal, shows many advantages, since as they are linked they offer a behavior as if they were a single entity, facilitating the treatments, the form and the dosage, among others. Another advantage mentioned in the document WO201 004341 2 is referred to bioavailability tests of the co-crystal of (rac)-tramadol-HCI- celecoxib ( 1 :1 ) , and it is indicated that an increase in the release of celecoxib is obtained when it is administered as co-crystal, compared with celecoxib when it is administered alone. However, the document does not show comparative experimental data to support said affirmations, as well as it is not either mentioned some example including tramadol and etoricoxib. In relation to the development of co-crystals for the treatment of pain, in the main claim of another patent application WO201 1044962, a co-crystal is claimed, comprising a combination of tramadol and at least one coxib, mentioned among these latter compounds is etoricoxib. Reviewing the subject matter disclosed in WO201 1044962 and WO201 004341 2 examples including tramadol and etoricoxib were not found, but they only referred to a co-crystal of tramadol and celecoxib.
Meanwhile, the patent application WO201 10 15360 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. In the specification of said document it is mentioned 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). Within the preferred COX-2 inhibitors, they include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib and cimicoxib. Although 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.
It is interesting to note that, comparatively, it was found that etoricoxib and rofecoxib are inhibitors of COX-2, which are more selective than celecoxib (Howard P. et al., J. Am. College of Cardiol. 43(4) : 5 12- 525, 2004.). On the other hand, it has been studied the analgesic efficacy of pre-surgery administration of etoricoxib versus celecoxib, for relieving the post-surgery pain after the reconstruction of the arthroscopic anterior cruciate ligament (Boonriong et al. , Musculoskeletal Disord. 11: 246, 201 0). It was found that the patients group which received etoricoxib had significantly less pain intensity than the pain of the other two groups, and by a period of up to 8 hours, while the group receiving celecoxib did not show significant difference with the placebo at any measured point of time. It was concluded that etoricoxib is more effective than celecoxib.
Patent application W00051 685 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. Said document indicates that the mentioned 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.
In the examples disclosed in this publication, it is indicated that 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. W00051 685 does not describe a pharmaceutical combination comprising tramadol and etoricoxib.
On the other hand, it has been found published a study regarding the interaction between etoricoxib and tramadol, in the mechanical hyperalgesia induced by spinal cord injury in rats (Singh V. et al. , Life Science 78: 168-1 174, 2006). The nature of the interaction between these two APIs was carried analyzing the synergistic interaction surface (SSI) and through a isobolographic analysis. Toricoxib as well as tramadol, when were individually administered to rats, showed different antihyperalgesic potencies. It was discovered that both drugs have a prolonged action against this model of hyperalgesia. Also, the etoricoxib and tramadol were co-administered in fixed proportions of fractions EDso, in the solution form , wherein the concomitant administration of these APIs resulted in the potentiation of the therapeutic effect, when the results were analyzed by SSI, and analyzing by isobologram, it was found that the experimental EDso was far below of the additivity line, which indicated that there is a significant synergistic antihyperalgesic effect (P <0.05). In patent application US20080026054 it is claimed a slow-release pharmaceutical composition comprising a core with a therapeutically effective amount of tramadol or a salt thereof, a slow-release coating, and an immediate-release layer comprising a therapeutically effective amount of a NSAID or a pharmaceutically acceptable salt, wherein said NSAI D can be etoricoxib, among others. It is exemplified a combination in individual presentations of 7.5 mg of immediate-release meloxicam on the one hand, and 100 mg of slow-release tramadol on the other hand, which were co-administered in clinical trials with 140 patients which presented pain for more than 6 months, including neuropathic pain , osteoarthritis, rheumatoid arthritis, fibromyalgia, low back pain and musculoskeletal pain , as fixed dose twice a day. The results showed that the pain significantly decreases compared with the application of each API separately.
Also, the slow-release of tramadol allowed to reduce in a 33% the dose of meloxicam maintaining the same level of relief in the patient. While in a dependent claim of the Application US20080026054 etoricoxib is mentioned as a possibility among the NSAIDs to use, it is not presented in any specific example including a combination of tramadol and etoricoxib, in a single formulation.
However, recently it has been published the W0201 7 1991 40 wherein a process and a pharmaceutical composition of a combination of tramadol and etoricoxib are claimed. In this publication a process for preparing the composition is described and different oral dosage forms are mentioned, but no formulation or advantage of this combination and / or process are disclosed.
Regarding the administration routes, the international filing W0200809221 9 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. Additionally, in another publication, W02009067703, it is described pharmaceutical compositions useful for treating pain, comprising slow-release tapentadol hydrochloride and a second analgesic which can be tramadol, an analogue of GABA or an NSAI D. Among the different exemplified formulations described in this latter document, it is mentioned a bilayer tablet comprising tapentadol hydrochloride and naproxen. It is not mentioned a combination between tramadol and etoricoxib.
Also, for disposing suitable administration forms, it is important that 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. In relation to the latter, 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. These aspects have been resolved in different ways, which include the use of crystalline forms of etoricoxib, of hydrated forms, of diverse salts of etoricoxib, and the use of certain excipients and combinations thereof.
This is how in WO201 2004677 new forms in solid state for etoricoxib are disclosed. Particularly, the oxalate, succinate, fumarate, besylate, hydrobromide, glutamate, benzoate, cinnamate and salicylate salts are claimed. Also, it is disclosed said etoricoxib salts in crystalline form , which present good flow properties and stability at room temperature, in relatively high humidity, and in aqueous medium. In this context, in the filing EP2601 952 succinate, adipate, fumarate, benzoate, salicylate, saccharinate, hydrochloride, hydrobromide, nitrate, sulfate salts, hydroxy naphthoic salts, and co-crystals of etoricoxib are claimed, indicating that with them it would be possible to modulate and improve the consistency of the physical-chemical properties of the etoricoxib allowing its administration in different dosage forms, including for oral administration.
In the international publication WO201 6036588, the problem of the restricted solubility of etoricoxib in aqueous solution is described. It is indicated that the use of typical solubilizing agents, such as buffers, counterions, solvents and/or surfactants in aqueous solutions are unable to overcome the low solubility of the etoricoxib for producing an injectable formulation. On the other hand, it is mentioned that the limited aqueous solubility of etoricoxib suggests that the injection of a suspension would result in a prolonged elimination of the drug from the intramuscular space and, consequently, it wou ld not result in therapeutic regimen of successful administration once a day, since the pharmacokinetics exposure after intramuscular injections of etoricoxib suspensions, heavily depend on the size of the particle of the drug. 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 0.2-1 4 pm and an aqueous injection carrier.
