BR102024026703A2 - SYNERGISTIC AND STABLE PHARMACEUTICAL COMPOSITION OF AN NSAID AND AN OPIOID ANALGESIC FOR PAIN AND INFLAMMATION - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising etoricoxib and tramadol, or a pharmaceutically acceptable salt thereof, for the treatment of pain. These compositions, in addition to offering the potential for analgesic effect with a reduction in adverse events due to a reduced dose of one or both compounds, also present improved stability, maintaining the dissolution and bioavailability of the composition to be administered. The composition overcomes the technological complexity of combining a drug with high sensitivity to light and moisture (tramadol) with another lipid-soluble drug with low flow and excessive adhesiveness (etoricoxib) in a delivery medium in which their absorption is not affected by a water-free process, without affecting the release of either drug.

Description

FIELD OF INVENTION

[001] The present invention relates to combination pharmaceutical compositions, synergy and methods of manufacturing the same in the field of treatment, control of pain and inflammation.

BACKGROUND OF THE INVENTION

[002] Pain management requires the development of analgesic strategies that ensure earlier, more effective, and safer relief, limiting its progression to chronic pain. Pain management should focus on immediate actions that prevent the development of future complications associated with disability, with the goal of improving the patient's quality of life.

[003] Given the complex pathophysiology of pain, multimodal analgesia has been implemented as a therapeutic strategy, defined as the simultaneous use of drugs with different, complementary mechanisms of action that generate a synergistic effect. Several drugs are commonly used in multimodal analgesia, including opioids, NSAIDs, and paracetamol.

[004] According to the International Association for the Study of Pain (IASP), neuropathic pain is pain that arises as a direct consequence of an injury or disease that affects the somatosensory system.

[005] It is known that patients with acute neuropathic pain sometimes do not respond to monotherapies, even at maximum doses. This is why treatment often involves the use of two or more drugs with complementary mechanisms of action.

[006] For example, tramadol of formula I, whose nomenclature is (1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol, is a synthetic codeine analogue and centrally acting analgesic that has opioid agonist properties and activates spinal monoaminergic inhibition of pain and is commonly used for the treatment of acute pain of neuropathic origin. Formula I

[007] It may be administered orally, rectally, intravenously, or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular tramadol has generally been shown to be equivalent in potency to pethidine (meperidine) and one-fifth the potency of nalbuphine. Tramadol has demonstrated analgesic activity in several animal models and in healthy volunteers with experimentally induced pain. Analgesia from orally administered tramadol is similar to that obtained intravenously (Lee, Rhoda; McTavish, Donna; Sorkin, Eugene; tramadol; A Preliminary Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Acute and Chronic Pain States, 1993).

[008] Adverse reactions commonly associated with tramadol administration may include constipation, nausea, vomiting, abdominal pain, dizziness, drowsiness, fatigue, and headache. Some of its adverse reactions can be serious, including: seizures, hives, blisters, difficulty swallowing, inflammation of the eyes, face, throat, tongue, lips, hands, feet, and ankles; and even changes in heart rate. However, the incidence of serious adverse reactions is less than 1%. Furthermore, tramadol is in Group IV of opioid medications: an opioid for medicinal use with low dependence potential. High doses of tramadol are known to cause major adverse reactions. Intentional and accidental overdoses of tramadol can cause respiratory arrest, as well as acute liver failure, with several fatal cases reported. In these cases, however, liver injury may have been caused by shock, hypoxia, or ischemia secondary to respiratory arrest. Liver injury attributed to tramadol overdose has also been associated with hyperammonemia, lactic acidosis, and hepatic steatosis, suggesting direct mitochondrial injury (Liver Tox Clinical and Research information of Drug-Induced Livered Injury, National Institutes of Health, December 5, 2012).

[009] On the other hand, there is etoricoxib, also known as 5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl)pyridine, of formula II. It is a synthetic non-steroidal anti-inflammatory drug (NSAID) with potential antipyretic, analgesic, and antineoplastic properties. Etoricoxib specifically binds to and inhibits the enzyme cyclooxygenase-2 (COX-2), resulting in inhibition of the conversion of arachidonic acid to prostaglandins. (https://pubchem.ncbi.nlm.nih.gov/compound/123619). o = s=o Formula II

[010] Etoricoxib is indicated for the treatment of chronic and acute pain, which is defined according to the International Association for the Study of Pain (IASP) as pain that persists for more than 3 to 6 months from the time of tissue injury. Large doses of etoricoxib can cause adverse reactions such as ulceration and intolerance in the gastrointestinal tract, blockage of platelet aggregation (inhibition of thromboxane synthesis), inhibition of uterine motility (prolongation of gestation), inhibition of prostaglandin-mediated renal function, hypersensitivity, among others.

[011] In the prior art, drug combinations involving the combination of active ingredients such as etoricoxib/tramadol have been developed as an alternative for the treatment of pain and inflammation. For example, patent application with international publication number WO 2019/130049 provides a pharmaceutical combination of extended-release tramadol hydrochloride and immediate-release etoricoxib in combination with solvents and vehicles, its manufacturing process in a single dosage form such as capsules, tablets, bilayer tablets, granules, and sachets. Furthermore, it provides methods for preventing and treating pain, such as acute pain. In one embodiment, the pharmaceutical combination comprises a first formulation of tramadol and a second formulation of etoricoxib that are in the form of granules.

[012] Subsequently, Mexican application MX/A/2016/006464 describes a pharmaceutical composition of a combination of tramadol hydrochloride/etoricoxib of specific particle size (d90 < 30 microns of etoricoxib) for the treatment of pain, as well as its production process for manufacturing a mixture of powders or tablets in a bilayer tablet with or without coating or in a capsule as granules and/or tablets with or without coating. The concentration of tramadol/etoricoxib is 10 to 120 mg of etoricoxib and 10 to 300 mg of tramadol.

[013] The patent application with international publication number WO 2019 021079 describes a process and pharmaceutical composition of a combination of tramadol hydrochloride/etoricoxib for the treatment of pain, the process for obtaining which is based on two active ingredients consisting of granules and/or multiparticles with tramadol hydrochloride and granules and/or multiparticles with etoricoxib, which may be contained in a mixture of powders or tablets in a bilayer tablet with or without coating or in a capsule as granules and/or tablets with or without coating of etoricoxib 0.15 to 0.85 in relation to the total etoricoxib administered plus tramadol hydrochloride or similar salts. The concentration of tramadol/etoricoxib is 10-300 mg to 10-120 mg, respectively. The concentration of tramadol/etoricoxib is 10-300 mg and 10-120 mg, respectively.

[014] Other examples of combinations include patent number MX 243332, which describes the use of a combination of an opioid analgesic together with a COX-2 inhibitor. The opioid analgesic and the COX-2 inhibitor can be administered orally, by implant, parenterally, sublingually, rectally, topically, or by inhalation. In other embodiments of the invention, the COX-2 inhibitor can be administered separately from the opioid analgesic. The pharmaceutical compositions containing the COX-2 inhibitors and the opioid drugs described in document MX 243332 are administered orally. Such oral dosage forms can contain one or both drugs in immediate or extended release form. For ease of administration, it is preferred that the oral dosage form contains both drugs. Oral dosage forms may be presented in the form of tablets, pieces, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, multiparticulate formulations, syrups, elixirs and the like.

[015] Similarly, patent application publication MX/A/2019/008577 describes the combination of etoricoxib/tramadol for the treatment of pain by means of a single-dose, independent dual-release system comprising a COX-2 inhibitor and a centrally acting opioid that is composed of two matrices and is useful in the treatment of moderate to severe pain. The process for obtaining said independent release matrix is also described.

[016] In turn, the United States patent document, US 2008/0026054, describes a slow-release pharmaceutical composition containing tramadol and an immediate-release layer of an NSAID that includes, but is not limited to, etoricoxib in the pharmaceutical form of a tablet or capsule.

[017] Tramadol/etoricoxib co-crystals were described in patent document MX 311821 for the preparation of a medicament indicated for the treatment of pain.

