Coated stable solid pharmaceutical composition of opioid analgesic for pain and antiepileptic drug

Abstract

The present invention relates to a pharmaceutical composition comprising tramadol and pregabalin, or pharma- ceutical acceptable salts thereof, for the treatment of neuropathic pain. The dosage of one or both compounds improves the stability, maintains the bioavailability and solubility of the administered composition. The composition overcomes the challenges in these technologies of the sensitivity of both drugs to moisture and light, and is made in a formulation medium that does not affect the absorption capacity by a light-protective coating or a water-free process without affecting either drug.

Description

[Technical field]

[0001] The present invention relates to combination pharmaceutical compositions for the treatment and control of pain. [Background technology]

[0002] As defined by the International Association for the Study of Pain Management (IASP), neuropathic analgesia is pain that occurs as a direct result of injury or disease affecting the somatosensory system.

[0003] It is known that patients with acute neuropathic pain may not respond to treatment or may develop resistance to existing medications.

[0004] According to the IASP, despite the availability of many effective medications and guidelines for the treatment of neuropathic pain, they are not commonly used in testing in the US and Western countries, suggesting that many cases go untreated or untreated.

[0005] For example, tramadol, designated (1R,2R)-2-[(dimethylamino)methyl]-1-(3-mexitophenyl)cyclohex-1-nol, and represented by formula I, is a synthetic codeine analogue, a centrally acting analgesic that has opioid agonist properties and activates monoaminergic spinal pain inhibition, and is commonly used to treat acute neuropathic pain. [ka]

[0006] The drug can be administered orally, orally, intravenously, or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular tramadol has generally been shown to be as effective as pethidine (meperidine) and one-fifth as effective as nalbuphine. Tramadol has demonstrated analgesic activity in a variety of animal models as well as in healthy volunteers with experimentally induced pain, and oral tramadol also shows similar analgesic activity (Non-Patent Document 1).

[0007] Common side effects of tramadol administration include constipation, nausea, vomiting, abdominal pain, dizziness, drowsiness, fatigue, and headache. Severe side effects may include seizures, hives, blisters, difficulty swallowing, swelling of the eyes, face, throat, tongue, lips, hands, feet, and ankles, as well as changes in heart rate. Long-term use of tramadol may also lead to addiction. High doses of tramadol are known to be more likely to cause increased side effects. Intentional and accidental overdoses of tramadol may also predispose to respiratory arrest and acute liver failure, and several deaths have been reported. However, in these instances, liver damage may have been caused by shock, hypoxia, or ischemia secondary to respiratory arrest. Liver damage from tramadol overdoses has also been associated with hyperammonemia, lactic acidosis, and fatty liver, suggesting direct mitochondrial damage (Non-Patent Document 2).

[0008] On the other hand, there is pregabalin, also known as (3S)-3-(aminomethyl)-5-methylhexanoic acid, represented by formula II. It is a drug belonging to the group of neuromodulators and has a better pharmacokinetic profile than previous drugs. It is also an analogue of GABA, but does not exert all GABAergic actions. Pregabalin also has analgesic effects due to its ability to bind to the alpha-2-delta protein subunit of the voltage-dependent calcium channel of the central nervous system with better affinity than gabapentin (Non-Patent Document 3). [ka]

[0009] Pregabalin can cause side effects such as fatigue, dizziness, headache, dry mouth, nausea, vomiting, constipation, bloating, slurred speech, depression, loss of balance, muscle spasms, and weakness. Some of these can be serious, such as blurred or double vision, hives, blisters, swelling of the face, arms, hands, or feet, shortness of breath, muscle pain, and chest pain. Side effects caused by the use of high doses of pregabalin include dizziness, somnolence, peripheral edema, dry mouth, headache, confusion, depression, and visual disturbances.