In one of the embodiments disclosed by the patent application WO201 4033526 a pharmaceutical composition in tablets or capsules form is provided, 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. Document WO201 4033526 indicates that the etoricoxib compositions can be prepared using techniques known in the prior art, but it is indicated that when the composition of etoricoxib is prepared by wet granulation using water, there is a polymorphic conversion of etoricoxib in the composition, which can lead to a decrease in the solubility and/or stability of the final composition, but the polymorphs which could be generated are not specified. Thus, this document proposed to use a dry granulation process and one solubility enhancer, conditions under which it was found that no polymorphic conversion of etoricoxib occurred in the composition, remaining stable, as well as the solubility of etoricoxib is not hampered.
In the patent application WO201 601 5776 is commented that by using excipients commonly used in the pharmaceutical industry it cannot achieve a desired in vitro-release profile of etoricoxib, due to the use of etoricoxib particles which form crystals in needles shape in aqueous solution, generally have the inconvenient that the particles stick to the equipment used during manufacturing of the pharmaceutical composition, such as the walls of a compression. In this document it was found that the dissolution in vitro and the manufacturing process of the pharmaceutical composition of etoricoxib, mainly depends on the excipients properties and the used technological processes. This is how a preferably solid pharmaceutical composition is proposed, which comprises etoricoxib, preferably the polymorphic form I or a pharmaceutically acceptable salt thereof and at least one pH modifying agent. However, this document does not indicate or suggests that the described formulation and procedures would be appropriate to be used in a combination with a second API .
Document CN1 05343002 describes the preparation of an etoricoxib oral microemulsion, suitable for large-scale production, wherein the emulsion comprises 1-3% of etoricoxib, 3-1 0% of oily phase, 3-1 0% of emulsifier, 3-1 0% of co-emulsifier, 0-0.2% of sweetener agent, 0-0.5% of essence, 0.1 -0.5% of preservative and 70-90% water. For solving the problem of the difficult dissolution of etoricoxib in 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. Thus, liquid drops of oil-in-water type microemulsion which coat the etoricoxib. On the other hand, document CN1 04586799 it is claimed dispersible tablets of etoricoxib and a preparation method thereof, wherein for obtaining a suitable sol ubility and speed of dissolution of the active principle, it is used a solid dispersion medium and lyophilization or spray drying.
In addition , in the publication W0201 7 1991 40 has been described a process to prepare a combination of tramadol and etoricoxib which consist in a simple dissolution of etoricoxib in a dissolvent, but it is not mentioned what dissolvent would be appropriated. According to the prior art, etoricoxib needs special dissolution in order to avoid the formation of crystals in needles shape or agglomerates that stick to manufacturing equipments (WO201 601 5776).
From the above-mentioned prior art, it is concluded that one of the current trends has been the development of pharmaceutical combinations of fixed-dose of two APIs, in order to obtain a therapeutic effect in the treatment of pain with lower doses and rapid action. One of the more interesting combinations is the association of tramadol and etoricoxib since, in the one hand, it has been observed its synergistic effect and fewer side effects, and on the other hand, it would exist therapeutic benefits by combining tramadol with etoricoxib in particular, since the etoricoxib is a selective NSAI D for COX-2 with proven analgesic superiority on its homologous celecoxib, as it has been previously mentioned, according to what is disclosed by Howard P. et al. in Journal of the American College of Cardiology 43(4) : 5 12-525, 2004. By having a single dosage form containing both APIs, it would be avoided the multiple dosing to achieve the beneficial effect that delivers the joint administration of tramadol plus etoricoxib. However 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. Thus, it is observed in the prior art that the use of typical solubilizing in aqueous solutions (buffers, counterions, co-solvents and/or surfactants) does not overcome the low solubility of etoricoxib and, although some strategies have been described in the prior art, such as the use of particulate etoricoxib, restriction of the polymorphic interconversion by dry granulation associated to a solubility enhancer, new forms of solid state such as etoricoxib salts, and the use of pH modify agents; nothing suggests about the possibility of combining tramadol and etoricoxib in a single pharmaceutical dosage forms taking into account their half-lives and their different solubility. Therefore, there is a need of having a single dosage form comprising a combination of tramadol and etoricoxib, along with the needed to provide formulations that meet the particular dosing requirements of each API , ensuring an appropriate release of each one according to their particular half- lives.
DETAILED DESCRIPTION OF THE INVENTION
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 inventors found that in addition to solve the solubility problems of etoricoxib, a particular formulation separated from each API allowed the development of a fixed-dose combination without negatively affecting the physical-chemical characteristics of each API during the manufacturing process, and the separation of the formulation of both APIs incorporating specific excipients for each one, lead to surprisingly find that the fixed-dose combination of the present invention released each API according to their requirements of daily dosing, therefore, it can be administered once a day, since it releases each active ingredient in a different manner.
Thus, as the inventors found that 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 . In this way, 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. Although in the prior art, on the one hand there are formulations of extended-release tramadol and, on the other hand, of immediate-release etoricoxib, there is no any single dosage form which comprises both types of release, as there is also no evidence to deduce that with the mere union of both formulations it would be possible to achieve a single dosage form to administer 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.
In more detail, 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 .
In a preferred embodiment, 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.
More preferably, the present invention relates to a pharmaceutical combi nation 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.
In a more preferred embodiment, 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.
According to a first aspect, 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.
Preferably, 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: 20.6% to 25% w/w of an extended-release matrix, 0.7% to 3.0% w/w of one or more lubricants, 8.7% to 12% w/w of a disintegrant; B) A second formulation of immediate-release etoricoxib containing from 6.0% to 18% w/w of etoricoxib as the second pharmaceutically active ingredient, and containing the following pharmaceutically acceptable excipients: 8.0% to 12.3% w/w of a surfactant, 29.1 % to 34.0% w/w of one or more disintegrants, 0.8% to 2.5% w/w of a binder, 2.0% to 3.0% w/w of a lubricant,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, pharmaceutically acceptable 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.