[018] On the other hand, the publication entitled “Analysis of interaction between etoricoxib and tramadol against mechanical hyperalgesia of spinal cord injury in rats”. (Pal Singh, Vijay; Patil, Chandrashekhar S.; Kulkarni, Shrinivas K.; Life Sciences (2006), 78(11), 1168-1174.) presents a non-clinical or preclinical study to evaluate the pharmacodynamic effects and any possible interactions (additive or potentiating) on the antinociceptive effects of etoricoxib; a cyclooxygenase-2 inhibitor and tramadol; a typical opioid agonist to test spinal cord injury-induced hyperalgesia in rats.

[019] In the prior art, there has been an attempt to solve the problem of combining both drugs for the treatment and control of pain and inflammation. The documents talk extensively about bilayers and independent systems. Some have approached the problem with a new crystalline form. The only way they approach the combination of tramadol and etoricoxib is that there is no actual physical interaction between the APIs; otherwise, they would not combine them.

[020] Similarly, there is a need to improve the synergistic effect, increase bioavailability, improve dissolution and stability, and at the same time ensure a reduction in side effects once administered to the patient. The lack of solutions and alternatives to the above means that the therapeutic effect takes time to occur or a higher dose is required. Furthermore, the patents and scientific contributions described above demonstrate no interest in resolving the impact of the drug's organoleptic properties, which affect its stability, dissolution, and bioavailability.

[021] On the other hand, in addition to the problems of side effects due to the formation of high doses of tramadol and etoricoxib, there is the technical problem of combining a drug with high sensitivity to light and humidity, with another liposoluble drug with low flow and excessive adhesiveness, as there may be interference in stability, absorption and release mechanism.

[022] Thus, the present invention relates to a pharmaceutical composition of a combination of tramadol and etoricoxib, a single monophasic system manufactured by fusion granulation, stable, immediate release, with synergistic effect and which maintains dissolution and bioavailability, in the field of treatment and control of pain and inflammation.

SUMMARY OF THE INVENTION

[023] The present invention relates to granulated and reconstitution pharmaceutical compositions comprising tramadol and etoricoxib, or a pharmaceutically acceptable salt thereof. The compositions of the present invention are used in the manufacture of a medicament useful in the treatment of pain and inflammation, which in addition to offering the possibility of an analgesic effect with a reduction in adverse events because the active ingredients are in an effective amount to provide a synergistic pharmacological effect, the reduction of the dose of one or both compounds, presents improved stability, maintaining the dissolution and bioavailability of the composition to be administered.

[024] The enhanced analgesic effect of the present invention is due to the combination of two pharmacodynamic mechanisms that complement each other thanks to the combination of an NSAID (etoricoxib) plus an opioid (tramadol). Additionally, this combination represents a superior safety profile compared to treatment with monodrugs, as it allows for a reduction in adverse events resulting from the use of opioids, since by combining etoricoxib with tramadol, therapeutic results are obtained with a single daily dose of the product. On the one hand, the pharmacokinetic profile of the etoricoxib/tramadol combination of the present invention demonstrates that the reduction in the tramadol dose (tramadol-sparing effect) is not related to pharmacokinetic differences in the fixed-dose formulation of etoricoxib/tramadol, but to a pharmacodynamic-based synergistic effect inherent in the mechanisms of action of the drugs when administered in combination and providing a multimodal therapeutic approach. On the other hand, the etoricoxib/tramadol-based treatment is more potent from a pharmacological standpoint, since the desired analgesic therapeutic effects are achieved with lower doses (90 mg/50 mg vs. 975 mg/112.5 mg). The results obtained through a clinical study by the applicant demonstrate analgesic synergy in patients suffering from acute low back pain, in addition to a tramadol-sparing effect. Furthermore, among all the adverse events reported in the clinical study conducted by the inventors, the etoricoxib/tramadol group reported a lower proportion of AEs compared to the paracetamol/tramadol group.

[025] On the other hand, in relation to the pharmaceutical profile, improved stability is presented.

[026] One embodiment of the invention comprises a synergistic composition in a single, stable, immediate-release, solid pharmaceutical form comprising tramadol hydrochloride at a concentration of 50 mg/5 g and etoricoxib 90 mg/5 g, respectively.

[027] In another embodiment of the invention the composition is in the form of granules. Preferably, it is in the form of a granule for reconstitution.

[028] The present invention also includes the excipients that make up the composition and provide it with essential characteristics that improve the pharmacokinetic profile, bioavailability, stability and dissolution.

[029] Another embodiment of the invention comprises the process of manufacturing the composition that does not require the incorporation of water and can overcome the technological complexity of having a drug with high sensitivity to light and humidity (tramadol), together with another liposoluble drug with low flow and excessive adhesiveness (etoricoxib), in a delivery medium in which the absorption of these is not affected through a melt granulation process, by which the release of both drugs is not affected.

[030] The process of manufacturing the pharmaceutical composition according to the present invention comprises the following steps: 1) mixing for approximately 5 minutes the active ingredients tramadol and etoricoxib with previously sieved pharmaceutically acceptable excipients; 2) granulating the mixture obtained in the previous step for 20 to 30 minutes until reaching a temperature between 54°C and 55.2°C; 3) cooling the granules from the previous step to a temperature of 25°C to 28°C; 4) sieving the granules obtained in the previous step; 5) mixing the sieving obtained in the previous step with the flavoring for 6 minutes.

[031] The invention also relates to a granulated pharmaceutical composition for reconstitution comprising tramadol and etoricoxib in an effective synergistic amount of 50/90 mg respectively obtained by the melt granulation process described; as well as its use for the manufacture of a medicament useful in the treatment and control of pain such as neuropathic pain and/or chronic and acute pain.

BRIEF DESCRIPTION OF THE FIGURES

[032] Figure 1. Dissolution result. Dissolution profiles of tramadol/etoricoxib HCl lot DFF1712-12.

[033] Figure 2. Comparison of the dissolution profiles of etoricoxib lot NO11650 & DFF1908-03.

[034] Figure 3. Comparison of dissolution profiles of tramadol batch 170111 & DFF1908-03.

[035] Figure 4. Comparison of the dissolution profiles of etoricoxib lot NO11650 & DFF1908-03 (B).

[036] Figure 5. Comparison of dissolution profiles of tramadol batch 170111 & DFF1908-03 (B).

[037] Figure 6. Comparison of the dissolution profiles of etoricoxib lot NO11650 & DFF1908-03 (B2C).

[038] Figure 7. Comparison of dissolution profiles of tramadol batch 170111 & DFF1908-03 (B2C).

[039] Figure 8. Mean pharmacokinetic profile of etoricoxib ± standard error in normal range. (A. reference drug (etoricoxib), C: test drug (etoricoxib - tramadol).

[040] Figure 9. Mean pharmacokinetic profile of etoricoxib ± standard error on a semi-logarithmic scale. (A. reference drug (etoricoxib), C: test drug (etoricoxib - tramadol).

[041] Figure 10. Mean pharmacokinetic profile of tramadol ± standard error in normal range. (B. reference drug (tramadol), C: test drug (etoricoxib - tramadol).

[042] Figure 11. Mean pharmacokinetic profile of tramadol ± standard error on a semi-logarithmic scale. (B. reference drug (tramadol), C: test drug (etoricoxib - tramadol).

[043] Figure 12. Comparative pharmacokinetic profiles of etoricoxib (normal range) (A): reference drug (etoricoxib), (C): test drug (etoricoxib - tramadol).

[044] Figure 13. Comparative pharmacokinetic profiles of etoricoxib (semi-logarithmic scale) (A): reference drug (etoricoxib), (C): test drug (etoricoxib - tramadol).

[045] Figure 14. Comparative pharmacokinetic profiles of tramadol (normal range) (B): reference drug (tramadol), (C): test drug (etoricoxib - tramadol).

[046] Figure 15. Comparative pharmacokinetic profiles of tramadol (semi-logarithmic scale) (B): reference drug (tramadol), (C): test drug (etoricoxib - tramadol).

[047] Figure 16. Dissolution profiles of etoricoxib mono-drug granules, tramadol HCl mono-drug, tramadol HCl batch DFF1908-03 and etoricoxib batch DFF1908-03 from Laboratórios Silanes S.A. de C.V. in 0.1 N hydrochloric acid dissolution medium.