[0010] In order to avoid the most common side effects and those caused by high doses of tramadol or pregabalin, combination drugs have been developed that provide analgesic effects without increasing the dose. For example, Patent Document 1 discloses a composition for pain treatment, which contains a pharma- ceutically acceptable analgesic and a GABA agonist such as gamma vinyl GABA to reduce or inhibit the addictive side effects of the analgesic. The above document does not mention or explain the synergistic effect of the combination of an analgesic and a GABA agent. Recently, Patent Document 2 mentions the sustained release formulation of an opioid and a GABA analog in different pharmaceutical layers to improve systemic absorption in pain treatment.

[0011] Patent Document 3 describes a pain management composition that combines an analgesic (tramadol) and an anticonvulsant (gabapentin) at concentrations of 3-8.3% and 16-83%, respectively. Gabapentin is absorbed slowly, resulting in a nonlinear dissolution profile with a saturation peak, which differs from pregabalin, which is rapidly absorbed into the blood.

[0012] As another example of combination, Patent Document 4 describes a composition in a gelatin capsule containing low concentrations of tramadol, pregabalin and dextromethorphan. However, no synergistic effect of this composition is described or suggested. Similarly, Patent Document 5 describes the combination of tramadol with gabapentin or pregabalin, the latter in a concentration of 15-30 mg. This combination is said to have a synergistic effect, but no evidence of such a synergistic effect is presented. Patent Document 6 describes the combination of an analog of gamma-aminobutyric acid (Gaba) with an opioid-type analgesic, the former being pregabalin and the latter being tramadol. However, the application does not claim or describe a method of combining both drugs without overcoming the stability issues and affecting the bioavailability and dissolution of both compounds. Also, patent application WO 2005 / 023363 describes a synergistic pharmaceutical combination containing tramadol hydrochloride and pregabalin in a ratio of 1:1.5 and 1:2.5 w / w, together with pharma- ceutical acceptable excipients, said synergistic combination being in oral or parenteral form. The invention also relates to a method for the treatment of neuropathic pain, in particular to a synergistic pharmaceutical combination for use in the treatment of neuropathic analgesia, which may be of the central or peripheral type. However, this document does not address the pharmacological problem of combining the active ingredients in a stable manner without affecting the parameters of stability, quality and efficacy.

[0013] Meanwhile, a publication called “Pregabalin Antinociception and Interaction with Tramadol in Acute Models of Analgesia” presents antinociception studies of pregabalin and tramadol and concludes that although both drugs have similar antinociception, their combined use results in a supra-additive interaction.

[0014] In Non-Patent Document 4, a double-blind study was carried out in which a combination of tramadol and duloxetine (30 mg / 75 mg doses) or tramadol and pregabalin (30 mg / 75 mg doses) was used as starting doses, compared to a placebo and the use of an initial daily dose of 100 mg tramadol. Each drug was administered separately. There are other problems in the development of formulations related to such analgesic therapeutics. Patent Document 8 points out problems with pregabalin formulations due to the presence of external factors such as humidity. This problem is solved by adding a large amount of colloidal silicon dioxide. In this patent, it is stated that the preferred formulation is a capsule, since the formulation of a tablet requires many steps.

[0015] However, this patent does not indicate or suggest how to formulate a second drug such as tramadol, or how to solve the problem of administering a high concentration of the drug due to the limited capsule size without affecting dissolution, bioavailability, or stability. Patent Document 9 claims a composition that is free of sugars, lactose, and more amino acids, and is formulated in the presence of water. No special coating system is mentioned, and the composition is not protected from external factors such as light, humidity, and temperature that may affect the release, which may cause various problems during storage. Patent Document 10 claims a sustained release pregabalin composition with a special coating system. Patent Document 11 also mentions the addition of a coating or gelling component that can delay the release of the drug. Furthermore, Patent Document 12 seeks to protect a coating system for three supplements that provide a sustained release.