More preferably, the present invention consists of a pharmaceutical combination comprising :
A) A first formulation of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as pharmaceutically active ingredient, and containing the following pharmaceutically acceptable excipients: 23.0% to 23.5% w/w of an extended-release matrix, 0.7% to 1.1% w/w of one or more lubricants, 10.0% to 10.6 % w/w of a disintegrant; B) A second formulation of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as pharmaceutically active ingredient, and containing the following pharmaceutically acceptable excipients: 11.6% to 12.3% w/w of a surfactant, 32.4% to 33.3% w/w of one or more disintegrants, 1.0% to 1.5% w/w of a binder, 2.2% to 2.5% w/w of a lubricant,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, pharmaceutically acceptable 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.
According to a second aspect, 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 3 1.0% w/w of etoricoxib,
13.8% to 2 1.2% w/w weight of meglumine, 5.4% to 8.6% w/w of sodium carboxymethyl starch, 44.8 to 50.0% w/w of microcrystalline cellulose, 1.4% to 4.3% w/w of polyvinylpyrrolidone, 3.4% to 5.2% w/w of magnesium stearate, 0.2% to 0.4% w/w of a pharmaceutically acceptable dye, and alcohol and water as solvents or carriers; wherein the solvents or carriers are not included within the total weight of the pharmaceutical formulation.
According to a third aspect, 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.
According to a fourth aspect, the present invention refers to a manufacturing process to prepare the pharmaceutical formulation of immediate-release etoricoxib.
In the present invention, 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.
In 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.
The term "pharmaceutically active ingredient" or "API", as it is used in the present invention, it refers to a substance having a therapeutic effect.
The term "pharmaceutically acceptable excipient", as used in the present invention, means that it is an acceptable excipient from the point of view of its toxicity to humans.
The term "disintegrant", as used in the present invention, 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.
The term "lubricant", as used in the present invention, 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. The term "extended-release matrix", as used in the present invention, refers to pharmaceutically acceptable excipients which are used in order to release the API in an extended period of time from its administration. 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) K 15M, HPMC K 1 00M and HPMC K200M, and polyacrylate polymers, such as Eudragit RL1 00 and Eudragit RS1 00, or a mixture thereof.
The term "surfactant", as used in the present invention, 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.
The term "binder", as used in the present invention , refers to those agents which maintain bound the combined products, thus maintaining the granulation. Examples of 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.
The term "solvent" or "carrier", as used in the present invention, 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. Within the used 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.
Other pharmaceutically acceptable excipients comprised by the present invention include flavoring agents, load agents, adhesives, dyes, and sweetening agents.
BRIEF DESCRIPTION OF THE FIGURES
The invention is illustrated, but is not limited by the attached drawi ngs, in which :
Figure 1. X-Ray powder diffraction (XRPD) pattern of etoricoxib polymorph I. The XRPD pattern of the etoricoxib polymorph I, the raw material used in the preparation of the pharmaceutical combination of the present invention, is shown. The diffraction pattern showed a crystalline structure and comprised distinctive reflections, expressed as values of 20°, in 7.5; 9.73; 11.8; 12.42; 13.01 ; 15.51 ; 16.58; 18 .14 ;
19 .19 ; 19.4; 20.07; 2 1.18 ; 2 1.51 ; 2 1 .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; 3 1 .28; 34.78; 35.83 and 39.27.
Figure 2. X-Ray powder diffraction (XRPD) pattern of the etoricoxib hemihydrate. The XRPD pattern of the etoricoxib hemihydrate, the species of etoricoxib present in the pharmaceutical combination of the present invention, is shown. 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; 6.1 3 ; 7 .10 ; 9.07; 9.85; 10.83; 13.46; 16.41 ; 24.54 and 35.95. Figure 3. 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.
Figure 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.
EXAMPLES
With the purpose of illustrating the present invention, the following examples are provided, which must be interpreted in a not limiting manner.
A skilled person in the art will appreciate variations and routine modifications can be performed to the following examples, without exceeding the scope of the invention.
Example 1 of pharmaceutical combination :
Pharmaceutical combination comprising a first formulation of extended-release tramadol hydrochloride and a second formulation of immediate-release etoricoxib and which contains the following ingredients:
*% w/w, it is referred to the total weight of the combination. * *The solvents or carriers are not included within the total weight of the pharmaceutical combination .
Example 2 of pharmaceutical combination :
Pharmaceutical combination comprising a first formulation of extended-release tramadol and a second formulation of immediate-release etoricoxib and which contains the following ingredients:
*% w/w, it is referred to the total weight of the combination. * *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.
Example 3 of pharmaceutical combination :
Pharmaceutical combination 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: *% w/w, it is referred to the total weight of the combination. * *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.
Example 4 of etoricoxib formulation
Pharmaceutical formulation of immediate-release etoricoxib comprising the following ingredients:
*% w/w, it is referred to the total weight of the combination. * *The solvents or carriers are not included within the total weight of the pharmaceutical combination.
Example 5 of etoricoxib formulation
Pharmaceutical formulation of immediate-release etoricoxib comprising the following ingredients: *% w/w, it is referred to the total weight of the combination. * *The solvents or carriers are not included within the total weight of the pharmaceutical combination .
Example of Manufacturing Process 1
The manufacture of a pharmaceutical combination comprising two formulations in accordance with the present invention comprises, at least, the following steps:
Provide the first formulation of extended-release tramadol hydrochloride by the following steps:
1.- Sieve tramadol, the extended-release matrix, disintegrant and the half of the lubricants;
2.- The mixture of step 1 is pre-compressed and then it is granulated to finally add the second fraction of lubricants.
Provide the second formulation of immediate-release etoricoxib by the following steps:
3.- Mixing one part of a first solvent, the binder and the dye;
4.- A sieved mixture of solids is prepared which comprises the surfactant, two disintegrants and etoricoxib;
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;
6.- The granulate obtained in step 5 it is placed in the fluid bed and it is dried;
7.- The granulate obtained in step 6 is sieved and lubricant is added.
To obtain capsules, according to the present invention, 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.
To obtain conventional tablets, according to the present invention, 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 .
To obtain tablets in the bilayer tablet form according to the present invention, a pre-compression of the granules obtained in step 2 is performed. Over it, the formulation obtained in step 7 is added and both are compressed together in a suitable tabletting press, obtaining the bilayer tablets. Finally it is determined the weight of the bilayer tablets, along with the other parameters specified 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:
Provide a composition for the first formulation of extended-release tramadol hydrochloride by the following steps:
1.- Sieve tramadol, the extended-release matrix, and the disintegrant agent by 0.3 to 1.0 mm mesh, preferably by 0.5 mm mesh. The mixing time is 10 to 20 minutes;
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;
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 ;
4.- 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.
