Synergic and stable pharmaceutical composition of nsaid and opioid analgesic for pain and inflammation

Abstract

To provide a pharmaceutical composition for treatment of pain.SOLUTION: The present invention relates to pharmaceutical compositions comprising etoricoxib and tramadol, or a pharmaceutically acceptable salt thereof, for the treatment of pain. In addition to offering the possibility of an analgesic effect with a decrease in adverse events due to the reduction of the dose of one or both compounds, this presents an improved stability and maintains the dissolution and bioavailability of the composition to be administered. The composition succeeds to overcome the technological complexity when making a drug (tramadol) with high sensitivity to light and humidity and another fat-soluble drug (etoricoxib) with poor flowability and excessive adhesiveness exist in a dispersed medium in which their absorption is not affected through a water-free process, without affecting the release of both drugs.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a combined pharmaceutical composition, a synergistic effect and a method for producing the same in the fields of treatment, pain control and inflammation.

Background Art

[0002] For pain management, there is a need to create analgesic strategies that ensure faster, more effective and safer relief and suppress the progression to chronic pain. Pain treatment should aim to improve the quality of life of patients and focus on urgent responses to prevent the onset of future complications related to the disorder.

[0003] Considering the complex pathophysiology of pain, multimodal analgesia has been implemented as a treatment strategy defined as the simultaneous use of drugs with complementary mechanisms of action that produce a synergistic effect. In multimodal analgesia, several drugs such as opioids, NSAIDs and paracetamol are commonly used.

[0004] According to the International Association for the Study of Pain (IASP), neuropathic pain is pain that results directly from injury or disease affecting the somatosensory system.

[0005] It is known that patients with acute neuropathic pain may not respond to monotherapy even at maximum doses. Therefore, usually two or more drugs with complementary mechanisms of action are used for treatment.

[0006] For example, tramadol of formula I, whose nomenclature is (1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol, has opioid agonist properties, is a synthetic codeine analogue that activates monoaminergic spinal pain inhibition, is a centrally acting analgesic, and is commonly used for the treatment of acute pain derived from neuropathy.

[0007]

Chemical Formula

[0008] This can be administered orally, rectally, intravenously or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular administration of tramadol has generally been shown to be as effective as pethidine (meperidine) and one-fifth as effective as nalbuphine. Tramadol has shown analgesic activity in various animal models and healthy volunteers with experimentally induced pain. The analgesia of orally administered tramadol is similar to that of intravenous administration (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).

[0009] Adverse reactions commonly associated with tramadol administration may include constipation, nausea, vomiting, abdominal pain, dizziness, drowsiness, fatigue, and headache. Some of the adverse reactions, such as convulsions, urticaria, blisters, dysphagia, inflammation of the eyes, face, throat, tongue, lips, hands, feet, and ankles; and further changes in heart rate, etc., may worsen, but the incidence of severe adverse reactions is less than 1%. Similarly, tramadol belongs to Group IV of opioid drugs and is an opioid with low potential for medicinal use and intoxication. High doses of tramadol are known to be potentially capable of causing greater adverse reactions. Intentional and accidental overdose of tramadol can cause respiratory arrest and acute liver failure, and several fatal cases have also been reported. However, in these cases, liver damage may have been caused by shock, hypoxia, or ischemia secondary to respiratory arrest. Liver damage resulting from tramadol overdose is also associated with hyperammonemia, lactic acidosis, and hepatic steatosis, which suggest direct mitochondrial damage (Liver Tox Clinical and Research information of Drug-Induce Livered Injury, National Institutes of Health, December 05, 2012).

[0010] On the other hand, there is etoricoxib of Formula II, also known as 5-chloro-2-(6-methylpyridin-3-yl)-3-(4-methylsulfonylphenyl)pyridine. It is a synthetic non-steroidal anti-inflammatory drug (NSAID) and may have antipyretic, analgesic, and anti-tumor properties. Etoricoxib specifically binds to and inhibits an enzyme called cyclooxygenase-2 (COX-2), thereby inhibiting the conversion of arachidonic acid to prostaglandins (https: / / pubchem.ncbi.nlm.nih.gov / compound / 123619).

[0011] [Chemical formula] Formula II

[0012] According to the International Association for the Study of Pain (IASP), etoricoxib is indicated for the treatment of chronic and acute pain defined as pain lasting from the moment of tissue injury for more than 3 months up to 6 months. High-dose administration of etoricoxib may cause adverse reactions such as ulcer formation and intolerance in the gastrointestinal tract, platelet aggregation inhibition (thromboxane synthesis inhibition), uterine motility inhibition (prolonged pregnancy), prostaglandin-mediated renal function impairment, and hypersensitivity, among others.

[0013] In the art, combination drugs containing combinations of active ingredients such as etoricoxib / tramadol have been developed as alternatives for the treatment of pain and inflammation. For example, the patent application of International Publication No. WO 2019 / 130049 provides a composite drug of sustained-release tramadol hydrochloride and immediate-release etoricoxib combined with a solvent and a vehicle, and a method for manufacturing the same in a single dosage form such as capsules, tablets, bilayer tablets, granules, and sachets. Furthermore, a method for preventing and treating pain such as acute pain is also provided. In one embodiment, the composite drug comprises a first formulation of tramadol in granular form and a second formulation of etoricoxib.

[0014] Subsequently, the Mexican application MX / a / 2016 / 006464 describes a pharmaceutical composition of a combination of tramadol hydrochloride / etoricoxib with a specific particle size (etoricoxib with d90 < 30 microns) for the treatment of pain, and a method for manufacturing the same in tablets or granules of capsules and / or tablets with or without coating, either as a powder mixture or bilayer tablets with or without coating. The concentration of tramadol / etoricoxib is such that etoricoxib is 10 - 120 mg and tramadol is 10 - 300 mg.

[0015] The patent application of International Publication No. WO 2019 / 021079 describes a pharmaceutical composition of a combination of tramadol hydrochloride / etoricoxib for the treatment of pain, a process for obtaining it from two active ingredients consisting of granules and / or multiparticulates having tramadol hydrochloride and granules and / or multiparticulates having etoricoxib, said active ingredients being contained in a powder mixture or a tablet of a bilayer tablet with or without coating or a capsule of granules or a tablet with or without coating, and etoricoxib is 0.15 to 0.85 with respect to the total of etoricoxib administered in combination with tramadol hydrochloride or a similar salt. The concentration of tramadol / etoricoxib is from 10 - 300 mg to 10 - 120 mg respectively. The concentration of tramadol / etoricoxib is from 10 - 300 mg to 10 - 120 mg respectively.

[0016] As another example of a combination, there is Patent No. MX243332 which describes a combination of an opioid analgesic and a COX-2 inhibitor. The opioid analgesic and the COX-2 inhibitor can be administered orally, by implantation, parenterally, sublingually, rectally, topically or by inhalation. In another embodiment of the present invention, the COX-2 inhibitor can be administered separately from the opioid analgesic. The pharmaceutical composition containing the COX-2 inhibitor and the opioid drug described in MX243332 is administered orally. Such oral dosage forms can contain one or both drugs in immediate release or sustained release form. To facilitate administration, it is preferred that the oral dosage form contains both drugs. The oral dosage form can be in the form of tablets, small pieces, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, multiparticulate formulations, syrups and elixirs, etc.

[0017] Similarly, the published patent publication MX / a / 2019 / 008577 describes the combination of etoricoxib / tramadol for the treatment of pain via an independent dual release single-dose system containing a COX-2 inhibitor and a centrally acting opioid, which consists of two matrices and is useful for the treatment of moderate to severe pain. A process for obtaining the said independent release matrix is also described.