[0016] These patents use various coating systems that affect drug release, but do not address the organoleptic properties of the drug, which affect drug stability, solubility, and bioavailability. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] International Publication No. 2002 / 091990 [Patent Document 2] Mexican Patent Application No. MX / a / 2013 / 000024 [Patent Document 3] International Publication No. 2007 / 052999 [Patent Document 4] US Patent Application Publication No. 2013 / 0189354 [Patent Document 5] US Patent Application Publication No. 2015 / 0313892 [Patent Document 6] Mexican Patent Application Publication No. 2017016720 [Patent Document 7] International Publication No. 2020 / 044140 [Patent Document 8] European Patent Application Publication No. 2343055 [Patent Document 9] International Publication No. 2008 / 128775 [Patent Document 10] Australian Patent Application Publication No. 2017300185 [Patent Document 11] Mexican Patent No. 276428 [Patent Document 12] International Publication No. 2006 / 078811 [Non-patent literature]

[0018] [Non-Patent Document 1] 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 [Non-Patent Document 2] Liver Tox Clinical and Research Information of Drug-Induce Livered Injury, National Institutes of Health, December 5, 2021 [Non-Patent Document 3] Gonzalez Escalada, RL; Pregabalin in the treatment of peripheral neuropathic pain, Spanish Journal of Analgesia, 2005 [Non-Patent Document 4] Efficacy, Safety, Tolerability and Pharmacokinetics of Concomitant Administration of Tramadol With Duloxetine or Pregabalin: a Randomized Controlled Flexible-dose Study in Patients With Neuropathic Pain. Summary of the Invention [Problem to be solved by the invention]

[0019] The current state of the art has not yet solved the problem of finding a combination of both drugs for pain treatment and management that achieves synergistic effects, improves bioavailability, solubility, and stability, while reducing side effects when administered to patients, in addition to maintaining a low dose. This lack of solutions and alternatives results in a longer therapeutic effect and the need for higher doses. There are also problems with synergistic effects and increased side effects due to the high dose combination of tramadol and pregabalin, as well as technical problems with combining two drugs that are sensitive to light and humidity.

[0020] Therefore, the present invention aims to provide a stable immediate release combination pharmaceutical composition in the field of analgesic treatment and pain control, which provides a synergistic effect while maintaining solubility and bioavailability. [Means for solving the problem]

[0021] The present invention relates to a pharmaceutical composition for neuropathic pain, preferably acute neuropathic pain, comprising tramadol and pregabalin, or pharma- ceutically acceptable salts thereof, which allows for analgesic effect and reduced adverse events due to a reduced dose of one or both compounds, while improving the stability, solubility and bioavailability of the administered composition.

[0022] One embodiment of the present invention includes a single dose composition containing 50-150 mg of tramadol hydrochloride and 50-150 mg of pregabalin, preferably 50-100 mg and 75 mg-150 mg, respectively.

[0023] In another embodiment of the invention, the composition is in the form of tablets, pills, caplets, granules, lozenges, capsules, preferably in the form of tablets and / or pills.

[0024] In another aspect of the invention, the dosage form is preferably a tablet, optionally in the form of a slotted caplet.

[0025] Excipients constituting the composition which confer essential characteristics to the present invention as improving the pharmacokinetic profile, bioavailability, stability and solubility are also an object of the present invention.

[0026] Another aspect of the present invention provides a method for preparing a composition that overcomes technical difficulties by providing a formulation medium that does not affect the absorption of two moisture and light sensitive drugs through the incorporation of water as a solvent with minimal contact with the tablet surface, and furthermore, the composition uses a light protective coating so that the release of both drugs is not affected. [Brief description of the drawings]

[0027] [Figure 1]Figure 1 shows a comparison of the dissolution profiles of pregabalin in the reference drug (Tramadol HCl 50 mg / Pregabalin 150 mg) and the test drug (Tramadol HCl 50 mg / Pregabalin 75 mg). Both lots are from Laboratorios Silanes SA de CV. The maximum difference in drug dissolution percentage is less than 2.0% within the sampling time. [Diagram 2] FIG. 1 shows a comparison of tramadol dissolution profiles for reference (tramadol HCl 50 mg / pregabalin 150 mg) and test (tramadol HCl 50 mg / pregabalin 75 mg) lots, both from Laboratorios Silanes SA de CV. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] One embodiment of the pharmaceutical composition according to the present invention will be described below.

[0029] definition Pharmaceutically acceptable salts: The term "pharmaceutical acceptable salts" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound. These salts 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)). Pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Examples of salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amine salts.