Provide a composition for the second formulation of immediate-release etoricoxib by the following steps:
5.- 50% of total ethanol is mixed with the binder which is slowly added over it, and all together it is stirred for about 30 to 45 minutes. Once the binder is dissolved the dye is added and the mixing is maintained during 15 to 30 more minutes.
6.- It is prepared a mixture of solids comprising the surfactant, two disintegrants, and etoricoxib, which are previously sieved in a 0.7 to 2.0 mm mesh, preferably in a 1.0 mm mesh. The mixing time is 5 to 15 minutes;
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;
8.- 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;
9.- 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.
To obtain capsules, according to the present invention , the granulates obtained in steps 4 and 9 , are encapsulated in hard capsules, procedure widely known and used in the pharmaceutical industry.
To obtain conventional tablets, according to the present invention, 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 . To obtain tablets in the bilayer tablet form according to the present invention, 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.
Example of Manufacturing Process 3
The manufacture of a pharmaceutical formulation comprising immediate-release etoricoxib in accordance with the present invention comprises, at least, the following steps:
1.- Slowly add 50% of total ethanol over the polyvinylpyrrolidone, and mix them by stirring during 30 to 45 minutes. Once the polyvinylpyrrolidone is dissolved, the dye is added and the mixing is maintained during 15 to 30 more minutes;
2.- Prepare a mixture of solids comprising meglumine, sodium carboxymethyl starch, microcrystalline cellulose, and etoricoxib, which are previously sieved in a 0.7 to 2.0 mm mesh, and mix during 5 to 15 minutes;
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;
4.- 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;
5.- 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;
6.- Compress the granulate obtained in step 5 or fill hard capsules with it.
Finally, determine the weight of the bilayer tablets, along with the other parameters specified in Tables 1 and 2 .
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 desired parameters in the present invention, in the mixture step, for each layer, are the indicated in the following Table 1:
In 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.
The desired parameters in the present invention, in the compression step, are the indicated in the Table 2 :
Assays of Solubility
In the present invention 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
In the present invention, 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 conditions of the dissolution assays are summarized in the following Table 3 :
X-rav powder diffraction (XRPD)
In the present invention, 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 °2 , with a step size of 0.5 °2 and a re-counting time per step of 30 seconds.
RESULTS
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 WO201 4033526. In mixtures of ethanol with polysorbate-type solvents (Tween 80) which are non-ionic surfactants, and with polyethylene glycols whose nature is hydrophilic character, it was observed a better solubility than by using water, alcohols and/or their mixtures, but only a partial solubilization of the API was obtained, which could lead to further troubles which make difficult the process of preparation of a pharmaceutical formulation comprising etoricoxib (WO201 601 5776).
Table 4. Solubility of etoricoxib in different solvents and/or mixtures of solvents. * Different proportions were assayed.
However the above results, the inventors tried with an alternative mixture and surprisingly found that by using meglumine, a hydrophilic organic base, mixed with ethanol and water, in specific proportions, the solubility of etoricoxib significantly improved, and even more, the full solubility of this API was obtained when it was used a w/w ratio of meglumine and ethanol in the range of from 0.5:1 0 to 3:1 0 along with a w/w ratio of water and ethanol in the range of from 1:5 to 1:1 2 . To obtain a faster solubi lization, heat can be applied in an interval between 25° to 35°C.
With this unexpected finding, it was possible to use meglumine in combination with indicated solvents in the described conditions, to prepare a formulation comprising immediate-release etoricoxib.
In the literature it is disclosed that 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). Meanwhile, document US47481 74 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 NSAI D, without adversely affecting the original pharmacological activity of the NSAID.
Thus, 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 . It is indicated that the preparation of the water-soluble salts are prepared by direct reaction between meglumine with NSAI Ds in equimolar amounts. Additionally, in the international publications W02007061 4 15 and WO201 0057449, it has been reported the use of meglumine along with other surfactants or basic agents, for solubilizing telmisartan. It is not described nor suggested in any of these documents the use of meglumine for solubilizing etoricoxib in aqueous medium, a medium wherein the etoricoxib is completely insoluble.
Furthermore, and as noted above, although in documents WO201 6036588, WO201 4033526, WO201 601 5776 and CN1 05343002 diverse techniques to solubilize the etoricoxib were used, namely: use of a specific particle size of etoricoxib, use of solubility enhancers, use of pH modifiers, preparation of a microemulsion and the use of dry granulation in combination with a pH modifier, it was not proposed in none of them the application of meglumine to achieve the solubilization of etoricoxib in aqueous medium, conversely, dry granulation is suggested in order to avoid the generation of insoluble products (WO201 4033526).
Therefore, despite the fact that in the prior art meglumine has been used to solubilize active principles other than etoricoxib, it has even been applied to solubilize many NSAI Ds, 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. Even more, it was needed to assay different solvents, testing different proportions of the ethanol/water/meglumine mixture, as well as different temperatures of said solvents for achieving the full solubilization of etoricoxib, and subsequently achieve a successful preparation process by wet granulation , which would lead to the preparation of the formulation comprising etoricoxib with an appropriate release profile which allows to elaborate the pharmaceutical combination of etoricoxib and tramadol, with different dissolution profiles for each API, according to what is proposed in the present invention.