[0018] On the one hand, U.S. Patent Application Publication No. 2008 / 0026054, a U.S. patent document, describes a sustained-release pharmaceutical composition in the pharmaceutical form of tablets or capsules, comprising tramadol and an immediate-release layer of an NSAID including but not limited to etoricoxib.

[0019] Patent document MX311821 even describes a tramadol / etoricoxib cocrystal for the preparation of a pharmaceutical product suitable for the treatment of pain.

[0020] On the other hand, the published document "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.) shows a non-clinical or pre-clinical study evaluating the pharmacodynamic effects and the possibility of interaction (additive or synergistic effect) in the anti-nociceptive action of etoricoxib, a cyclooxygenase-2 inhibitor, and tramadol, a typical opioid agonist, for testing spinal cord injury-induced mechanical hyperalgesia in rats.

[0021] In the prior art, attempts have been made to solve the problem of combining both drugs for the treatment and control of pain and inflammation. The literature has written a lot about bilayer and independent systems. Some have also approached this problem from new crystal forms. The only way they approach the combination of tramadol and etoricoxib is that there is no actual physical interaction of the APIs, otherwise they do not combine.

[0022] Similarly, it is necessary to improve the synergistic effect, enhance bioavailability, improve solubility and stability, and at the same time ensure a reduction in side effects after administration to patients. Since there are no solutions and alternatives to the above, it takes time for the therapeutic effect to appear or a high dose is required. Furthermore, the above-mentioned patents and scientific contributions have shown no interest in solving the influence on the sensory irritation characteristics of drugs that affect stability, solubility and bioavailability.

[0023] On the other hand, in addition to the problem of side effects due to the conformation of high-dose tramadol and etoricoxib, combining a drug that is highly sensitive to light and humidity with another lipophilic drug that has poor fluidity and excessive adhesiveness may cause problems in stability, absorbability and release mechanism, so there are technical problems.

[0024] Accordingly, the present invention refers to a pharmaceutical composition of a combination of tramadol - etoricoxib, which is a single - phase system produced by fusion granulation, stable, immediate - release, having a synergistic effect, and maintaining solubility and bioavailability, in the field of the treatment and control of pain and inflammation.

Summary of the Invention

Problems to be Solved by the Invention

[0025] The present invention relates to a granular reconstituted pharmaceutical composition comprising tramadol and etoricoxib, or a pharmaceutically acceptable salt thereof. The composition of the present invention is used in the manufacture of a medicament useful for the treatment of pain and inflammation, which provides a synergistic pharmacological effect with an effective amount of the active ingredient, thus bringing the possibility of an analgesic effect while reducing adverse events and reducing the dose of one or both compounds, and showing an improvement in stability while maintaining the solubility and bioavailability of the administered composition.

[0026] The enhancement of the analgesic effect of the present invention is due to a combination of two pharmacodynamic mechanisms that complement each other by the combined use of an NSAID (etoricoxib) and an opioid (tramadol). Furthermore, this combination can reduce the adverse events resulting from the use of opioids because a therapeutic result can be obtained with once-daily administration of the formulation when etoricoxib and tramadol are used in combination, and shows a better safety profile than treatment with a single agent. On the other hand, the pharmacokinetic profile of the etoricoxib / tramadol combination of the present invention is due to a synergistic effect based on pharmacodynamics inherent in the mechanism of action of the drugs upon combined administration, rather than being related to the pharmacokinetic differences of the etoricoxib / tramadol multi-drug combination formulation, indicating that it provides a multimodal therapeutic approach. On the other hand, the treatment based on etoricoxib / tramadol is more potent from a pharmacological point of view because a desired analgesic treatment effect can be obtained at a low dose (90 mg / 50 mg vs. 975 mg / 112.5 mg). The results obtained from the clinical trials by the present applicant demonstrate an analgesic synergistic effect in addition to the tramadol-sparing effect in patients with acute low back pain. Also, among all the adverse events reported in the clinical trials conducted by the present inventors, the proportion of reported AEs in the etoricoxib / tramadol group was lower than that in the paracetamol / tramadol group.

[0027] Furthermore, the stability has also been improved with respect to the profile of the pharmaceutical product.

[0028] One embodiment of the present invention includes a synergistic composition in a single stable immediate-release solid dosage form containing tramadol hydrochloride at a concentration of 50 mg / 5 g and etoricoxib at a concentration of 90 mg / 5 g, respectively.

[0029] In another embodiment of the present invention, the composition is found in the form of granules. Preferably, it takes the form of granules for reconstitution.

[0030] Excipients that constitute the composition and provide essential features for improving pharmacokinetic profiles, bioavailability, stability, and solubility are also an object of the present invention.

[0031] Another embodiment of the present invention includes a manufacturing process for a composition that does not require the incorporation of water, and has successfully overcome the technical complexities involved in introducing a drug (tramadol) highly sensitive to light and humidity and another lipophilic drug (etoricoxib) with poor fluidity and excessive adhesiveness into a powder medium that does not affect their absorption through a melt granulation process. Thus, the release of both drugs is not affected.

[0032] The manufacturing process of the pharmaceutical composition according to the present invention is as follows: 1) Mixing the active ingredients tramadol and etoricoxib with a pre-screened pharmaceutically acceptable excipient for about 5 minutes; 2) Granulating the mixture obtained in the previous step for 20 - 30 minutes until it reaches a temperature of 54°C - 55.2°C; 3) Cooling the granules from the previous step to a temperature of 25°C - 28°C; 4) Screening the granules obtained in the previous step; 5) Mixing the resulting screening product and a fragrance from the previous step for 5 minutes.

[0033] The present invention also relates to a granular pharmaceutical composition for reconstitution, containing tramadol and etoricoxib in an effective synergistic amount of 50 / 90 mg each, obtained by the described melt granulation process, and its use in the manufacture of a medicament useful for the treatment and control of pain such as neuropathic pain and / or chronic and acute pain.

Brief Description of the Drawings

[0034]

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Mode for Carrying Out the Invention

[0035] Definitions Pharmaceutically acceptable salt: The "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not undesirable biologically or otherwise (P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2d Revised Edition (May 16, 2011)).

[0036] Neuropathic pain: According to the International Association for the Study of Pain, neuropathic pain is pain that is a direct result of damage or disease in the somatosensory system. And this type of pain is seen in various neuropathies, polyneuritis, post-treatment neuralgia, other common central pain syndromes, such as spinal cord injury, spinal cord tumor, syringomyelia, and cancer associated with neuropathic pain.

[0037] Excipient: A component that is part of a pre-set pharmaceutical composition, including binders, disintegrants, sweeteners, flavors, etc.

[0038] Synergistic effect: A combined technical effect. The most favorable case is when the combination of active ingredients produces a synergistic effect, that is, when the functions of two features are linked, in which case these features act synergistically with each other, and each of these features produces an additional effect that exceeds the sum of the effects produced by considering each individual active ingredient separately in this case.

[0039] The present invention relates to a pharmaceutical composition of a combination of an opioid analgesic and a non-steroidal anti-inflammatory drug in a single monophasic system, which composition is in the form of granules for reconstitution, stable, immediate-release, has a synergistic effect in the field of treatment and control of pain and inflammation, and maintains solubility and bioavailability.

[0040] The opioid analgesic used is tramadol or a pharmaceutically acceptable salt thereof, such as its hydrochloride salt, and the NSAID is etoricoxib or a pharmaceutically acceptable salt thereof.