[048] Figure 17. Dissolution profiles of reference drug Tradol [50 mg of tramadol hydrochloride] and Arcoxia 90 mg of etoricoxib, etoricoxib, tramadol HCl batch DFF1908-03 and etoricoxib batch DFF1908-03 from Laboratórios Silanes S.A. de C. V. in 0.1 N hydrochloric acid dissolution medium.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[049] Pharmaceutically acceptable salt: The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and that are not biologically or otherwise undesirable (P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2nd Revised Edition (May 16, 2011)).

[050] Neuropathic pain: According to the International Association for the Study of Pain, neuropathic pain is pain that is a direct consequence of an injury or disease of the somatosensory system. This type of pain is present in various neuropathies, polyneuropathies, post-therapeutic neuralgia, and other common central pain syndromes, such as spinal cord injury, spinal cord tumor, syringomyelia, and cancer associated with neuropathic pain.

[051] Excipient: is the ingredient that is part of the present pharmaceutical composition, among them are binders, disintegrants, sweeteners, flavorings, among others.

[052] Synergy: a combined technical effect. The most favorable case is when the combination of active ingredients produces a synergistic effect, that is, two characteristics interact synergistically with each other if their functions are linked and if they give rise to an additional effect that goes beyond the sum of the effects produced by each of these characteristics considered in isolation, in this case, the individual active ingredients.

[053] The present invention relates to a pharmaceutical composition combining an opioid analgesic and a non-steroidal anti-inflammatory in a single monophasic system that is a granule for reconstitution, stable, immediate release, with a synergistic effect and that maintains dissolution and bioavailability, in the field of treatment and control of pain and inflammation.

[054] The opioid analgesic used is tramadol or a pharmaceutically acceptable salt thereof, for example; its hydrochloride salt and the NSAID is etoricoxib or a pharmaceutically acceptable salt thereof.

[055] The present invention comprises the combination of etoricoxib and tramadol or a pharmaceutically acceptable salt thereof in doses of 50 mg of tramadol and 90 mg of etoricoxib; with at least one pharmaceutically acceptable excipient.

[056] As indicated above, the solid pharmaceutical composition is in the form of a granule for reconstitution. The most preferred pharmaceutical form of the invention is “granules for reconstitution” because the dissolution results do not present problems for tramadol hydrochloride or etoricoxib, releasing 100% of the active ingredients, in addition to being a pharmaceutical form of better acceptance due to its easy swallowing.

[057] The combination of tramadol and etoricoxib represents a set of important technological challenges due to the physicochemical properties of the drugs, the appropriate selection of excipients and the manufacturing conditions play, in the development of pharmaceutical compositions, a very important role in relation to the release of the drug and the speed of absorption in the body. Thus, the composition manages to overcome the technological complexity of having a drug with high sensitivity to light and moisture (tramadol), together with another liposoluble drug, with low flow and excessive adhesiveness (etoricoxib); in a delivery medium in which the absorption of these is not affected through a melt granulation process, by which the release of both drugs is not affected.

[058] Regarding excipients, in one embodiment, the pharmaceutical composition of the present invention comprises at least one of a binder, a disintegrant, a sweetener, a flavoring, and a diluent.

[059] Examples of pharmaceutically acceptable disintegrants include, but are not limited to, croscarmellose, cellulose derivatives such as hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; povidone derivatives such as crospovidone; starch derivatives such as pregelatinized starch, sodium starch glycolate and corn starch. The disintegrant may be present in an amount ranging from 0.5 to 15% by weight, preferably between 0.5 to 5% by weight. The preferred disintegrant for the present formulation is croscarmellose sodium.

[060] Examples of pharmaceutically acceptable binders include, but are not limited to, polyethylene glycol 6000, polyoxyethylene alkyl ethers, polyethylene oxide; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates, and suppository bases. In a preferred embodiment, the binder is polyethylene glycol 6000, which may be present in an amount of approximately 43% by weight in the formulation.

[061] Examples of diluents include, but are not limited to, isomalt 801; cellulose derivatives such as microcrystalline cellulose; phosphate salts such as dibasic calcium phosphate; and starch derivatives such as pregelatinized starch. In a preferred embodiment, the diluent is isomalt 801, which may be present in an amount of approximately 36% by weight.

[062] Examples of pharmaceutically acceptable sweeteners include, but are not limited to, acesulfame potassium, sucralose, alitame, aspartame, isomalt, lactilol, maltitol, mannitol, neotame, ammonium saccharin, calcium saccharin, sodium saccharin, sodium cyclamate, sorbitol, sucralose, tagatose, thaumatin, and xylitol. Preferred sweeteners for the present formulation are acesulfame potassium and sucralose.

[063] Acesulfame potassium is present in an amount of approximately 3.0% by weight, while sucralose is used at 2.0% by weight in the formulation.

[064] Pharmaceutically acceptable flavoring agents include, but are not limited to, peppermint flavor, d-menthol; l-menthol; or thymol. The tastant is present in a use range of 7 to 9% LD50 (rat, oral): 3.18 g/kg, preferably, is used in the formulation at approximately 8% by weight. The preferred tastant for the present formulation is peppermint flavor.

[065] In a more preferred embodiment, the composition comprises a diluent, a binder and two sweeteners, wherein the diluent is isomalt 801, the binder is polyethylene glycol, the first sweetener is acesulfame potassium and the second sweetener is sucralose. In relation to the other excipients, the disintegrant is croscarmellose sodium and the flavoring is mint flavor.

[066] On the other hand, the combination of both drugs tramadol and etoricoxib suggests a synergistic antihyperalgesic effect in animal models (Pal Singh, Vijay; Patil, Chandrashekhar S.; Kulkarni, Shrinivas K.; Analysis of interaction between etoricoxib and tramadol against mechanical hyperalgesia of spinal cord injury in rats. Life Sciences (2006), 78(11), 1168-1174.).

[067] In another embodiment of the invention, it was found that the pharmaceutical composition does not present pharmacokinetic interaction when the combined formulation of tramadol with etoricoxib is administered.

[068] Accordingly, in another aspect, the present invention provides a method of treating pain and inflammation, which comprises administering a composition as described above to a patient in need thereof, preferably every 24 hours.

[069] In a preferred embodiment, the type of pain that can be treated with the present invention consists of nociceptive, neuropathic or mixed pain. Furthermore, depending on the duration of the clinical condition, chronic and acute pain can be treated with it.

Manufacturing and evaluation of tests performed to obtain an optimal formula

[070] In the prior art, even when teaching the tramadol-etoricoxib combination, manufacturing processes, pharmaceutical forms, and dosage forms are described that differ from those of the present invention. The prior art describes bilayers and independent systems for the tramadol-etoricoxib combination. Some have approached the problem with a new crystalline form. The only way to address the combination is that there is no real physical interaction between the APIs; otherwise, they would not combine, and therefore, there is a need for a monophasic tramadol-etoricoxib combination in a single pharmaceutical form. This document describes the manufacturing process for a single monophasic system for the tramadol-etoricoxib combination that also presents stability and synergy results.

[071] The manufacturing process of the present pharmaceutical composition of tramadol - etoricoxib combination proposed by the inventors, refers more particularly to a granulation by fusion in a single monophasic, stable, immediate release system, with synergistic effect and that maintains dissolution and bioavailability, in the field of treatment and control of pain and inflammation.

Example 1. Formula of a composition containing tramadol-etoricoxib

[072] The following describes the qualitative and quantitative formula of a granulated composition for reconstitution comprising the two active ingredients tramadol hydrochloride and etoricoxib, or any pharmaceutically acceptable salts thereof. Table 1. Quantitative formula *Equivalent to acesulfame potassium.

Example 2. Process for manufacturing granulated composition by melting for reconstitution

[073] The product combined the drugs (hydrochloride) tramadol and etoricoxib in a single dose, with doses of 50 mg/90 mg respectively; which represents a set of important technological challenges due to the physicochemical properties and the difference in doses to ensure obtaining a stable product.