In relation to the manufacturing process of the pharmaceutical combination disclosed in the examples of the present invention, as indicated, with in the steps for the preparation of the formulation comprising etoricoxib, a wet granulation process was used, conversely to what is suggested in the prior art which teaches the use of dry granulation to prevent the formation of insoluble and unstable species of etoricoxib (WO201 4033526). However, in the present invention surprising results have been obtained which demonstrate that in aqueous solution, with the manufacturing process used in the present invention, it is generated only the etoricoxib hemihydrate, stable and soluble specie of this API . In relation to the latter, 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, while 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. From the analysis and comparison of both XRPD (Figures 1 and 2) with the prior art, it was confirmed that: i) the raw material (Figure 1) actually is the etoricoxib in its polymorphic I form, since the main peaks in the XRPD of the raw material positioned in 11.8, 9.73, 15.51 , 20.07, 22.77 and 24.1 9 match the reported peaks for the etoricoxib polymorph I, as it has been disclosed in WO2001 037833; and, ii) the etoricoxib polymorph I is transformed to the etoricoxib hemihydrate specie (Figure 2) after the manufacturing process of the formulation of the present invention, which remained stable as can be seen in the patterns collected from the 6 evaluated samples, which main peaks obtained in 3.49, 3.62, 3.79, 3.94, 4.04, 4.1 4 , 4.43, 4.54, 5.03,
5.26, 5.53, 5.73, 6.1 3 and 10.83 showed a good fit to those reported for the etoricoxib hemihydrate in the WO2001 092230 publication. While this conversion would be expected according to what was reported by
Dalton CH. et al. in Journal of Pharm . Sc. 95(1 ) 2006, wherein it is indicated that in aqueous solution the etoricoxib polymorph I is transformed to the hemihydrate, the interesting thing is that through the experimental conditions used to carry out the process of preparation of the pharmaceutical combination proposed, that is, achieving a suitable solubilization of etoricoxib and then using a wet granulation process, a pharmaceutical combination comprising only the etoricoxib hemihydrate was obtained, which is a stable specie (Ramukutty S. et al. , Int. J. of Biological & Pharmaceutical Res. 10(5) : 783-785, 201 4), without the presence of other unstable and insoluble species which should have been generated by decreasing the solubility of the API, as described in the publication WO201 4033526. According to the results shown below, the manufacturing process used in the present invention , which led to the generation of only the etoricoxib hemihydrate, allowed to obtain a suitable dissolution of the etoricoxib and independently the dissolution of the another API, tramadol, from the pharmaceutical combination prepared according to the present invention.
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 10 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.
Table 5. Percentage of dissolution of etoricoxib at pH 1.2 in the indicated times, from bilayer tablets according to Example 3 of the pharmaceutical combination of the present invention.
On the other hand, having in consideration that the release of the tramadol must be extended once the formulation is orally ingested, 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. For this, 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 information/guidances/ucm070239.pdf). 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.
In summary, from the pharmaceutical combination designed from the present invention, the independent release of both APIs was achieved, i.e., the immediate release of etoricoxib in 10 minutes was reached, with an average value of 86%, and the extended-release of tramadol was obtained, releasing this
API from initial times reaching 32% in 30 minutes and a full dissolution in 8 hours.
Table 6. Percentage of dissolution of the tramadol at pH between 1.2 and 7.2 in the indicated times, from bilayer tablets according to Example 3 of the pharmaceutical combination of the present invention.
Therefore, from the obtained data, it is possible to conclude that, the appropriate solubilization of etoricoxib, the manufacturing process of the formulation that comprises it, as well as the excipients and the proportions thereof used in each one of the formulations of the pharmaceutical combination according to the present invention, allowed to achieve in a surprising way the independent release of each API, and thus achieve an oral pharmaceutical combination which comprises extended-release tramadol and immediate- release etoricoxib in a single dosage form which is appropriate for being administered once a day, according to its dissolution profiles obtained in the present invention. CLAIMS
1. A pharmaceutical combination comprising: 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 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; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
2 . A pharmaceutical combination according to claim 1 comprising: 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, 20.6% to 25% w/w of an extended-release matrix, 0.7% to 3.0% w/w of one or more lubricants, 8.7% to 12% w/w of a disintegrant; and b) a second formulation of immediate-release etoricoxib containing from 6.0% to 18% w/w of etoricoxib as the second pharmaceutically active ingredient, 8.0% to 12.3% w/w of a surfactant, 29.1 % to 34.0% w/w of one or more disintegrants, 0.8% to 2.5% w/w of a binder, 2.0% to 3.0% w/w of a lubricant,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
3 . A pharmaceutical combination according to any of the previous claims comprising: a) a first formulation of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of an extended-release matrix,
0.7% to 1. 1 % w/w of one or more lubricants, 10.0% to 10.6% w/w of a disintegrating, and b) a second formulation of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of a surfactant, 32.4% to 33.3% w/w of one or more disintegrants, I .0% to 1.5% w/w of a binder, 2.2% to 2.5% w/w of a lubricant, 0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
4 . A pharmaceutical combination according to any of the previous claims 1 to 3 wherein the surfactant is selected from phospholipids, polyethylene glycols, meglumine, sorbitol esters, polysorbates, polyoxyethylene ethers, or mixtures thereof.
5 . A pharmaceutical combination according to any of the previous claims 1 to 3 wherein the solvents or carriers are selected from ethanol and water or mixtures thereof.
6 . A pharmaceutical combination according to any of the previous claims comprising: a) a first formulation of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second formulation of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, I I .6% to 12.3% w/w of a meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, 1.0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
7 . A pharmaceutical combination according to claim 6, wherein meglumine, ethanol and water, in the second formulation of immediate-release etoricoxib, are comprised in particular w/w ratios between them.
8 . A pharmaceutical combination according to claim 7 wherein the w/w ratio of meglumine and ethanol is in the range of from 0.5:1 0 to 3:1 0, and the w/w ratio of water and ethanol is in the range of from 1:5 to 1: 1 2 .
9 . A pharmaceutical combination according to claim 1, wherein the first formulation of extended-release tramadol hydrochloride a) and the second formulation of immediate- release etoricoxib b) are in the granulate form.
10 . A pharmaceutical combination according to claim 1, wherein the first formulation of extended-release tramadol hydrochloride a) and the second formulation of immediate- release etoricoxib b) are in the layer form.
11. A pharmaceutical combination according to claim 1, wherein said combination is an oral dosage pharmaceutical form.
12 . A pharmaceutical combination according to claim 1, wherein said combination is an oral dosage pharmaceutical form comprising capsules, tablets, bilayer tablets, granulates or sachets.
13 . A pharmaceutical combination according to claim 1, wherein said combination is in the capsule form.
14 . A pharmaceutical combination according to claim 1, wherein said combination is in the tablet form.
15 . A pharmaceutical combination according to claim 1, wherein said combination is in the bilayer tablet form.
16 . A pharmaceutical combination according to claim 1, wherein said combination is in granulate form. 17 . A pharmaceutical combination according to claim 1, wherein said combination is in sachet form.