[0041] The present invention comprises a combination of etoricoxib and tramadol or a pharmaceutically acceptable salt thereof in a dose of 50 mg of tramadol and 90 mg of etoricoxib; and at least one pharmaceutically acceptable excipient.

[0042] As shown above, the solid pharmaceutical composition is in the form of granules for reconstitution. The most preferred pharmaceutical form of the present invention is "granules for reconstitution", which is a pharmaceutical form that does not present problems with respect to the dissolution results for tramadol hydrochloride or etoricoxib, releases the active ingredient 100%, and is more readily accepted due to its easy swallowing.

[0043] The combination of tramadol and etoricoxib presents a series of important technical challenges due to the physicochemical properties of the drugs, and the appropriate selection of excipients and manufacturing conditions plays a very important role in relation to drug release and in vivo absorption rate in the development of pharmaceutical compositions. Therefore, this composition has successfully overcome the technical complexity in combining a drug (tramadol) that is highly sensitive to light and humidity and another lipophilic drug (etoricoxib) that has poor fluidity and excessive adhesiveness in a powder medium that does not affect their absorption by means of a melt granulation process, and thus the release of both drugs is not affected.

[0044] Regarding excipients, in one embodiment, the pharmaceutical composition of the present invention includes at least one of a binder, a disintegrant, a sweetening agent, a flavoring agent, and a diluent.

[0045] Examples of pharmaceutically acceptable disintegrants include cellulose derivatives such as croscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose; povidone derivatives such as crospovidone; starch derivatives such as pregelatinized starch, sodium starch glycolate, and corn starch, but are not limited thereto. The disintegrant may be present in an amount in the range of 0.5% to 15% by weight, preferably 0.5% to 5% by weight. The preferred disintegrant for this formulation is sodium croscarmellose.

[0046] 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 stearate and suppository bases. In a preferred embodiment, the binder is polyethylene glycol 6000, which may be present in the formulation in an amount of about 43% by weight.

[0047] In a preferred embodiment, the diluent is isomalt 801, which may be present in an amount of about 36% by weight.

[0048] Examples of pharmaceutically acceptable sweeteners include, but are not limited to, acesulfame potassium, sucralose, alitame, aspartame, isomalt, lactitol, maltitol, mannitol, neotame, saccharin ammonium, saccharin calcium, saccharin sodium, sodium cyclamate, sorbitol, sucralose, tagatose, thaumatin and xylitol. Preferred sweeteners for the present formulation are acesulfame potassium and sucralose.

[0049] Acesulfame potassium is present in an amount of about 3.0% by weight, while sucralose is used at 2.0% by weight in the formulation.

[0050] Examples of pharmaceutically acceptable flavors include, but are not limited to, mint - peppermint flavor, d - menthol; l - menthol; or thymol. The flavor is present in the range of 7 - 9% use, LD 50 (rat, oral): 3.18 g / kg, preferably used at about 8% by weight in the formulation. The preferred flavor for the present formulation is mint - peppermint flavor.

[0051] In a more preferred embodiment, the composition comprises a diluent, a binder and two sweeteners, the diluent is isomalt 801, the binder is polyethylene glycol, the first sweetener is acesulfame potassium, and the second sweetener is sucralose. Regarding the remaining excipients, the disintegrant is croscarmellose sodium and the flavor is mint - peppermint flavor.

[0052] On the other hand, the combined use of tramadol and etoricoxib suggests a synergistic anti - hyperalgesic 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.).

[0053] In another embodiment of the present invention, it has been found that even when a combined preparation of tramadol and etoricoxib is administered, the pharmaceutical composition does not exhibit pharmacokinetic interactions.

[0054] Accordingly, in another aspect, the present invention provides a method for treating pain and inflammation, the method comprising administering the above - mentioned composition to a patient in need thereof, preferably every 24 hours.

[0055] In a preferred embodiment, the types of pain treatable by the present invention are nociceptive, neuropathic or mixed pain. Further, depending on the duration of the clinical condition, chronic pain and acute pain are the subjects of treatment using it.

[0056] Evaluation of manufacturing and testing carried out to obtain an optimal formulation In the prior art, even when the combined use of tramadol and etoricoxib is taught, manufacturing processes, pharmaceutical forms, and dosage forms different from those of the present invention are described. The prior art describes bilayer and independent systems of combinations of tramadol and etoricoxib. There have even been approaches from new crystal forms. The only approach to these combinations is that there is no actual physical interaction of the APIs, otherwise they are not combined, and thus a single-phase formulation of tramadol and etoricoxib in a single dosage form is required. Thus, in this application, a manufacturing process for a single single-phase system of tramadol and etoricoxib formulation that also results in stability and synergy is described.

[0057] More specifically, the manufacturing process of the tramadol and etoricoxib formulated pharmaceutical composition of the present disclosure proposed by the inventors refers to melt granulation in a single single-phase and stable immediate release system that has a synergistic effect and maintains solubility and bioavailability in the field of treatment and control of pain and inflammation.

Example

[0058] Example 1. Formulation of a Composition Containing Tramadol and Etoricoxib Next, the formulation of a granular composition for reconstitution containing either of the two active ingredients, tramadol hydrochloride and etoricoxib, or their pharmaceutically acceptable salts, will be described.

[0059]

Table 1

[0060] Example 2. Manufacturing Process of a Melt-Granulated Composition for Reconstitution This formulation combines tramadol (hydrochloride) and etoricoxib at a dosage of 50 mg / 90 mg per administration unit, presenting a series of important technical issues due to the physicochemical properties and the difference in dosage to ensure a stable formulation.

[0061] In the patent of the closest prior art, a wet granulation process for incorporating water is carried out. In such a case, in the present invention, when it is desired to incorporate water in the process of formulating tramadol (hydrochloride), which is the active ingredient, and etoricoxib, the formulation result is adversely affected. The following shows the tests carried out on the combination of tramadol (hydrochloride) and etoricoxib of the present invention by the wet method, but in this method, a combination of stable quality cannot be obtained, while melt granulation is a unified operation capable of implementing the present invention.

[0062] Formulation evaluation of an extrusion - spheronization test incorporating ethyl cellulose as a spheronization promoter.

[0063] Test: 1712 - 12 (Figure 1).

[0064] % Material 19.94 Tramadol hydrochloride 19.94 Etoricoxib 15.95 Microcrystalline cellulose PH101 44.17 Ethyl cellulose E - 7 - 7050

[0065] Purpose Formulation evaluation of an extrusion - spheronization test incorporating ethyl cellulose as a spheronization promoter.

[0066] Physical results: Disintegration 8 hours 30 minutes, total weight of combined capsules 458.45 mg.

[0067] Findings: Encapsulate the spheres of tramadol hydrochloride and etoricoxib; send the capsule weight of tramadol HCl of capsule number 0, 251 mg, and etoricoxib 112.45 mg for analysis.

[0068] According to the dissolution results, the release of tramadol HCl exceeded 100%, and the release of etoricoxib was less than about 80%, and problems were found in both. This phenomenon is due to the insufficient distribution of the active ingredients in the spherical formulation. It was proposed to change the pharmaceutical form from extrusion-spheronization to granulation for reconstitution by the wet granulation method.

[0069] Manufacture of batches for evaluating the sensory irritation characteristics of the formulation.