[074] In the patents of the closest prior art, wet granulation processes that incorporate water are performed. Such is the case, in the present invention, where if it is desired to incorporate water in the process of combining the active ingredients tramadol (hydrochloride) and etoricoxib, the result of the combination is negatively affected. Below are the tests performed for the combination of tramadol (hydrochloride) and etoricoxib of the present invention by the wet method, which does not allow obtaining a stable and quality combination, while fusion granulation represents the unitary operation that allows putting the invention into practice.

Evaluation of formulas for extrusion-spheronization tests, incorporating ethylcellulose as a spheronization promoter

[075] Test: 1712-12 (Figure 1). % Materials 19.94 tramadol hydrochloride 19.94 etoricoxib 15.95 microcrystalline cellulose PH 101 44.17 ethylcellulose E-7-7050 Objective:

[076] Evaluation of formulas for extrusion-spheronization tests, incorporating ethylcellulose as a spheronization promoter. Physical results:

[077] Disintegration 8 h 30 minutes, total weight with capsule 458.45 mg. Observations:

[078] Tramadol hydrochloride and etoricoxib spheres are encapsulated; capsule weight 251 mg for tramadol HCl and 112.45 mg for etoricoxib in capsule number zero, are sent for analysis.

[079] According to the dissolution results, problems were found both for the release of tramadol HCl, whose release is above 100%, and for etoricoxib, below approximately 80%. This behavior is attributable to the poor distribution of the active ingredients in the sphere formulation. It is proposed to change the pharmaceutical form; from extrusion-spheronization to granulation for reconstitution by wet granulation.

Batch production for evaluation of organoleptic properties in formula

[080] Test: 1810-29% Materials 1.00 Tramadol HCl 1.80 Etoricoxib 40.00 Isomalt 801 52.20 Polyethylene glycol 6000 3.0 Acesulfame potassium 2.0 Sucralose Purified water (mL) Objective:

[081] Batch production for formula evaluation. Observations:

[082] Wet granulation was performed to integrate the active ingredients into the granules. For this type of dosage form, it is important to incorporate a flavor; since the active ingredients provide a bitter taste, it is necessary to incorporate a flavoring agent to improve their organoleptic properties. Different flavors were tested to evaluate their organoleptic properties. According to the results of the organoleptic properties, the orange bubblegum, grape, mint, and strawberry flavors did not help mask the bitter taste of the active ingredients, so the use of another flavoring agent was proposed (Table 2). Table 2. Organoleptic properties

Evaluation of the formula by wet granulation

[083] Test: 1810-29 (Figure 2 and 3). % Materials 1.00 etoricoxib 1.80 tramadol HCl 36.0 isomalt 801 45.7 polyethylene glycol 6000 2.50 croscarmellose sodium 3.00 acesulfame potassium 2.00 sucralose 8.00 spearmint 0.35 purified water (mL) Objective

[084] Formula evaluation by wet granulation. Physical tests % R.H. =-0.93 Disintegration 5 minutes Similarity factor

[085] etoricoxib F2 = 57.51% (Reference, innovative product).

[086] Tramadol HCl F2 = 88.05% (Reference, innovative product). Dissolution result

[087] Dissolution medium: pH 2.0 buffer solution: Chromatographic grade acetonitrile (75:25); dissolution medium: HCl. Observations:

[088] In this test, peppermint flavoring is added and 2.5% croscarmellose sodium is added. The samples were sent for analysis.

[089] It is proposed to switch to melt granulation, as the amount of water required is minimal and a solid binder with a low melting point, between 55°C and 62°C, was used as an excipient.

[090] According to the dissolution results, no problems were found for either tramadol HCl or etoricoxib, releasing 100% of the active ingredients, with the innovative batch for each active ingredient as a reference.

[091] The samples obtained were subjected to a preliminary stability assessment, which revealed incompatibility of tramadol in the presence of residual moisture resulting from wet granulation, presenting a change in color in the tablet and degradation of tramadol, therefore this manufacturing route is not viable to guarantee compliance of quality attributes.

Formula evaluation by fusion granulation

[092] On the other hand, during melt granulation, the physical union of the tramadol - etoricoxib components incorporates at least one binding agent that is melted between 50 and 80 °C, this allows the inclusion of the active ingredients without the need to incorporate water and eliminates the drying step, which positively favors the combination of the active ingredients of the present invention.

[093] Test: 1908-03 (B) (Figures 4 and 5). % Materials 1.00 etoricoxib 1.80 tramadol HCl 36.0 isomalt 801 43.2 polyethylene glycol 6000 2.50 croscarmellose sodium 3.00 acesulfame potassium 2.00 sucralose 8.00 spearmint Objective

[094] Formula evaluation by fusion granulation. Physical tests

[095] No physical test was performed. Similarity factor

[096] etoricoxib F2 = 60.51% (Reference, innovative product).

[097] Tramadol HCl F2 = 86.43% (Reference, innovative product). Dissolution results

[098] Dissolution medium: pH 2.0 buffer solution: Chromatographic grade acetonitrile (75:25); dissolution medium: HCl.

Observations

[099] The melting temperature range between 54.4 °C and 57.5 °C was determined for the excipient Polyethylene glycol 6000. It is proposed to perform when doubling the amount of disintegrant up to 5%.

[100] The dissolution results showed no problems for either tramadol HCl or etoricoxib, releasing 100% of the active ingredients, being an innovative batch reference for each active ingredient.

Formula evaluation by fusion granulation

[101] Test: 1908-03 (B2C) (Figures 6 and 7). % Materials 1.00 etoricoxib 1.80 tramadol HCl 36.0 isomalt 801 43.2 polyethylene glycol 6000 2.50 croscarmellose sodium 3.00 acesulfame potassium 2.00 sucralose 8.00 spearmint Physical tests

[102] I.H. = 1.09 IC = 8.5, angle of repose 8.0, flow velocity 10.26 g/s, mean particle size 786.7. Similarity factor

[103] etoricoxib F2 = 63.06% (Reference, innovative product).

[104] Tramadol HCl F2 = 56.12% (Reference, innovative product). Dissolution results

[105] Dissolution medium: pH 2.0 buffer solution: Chromatographic grade acetonitrile (75:25); dissolution medium: HCl. Observations

[106] The formula met the similarity factors of each drug and there is reproducibility in the manufacturing process.

[107] The similarity factor with monodrugs prepared in the same pharmaceutical form and with innovative drugs was determined for each active ingredient.

[108] These results serve as a basis for the preparation of stability batches, since an optimal formula is obtained.

[109] According to the tests presented previously, surprisingly it was possible to develop a process that guarantees a stable product and that meets the established quality characteristics, for which a melt granulation process was selected, placing the specific excipients and additives previously mentioned, capable of maintaining the chemical integrity of both drugs together.

[110] Below, the manufacturing process by melt granulation of the granules for reconstitution of the present invention, comprising etoricoxib and tramadol and/or their pharmaceutically acceptable salts, is presented in a non-limiting manner: 1. Sieve the Polyethylene Glycol 6000 (Sieving 1).

[111] 2. Sieve etoricoxib, tramadol hydrochloride, Isomalt 801, Croscarmellose sodium, Acesulfame potassium and Sucralose (Sieving 2).

[112] 3. Mix Sieve 1 with Sieve 2 for 5 minutes (Mixture 1).

[113] 4. Granulate Mixture 1 for 20 to 30 minutes until it reaches a temperature between 54 and 55.2 °C.

[114] 5. Cool the granules to a temperature of 25 to 28 °C.

[115] 6. Sieve the granules from step 5 (Sieving 3).

[116] 7. Mix Sieve 3 with the peppermint flavor for 5 minutes (Mixture 2).

[117] During melt granulation, the physical union of the tramadol - etoricoxib components incorporates at least one binding agent that is melted between 50 and 80 °C, this allows the inclusion of the active ingredients without the need to incorporate water and eliminates the drying step. On the other hand, the patents of the closest prior art perform processes, for example, wet granulation in which they incorporate water.

[118] The product combines the drugs (hydrochloride) tramadol and etoricoxib in a single dose, with doses of 50 mg/90 mg respectively; which represents a set of important technological challenges due to the physicochemical properties and the difference in doses to ensure obtaining a stable product.