18 . A pharmaceutical combination according to claims 1, 9, 12 or 13 wherein said combination is in the capsule form, comprising: a) a first granulate of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second granulate of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of a meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, I .0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate, 0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, one or more solvents or carriers such as ethanol and water or mixtures thereof; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
19 . A pharmaceutical combination according to claims 1, 10, 12 or 15 wherein said combination is in the bilayer tablet form, comprising: a) a first layer of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second layer of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, I I .6% to 12.3% w/w of a meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, 1.0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye,
one or more solvents or carriers such as ethanol and water or mixtures thereof; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
20. A pharmaceutical combination according to claim 19 wherein said combination is in the bilayer tablet form, comprising: a) a first layer of extended-release tramadol hydrochloride containing 5.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.3% w/w of hypromellose, 0.4% w/w of colloidal silicon dioxide, 0.42% w/w of magnesium stearate, 10.4% w/w of microcrystalline cellulose; and b) a second layer of immediate-release etoricoxib containing 12.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 12.0% w/w of a meglumine, 4.7% w/w of sodium carboxymethyl starch, 28.1 % w/w of microcrystalline cellulose, 1.2% w/w of polyvinylpyrrolidone, 2.4% w/w of magnesium stearate,
0.1 % w/w of a pharmaceutically acceptable dye, ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
2 1. A pharmaceutical formulation of immediate-release etoricoxib comprising:
10.3% to 3 1.0% w/w of etoricoxib,
13.8% to 2 1.2% w/w weight of meglumine, 5.4% to 8.6% w/w of sodium carboxymethyl starch, 44.8 to 50.0% w/w of microcrystalline cellulose, 1.4% to 4.3% w/w of polyvinylpyrrolidone,
3.4% to 5.2% w/w of magnesium stearate, 0.2% to 0.4% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
22. A pharmaceutical formulation of immediate-release etoricoxib according to claim
2 1 comprising:
18.0% to 2 1.5% w/w of etoricoxib 19.2% to 20.2% w/w of meglumine, 7.3% to 8.0% w/w of sodium carboxymethyl starch, 46.4 to 46.9% w/w of microcrystalline cellulose, 1.7% to 2.5% w/w of polyvinylpyrrolidone, 3.7% to 4.1 % w/w of magnesium stearate, 0.2% to 0.3% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
23. A pharmaceutical formulation of immediate-release etoricoxib according to claim 22 comprising: 20.0% w/w of etoricoxib, 20.0% w/w of meglumine, 7.8% w/w of sodium carboxymethyl starch, 46.0% w/w of microcrystalline cellulose, 2.0% w/w of polyvinylpyrrolidone, 4.0% w/w of magnesium stearate, 0.2% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
24. A pharmaceutical formulation according to claim 23, wherein meglumine, ethanol and water are comprised in particular w/w ratios between them. 25. A pharmaceutical combination according to claim 24 wherein the w/w ratio of meglumine and ethanol is in the range of from 0.5:1 0 to 3:1 0, and the w/w ratio of water and ethanol is in the range of from 1:5 to 1: 1 2 .
26. A manufacturing process of the pharmaceutical combination according to claims 1 to 5 comprising the following steps:
i) provide a first formulation comprising tramadol hydrochloride as the first pharmaceutically active ingredient, which comprises the next steps: a) sieve tramadol, the extended-release matrix, disintegrant and the half of the lubricants, b) the mixture of the previous step is pre-compressed and then it is granulated to finally add the second fraction of lubricants, thus obtaining the first formulation; and ii) provide a second formulation comprising etoricoxib as the second pharmaceutically active ingredient which comprises the next steps: a) mix one part of a first solvent with the binder and the dye; b) mix and sieve the surfactant, two disintegrants and etoricoxib;
c) perform the wet granulation by adding the mixture obtained in step a) to the mixture obtained in step b) and add the second part of the first solvent along with a second solvent;
d) place the granulate obtained in step c) in the fluid bed and dry it;
e) sieve the granulate obtained in step d) and add the lubricant to obtain the second formulation; and iii) encapsulate, fill sachets or compress to a conventional or bilayer tablet forms the formulations obtained in i) and ii).
27. A manufacturing process of the pharmaceutical combination in the bilayer tablet form according to claim 26 comprising the following steps:
i) provide a composition for the first formulation comprising tramadol hydrochloride as the first pharmaceutically active ingredient by the next steps: a) sieve tramadol, the extended-release matrix, and the disintegrant by 0.3 to 1.0 mm mesh, and mix during 10 to 20 minutes;
b) over the mixture obtained in step a), it is added the 50% of a mixture which contains lubricants and it is mixed during 1 to 5 minutes; c) perform a pre-compression of the mixture obtained in step b) and re-granulated it by 0.7 to 2.0 mm mesh; d) over the granulate obtained in step c), the remaining 50% of the mixture which contains lubricants is added and it is mixed during 1 to 5 minutes; and ii) provide a composition for the second formulation comprising etoricoxib as the second pharmaceutically active ingredient by the next steps: a) 50% of total ethanol is mixed with the binder which is slowly added over it, and all together it is stirred during 30 to 45 minutes. Once the binder is dissolved the dye is added and the mixing is maintained during 15 to 30 more minutes; b) prepare a mixture of solids comprising the surfactant, two disintegrants, and etoricoxib, which are previously sieved in a 0.7 to 2.0 mm mesh, and mix during 5 to 15 minutes; c) perform a wet granulation by adding the solution prepared in step a) to the mixing of solids obtained in step b) and add water and the remaining 50% of ethanol;
d) the granulate obtained in step c) it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C;
e) the granulate obtained in step d) is sieved by 0.7 to 2.0 mm mesh, and over it, the lubricant is sieved by 0.3 to 1.0 mm mesh, and it is mixed during 1 to 5 minutes;
iii) perform a pre-compression of the granulates obtained in step i) d) and add over it the formulation obtained in step ii) e) and compress them together in a tabletting press.
28. A manufacturing process of the pharmaceutical formulation according to claim 2 1 comprising the following steps: a) slowly add 50% of total ethanol over the polyvinylpyrrolidone, and mix them by stirring during 30 to 45 minutes. Once the polyvinylpyrrolidone is dissolved, the dye is added and the mixing is maintained during 15 to 30 more minutes; b) prepare a mixture of solids comprising meglumine, sodium carboxymethyl starch, microcrystalline cellulose, and etoricoxib, which are previously sieved
in a 0.7 to 2.0 mm mesh, and mix during 5 to 15 minutes; c) perform a wet granulation by adding the solution prepared in step a) to the
mixing of solids obtained in step b) and add water and the remaining 50% of ethanol;
d) the granulate obtained in step c) it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C; e) the granulate obtained in step d) 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; f) compress the granulates obtained in step e) or fill hard capsules with them.