[0070] Test: 1810 - 29

[0071] % Material 1.00 Tramadol hydrochloride 1.80 Etoricoxib 40.00 Isomalt 801 52.20 Polyethylene glycol 6000 3.0 Acesulfame potassium 2.0 Sucralose Purified water (mL)

[0072] Objective: Manufacture of batches for prescription evaluation

[0073] Findings: Wet granulation was performed to incorporate the active ingredients into the granules. In the case of this type of pharmaceutical form, it is important to incorporate flavors. Since the active ingredients are bitter, it is necessary to incorporate fragrances to improve the sensory irritation characteristics of the active ingredients. Tests were conducted to evaluate the sensory irritation characteristics for various flavors. According to the results of the sensory irritation characteristics: each of the flavors of bubble gum orange, grape, mint and strawberry was not useful for masking the bitterness of the active ingredients, and therefore, it was proposed to use another flavor (Table 2).

[0074]

Table 2

[0075] Evaluation of the prescription by wet granulation

[0076] Test: 1810-29 (Figs. 2 and 3).

[0077] % Material 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 Mint - Peppermint 0.35 Purified water (mL)

[0078] Purpose Evaluation of formulation by wet granulation

[0079] Physical tests %H.R. = -0.93 Disintegration: 5 minutes.

[0080] Similarity coefficient Etoricoxib F2 = 57.51% (control, innovative formulation) Tramadol hydrochloride F2 = 88.05% (control, innovative formulation)

[0081] Dissolution results Dissolution medium: buffer pH 2.0: chromatographic grade acetonitrile (75:25); dissolution medium: HCl.

[0082] Findings: In this test, peppermint flavor was added and 2.5% of croscarmellose sodium was added. Samples were sent for analysis.

[0083] Since the amount of water required is minimal, it is proposed to change to melt granulation and use a low melting point solid binder at 55°C - 62°C as an excipient.

[0084] According to the dissolution results, there were no problems with both tramadol hydrochloride and etoricoxib, and as innovative batch criteria for each active ingredient, 100% release of the active ingredient was achieved.

[0085] When the obtained samples were subjected to preliminary stability evaluation, incompatibility of tramadol was recognized in the presence of residual moisture resulting from wet granulation, color change occurred in the tablets, and decomposition of tramadol was observed. Therefore, this manufacturing route is not feasible to guarantee compliance with quality characteristics.

[0086] Evaluation of the formulation by melt granulation Conversely, in melt granulation, incorporating at least one binder that melts at 50 - 80 °C for the physical binding of the components tramadol - etoricoxib makes it possible to contain the active ingredients without the need to incorporate water, eliminates the drying stage, and is advantageous for the combination of active ingredients of the present invention.

[0087] Test: 1908 - 03(B) (Figures 4 and 5).

[0088] % Material 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 Mint - Peppermint

[0089] Purpose Evaluation of the formulation by melt granulation

[0090] Physical tests Physical tests were not conducted

[0091] Similarity coefficient Etoricoxib F2 = 60.51% (control, innovative formulation) Tramadol hydrochloride F2 = 86.43% (control, innovative formulation)

[0092] Dissolution results Dissolution medium: buffer solution pH 2.0: chromatographic grade acetonitrile (75:25); dissolution medium: hydrochloric acid

[0093] Findings For the excipient polyethylene glycol 6000, a melting temperature range of 54.4 °C to 57.5 °C was determined. It was proposed to do this by increasing the amount of the disintegrant up to 2 times 5%.

[0094] The dissolution results showed no problems for both tramadol HCl and etoricoxib, and 100% release of the active ingredients was achieved as the innovative batch criteria for each active ingredient.

[0095] Evaluation of the formulation by melt granulation

[0096] Test: 1908 - 03 (B2C) (Figures 6 and 7).

[0097] % Material 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 Mint - Peppermint

[0098] Physical tests I.H. = 1.09 I.C. = 8.5, inertia angle 8.0, flow rate 10.26 g / s, average particle size 786.7

[0099] Similarity coefficient Etoricoxib F2 = 63.06% (control, innovative formulation) Tramadol hydrochloride F2 = 56.12% (control, innovative formulation)

[0100] Dissolution result Dissolution medium: buffer solution pH 2.0: chromatographic grade acetonitrile (75:25); dissolution medium: HCl.

[0101] Findings The formulation meets the similarity coefficient of each drug and the manufacturing process is reproducible.

[0102] The similarity coefficient was measured for each active ingredient between a single agent prepared in the same pharmaceutical form and the innovative drug.

[0103] These results serve as the basis for preparing stability batches in order to obtain an optimal formulation.

[0104] According to the aforementioned tests, surprisingly, it is possible to develop a process that guarantees a stable formulation meeting established quality characteristics. For this purpose, the aforementioned specific excipients and additives were arranged and a melt granulation process was selected that can maintain the chemical integrity of both drugs.

[0105] The following shows non - limitatively the manufacturing process by melt granulation of the granules for reconstitution of the present invention containing etoricoxib and tramadol and / or their pharmaceutically acceptable salts:

[0106] 1. Screen polyethylene glycol 6000 (Screening item 1). 2. Screen etoricoxib, tramadol hydrochloride, isomalt 801, croscarmellose sodium, acesulfame potassium and sucralose (Screening item 2). 3. Mix Screening item 1 and Screening item 2 for 5 minutes (Mixture 1). 4. Granulate Mixture 1 for 20 - 30 minutes until the temperature reaches 54 - 55.2 °C. 5. Cool the granules to a temperature of 25 - 28 degrees. 6. Screen the granules from Step 5 (Screening item 3). 7. Mix the screening agent 3 with the meta-peppermint flavor for 5 minutes (mixture 2).

[0107] During melt granulation, at least one binder that melts at 50 - 80 °C for the physical binding of the tramadol-etoricoxib components is incorporated, which enables the inclusion of the active ingredients without the need to incorporate water and eliminates the drying stage. In contrast, the closest prior art patents, for example, perform a process where wet granulation takes in water.

[0108] This formulation combines tramadol (hydrochloride) and etoricoxib at doses of 50 mg / 90 mg per administration unit respectively, presenting a series of important technical challenges due to the physicochemical properties and the differences in doses to ensure a stable formulation.

[0109] The technical complexity lies in the combination of two drugs with different rheological and dissolution properties. One is a drug sensitive to humidity and light, and the other is a lipophilic drug (etoricoxib) with poor fluidity and excessive adhesiveness, which may interfere with the stability, absorption, and release mechanisms.

[0110] By combining both drugs, a better analgesic effect can be obtained with a reduced dose, and the harmful effects are also reduced.

[0111] Example 3 Stability Test The stability test was carried out on 3 batches of the described pharmaceutical composition in accordance with the current regulations. The results for 6 months under the conditions of 40 °C and 75% relative humidity are shown below (Table 3):

[0112]

Table 3

[0113] Example 4 Comparative Bioavailability Test From the results obtained in the bioavailability comparative study on the combined use of etoricoxib and tramadol, the inventors were able to conclude that the pharmacokinetic profile of this formulation was appropriate when compared to single-agent administration alone. On the other hand, the inventors were also able to guarantee the quality of the formulation prescription in the combined use of etoricoxib and tramadol and its excipients. Furthermore, from the results obtained, the inventors were able to conclude that there was no interaction in the bioavailability of the co-administered formulation. Additionally, it was verified that the established quality standards, current NOM-177-SSA1, procedures, protocols, GLP, and Good Documentation Practice were fully complied with, which supported the authenticity of the test results.

[0114] For pharmacokinetic and statistical analysis, data were obtained from 42 study subjects for three treatments, six sequences, and three periods (3×6×3) in a randomized crossover design. Plasma concentration data were obtained each time for each dosing. Parameters: C max and ABC 0-72 were subjected to analysis of variance (ANADEVA). In addition to descriptive statistics, the following tests were performed: classical confidence intervals, 90% (95%), and Schuirmann test. The calculations were performed using the WINNONLIN® version 8.0 program.