[0030] Specific examples of suitable amines include isopropynamine, trimethinamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenamine, glucosamine, n-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, n-ethylpiperidine, and the like.

[0031] Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0032] For example, two pregabalin salts, pregabalin besylate and tosylate, derived from sulfuric acid and described in WO 2009 / 080365, "Pregabalin salts", have been synthesized. The acid anion is assumed to be non-toxic to humans. Other salts prepared were pregabalin hydrochloride (WO 2005 / 041927) and pregabalin mandelate (WO 96 / 40617).

[0033] Pharmaceutical Compositions: The compositions of the present embodiments comprise pharma- ceutically acceptable forms of pregabalin and / or tramadol, including pharma- ceutically acceptable complexes, salts, solvates, hydrates and polymorphs.

[0034] Neuropathic Pain: According to the International Association for the Study of Pain (IASP), neuropathic pain is pain that is a direct result of damage or disease of somatosensation. This type of pain can be caused by a variety of neuropathies, polyneuropathies, post-treatment neuralgia, and other common central pain syndromes, such as spinal cord injury, spinal tumors, syringomyelia, and cancer-related neuropathic pain.

[0035] Excipients: Components that constitute part of the pharmaceutical composition of the present embodiment, including diluents, disintegrants, lubricants, coating systems, absorbents, etc.

[0036] The present invention relates to a stable immediate release pharmaceutical composition having synergistic effects and improved stability while maintaining the solubility and bioavailability of an opioid analgesic and an antiepileptic / analgesic drug, which can be administered as a therapeutic agent to treat pain, the pain of interest being neuropathic pain, preferably acute neuropathic pain.

[0037] The opioid analgesics used are tramadol or a pharma- ceutically acceptable salt thereof, such as the hydrochloride salt, and the antiepileptic / analgesic pregabalin or a pharma- ceutically acceptable salt thereof.

[0038] The combination of tramadol and pregabalin has shown antinociceptive effects in animal models and reduced adverse events of tramadol, such as seizures (Fariborz, 2012; Tewari, 2015). The combination of these drugs allows for reduced doses of one or both compounds, potentially providing effective analgesia and reducing adverse events reported with the drugs alone (Suthakaran, 2017).

[0039] The combination of tramadol and pregabalin represents a series of important technical challenges due to the physicochemical properties of the drugs. The appropriate choice of excipients and manufacturing conditions plays a key role in the development of a pharmaceutical composition, as it is related to the release and absorption rate of the drugs in the body. In this way, the composition overcomes the technical difficulty of having both moisture- and light-sensitive drugs in a formulation medium that does not affect their absorption, due to the process of incorporating water as a solvent, since the contact with the tablet surface is minimized. The composition also has a coating that protects it from light, which does not affect the release of both drugs and improves their stability.

[0040] This embodiment includes a combination of tramadol and pregabalin or a pharma- ceutically acceptable salt thereof in a dose of 50-150 mg tramadol and 50-150 mg pregabalin, preferably in a lower dose of 50-100 mg tramadol or one of its pharma- ceutically acceptable salts, and 75-150 mg pregabalin or one of its pharma- ceutically acceptable salts, together with at least one pharma- ceutically acceptable excipient.

[0041] The solid pharmaceutical composition may be found as a tablet, a monolayer tablet, a granule, a caplet, a lozenge or a pill, preferably in the form of a tablet or a pill.

[0042] The most preferred dosage form of this invention is a "tablet" due to its accuracy of dosage. Unlike capsules, it is easy to administer, so it is the most widely accepted dosage form and can administer a high concentration of drug. In the case of tablets, it is possible to reduce the volume of powder, making it easier to handle and administer.

[0043] The preferred dosage form for this embodiment is a grooved caplet-like tablet.

[0044] In another embodiment, the more preferred dosage form is a biconvex tablet.

[0045] Examples of pharma- ceutically acceptable diluents include, but are not limited to, cellulose derivatives such as microcrystalline cellulose PH102, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch and corn starch, as well as mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose, or combinations thereof. The most preferred diluent of the present invention is PH102 microcrystalline cellulose. The diluent is preferably at a concentration of 5-90% by weight.