[119] The technological complexity lies in the combination of two drugs with different rheological and solubility characteristics. On the one hand, we have a drug that is sensitive to humidity and light, and on the other, we have a liposoluble drug with poor flow and excessive adhesiveness (etoricoxib), which could cause interference in stability, absorption and release mechanism.

[120] The combination of both drugs will allow better analgesia in reduced doses and a reduction in adverse effects.

Example 3 Stability Tests

[121] Stability studies were performed in accordance with current standards on three batches of the described pharmaceutical composition. The results at 6 months at 40°C and 75% relative humidity are shown below (Table 3). Table 3. Tramadol 50 mg/etoricoxib 90 mg Example 4. Comparative bioavailability test

[122] The results obtained in a comparative bioavailability study of the combination of etoricoxib and tramadol allow us to conclude that the pharmacokinetic profile of the product is adequate when compared with the administration of the monodrugs alone. On the other hand, they allow us to guarantee the quality of the product formulation in combination with etoricoxib and tramadol and their excipients. Furthermore, the results obtained allow us to conclude that there is no interaction in the bioavailability of the formulations administered in combination. Additionally, satisfactory compliance with the established quality standards, the current NOM-177-SSA1, procedures, protocols, GLP, and Good Documentation Practices was verified, supporting the veracity of the study results.

[123] For pharmacokinetic and statistical analysis, data were received from 42 individuals in the randomized crossover study design, for three treatments, six sequences and three periods (3 x 6 x 3). Plasma concentration data were obtained for each time point, per drug. Analysis of variance (ANADEVA) was performed for the parameters: Cmax and ABC0-72. In addition to descriptive statistics, the following tests were performed: Classical Confidence Intervals, 90% (95%) and the Schuirmann Test. Calculations were performed using the WINNONLIN® program version 8.0.

[124] Statistical analysis to establish the non-pharmacokinetic interaction of the combination of etoricoxib + tramadol (equivalence in bioavailability) was performed with data from 38 individuals who completed the study.

[125] The participating individuals were 42, who received three treatments corresponding to a single oral dose: Reference Drug “A” (90 mg etoricoxib), Reference Drug “B” (50 mg tramadol) and Test Drug “C” (etoricoxib 90 mg/tramadol 50 mg, Laboratórios Silanes, SA de CV), which were administered in three periods (separated by a 14-day washout period) and six sequences. The total dose administered was: etoricoxib 90 mg and tramadol 50 mg, see Table 4. Table 4. Evaluated drugs

[126] To visualize the possible differences between the formulations and/or treatments, the plasma concentration profiles (± standard error) were plotted against time, obtained in the participating individuals (see Figures 8 to 15).

[127] Statistics to establish pharmacokinetic bioavailability equivalence should evaluate the difference between the treatments under study, through the logarithmic comparison of the pharmacokinetic parameters: Cmax and ABC0-72.

a) Confidence intervals

[128] The statistical analysis on the bioavailability equivalence of the drugs of interest was performed by constructing confidence intervals, which conclude in favor of bioavailability equivalence (without pharmacokinetic interaction) if the calculated limits are included in the pre-established range of 80 to 125, the above with logarithmically transformed data. These were analyzed with a 90% (95%) confidence level and considering that the power of the statistical test should be greater than 0.80.

b) Limit tests

[129] Limit tests are based on the rejection of the null hypothesis of non-equivalence to conclude with a significance level of alpha (α = 0.05) and a 90% confidence level that the analytes present pharmacokinetic equivalence. The limit tests applied are the two-tailed Schuirmann t-test and the Anderson Hauck test on the quotient between the means of the test and reference drugs for the pharmacokinetic parameters of Cmax and ABC0-72.

[130] Limit tests concluded in favor of bioavailability equivalence if the probability that the ratio is less than 80% and greater than 125% (less than 75% and greater than 133% in the case of high pharmacokinetic variability) is less than 0.05.

[131] Table 5 below presents the results of the statistical tests applied to the pharmacokinetic parameters of Cmax and ABC0-72 of etoricoxib, obtained for the two treatments evaluated (A vs C). The purpose is to evaluate the possible differences between the treatments, the former by applying a 90% (95%) confidence level and considering all 38 individuals who completed the study. Table 5. Confidence intervals and limit tests for the pharmacokinetic parameters of etoricoxib transformed into logarithmically (Treatment A vs Treatment C)

[132] A = Treatment A (Etoricoxib), C = Treatment C (Etoricoxib - Tramadol), CI = Confidence Interval, LI = Lower Limit, LS = Upper Limit, AH = Anderson Hauck. A p-value of 0.0001 is reported when the exact p-value is less than or equal to 0.0001.

[133] Table 6 below presents the results of the statistical tests applied to the pharmacokinetic parameters of Cmax and ABC0-72 of tramadol, obtained for the two treatments evaluated (B vs C). The purpose is to evaluate the possible differences between the treatments, the former by applying a 90% (95%) confidence level and considering all 38 individuals who completed the study. Table 6. Confidence intervals and limit tests for the logarithmically transformed pharmacokinetic parameters of tramadol (Treatment B vs Treatment C)

[134] B = Treatment B (Tramadol), C = Treatment C (etoricoxib - Tramadol), CI = Confidence Interval, LI = Lower Limit, LS = Upper Limit, AH = Anderson Hauck. A p-value of 0.0001 is reported when the exact p-value is less than or equal to 0.0001.

[135] After administering a single oral dose corresponding to 90 mg of etoricoxib and 50 mg of tramadol with a tablet and capsule pharmaceutical form, reference drug A, etoricoxib, 90 mg tablet of reference drug B, tramadol, 50 mg capsule, and test drug C, etoricoxib/tramadol with a pharmaceutical form of envelope with granules to be diluted in 100 mL of water, etoricoxib 90 mg/tramadol 50 mg, prepared by Laboratórios Silanes, S.A. de C.V., batch 20A081G1, the pharmacokinetic parameters of Cmax and area under the plasma concentration-time curve (ABC0-72) were determined.

[136] The comparative analysis of pharmacokinetic parameters was performed using the classical Schuirmann confidence interval approach. In the case of the classical confidence interval, it is a symmetrical interval around the difference in means between the test and reference drug (CP-CR) and is not symmetrical around zero, in the same way the classical confidence interval is symmetrical around the CP/CR ratio and not around unity.

[137] The classical confidence intervals for etoricoxib (contrast A vs C) met the 80 to 125% criterion for logarithmically transformed data, in each of the two pharmacokinetic variables, Ln(Cmax) and Ln(ABC0-72).

[138] Regarding the pharmacokinetic parameter ABC0-72, which is related to the degree or magnitude of absorption, in the classical confidence intervals, these values are in the range of 80 to 25% for logarithmically transformed data, even though the Schuirmann and Anderson Hauck tests (5) show a low probability that the ABC0-72 values of the test drug (etoricoxib/tramadol) are outside of 80 to 125% (“p” value less than 0.05).

[139] Classical tramadol confidence intervals (contrast B vs C) met the 80 to 125% criterion for logarithmically transformed data on each of the two pharmacokinetic variables, Ln(Cmax) and Ln(ABC0-72).

[140] Regarding the pharmacokinetic parameter ABC0-72 associated with tramadol, the classical confidence intervals are in the range of 80 to 125% for logarithmically transformed data, even though the Schuirmann and Anderson Hauck tests (5) show a low probability that the ABC0-72 values of the test drug (etoricoxib/tramadol) are outside of 80 to 125% (“p” value less than 0.05).

[141] All criteria used for non-pharmacokinetic interaction were met, since for each of the contrasts (C vs A and C vs B) where: A is etoricoxib monotherapy, reference drug, B is tramadol monotherapy, reference drug, C is the fixed-dose etoricoxib/tramadol combination, test drug, it is found that in the variables Ln(Cmax) and Ln(ABC0-72): (1) the lower limit of the classical interval (90% CI) is greater than 80 and the upper limit of the classical interval is less than 125, (2) the classical 95% confidence interval does not present values outside the range of 80 to 125%, (3) the p-values associated with the Schuirmann test for P < 80 are less than 0.05 (p < 0.0001), (4) the p-values associated with the Schuirmann test for P > 125 are less than 0.05 (p < 0.0161), (5) the Anderson Hauck test provides p values lower than 0.05, (p < 0.02), making it possible to reject the hypothesis of no pharmacokinetic interaction (α = 0.05).