[0115] The statistical analysis to establish the absence of pharmacokinetic interaction (bioavailability equivalence) by the combined use of etoricoxib + tramadol was performed using the data of 38 subjects who completed the test.

[0116] Forty-two subjects participated and received three treatments corresponding to a single oral dose: control drug A (etoricoxib 90 mg), control drug B (tramadol 50 mg), and test drug C (etoricoxib 90 mg / tramadol 50 mg, Laboratorios Silanes) were administered in six divided doses over three periods (with a 14-day washout period in between). The total dose administered was 90 mg of etoricoxib and 50 mg of tramadol (see Table 4).

[0117]

Table 4

[0118] To visualize the possible differences between formulations and / or treatment methods, the plasma concentration profiles (± standard error) over time obtained in the participating subjects were graphed (see Figures 8 - 15).

[0119] In the statistics for demonstrating pharmacokinetic bioequivalence, the differences between the treatment methods during the test must be evaluated through the logarithmic comparison of the pharmacokinetic parameters: C max and ABC 0-72 must be evaluated through the logarithmic comparison of the pharmacokinetic parameters: C

[0120] a) Confidence interval Statistical analysis was performed on the bioequivalence of the test drug based on the construction of the confidence interval, and when the calculated limit values were included in the preset interval from 80 to 125, it was concluded that bioequivalence (without pharmacokinetic interaction) was supported. These were analyzed considering that the confidence level was 90% (95%) and the power of the statistical test should exceed 0.80.

[0121] b) Limit test The limit test leads to the conclusion that the analyte shows pharmacokinetic equivalence at a significance level α (α = 0.05) and a confidence level of 90% based on the rejection of the null hypothesis of non - equivalence. The limit tests applied were the Schuirmann two - sided t - test for the pharmacokinetic parameters C max and AUC 0-72 and the Anderson Hauck test for the ratio between the means of the test drug and the reference drug.

[0122] The limit test concludes that bioequivalence is supported if the probability that the ratio is less than 80% and greater than 125% (less than 75% and greater than 133% when there is large pharmacokinetic variability) is less than 0.05.

[0123] The following Table 5 shows the pharmacokinetic parameters C of etoricoxib obtained for the two evaluated therapies (A vs C). max and AUC 0-72 and the results of the statistical tests applied thereto. The objective was to apply a confidence level of 90% (95%) and evaluate the possible differences between the therapies, considering all 38 subjects who completed the trial.

[0124]

Table 5

[0125] The following Table 6 shows the pharmacokinetic parameters C of tramadol obtained for the two evaluated therapies (B vs C). max and AUC 0-72 and the results of the statistical tests applied thereto. The objective was to apply a confidence level of 90% (95%) and evaluate the possible differences between the therapies, considering all 38 subjects who completed the trial.

[0126]

Table 6

[0127] After administration of the single oral doses corresponding to 90 mg of etoricoxib and 50 mg of tramadol in tablet and capsule dosage forms, i.e., 90 mg etoricoxib tablets as control formulation A, 50 mg tramadol capsules as control formulation B, and the granule etoricoxib / tramadol in sachet dosage form of batch 20A081G1 from Laboratorios Silanes as test drug C diluted with 100 mL of water (90 mg etoricoxib / 50 mg tramadol), C max and the area under the plasma concentration curve (AUC 0-72 ) as pharmacokinetic parameters were measured.

[0128] Comparative analysis of pharmacokinetic parameters was performed using classical and Schuirmann confidence interval methods. Classical confidence intervals are symmetrical around the difference between the mean values of test drug and control (CP-CR) and not around zero, whereas classical confidence intervals are symmetrical around the CP / CR ratio and not around unity.

[0129] The classical confidence intervals for etoricoxib (contrast A vs. C) are for two pharmacokinetic variables, Ln(C max ) and Ln(AUC 0-72 ) met the 80–125% criterion for log-transformed data.

[0130] Pharmacokinetic parameters related to the degree or magnitude of absorption: ABC 0-72 The classical confidence intervals for the log-transformed data were found to be within the 80-25% range, and the AUC 0-72 This is the same as the Schuirmann and Anderson Hauck test (5) which indicates that values are unlikely to be outside the 80-125% range ("p" value less than 0.05).

[0131] The classical confidence interval for tramadol (contrast B vs. C) is the confidence interval for the two pharmacokinetic variables Ln(C max ) and Ln(AUC 0-72 ) met the 80-125% criterion for log-transformed data.

[0132] ABC Pharmacokinetic Parameters Related to Tramadol 0-72 Regarding the AUC of the test drugs (etoricoxib / tramadol), the classical confidence intervals are understood to be within the range of 80-125% for the log-transformed data. 0-72 This is the same as the Schuirmann and Anderson Hauck test (5) which indicates that values are unlikely to be outside the 80-125% range (low “p” value of 0.05).

[0133] For each of the comparisons (C vs A and C vs B) (where A is etoricoxib monotherapy as the control drug, B is tramadol monotherapy as the control drug, and C is a fixed-dose combination of etoricoxib / tramadol as the test drug), the following criteria for being used without pharmacokinetic interaction were all met for the variables Ln(C max ) and Ln(ABC 0-72 ): (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) In the classical 95% confidence interval, no values outside the 80 - 125% interval are shown, (3) The p - value associated with the Schuirmann test for P < 80 is less than 0.05 (p ≤.0001), (4) The p - value associated with the Schuirmann test for P > 125 is less than 0.05 (p ≤.0161), (5) In the Anderson Hauck test, the p - value is lower than.05 (p ≤.02), so the hypothesis of no pharmacokinetic interaction can be rejected (α = 0.05).

[0134] Furthermore, referring to Tables 6 and 7, for the two variables of the study subjects, Ln(Cmax) and Ln(ABC 0-72 ), there was sufficient power exceeding 0.99 in both comparisons.

[0135] Thus, in the pharmacokinetic profiles of the fixed - dose combination of etoricoxib / tramadol and its combined administration, for C max , AUC 0-t , AUC 0-infの values, no statistically significant differences were observed, and for C of the fixed - dose combination maxThe time to reach was shorter than that of etoricoxib as a single agent, while it was comparable to tramadol. The 90% confidence intervals (CIs) observed for etoricoxib were 95.92 - 114.26, 96.84 - 105.20, and 95.99 - 105.10, respectively, and those for tramadol were 99.42 - 116.16, 110.65 - 122.91, and 110.25 - 121.87, respectively. From these results, the reduction in tramadol dosage (tramadol - sparing effect) is not related to the difference in pharmacokinetics by the fixed - dose combination of etoricoxib / tramadol, but rather is due to the synergistic effect based on the pharmacodynamics inherent in the mechanism of action of both drugs during combined administration, and it has been shown to provide a multimodal treatment approach.

[0136] Example 5. Dissolution Test The dissolution test (in vitro test) plays a role in determining the rate (amount / time) and extent (total amount) at which a drug is released from a dosage form; in the case of a dissolution profile, it corresponds to the quantification of the drug eluted at different times under standardized conditions. The importance of the dissolution test lies in the following points: a) It serves as a guideline for the development of new formulations in product development: It is possible to evaluate the potential interference of excipients or the manufacturing process on drug release. b) Process control and quality assurance help to ensure the continuity and optimization of product quality even after changes in manufacturing, formulation, manufacturing site, and process scale - up. c) It is an indicator for in vivo development: It is an indicator of bioavailability and enables the establishment of a correlation between in vitro parameters and bioavailability results.

[0137] A dissolution profile test was performed on granulated tramadol hydrochloride / etoricoxib for reconstitution of 50 / 90 mg.