[0046] Pharmaceutically acceptable disintegrants include, but are not limited to, 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. The disintegrant may be present at 0.5-15% by weight, preferably 0.5-3% by weight. The most preferred disintegrant in this embodiment is croscarmellose sodium.

[0047] Examples of pharma- ceutically acceptable lubricants include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearin fumarate, talc, and sulfated derivatives such as magnesium lauryl sulfate. The lubricant should be present in an amount of 0.25-10% by weight, preferably 0.8-1% by weight. The preferred lubricant for the composition of this embodiment is magnesium stearate.

[0048] Another embodiment is a manufacturing method that overcomes the technical challenge of mixing both moisture and light sensitive drugs in a formulation medium that does not affect absorption, through a process that incorporates water as a solvent, with minimal contact with the tablet surface. The composition is further provided with a light-protective coating system that does not affect the release of both drugs, while at the same time improving their stability. Tramadol and pregabalin are known to be light and moisture sensitive drugs. For this reason, no drug has been able to combine these two drugs in a single formulation to date without being affected by these effects. We have succeeded in developing a process that minimizes water-drug contact. To achieve this, we have chosen a process that obtains a core (uncoated tablet) with specific excipients and additives that maintain the chemical integrity of both drugs and the physical integrity of the tablet.

[0049] In this sense, in another embodiment, the manufacturing process for the tablets is based on the selection of unit operations, their sequence and duration to control the various physicochemical properties of the drug, which consists in choosing the appropriate coating components and the ideal temperature to avoid prolonged contact of the drug with water and at the same time ensure a barrier against light.

[0050] The coating system is preferably selected from cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinyl derivatives such as polyvinyl alcohol, polyethylene glycol, all K grade povidone derivatives and their derivatives. Preferably, the concentration of hydroxypropylcellulose is 0.5-6% by weight, most preferably 2.5-3.5% by weight. Preferably, no alcohol-based vehicle is used for the coating, and preferably the vehicle is water.

[0051] In another embodiment, it is important that the solids concentration of the coating system does not exceed 19.6% as this minimizes contact of the solid dosage form or tablet surface with the solvent, ensuring film addition to the final dosage form.

[0052] Further, the composition of the present embodiment may include, as an absorbent for residual water from the tablet, aluminum derivatives (aluminum hydroxide, aluminum oxide, aluminum phosphate), clays or earths (attapulgite, bentonite, hectorite, kaolin, pectin), silica derivatives (calcium silicate, colloidal silicon dioxide, magnesium aluminum silicate), cellulose derivatives (microcrystalline cellulose, cellulose), magnesium derivatives (magnesium carbonate, magnesium silicate), but are not limited to these. A preferred absorbent is magnesium aluminum metasilicate in amorphous form, with a concentration of 0.5-90% by weight, most preferably 1-1.5% by weight.

[0053] An additional advantage provided by the coating system of this embodiment as a tablet dosage form, preferably a caplet, is that it does not impede or slow down the dissolution process, as detailed in the dissolution test examples.

[0054] In another embodiment, the pharmaceutical compositions did not exhibit pharmacokinetic interactions when administered as a combined formulation of tramadol and pregabalin.

[0055] In another embodiment, the dissolution profile of the above mentioned pharmaceutical combination includes a comparison between both concentrations to demonstrate bioimmunity. EXAMPLES

[0056] Example 1. Tablet manufacturing process The pharmaceutical composition of this embodiment is manufactured by selecting unit operations, sequences and durations to control different physicochemical properties of the drug. The process avoids prolonged contact between water and the drug by selecting appropriate coating ingredients and ideal temperatures, and also ensures a barrier against light. Among the unit operations are sieving, blending and compression.