[142] Furthermore, it is noted that the powers were adequate, greater than 0.99 for the two variables under study, Ln(Cmax) and Ln(ABC0-72), in both contrasts, see Tables 6 and 7.

[143] Thus, in the pharmacokinetic profile of the fixed-dose combination of etoricoxib/tramadol and its concomitant dosing, it was observed that there are no statistically significant differences in the values of Cmax, ABC0-t and ABC0-inf, the time to reach Cmax for the fixed-dose combination was shorter than that of etoricoxib as a single drug, while for tramadol it was similar. The 90% confidence intervals (CI) observed for etoricoxib were 95.92-114.26, 96.84-105.20 and 95.99-105.10, respectively, and 90% CI for tramadol; 99.42-116.16, 110.65-122.91 and 110.25-121.87, respectively. These results demonstrate that the reduction in tramadol dose (tramadol-sparing effect) is not related to pharmacokinetic differences of the fixed-dose formulation of etoricoxib/tramadol, but to a pharmacodynamic-based synergistic effect inherent in the mechanisms of action of the drugs when administered in combination and providing a multimodal therapeutic approach.

Example 5. Dissolution tests

[144] The dissolution test (in vitro test) is used to determine the speed (quantity/time) and extent (total quantity) at which a drug is released from the dosage form; in the case of the dissolution profile, it corresponds to the quantification at different times of the dissolved drug under standardized conditions. The importance of the dissolution test lies in the following: a) It is a guide for the development of new formulations during product development: it allows to evaluate the possible interference of excipients or the manufacturing process on the release of the drug.

[145] b) Process control and quality assurance: helps ensure continued product quality and optimization after a change in manufacturing, formulation, manufacturing location, and process scaling.

[146] c) In vivo development indicator: it is a bioavailability indicator, it allows establishing the correlation between in vitro parameters and bioavailability results.

[147] Dissolution profile testing was performed for tramadol hydrochloride/etoricoxib granules to reconstitute 50/90 mg.

[148] The quantification of etoricoxib in the study was performed using a method previously validated under the criteria of the Official Mexican Standard NOM-177-SSAA-2013, the method was performed using high-performance liquid chromatography when collecting samples at 20, 40, 60 and 80 minutes. The dissolution medium used consisted of a 0.1 N hydrochloric acid solution.

[149] The method for the quantification of tramadol hydrochloride was similarly validated under the criteria of the Official Mexican Standard NOM-177-SSAA-2013, the method was performed using high-performance liquid chromatography by collecting samples at 20, 40, 60 and 80 min. The dissolution medium employed consisted of a 0.1 N hydrochloric acid solution.

[150] The percentage of tramadol hydrochloride and etoricoxib in their respective dissolution media for both the reference drug and the test drug was greater than 85% within the first 20 minutes, therefore these results show that the evaluated products can be accepted as equivalent (see Figures 16 and 17).

Example 6. Clinical trials of efficacy and safety of the fixed-dose combination of etoricoxib and tramadol for the treatment of acute pain and their synergy

[151] In the available literature, a preclinical study evaluated possible interactions (additive or potentiating) in the antinociceptive effects of etoricoxib and tramadol in combination against mechanical hyperalgesia induced by spinal cord injury in rats. The authors concluded that the synergistic antihyperalgesic action of this combination is useful in mechanical hyperalgesia associated with spinal injury that could be extrapolated to clinical application.

[152] Different fixed-dose combinations have been evaluated in the treatment of pain, including tramadol/paracetamol, tramadol/diclofenac, codeine/ibuprofen, codeine/paracetamol, oxycodone/paracetamol, and tramadol/dexketoprofen, either compared with the monodrug or in relation to any of these combinations. As with etoricoxib/tramadol, other NSAID combinations with tramadol in relation to paracetamol/tramadol have been evaluated, showing similar results in the treatment of pain.

[153] In 2006, Chandenwale et al. evaluated the analgesic efficacy of fixed-dose combinations of diclofenac/tramadol compared to paracetamol/tramadol in patients with acute musculoskeletal conditions, postoperative pain after orthopedic surgery, osteoarthritis, and rheumatoid arthritis, identifying a greater reduction in pain intensity and a lower frequency of adverse events with the diclofenac combination after 5 days of treatment. This study showed superior results with the fixed-dose combination of Diclofenac/Tramadol through a lower-dose regimen (1 tablet twice daily vs. 2 tablets every 4 to 6 hours without exceeding 8 tablets), greater adherence, and fewer adverse events.

[154] Currently, the use of Paracetamol 325 mg/Tramadol 37.5 mg is recommended for the treatment of low back pain, based on a minimum dosage regimen of 3 doses and a maximum of 10 doses in 24 hours, equivalent to 975 mg to 3250 mg of paracetamol and 112.5 mg to 375 mg of Tramadol per day, for a period of up to 4 weeks, this treatment is one of the most used, although it is not necessarily the safest analgesic.

[155] The etoricoxib/tramadol combination provides effective pain relief through multimodal treatment due to the different mechanisms of action of its components, achieving a faster reduction in pain intensity compared to conventional therapy. The multimodal approach provided by this combination not only improves treatment adherence but also achieves a tramadol-sparing effect (pain control with lower doses of tramadol and, therefore, a lower incidence of tramadol-related adverse events). For the relief of acute pain of moderate to severe intensity, multimodal analgesic regimens are preferred over monotherapy and, moreover, over tramadol treatment, with timely interventions, to provide immediate pain relief and prevent the development of associated complications. One of the most widely used models for evaluating the development of pharmacological products with analgesic therapeutic potential is low back pain, where the therapeutic effects of new analgesic agents can be studied.

[156] The definition of a clinically significant change in pain intensity is undoubtedly highly variable from study to study. Therefore, a study was performed to evaluate the efficacy and safety of the fixed-dose combination of etoricoxib 90 mg and tramadol 50 mg compared with the fixed-dose therapy of paracetamol 325 mg and tramadol 37.5 mg for the treatment of acute low back pain.

[157] In the “Confirmatory study of efficacy and safety of the fixed dose combination of Etoricoxib/Tramadol versus Paracetamol/Tramadol for the treatment of acute low back pain” conducted by Laboratórios Silanes S.A de C.V., the drug under investigation (Etoricoxib 90 mg/Tramadol 50 mg) is indicated in a single dosage regimen every 24 hours, obtaining the same therapeutic effect as the combination of Paracetamol/Tramadol 325 mg/37.5 mg (administered every 8 hours for a final dose of 975 mg/112.5 mg, respectively).

[158] The study design was a phase IIIb, longitudinal, multicenter, randomized, open-label clinical trial to evaluate the efficacy and safety of the fixed-dose combination of etoricoxib 90 mg and tramadol 50 mg compared with fixed-dose therapy of paracetamol 325 mg and tramadol 37.5 mg for the treatment of acute low back pain in 62 adult patients per treatment group (for a total of 124 patients).

[159] Inclusion criteria included: 1. Any sex.

[160] 2. Acceptance to participate in the study and written informed consent.

[161] 3. Age >18 years and <60 years completed at the beginning of the study.

[162] 4. Diagnosis of acute low back pain as the first episode or after another episode no more than 6 months previously and lasting no more than 6 weeks.

[163] 5. Patient with low back pain reported as moderate to severe in intensity (Visual Analogue Pain Scale VAS > 4 cm).

[164] 6. Women of childbearing potential using an acceptable method of contraception (e.g., barrier, oral hormonal, injectable, subdermal).

[165] Table 7 shows the test and reference products. Table 7. Test and reference products

[166] For the evaluation and efficacy criteria, the following parameters were followed: Efficacy Primary variables: • Mean change in pain reported through the VAS at 3, 5, and 7 days compared to baseline by treatment group. Secondary variables: • Proportion of patients who achieved a 30% reduction in pain intensity at 7 days by treatment group. • Degree of disability due to low back pain measured using the Oswestry Disability Scale at baseline and at 7 days, by treatment group. • Degree of disability to perform activities of daily living using the Roland-Morris scale, at baseline and at 7 days by treatment group. Safety • Frequency and intensity of adverse events presented during the study between treatment groups.