[0138] The quantification of etoricoxib in this test was carried out by a method pre - validated based on the criteria of the Mexican Official Standard NOM - 177 - SSAA - 2013. This method was carried out by collecting samples at 20 minutes, 40 minutes, 60 minutes, and 80 minutes using high - performance liquid chromatography. The elution medium used consisted of 0.1N hydrochloric acid solution.

[0139] The quantification method of tramadol hydrochloride was also validated based on the criteria of the Mexican Official Standard NOM - 177 - SSAA - 2013. This method was carried out by collecting samples at 20 minutes, 40 minutes, 60 minutes, and 80 minutes using high - performance liquid chromatography. The elution medium used consisted of 0.1N hydrochloric acid solution.

[0140] The proportion of tramadol hydrochloride and etoricoxib in each elution medium was more than 85% in the first 20 minutes for both the control drug and the test drug. From this result, it is recognized that the evaluated formulations are equivalent (see Figures 16 and 17).

[0141] Example 6. Clinical trial of the efficacy and safety of an etoricoxib - tramadol fixed - dose combination for acute pain management and its synergistic effect Among the available literature, in pre - clinical trials, the possibility of interaction (additive or synergistic) in the anti - nociceptive effect of the combination of etoricoxib and tramadol against mechanical hyperalgesia induced by spinal cord injury in rats was evaluated. The authors concluded that the synergistic anti - hyperalgesic effect of this combination is useful for mechanical hyperalgesia associated with spinal cord injury and can be extrapolated to clinical applications.

[0142] Various fixed-dose combinations, such as tramadol / paracetamol, tramadol / diclofenac, codeine / ibuprofen, codeine / paracetamol, oxycodone / paracetamol, and tramadol / dexketoprofen, have been evaluated in the treatment of pain in relation to comparison with monotherapies or any of these combinations. Similar to etoricoxib / tramadol, other combinations of NSAIDs and tramadol versus paracetamol / tramadol have also been evaluated and shown similar results in pain treatment.

[0143] In 2006, Chandenwale et al. evaluated the analgesic effects of fixed-dose combinations of diclofenac / tramadol and paracetamol / tramadol in patients with acute musculoskeletal disorders, postoperative pain after orthopedic surgery, osteoarthritis, and rheumatoid arthritis, and revealed that the diclofenac combination had a greater reduction in pain intensity after 5 days of treatment and a lower frequency of adverse events. In this trial, for the fixed-dose combination of diclofenac / tramadol, an excellent result was shown with a higher adherence and fewer adverse events in a lower-dose (administering 2 tablets every 4 - 6 hours and not exceeding 8 tablets per day, as opposed to 1 tablet twice a day) schedule.

[0144] Currently, the use of paracetamol 325 mg / tramadol 37.5 mg is recommended for the treatment of low back pain, and the minimum dosing regimen is based on taking the equivalent amount of paracetamol 975 mg - 3250 mg and tramadol 112.5 mg - 375 mg up to 4 weeks at most, 3 times a day for a maximum of 10 times a day. This treatment method is one of the most commonly used treatment methods but is not necessarily the safest analgesic.

[0145] The combination of etoricoxib / tramadol provides effective pain relief through multimodal management due to the different mechanisms of action of each component, achieving a rapid reduction in pain intensity compared to conventional therapies. 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, consequently, a reduced incidence of related adverse events). For the relief of moderate to severe acute pain, a multimodal analgesic regimen is more desirable than monotherapy, and furthermore, management with tramadol by timely intervention is desirable to provide immediate pain relief and prevent the development of associated complications. One of the most commonly used models for evaluating the development of pharmaceuticals with analgesic potential is low back pain, where the therapeutic effects of new analgesics can be studied.

[0146] It is certain that the definition of a clinically significant change in pain intensity varies greatly depending on the study. Therefore, a study was conducted to evaluate the efficacy and safety of a fixed-dose combination of 90 mg of etoricoxib and 50 mg of tramadol compared to a fixed-dose therapy of 325 mg of paracetamol and 37.5 mg of tramadol for the management of acute low back pain.

[0147] In the "Confirmation Study of the Efficacy and Safety of a Fixed-Dose Combination of Etoricoxib / Tramadol vs. Paracetamol / Tramadol for the Management of Acute Low Back Pain" conducted by Laboratorios Silanes, the test drug (90 mg of etoricoxib / 50 mg of tramadol) was administered according to a once-daily regimen every 24 hours, and a therapeutic effect equivalent to that of the paracetamol / tramadol 325 mg / 37.5 mg combination (administered every 8 hours, with final doses of 975 mg / 112.5 mg respectively) was obtained.

[0148] The trial design was a Phase IIIb, longitudinal, multi-site, randomized, open-label clinical trial evaluating the efficacy and safety of a fixed-dose combination of etoricoxib 90 mg and tramadol 50 mg compared to a fixed-dose therapy of paracetamol 325 mg and tramadol 37.5 mg for the management of acute low back pain in 62 adult patients per treatment group (124 patients in total).

[0149] The inclusion criteria were as follows: 1. Gender was not restricted. 2. Agreed to participate in the study and provided written informed consent. 3. Age ≥ 18 and ≤ 60 at the start of the trial. 4. Diagnosed with first-onset acute low back pain or another episode of low back pain with a duration of ≤ 6 weeks up to 6 months prior. 5. Patients reporting moderate to severe low back pain (Visual Analogue Scale for pain VAS > 4 cm). 6. Women of childbearing age with an acceptable method of contraception (barrier, oral hormone, injection, subcutaneous, etc.).

[0150] Table 7 shows the test formulation and the control formulation.

[0151]

Table 7

[0152] The evaluation and efficacy criteria were as follows:

[0153] Efficacy Primary variable: · Mean change by treatment group from baseline pain measurements reported by VAS at day 3, 5, and 7.

[0154] Secondary variable: · Percentage of patients with a 30% reduction in pain intensity at day 7 by treatment group. ·Degree of disability due to low back pain measured using the Oswestry Disability Scale at baseline and 7 days later, by treatment group. ·Degree of disability in daily activities using the Roland-Morris Scale, at baseline and 7 days later, by treatment group.

[0155] Safety ·Frequency and intensity of adverse events that occurred during the trial, between treatment groups.

[0156] From the efficacy results, it was shown that etoricoxib-tramadol was comprehensively non-inferior in terms of efficacy and safety after 7 days of treatment for the management of acute low back pain. Data obtained from the enrolled patients in this trial confirmed that the combination therapy based on 90 mg of etoricoxib / 50 mg of tramadol was effective in the management of acute low back pain during the 7-day follow-up period. It was observed that the pain intensity always decreased, the degree of disability due to low back pain improved, and daily activities could be performed.

[0157] By analyzing the data at each follow-up observation, the test preparation based on etoricoxib / tramadol was shown to be superior because it obtained an analgesic treatment effect earlier than the standard paracetamol / tramadol therapy, and the proportion of patients with a reduced pain score was large. In the fixed-dose combination group of etoricoxib / tramadol, a greater reduction in pain was observed during the first few days of treatment (3 days and 5 days) compared with the paracetamol / tramadol therapy. Therefore, the treatment effect of the test preparation was obtained early, showing superiority over the comparison group. On the 3rd and 5th days, the proportion of patients whose degree of pain intensity changed from the initial severe and moderate categories to the mild and painless categories was also higher in the etoricoxib / tramadol group, again indicating that the test preparation was superior to the control preparation. Furthermore, the proportion of patients who responded to the treatment was significantly higher, and the pain intensity decreased by at least 30% as considered by the VAS, which was reported on the 3rd day of follow-up.