[0057] On the other hand, at any coating stage, the temperature is very important to ensure that the film adheres to the surface of the core. Generally, for this type of hydroxypropylcellulose-based system, a temperature of 40°C to 45°C is used. In this embodiment, it was possible to carry out the coating process at a core temperature in the range of 45-50°C, with the aim of ensuring that the film adheres to the surface of the core and reducing contact with water. In this way, the stability of the product is maintained during the coating process by also including a coating suspension, and at the end of the process, it is protected from light. Some steps of the method for producing tablets (caplet form) of this embodiment containing tramadol and / or pregabalin or their pharma- ceutically acceptable salts are given below, but not limited to: 1. Mix 45% diluent, 50% adsorbent, and drug 1 for 3 minutes and sieve (sieving material 1). 2. Mix the diluent, remaining adsorbent and drug 2 for 3 minutes and sieve (sieving material 2). 3. Mix sieved material 1, sieved material 2 and disintegrant for 5 minutes (mixture 33). 4. Sift the lubricant and mix in the powder of Mix 3 for 3 minutes. 5. Compress according to specifications. 6. Mix the solvent and moisture retarder for 45 minutes. 7. Coat with the above system according to specifications.

[0058] Example 2. Pharmaceutical solid composition A pharmaceutical composition containing 50 mg of tramadol hydrochloride and 75 mg of pregabalin is prepared by adding the following excipients (Table 1):

[0059] [Table 1]

[0060] The solid pharmaceutical composition is in the form of a solid dosage form such as a tablet, a monolayer tablet, a granule, a caplet, a lozenge, a pill, etc. Most preferably, it is in the form of a tablet and / or a pill. More preferably, the pharmaceutical composition containing 50 mg of tramadol hydrochloride and 75 mg of pregabalin is in the pharmaceutical form of a biconvex tablet.

[0061] Example 3. Pharmaceutical solid composition A pharmaceutical composition containing 50 mg of tramadol hydrochloride and 150 mg of pregabalin was prepared by adding the following excipients (Table 2):

[0062] [Table 2]

[0063] The solid pharmaceutical composition is in a solid dosage form such as, but not limited to, a tablet, a monolayer tablet, a granule, a caplet, a lozenge or a pill, preferably in the form of a tablet or pill.

[0064] Example 4. Pharmaceutical solid composition A pharmaceutical composition containing 100 mg of tramadol hydrochloride and 75 mg of pregabalin is prepared by adding the following excipients (Table 3):

[0065] [Table 3]

[0066] The solid pharmaceutical composition includes, but is not limited to, tablets, monolayer tablets, granules, caplets, lozenges, pills, and is preferably in the form of a tablet or pill.

[0067] Example 5. Stability study Stability studies were carried out in accordance with current regulations on three batches of the pharmaceutical compositions described in embodiment 2 and example 3. The results after 6 months at 40° C. and 75% relative humidity are shown below (Tables 4 and 5):

[0068] [Table 4]

[0069] [Table 5]

[0070] Example 6. Bioavailability test The pharmacokinetic profile (C max and AUC) were compared in healthy male and female subjects under fasting conditions to ensure the absence of interactions with concomitant drugs.

[0071] Pharmacokinetic parameters of the combination of pregabalin and tramadol after single oral administration C max ,A.U.C.,T. max ,Ke,and T 1 / 2 We characterized pregabalin 150 mg / tramadol 50 mg tablets (treatment C, Laboratorios Silanes test drug) compared with each component administered separately, using pregabalin 150 mg capsules (treatment A, regulatory agency reference drug) or tramadol 50 mg capsules (treatment B, regulatory agency reference drug) as reference drugs, in healthy male and female subjects under fasting conditions.

[0072] A single dosing frequency was established following administration of a single dose of the formulation.

[0073] The study design consisted of a crossover, 3x6x3, prospective, longitudinal, single-dose combination of oral pregabalin 150mg / tramadol 50mg with a single dose of each component, in 30 healthy subjects under fasting conditions, with 3 treatments, 3 periods, and 6 sequences including a 7-day washout period.

[0074] Sampling times: 18 samples were taken from each subject at the following times: 0.00 (pre-dose), 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours, three periods each after a single dose.