29. Use of the pharmaceutical combination according to claim 1, characterized by it is used to prepare a medicament useful for the prevention and treatment of pain.
30. Use of the pharmaceutical combination according to claim 29, characterized by the pain is an acute pain.
3 1. Use of the pharmaceutical combination according to claim 29, characterized by the pain is a pain associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arthritis, and painful musculoskeletal affections.
32. A method for preventing and treating pain comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof.
33. A method for preventing and treating acute pain comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof.
34. A method for preventing and treating pain associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arthritis, and painful musculoskeletal affections comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof. AMENDED CLAIMS received by the International Bureau on 20.06.201 8
1. A pharmaceutical combination comprising: 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 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, among which is included a surfactant selected from phospholipids, polyethylene glycols, meglumine, sorbitol esters, polysorbates, polyoxyethylene ethers, or mixtures thereof, along with pharmaceutically acceptable solvents or carriers selected from ethanol and water or a mixture thereof; wherein at least 80% of etoricoxib is dissolved on average in 10 minutes; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
2 . A pharmaceutical combination according to claim 1 comprising: 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, 20.6% to 25% w/w of an extended-release matrix, 0.7% to 3.0% w/w of one or more lubricants, 8.7% to 12% w/w of a disintegrant; and b) a second formulation of immediate-release etoricoxib containing from 6.0% to 18% w/w of etoricoxib as the second pharmaceutically active ingredient, 8.0% to 12.3% w/w of meglumine, 29.1 % to 34.0% w/w of one or more disintegrants, 0.8% to 2.5% w/w of a binder, 2.0% to 3.0% w/w of a lubricant,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water or a mixture thereof as pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
3 . A pharmaceutical combination according to any of the previous claims comprising: a) a first formulation of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of an extended-release matrix,
0.7% to 1. 1 % w/w of one or more lubricants, 10.0% to 10.6% w/w of a disintegrating, and b) a second formulation of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of meglumine, 32.4% to 33.3% w/w of one or more disintegrants, 1.0% to 1.5% w/w of a binder, 2.2% to 2.5% w/w of a lubricant, 0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water or a mixture thereof as pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
4 . A pharmaceutical combination according to any of the previous claims comprising: a) a first formulation of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second formulation of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of a meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, 1.0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate,
0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
5 . A pharmaceutical combination according to claim 4, wherein meglumine, ethanol and water, in the second formulation of immediate-release etoricoxib, are comprised in particular w/w ratios between them.
6 . A pharmaceutical combination according to claim 5 wherein the w/w ratio of meglumine and ethanol is in the range of from 0.5:1 0 to 3:1 0, and the w/w ratio of water and ethanol is in the range of from 1:5 to 1: 1 2 .
7 . A pharmaceutical combination according to claim 1, wherein the first formulation of extended-release tramadol hydrochloride a) and the second formulation of immediate-release etoricoxib b) are in the granulate form.
8 . A pharmaceutical combination according to claim 1, wherein the first formulation of extended-release tramadol hydrochloride a) and the second formulation of immediate-release etoricoxib b) are in the layer form.
9 . A pharmaceutical combination according to claim 1, wherein said combination is an oral dosage pharmaceutical form.
10 . A pharmaceutical combination according to claim 1, wherein said combination is an oral dosage pharmaceutical form comprising capsules, tablets, bilayer tablets, granulates or sachets. 11. A pharmaceutical combination according to claim 1, wherein said combination is in the capsule form.
12 . A pharmaceutical combination according to claim 1, wherein said combination is in the tablet form.
13 . A pharmaceutical combination according to claim 1, wherein said combination is in the bilayer tablet form.
14 . A pharmaceutical combination according to claim 1, wherein said combination is in granulate form.
15 . A pharmaceutical combination according to claim 1, wherein said combination is in sachet form.
16 . A pharmaceutical combination according to claims 1, 7, 10 or 11 wherein said combination is in the capsule form, comprising: a) a first granulate of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second granulate of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, 1.0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate, 0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water or a mixture thereof as pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
17 . A pharmaceutical combination according to claims 1, 8, 10 or 13 wherein said combination is in the bilayer tablet form, comprising: a) a first layer of extended-release tramadol hydrochloride containing from 4.0% to 6.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.0% to 23.5% w/w of hypromellose, 0.3% to 0.6% w/w of colloidal silicon dioxide, 0.4% to 0.5% w/w of magnesium stearate, 10.0% to 10.6% w/w of microcrystalline cellulose; and b) a second layer of immediate-release etoricoxib containing from 11.0% to 13.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 11.6% to 12.3% w/w of meglumine, 4.4% to 4.8% w/w of sodium carboxymethyl starch, 28.0 to 28.5% w/w of microcrystalline cellulose, 1.0% to 1.5% w/w of polyvinylpyrrolidone, 2.2% to 2.5% w/w of magnesium stearate, 0.1 % to 0.2% w/w of a pharmaceutically acceptable dye, ethanol and water or a mixture thereof as pharmaceutically acceptable solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
18 . A pharmaceutical combination according to claim 17 wherein said combination is in the bilayer tablet form, comprising: a) a first layer of extended-release tramadol hydrochloride containing 5.0% w/w of tramadol hydrochloride as the first pharmaceutically active ingredient, 23.3% w/w of hypromellose, 0.4% w/w of colloidal silicon dioxide, 0.42% w/w of magnesium stearate, 10.4% w/w of microcrystalline cellulose; and b) a second layer of immediate-release etoricoxib containing 12.0% w/w of etoricoxib as the second pharmaceutically active ingredient, 12.0% w/w of a meglumine, 4.7% w/w of sodium carboxymethyl starch, 28.1 % w/w of microcrystalline cellulose, 1.2% w/w of polyvinylpyrrolidone, 2.4% w/w of magnesium stearate,
0.1 % w/w of a pharmaceutically acceptable dye, ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the combination, and wherein the solvents or carriers are not included within the total weight thereof.