[0158] This is because the test formulation, which is a fixed-dose combination of etoricoxib / tramadol, is formulated in the form of a granular pharmaceutical product, which promotes absorption in the digestive tract. As a result, the blood concentration increases early, leading to the expected analgesic effect. On the other hand, the control drug based on the paracetamol / tramadol pharmaceutical tablet has to undergo a disintegration process at the digestive tract level, so absorption is delayed and the analgesic effect is postponed.

[0159] On the other hand, within each treatment group, significant changes from the baseline measurement values were confirmed in the median pain on the 3rd, 5th, and 7th days (p = 0.001). When determining the magnitude of the change in pain assessment on the 3rd, 5th, and 7th days relative to the baseline, differences between the treatment groups were observed on the 3rd day (p = 0.054) and the 5th day (p = 0.041). When evaluating the proportion of patients who had a response to treatment (a 30% (3 cm) decrease on the VAS), a statistically significant difference was observed when comparing the treatment groups on the 3rd day of follow-up [p = 0.008, 95% CI 0.241 (0.061 - 0.421)], which was equivalent to the effectiveness on the 5th and 7th days. Therefore, although no inferiority was observed between the administered treatments in the final follow-up on the 7th day, the test drug, etoricoxib / tramadol, was able to exhibit a better analgesic effect earlier from the 3rd day of follow-up.

[0160] In addition to the VAS, in the patient group administered etoricoxib / tramadol, improvement in disability due to low back pain (Oswestry and Roland-Morris), especially improvement in the inability to perform daily activities, was evaluated (p = 0.068). According to the results of the Oswestry scale and the Roland-Morris scale, in the etoricoxib / tramadol group, a higher proportion of patients with improved disabilities was reported compared to the paracetamol / tramadol group, and the grade classification of the disabilities changed from severe to moderate and mild.

[0161] Finally, compared with the paracetamol / tramadol group that requires administration every 8 hours (three times a day), due to the pharmaceutical form (granules) and the pharmacokinetics that enable administration every 24 hours (once a day) when administering etoricoxib / tramadol, it is important to emphasize that higher adherence was observed in the group treated with the etoricoxib / tramadol test drug compared to treatment with paracetamol / tramadol.

[0162] From the above, the inventors were able to identify the clinical advantages and superiority of the combination of etoricoxib / tramadol. For example, a high treatment response achievement rate, an early analgesic response can be obtained, the same degree of pain reduction as paracetamol / tramadol can be obtained 7 days after treatment, and the tramadol usage per day can be reduced (opioid sparing effect), etc.; this leads to a reduction in the risk of dependence, a decrease in the use of opiates, and an improvement in treatment adherence.

[0163] Regarding the safety of the test formulation, no relevant data that have not been reported so far were found for the formulations used in monotherapy. Among all the adverse events reported in the Silanes test, in the etoricoxib / tramadol group, the proportion of subjects reporting AEs was lower than that in the paracetamol / tramadol administration group. For example, in the safety results, the information of 124 patients was evaluated, among which 38 showed at least one adverse event (AE). In the etoricoxib / tramadol group, 16 subjects, and in the paracetamol / tramadol group, 22 subjects reported a total of 79 AEs (38 (48.1%) with the test drug and 41 (51.9%) with the comparator drug). Regarding severity, all events were classified as non-severe (100%). No deaths were reported in this trial. According to the severity of the events, a higher proportion of AEs classified as "mild" compared to "moderate" was observed in both treatment methods (73.4% vs. 26.6%). In the paracetamol / tramadol group, more severe adverse events were reported compared to the etoricoxib / tramadol group, but the degree was moderate (41.5% vs. 10.5%), and this difference was considered statistically significant (p = 0.002). The most affected SOCs were gastrointestinal disorders and nervous system disorders, with 33 cases (41.7%) [19 cases (57.5%) in the etoricoxib / tramadol group and 14 cases (42.5%) in the paracetamol / tramadol group] and 32 cases (40.5%) [14 cases (43.7%) in the etoricoxib / tramadol group and 18 cases (56.3%) in the paracetamol / tramadol group], respectively. The most frequent events were nausea (17.7%) and dizziness (16.4%). No clinically significant differences were observed in biochemical markers and vital signs. From the above, it was concluded that at the time of evaluation, no safety or risk signals that could change the benefit-risk balance of patients associated with the use of the test drug were confirmed. Therefore, according to the information described, the safety profile remains favorable.

[0164] In this way, it was confirmed that in the etoricoxib / tramadol group, a higher proportion of patients reported a pain intensity reduction of ≧30% in the more acute phase (the first 3 days) compared to the paracetamol / tramadol group. These data are consistent with those reported by Meloncelli et al. in a study comparing the analgesic effect and tolerability of the combination of tramadol / dexketoprofen 75 mg / 25 mg with diclofenac / thiocolchicoside 75 mg / 4 mg in patients with acute low back pain. Furthermore, it was observed that the group with the highest proportion of subjects who responded to treatment (defined as a pain intensity reduction of at least 30%) was the group receiving the combination of tramadol / dexketoprofen.

[0165] In conclusion, the data obtained from the patients included in this study confirm the efficacy and safety of the combination of etoricoxib / tramadol for the treatment of acute low back pain. During the 7-day follow-up, a constant reduction in pain intensity (VAS) was observed, as well as improvements in the degree of disability due to low back pain (Oswestry) and the performance of daily activities (Roland-Morris).

[0166] It is important that a higher proportion of adherence was observed in the etoricoxib / tramadol pharmaceutical form (granules) and dosage compared to the paracetamol / tramadol treatment group (98.3 [CI95%, 96.0 - 100] vs 94.5 [CI95%, 90.5 - 98.5]).

[0167] By comparing the doses used, it was possible to prove that both therapeutic agents administered had equivalent therapeutic effects. However, the treatment based on etoricoxib / tramadol is more potent from a pharmacological point of view because the desired analgesic therapeutic effect can be obtained at a lower dose (90 mg / 50 mg vs. 975 mg / 112.5 mg). The results obtained in the clinical trial showed an analgesic synergistic effect in patients with acute low back pain in addition to the tramadol-sparing effect. The above results indicate the clinical advantages of the simple dosing schedule of etoricoxib / tramadol, such as a faster treatment response, therapeutic equivalence at the end of the evaluation period, and a tramadol-sparing effect (a 66.6% reduction in the daily tramadol dose), which leads to a reduction in the risk of dependence, a reduction in the incidence of adverse events (nausea, vomiting, drowsiness, etc.) dependent on the tramadol dose, and a reduction in the tablet burden leading to an improvement in treatment adherence.

[0168] No safety or risk signals that could change the patient's benefit-risk balance associated with the use of the investigational drug were identified at the time of evaluation. Therefore, according to the information described above, the safety profile remains favorable.

[0169] By reducing the daily dose of tramadol, the number of patients with adverse events related to this formulation decreased in the etoricoxib-tramadol combination.

[0170] Advantages and Industrial Applications of the Present Invention One of the main problems with drugs having a synergistic composition of known drugs and known concentrations is that, after improving their organic properties, when administered to patients; especially when the drug has high sensitivity to light and humidity, it is difficult to ensure its stability, solubility, and bioavailability.

[0171] In this sense, although within the regulatory parameters of elution and bioavailability, the results often tend to be data close to the lower limit of the specification, resulting in a longer time for the manifestation of the therapeutic effect or the need for a higher dose.