[0075] Analytical methods: The analytical method for plasma quantification of pregabalin and tramadol was based on the method published by Patel et al. with some modifications (J. Pharm. Biomed. 2009,49(29),354-66; Liu et. al., Eur. J. Drug Metab. Pharm.2009,34(3),185-92; Vaidya et. al., Chromatographia 2007,66(11),925-8; and Mandal et. al., Chromatographia 2008,67(8),237-43). Blood samples at each period were collected in glass tubes containing sodium citrate as anticoagulant. Samples were treated by precipitation and separated by HPLC with mass spectrometry detection. The analytical method met the validation parameters established in NOM 177-SSA1-2013.

[0076] Statistical analysis: Pharmacokinetic parameters C obtained with the three treatments evaluated max , A.B.C. 0-t ,A.B.C. 0-∞ Results of statistical tests applied to indicate that there are no differences in pharmacokinetic bioavailability between the oral formulations.Comparison of pregabalin tablets with tramadol tablets and each component administered separately:Pregabalin capsules or tramadol capsules were administered to healthy subjects in the fasted state.

[0077] The results obtained allow us to conclude about the equivalence of the pharmacokinetic bioavailability of the three analyzed formulations, and furthermore, that there is no interaction in the bioavailability of the combined administered formulations.

[0078] [Table 6]

[0079] [Table 7]

[0080] Example 7. Dissolution test Dissolution tests (in vitro tests) are used to determine the rate (amount, time) and extent (total amount) of drug released from a dosage form. A dissolution profile is a quantification of the amount of drug dissolved at various time points under standardized conditions. The importance of dissolution tests lies in: a) A guide for the development of new formulations during product development, allowing the evaluation of possible excipient or manufacturing process interference with drug release. b) Process Control and Quality Assurance: Helps to ensure the continued quality of the product and its optimization after changes in production, formulation, manufacturing site and process scale. c) In vivo developmental parameters: These are parameters of bioavailability, allowing the establishment of correlations between in vitro parameters and bioavailability results.

[0081] The dissolution profiles of tramadol hydrochloride / pregabalin 50 / 75 mg tablets and tramadol hydrochloride / pregabalin 50 / 150 mg tablets were studied.

[0082] Quantification of pregabalin in the study was performed using a previously validated method based on the criteria of the Mexican official standard NOM-177-SSAA-2013. The method was carried out using high-performance liquid chromatography coupled to a UV-Vis detector at a wavelength of 210 nm, with nominal concentrations ranging from 16.6 to 99.6 mcg / mL, with samples taken at 10, 15, 20, 30 and 45 min. The dissolution medium used was a 0.06 N hydrochloric acid solution.

[0083] Similarly, the quantification of tramadol hydrochloride was also validated based on the criteria of the Mexican official standard NOM-177-SSAA-2013. The method was carried out using high-resolution liquid chromatography coupled to a UV-Vis detector at a wavelength of 270 nm, with nominal concentrations ranging from 11.1 to 66.6 mcg / mL, with samples taken at 10, 15, 20, 25 and 30 min. The dissolution medium used was a 0.1 N hydrochloric acid solution.

[0084] These results indicate that the evaluated products can be considered equivalent, since the percentage of tramadol hydrochloride and pregabalin in the respective dissolution media of both the reference and test drugs was greater than 85% within the first 15 min (Figures 1 and 2).

[0085] Under the evaluation conditions, the coefficient of variation for the percentage of dissolved drug for both drugs, tramadol HCl and pregabalin, was less than 20% at the first sampling time and less than 10% at subsequent sampling times. The percentage of tramadol HCl and pregabalin in the dissolution medium for both reference and test drugs was greater than 85% within the first 15 minutes. These results indicate that the evaluated products dissolve so rapidly that they can be considered similar without the need to calculate the similarity factor f2. The values ​​of the similarity factor f2 are reported to be 96.2 for tramadol HCl and 85.0 for pregabalin. [Industrial Applicability]

[0086] One of the main problems with pharmaceuticals containing synergistic compositions of known drugs and known concentrations is the difficulty of maintaining their stability, solubility and bioavailability after they are administered to the patient, especially if the drugs are highly sensitive to light and moisture. In this sense, even within the range of regulatory solubility and bioavailability parameters, the results tend to be closer to the lower limit of use, meaning that the therapeutic effect takes longer to manifest or higher doses are required.