[167] The efficacy results showed the overall non-inferiority of etoricoxib-tramadol in terms of efficacy and safety for the treatment of acute low back pain after 7 days of treatment. The data obtained from the patients included in the present study allow us to confirm the efficacy of the combined treatment based on etoricoxib 90 mg/tramadol 50 mg in the treatment of acute low back pain during a 7-day follow-up, observing a constant reduction in pain intensity and improvement in the degree of disability due to low back pain and in performing activities of daily living.

[168] Analyzing the data at each follow-up time point, the etoricoxib/tramadol-based test product was shown to be superior to standard paracetamol/tramadol therapy, as the analgesic therapeutic effect is achieved at an earlier stage and the proportion of patients with a decrease in pain scores is higher. In the etoricoxib/tramadol fixed-dose combination group, a greater reduction in pain was observed in the first days of treatment (days 3 and 5) compared to paracetamol/tramadol therapy; therefore, the therapeutic effects of the test product are achieved earlier, representing an advantage over the comparison group. The proportion of patients who achieved a change in pain intensity from the initial severe and moderate categories to mild and pain-free at days 3 and 5 was also higher in the etoricoxib/tramadol group, demonstrating once again that the test product is superior to the reference product. Furthermore, a significantly higher proportion of patients were reported to have responded to treatment, defined as a decrease in pain intensity of at least 30% on the VAS, reported on the third day of follow-up.

[169] This occurs because the test product in the fixed-dose combination of etoricoxib/tramadol was formulated with a granule dosage form, which facilitates absorption in the gastrointestinal tract and, therefore, early blood concentrations resulting in an early analgesic effect. In turn, the paracetamol/tramadol-based reference drug in the tablet dosage form must undergo a disintegration process in the gastrointestinal tract, which delays its absorption and causes a delayed analgesic effect.

[170] On the other hand, within each treatment group, significant changes were identified in the median pain on the third, fifth, and seventh day, in relation to their baseline measurement (p = 0.001). From obtaining the magnitude of change in pain assessments on days 3, 5, and 7 in relation to their baseline, differences were observed between the treatment groups at 3 days (p = 0.054) and 5 days (p = 0.041). When evaluating the proportion of patients with a response to treatment (30% reduction (3 cm) in the VAS), the results show statistically significant differences when comparing the treatment groups on the third day of follow-up [p = 0.008, 95% CI 0.241 (0.061 0.421)] equaling their efficacy at 5 and 7 days. Therefore, although at the final follow-up on day 7 there is no inferiority between the treatments administered, the etoricoxib/tramadol test drug is able to provide earlier and superior analgesic effects from the third day of follow-up.

[171] In addition to the VAS, the improvement in disability due to low back pain to perform activities of daily living (Oswestry and Roland-Morris) was evaluated in the group of patients who received etoricoxib/tramadol, especially the improvement in the disability to perform activities of daily living (p = 0.068). According to the results of the Oswestry and Roland-Morris scales, the etoricoxib/tramadol group reported a higher proportion of patients with improvement in disability compared to the paracetamol/tramadol group, reporting a change in the classification of the degree of disability from severe to moderate and minimal.

[172] Finally, it is important to highlight that, due to the pharmaceutical form (granules) and its pharmacokinetics that allow administration every 24 hours (once a day) of the etoricoxib/tramadol dosage, in comparison to the paracetamol/tramadol group that requires administration every 8 hours (3 times a day), greater adherence was observed in the group under treatment with the etoricoxib/tramadol test medication in comparison to the treatment with paracetamol/tramadol.

[173] The above allows us to identify the clinical benefits and superiority of the etoricoxib/tramadol combination, such as greater speed in achieving therapeutic response, an early analgesic response, pain reduction similar to paracetamol/tramadol after 7 days of treatment, use of smaller doses of tramadol per day (opioid-sparing effect) resulting in lower risks of dependence, reduced use of opioids and better adherence to treatment.

[174] Regarding the safety of the investigational products, no relevant data were found that had not been previously reported on the products used in monotherapy. Among all the adverse events reported in the Silanes study, the Etoricoxib/Tramadol group reported a lower proportion of AEs compared to the group that received Paracetamol/Tramadol. In the safety results, for example, information from 124 patients was evaluated, of which 38 presented at least one adverse event (AE), 16 individuals in the etoricoxib/tramadol group and 22 in the Paracetamol/tramadol group, reporting a total of 79 AEs (38 events (48.1%) with the test drug and 41 events (51.9%) with the comparator). Regarding severity, in total, the events were classified as non-serious (100%). No deaths were reported in the study. According to the severity of the event, a higher proportion of AEs classified as “mild” compared to “moderate” was observed in both treatments (73.4% vs. 26.6%). The paracetamol/tramadol group reported adverse events with greater severity, which were moderate compared to etoricoxib/tramadol (41.5% vs. 10.5%), this difference was considered statistically significant (p = 0.002). The most affected SOCs were gastrointestinal disorders and nervous system disorders, with 33 (41.7%) events [19 (57.5%) of them in the etoricoxib/tramadol group and 14 (42.5%) in the paracetamol/tramadol group] and 32 (40.5%) events [14 (43.7%) of them in the etoricoxib/tramadol group and 18 (56.3%) in the paracetamol/tramadol group], respectively. The most common events were nausea (17.7%) and dizziness (16.4%). No clinically significant differences were observed in biochemical markers or vital signs. All of the above suggests that no safety or risk signals were identified at the time of the assessment that could alter the benefit-risk balance of patients using the study drugs, and therefore the safety profile remains favorable based on the information provided.

[175] Thus, it was possible to identify that a greater proportion of patients in the Etoricoxib/Tramadol group reported a reduction in pain intensity > 30% in the more acute period (during the first 3 days) compared to the Paracetamol/Tramadol group. These data coincide with those reported by Meloncelli et al. in a study that compared the analgesic efficacy and tolerability of the combination Tramadol/Dexketoprofen 75 mg/25 mg versus diclofenac/thiocolchicoside 75 mg/4 mg in patients with acute low back pain. Furthermore, they observed that the greater proportion of individuals who responded (defined as a reduction in pain intensity of at least 30%) to treatment corresponded to the group with the tramadol/dexketoprofen combination.

[176] In conclusion, the data obtained from the patients included in the present study allow us to confirm the efficacy and safety of the etoricoxib/tramadol combination for the treatment of acute low back pain during a 7-day follow-up, observing a constant reduction in pain intensity (VAS) and improvement in the degree of disability due to low back pain (Oswestry) and in performing daily activities (Roland-Morris).

[177] It is important to highlight that, due to the pharmaceutical form (granules) and dosage of etoricoxib/tramadol, a higher percentage of adherence was observed compared to treatment with Paracetamol/tramadol (98.3 [95% CI, 96.0-100] vs 94.5 [95% CI, 90.5-98.5]).

[178] By comparing the doses used, it can be demonstrated that both treatments administered have comparable therapeutic efficacy, although the treatment based on Etoricoxib/Tramadol is more potent from a pharmacological point of view, since with lower doses (90 mg/50 mg vs. 975 mg/112.5 mg) the desired analgesic therapeutic effects are achieved. The results obtained through the clinical study demonstrate analgesic synergy in patients suffering from acute low back pain, in addition to a tramadol-sparing effect. Previous results show the clinical benefits of Etoricoxib/Tramadol in a convenient dosing regimen, such as a faster therapeutic response, therapeutic equivalence at the end of the evaluation period and a tramadol-sparing effect (66.6% reduction in the dose of tramadol per day) resulting in a reduced risk of dependence, incidence of dose-dependent adverse events of tramadol (such as nausea, vomiting, drowsiness, etc.), reduced pill burden resulting in better therapeutic adherence.

[179] At the time of the assessment, no safety or risk signal was identified that could modify the benefit-risk relationship of patients using the study drugs, therefore the safety profile remains favorable according to the information described.

[180] By decreasing the dose of tramadol per day, a lower number of patients with adverse events related to this product was observed in the etoricoxib-tramadol combination.