[0172] In the prior art, attempts have been made to solve the problem of combining both drugs for the treatment and control of pain and inflammation. Much has been written in the literature about bilayer and independent systems. There have even been those who have approached this problem from new crystal forms. The only way they approach the combination of tramadol and etoricoxib is that there is no actual physical interaction of the APIs, otherwise they do not combine. Similarly, it is necessary to improve the synergistic effect, enhance bioavailability, improve solubility and stability, and at the same time ensure a reduction in side effects after administration to patients. Due to the lack of solutions or alternatives to the above, it takes time for the therapeutic effect to appear or high doses are required. Furthermore, the above-mentioned patents and scientific contributions have shown no interest in solving the influence on the sensory stimulation properties of drugs, which affect stability, solubility and bioavailability.

[0173] On the other hand, in addition to the problem of side effects caused by the combination of high doses of tramadol and etoricoxib, combining a drug that is highly sensitive to light and humidity with another lipophilic drug that has poor fluidity and excessive adhesiveness may pose technical problems because it may interfere with stability, absorbability and release mechanisms.

[0174] The present invention relates to a pharmaceutical composition in which an opioid analgesic such as tramadol and an NSAID such as etoricoxib are formulated in a single monophasic and stable immediate release system for producing a drug useful for the treatment and control of neuropathic pain and / or pain such as chronic and acute pain. This has a synergistic effect in the field of treatment and control of pain and inflammation and maintains dissolution and bioavailability, as demonstrated with respect to the pharmacokinetic bioavailability after administration of the composition of the present invention and a control oral formulation, and a synergistic effect of the drug at a low dose is obtained while maintaining the dissolution and bioavailability of the composition without loss of the therapeutic effect after administration.

[0175] On the one hand, in the case of combined use of active ingredients, it would be sufficient to prove that the effect of the combination is greater than the effects obtained when each active ingredient is used separately. This combined technical effect can also be based on more indirect aspects, such as reduction of harmful side effects, optimization of the pharmacokinetics or bioavailability of at least one of the active ingredients, the possibility of administering the drug by different routes, improvement of patient compliance with the treatment, reduction of the number of administrations, etc. Such a technical effect (whether it is a synergistic effect or any other advantage) is not suggested by the prior art.

[0176] The enhancement of the analgesic effect of the present invention is due to the combination of two pharmacodynamic mechanisms that complement each other by the combined use of an NSAID (etoricoxib) and an opioid (tramadol). Furthermore, since this combination can achieve a therapeutic effect with once-daily administration of the formulation when etoricoxib and tramadol are combined, it can reduce the adverse events resulting from the use of opioids, and thus shows a better safety profile than treatment with a single agent. Furthermore, an improvement in stability has also been shown with respect to the pharmaceutical profile.

[0177] Currently, the use of paracetamol 325 mg / tramadol 37.5 mg is recommended for the treatment of low back pain, and doses corresponding to 975 mg to 3250 mg of paracetamol and 112.5 mg to 375 mg of tramadol per day are prescribed at least 3 times and up to 10 times in 24 hours for up to 4 weeks [Dhillon, S., Tramadol / paracetamol fixed-dose combination. Clinical drug investigation, 2010. 30(10): p. 711-738].

[0178] However, the combination of etoricoxib / tramadol results in effective pain relief through a multimodal approach due to the different mechanisms of action of the components, achieving a rapid reduction in pain intensity compared to conventional therapies. This multimodal approach not only improves treatment adherence but also achieves a tramadol-sparing effect (pain control with lower doses of tramadol and a resulting reduction in the incidence of adverse events associated with tramadol). For the relief of moderate to severe acute pain, a multimodal analgesic regimen is more desirable than monotherapy. Furthermore, for immediate pain relief and prevention of the development of associated complications, management with tramadol through up-to-date interventions is desirable. Thus, and in comparison, the test formulation (etoricoxib 90 mg / tramadol 50 mg) was shown to be able to achieve the same therapeutic effect with a dosing schedule of once-daily administration every 24 hours. From the data obtained, it was found that this analgesic synergy is more potent (the same therapeutic effect can be obtained with lower doses) than the combination of paracetamol 325 mg / tramadol 37.5 mg. For example, it was confirmed that the proportion of patients reporting a ≧30% reduction in pain intensity in the more acute phase (the first 3 days) was higher in the etoricoxib / tramadol group compared to the paracetamol / tramadol group. Furthermore, among all the adverse events reported in the Silanes trial, the etoricoxib / tramadol group was reported to have a lower proportion of AEs compared to the paracetamol / tramadol group.

[0179] Furthermore, the pharmacokinetic profile of the combination of etoricoxib / tramadol of the present invention demonstrates that the reduction in the dose of tramadol (tramadol-sparing effect) is not related to the pharmacokinetic differences of the fixed-dose formulation of etoricoxib / tramadol, but rather is related to a synergistic effect based on the pharmacodynamics inherent to the mechanism of action of the drugs when administered in combination, providing a multimodal therapeutic approach.

[0180] From the previous results, the clinical advantages of the combination of etoricoxib / tramadol, such as the treatment effect can be obtained in a shorter period, the treatment effect at the end of the evaluation period is equivalent, and the daily tramadol usage is less (a 66.6% decrease per day) are shown, and these lead to the following: a decrease in the risk of dependence, a decrease in the incidence of dose-dependent adverse events of tramadol, and an increase in treatment adherence. Therefore, no warning signs or risks that could change the risk-benefit balance associated with the use of the combination of etoricoxib / tramadol of the present invention were identified.

Claims

1. A pharmaceutical composition comprising an effective amount of 50 mg of tramadol and an effective amount of 90 mg of etoricoxib, wherein the composition is a granule for reconstitution.

2. The pharmaceutical composition according to claim 1, further comprising at least one of a binder, a disintegrant, a sweetening agent, a flavoring agent, and a diluent.

3. The pharmaceutical composition according to claim 2, further comprising a diluent, a binder, and two sweetening agents.

4. In the pharmaceutical composition according to claim 3: - an effective amount of 50 mg of tramadol hydrochloride; - an effective amount of 90 mg of etoricoxib; - isomalt 801 as a diluent in an amount of 36% by weight of the composition; - polyethylene glycol as a binder in an amount of 43.20% by weight of the composition; - croscarmellose sodium as a disintegrant in an amount of 5.0% by weight of the composition; - acesulfame potassium as a first sweetening agent in an amount of 3.0% by weight of the composition; - sucralose as a second sweetening agent in an amount of 2.0% by weight of the composition; - a mint - peppermint flavor in an amount of 8.0% by weight of the composition.

5. In a process for the manufacture of the pharmaceutical composition according to any one of claims 1 to 4, the following: a) mixing the active ingredients (tramadol and etoricoxib) with pre - screened pharmaceutically acceptable excipients (polyethylene glycol, isomalt 801, croscarmellose sodium, acesulfame potassium, and sucralose) for 5 minutes (mixture 1); b) granulating mixture 1 for 20 - 30 minutes until a temperature of 54 - 55.2 °C is reached; c) cooling the granules to a temperature of 25 - 28 °C; d) screening the granules of step d) to obtain a screened product 3; e) mixing screened product 3 with a mint - peppermint flavor for 5 minutes.

6. The process according to claim 5, wherein the granulation is carried out by a melt granulation process.

7. The pharmaceutical composition according to any one of claims 1 to 4 for use in the treatment of pain and inflammation.

8. The pharmaceutical composition for use according to claim 7, wherein the pain is selected from the group consisting of neuropathic pain, chronic pain, and acute pain.

9. The pharmaceutical composition for use according to claim 7 or 8, wherein the composition is adapted to be administrable every 24 hours.

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