19 . A pharmaceutical formulation of immediate-release etoricoxib comprising:
10.3% to 3 1.0% w/w of etoricoxib,
13.8% to 2 1.2% w/w of meglumine, 5.4% to 8.6% w/w of sodium carboxymethyl starch, 44.8 to 50.0% w/w of microcrystalline cellulose, 1.4% to 4.3% w/w of polyvinylpyrrolidone, 3.4% to 5.2% w/w of magnesium stearate, 0.2% to 0.4% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
20. A pharmaceutical formulation of immediate-release etoricoxib according to claim 19 comprising:
18.0% to 2 1.5% w/w of etoricoxib 19.2% to 20.2% w/w of meglumine, 7.3% to 8.0% w/w of sodium carboxymethyl starch, 46.4 to 46.9% w/w of microcrystalline cellulose, 1.7% to 2.5% w/w of polyvinylpyrrolidone, 3.7% to 4.1 % w/w of magnesium stearate, 0.2% to 0.3% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
2 1. A pharmaceutical formulation of immediate-release etoricoxib according to claim 20 comprising: 20.0% w/w of etoricoxib, 20.0% w/w of meglumine, 7.8% w/w of sodium carboxymethyl starch, 46.0% w/w of microcrystalline cellulose, 2.0% w/w of polyvinylpyrrolidone, 4.0% w/w of magnesium stearate, 0.2% w/w of a pharmaceutically acceptable dye, and ethanol and water as solvents or carriers; being the % w/w referred to the total weight of the second immediate-release formulation, and wherein the solvents or carriers are not included within the total weight thereof.
22. A pharmaceutical formulation according to claim 2 1, wherein meglumine, ethanol and water are comprised in particular w/w ratios between them.
23. A pharmaceutical combination according to claim 22 wherein the w/w ratio of meglumine and ethanol is in the range of from 0.5:1 0 to 3:1 0, and the w/w ratio of water and ethanol is in the range of from 1:5 to 1: 1 2 .
24. A manufacturing process of the pharmaceutical combination according to claims 1 to 3 comprising the following steps:
i) provide a first formulation comprising tramadol hydrochloride as the first pharmaceutically active ingredient, which comprises the next steps: a) sieve tramadol, the extended-release matrix, disintegrant and the half of the lubricants, b) the mixture of the previous step is pre-compressed and then it is
granulated to finally add the second fraction of lubricants, thus obtaining
the first formulation; and ii) provide a second formulation comprising etoricoxib as the second pharmaceutically active ingredient which comprises the next steps: a) mix one part of a first solvent with the binder and the dye; b) mix and sieve the surfactant, two disintegrants and etoricoxib;
c) perform the wet granulation by adding the mixture obtained in step a) to
the mixture obtained in step b) and add the second part of the first solvent along with a second solvent;
d) place the granulate obtained in step c) in the fluid bed and dry it; e) sieve the granulate obtained in step d) and add the lubricant to obtain the second formulation; and iii) encapsulate, fill sachets or compress to a conventional or bilayer tablet forms the formulations obtained in i) and ii).
25. A manufacturing process of the pharmaceutical combination in the bilayer tablet form according to claim 24 comprising the following steps:
i) provide a composition for the first formulation comprising tramadol hydrochloride as the first pharmaceutically active ingredient by the next steps: a) sieve tramadol, the extended-release matrix, and the disintegrant by 0.3 to 1.0 mm mesh, and mix during 10 to 20 minutes; b) over the mixture obtained in step a), it is added the 50% of a mixture which contains lubricants and it is mixed during 1 to 5 minutes;
c) perform a pre-compression of the mixture obtained in step b) and re granulated it by 0.7 to 2.0 mm mesh; d) over the granulate obtained in step c), the remaining 50% of the mixture which contains lubricants is added and it is mixed during 1 to 5 minutes; and ii) provide a composition for the second formulation comprising etoricoxib as the second pharmaceutically active ingredient by the next steps: a) 50% of total ethanol is mixed with the binder which is slowly added over it, and all together it is stirred during 30 to 45 minutes. Once the binder is dissolved the dye is added and the mixing is maintained during 15 to 30 more minutes; b) prepare a mixture of solids comprising the surfactant, two disintegrants,
and etoricoxib, which are previously sieved in a 0.7 to 2.0 mm mesh, and mix during 5 to 15 minutes; c) perform a wet granulation by adding the solution prepared in step a) to
the mixing of solids obtained in step b) and add water and the remaining 50% of ethanol; d) the granulate obtained in step c) it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C; e) the granulate obtained in step d) is sieved by 0.7 to 2.0 mm mesh, and
over it, the lubricant is sieved by 0.3 to 1.0 mm mesh, and it is mixed during 1 to 5 minutes;
iii) perform a pre-compression of the granulates obtained in step i) d) and add over it the formulation obtained in step ii) e) and compress them together in a tabletting press.
26. A manufacturing process of the pharmaceutical formulation according to claim 19 comprising the following steps: a) slowly add 50% of total ethanol over the polyvinylpyrrolidone, and mix them by stirring during 30 to 45 minutes. Once the polyvinylpyrrolidone is dissolved, the dye is added and the mixing is maintained during 15 to 30 more minutes; b) prepare a mixture of solids comprising meglumine, sodium carboxymethyl starch, microcrystalline cellulose, and etoricoxib, which are previously sieved in a 0.7 to 2.0 mm mesh, and mix during 5 to 15 minutes; c) perform a wet granulation by adding the solution prepared in step a) to
the mixing of solids obtained in step b) and add water and the remaining 50% of ethanol; d) the granulate obtained in step c) it is placed in the fluid bed and it is dried at a temperature from 28°C to 32°C; e) the granulate obtained in step d) 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; f) compress the granulates obtained in step e) or fill hard capsules with them.
27. Use of the pharmaceutical combination according to claim 1, characterized by it is used to prepare a medicament useful for the prevention and treatment of pain.
28. Use of the pharmaceutical combination according to claim 27, characterized by the pain is an acute pain.
29. Use of the pharmaceutical combination according to claim 27, characterized by the pain is a pain associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arthritis, and painful musculoskeletal affections.
30. A method for preventing and treating pain comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof.
3 1. A method for preventing and treating acute pain comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof.
32. A method for preventing and treating pain associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, pain and signs of inflammation associated with acute gouty arthritis, and painful musculoskeletal affections comprising administering the pharmaceutical combination according to claim 1 to a patient in need thereof.
INTERNATIONAL SEARCH REPORT International application No PCT/IB2017/058519