Advantages of the invention and industrial application

[181] One of the main problems of those medicines with synergistic compositions of known drugs and known concentrations is the difficulty in maintaining their stability, dissolution and bioavailability, after improving their organoleptic properties and once administered to the patient; especially when the drugs are highly sensitive to light and humidity.

[182] In this sense, even and despite being within the normative parameters of dissolution and bioavailability, the results often tend towards data close to the lower limit of the specification, which means that the therapeutic effect takes time to be produced or a higher dose is required.

[183] In the prior art, there has been an attempt to solve the problem of combining both drugs for the treatment and control of pain and inflammation. The documents discuss bilayers and independent systems. Some have approached the problem using a new crystalline form. The only way they approach the combination of tramadol and etoricoxib is that there is no real physical interaction between the APIs; otherwise, they would not be combined. Similarly, there is a need to improve the synergistic effect, increase bioavailability, improve dissolution and stability, and at the same time ensure a reduction in side effects once administered to the patient. The lack of solutions and alternatives to the above results in delayed therapeutic effects or the need for a higher dose. Furthermore, the patents and scientific contributions described above demonstrate no interest in addressing the impact of the drug's organoleptic properties, which affect its stability, dissolution, and bioavailability.

[184] On the other hand, in addition to the problems of side effects due to the formation of high doses of tramadol and etoricoxib, there is the technical problem of combining a drug with high sensitivity to light and humidity, with another liposoluble drug with low flow and excessive adhesiveness, as there may be interference in stability, absorption and release mechanism.

[185] The present invention relates to a pharmaceutical composition combining an opioid analgesic drug, such as tramadol, with an NSAID, such as etoricoxib, for the manufacture of a drug useful in the treatment and control of pain, such as neuropathic pain and/or chronic and acute pain, in a single, stable, immediate-release monophasic system, with a synergistic effect and which maintains dissolution and bioavailability in the field of treatment and control of pain and inflammation, since the synergistic effect of the drugs at low doses is maintained while the dissolution and bioavailability of the composition are maintained without losing the therapeutic effect once administered, as demonstrated with respect to the pharmacokinetic bioavailability after administering the composition of the present invention and the reference oral formulations.

[186] On the other hand, in the case of a combination of active ingredients, it may be sufficient to demonstrate that the effect of the combination is greater than that obtained with each of the active ingredients used separately. This combined technical effect may also be based on more indirect aspects, such as the reduction of harmful side effects, the optimization of the pharmacokinetics or bioavailability of at least one of the active ingredients, the possibility of administering the drug by a different route, improving patient adherence to treatment, reducing the frequency of dosing, etc. This technical effect (whether synergy or any other advantage) is not suggested by the prior art.

[187] The increased analgesic effect of the present invention is due to the combination of two pharmacodynamic mechanisms that complement each other thanks to the combination of an NSAID (etoricoxib) plus an opioid (tramadol). Additionally, this combination represents a superior safety profile to treatment with monodrugs, as it allows for a reduction in adverse events resulting from the use of opioids, since by combining etoricoxib with tramadol, therapeutic results are obtained with a single daily dose of the product. On the other hand, in relation to the pharmaceutical profile, it presents improved stability.

[188] Currently, the use of paracetamol 325 mg/tramadol 37.5 mg is recommended for the treatment of low back pain, prescribed in a dosage regimen of a minimum of 3 doses and a maximum of 10 doses in 24 hours, equivalent to 975 mg to 3250 mg of paracetamol and 112.5 mg to 375 mg of Tramadol per day, for a period of up to 4 weeks [Dhillon, S., Tramadol/paracetamol fixed-dose combination. Clinical drug investigation, 2010. 30(10): p. 711-738].

[189] However, the etoricoxib/tramadol combination provides effective pain relief through multimodal treatment due to the different mechanisms of action of its components, achieving a faster reduction in pain intensity compared to conventional therapy. The multimodal approach provided by this combination not only improves treatment adherence but also achieves a tramadol-sparing effect (pain control with lower doses of tramadol and, therefore, a lower incidence of tramadol-related adverse events). For the relief of acute pain of moderate to severe intensity, multimodal analgesic regimens are preferred over monotherapy and, moreover, over tramadol treatment, through timely interventions, to provide immediate pain relief and prevent the development of pain-associated complications. Therefore, and in comparison, the investigational product (etoricoxib 90 mg/tramadol 50 mg) is indicated in a single-dose regimen every 24 hours, achieving the same therapeutic effect. The data obtained demonstrate that this analgesic synergy ends up being more potent (same therapeutic effect obtained with a lower dose) than the combination of paracetamol 325 mg/tramadol 37.5 mg. For example, it was possible to identify that a greater proportion of patients in the etoricoxib/tramadol group reported a reduction in pain intensity > 30% in the more acute period (during the first 3 days) compared to the paracetamol/tramadol group. Furthermore, among all the adverse events reported in the Silanes study, the etoricoxib/tramadol group reported a lower proportion of AEs compared to the paracetamol/tramadol group.

[190] Furthermore, the pharmacokinetic profile of the etoricoxib/tramadol combination of the present invention demonstrates that the reduction in tramadol dose (tramadol-sparing effect) is not related to pharmacokinetic differences from the fixed-dose formulation of etoricoxib/tramadol, but to a pharmacodynamic-based synergistic effect inherent in the mechanisms of action of the drugs when administered in combination and providing a multimodal therapeutic approach.

[191] The preliminary results allow us to demonstrate the clinical benefits of the etoricoxib/tramadol combination, such as obtaining a therapeutic response in a shorter period of time, therapeutic equivalence at the end of the evaluation period, use of lower doses of tramadol per day (66.6% reduction per day), resulting in a reduced risk of dependence, a low incidence of dose-dependent adverse events of tramadol and better therapeutic adherence. Therefore, no warning signs or risks were identified that could modify the risk-benefit relationship with the use of the etoricoxib/tramadol combination of the present invention.

Claims (9)

1. Pharmaceutical composition, characterized by the fact that it comprises tramadol in an effective amount of 50 mg and etoricoxib in an effective amount of 90 mg, in which the composition is a granule for reconstitution. 2. Pharmaceutical composition, according to claim 1, characterized by the fact that it additionally comprises at least one of a binder, a disintegrant, a sweetener, a flavoring and a diluent. 3. Pharmaceutical composition, according to claim 2, characterized by the fact that it additionally comprises a diluent, a binder and two sweeteners. 4. Pharmaceutical composition according to claim 3, characterized in that it additionally comprises: - tramadol hydrochloride in an effective amount of 50 mg; - etoricoxib in an effective amount of 90 mg; - isomalt 801 as diluent in an amount of 36% by weight of the composition; - polyethylene glycol as binder in an amount of 43.20% by weight of the composition; - croscarmellose sodium as disintegrant in an amount of 5.0% by weight of the composition; - acesulfame potassium as first sweetener in an amount of 3.0% by weight of the composition; - sucralose as second sweetener in an amount of 2.0% by weight of the composition; and - mint-spearmint flavor in an amount of 8.0% by weight of the composition. 5. Process for the manufacture of a pharmaceutical composition, defined in any one of claims 1 to 4, characterized by the fact that it comprises the following steps: a) mixing the active ingredients (tramadol and etoricoxib) with pharmaceutically acceptable excipients (polyethylene glycol, isomalt 801, croscarmellose sodium, acesulfame potassium and sucralose) previously sieved for 5 minutes (mixture 1); b) granulating mixture 1 for 20 to 30 minutes until reaching a temperature between 54 and 55.2 °C; c) cooling the granules to a temperature of 25 to 28 °C; d) sieving the granules from step d), thus obtaining a sieving 3; e) mixing Sieving 3 with the mint-spearmint flavor for 5 minutes. 6. Process according to claim 5, characterized in that the granulations are carried out by a fusion granulation process. 7. Use of a pharmaceutical composition, defined in any one of claims 1 to 4, characterized in that it is for the manufacture of a medicament useful in the treatment of pain and inflammation. 8. Use according to claim 7, characterized in that the pain is selected from the group consisting of neuropathic pain, chronic pain and acute pain. 9. Use according to claim 7 or 8, characterized in that the composition is adapted to be administered every 24 hours.