[0087] The present invention relates to a stable combination pharmaceutical composition in immediate release form, in which an opioid analgesic, such as tramadol, is combined with an antiepileptic / analgesic, such as pregabalin. As demonstrated by the pharmacokinetic bioavailability after administration of the composition of the present invention and the reference oral formulation, the synergistic effect of the drugs is maintained at a low dose while maintaining the solubility and bioavailability of the composition without losing therapeutic effect once administered, making it useful for treating and controlling pain, such as neuropathic pain and / or acute neuropathic pain.

Claims

1. a combination of 50 mg to 150 mg of tramadol or a pharma- ceutically acceptable salt thereof and 50 mg to 150 mg of pregabalin or a pharma- ceutically acceptable salt thereof; a photoprotective coating system that improves stability without altering solubility and bioavailability; at least one pharma- ceutically acceptable excipient selected from diluents, disintegrants, lubricants, and absorbents; Including, The light protective coating system is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, and povidone of all K values; A coated stable solid pharmaceutical composition for pain that is neuropathic pain and / or acute neuropathic pain.

2. 2. The pharmaceutical composition according to claim 1, wherein the concentration of tramadol or a pharma- ceutically acceptable salt thereof is from 50 mg to 150 mg, and the concentration of pregabalin or a pharma- ceutically acceptable salt thereof is from 75 mg to 150 mg.

3. The pharmaceutical composition of claim 1 or 2, wherein the diluent is selected from microcrystalline cellulose, dibasic calcium phosphate, pregelatinized starch, corn starch, mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose, or combinations thereof.

4. The pharmaceutical composition of claim 3, wherein the diluent is present in an amount of 5 to 90% by weight.

5. The pharmaceutical composition of claim 1, wherein the disintegrant is selected from croscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, crospovidone, pregelatinized starch, sodium starch glycolate or corn starch.

6. The pharmaceutical composition according to claim 5, wherein the disintegrant is present in an amount of 0.5% to 15% by weight.

7. The pharmaceutical composition of claim 6, wherein the disintegrant is contained in an amount of 0.5% to 3% by weight.

8. The pharmaceutical composition of claim 1, wherein the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearyl fumarate, talc or magnesium lauryl sulfate.

9. The pharmaceutical composition of claim 8, wherein the lubricant is present in an amount of 0.25% to 10% by weight.

10. The pharmaceutical composition of claim 8, wherein the lubricant is contained in an amount of 0.8% to 1% by weight.

11. The pharmaceutical composition of claim 1 or 2, wherein the absorbent is selected from aluminum hydroxide, aluminum oxide, aluminum phosphate, attapulgite, bentonite, hectorite, kaolin, pectin, calcium silicate, colloidal silicon dioxide, magnesium aluminum silicate, microcrystalline cellulose, cellulose, or magnesium carbonate.

12. The pharmaceutical composition of claim 11, wherein the absorbent is present in an amount of 0.5% to 90% by weight.

13. The pharmaceutical composition of claim 12, wherein the absorbent is contained in an amount of 1% to 1.5% by weight.

14. The pharmaceutical composition of claim 1, wherein the concentration of the coating system is 0.5% to 6% by weight.

15. The pharmaceutical composition of claim 14, wherein the concentration of the coating system is 2.5% to 3.5% by weight.

16. 16. The pharmaceutical composition of any one of claims 1 to 15, in the form of a tablet, pill, caplet, granule, troche, or capsule.

17. The pharmaceutical composition of claim 16 in the form of a tablet or pill.

18. The pharmaceutical composition of claim 16, which is caplet-shaped and has a groove formed therein.

19. 18. The pharmaceutical composition according to claim 17, wherein the tablet is in the form of a biconvex tablet or caplet.

20. 20. A pharmaceutical composition according to any one of claims 1 to 19 for use in the manufacture of a medicament useful for the treatment of pain.

21. The pharmaceutical composition of claim 20, wherein the pain is neuropathic pain.

22. The pharmaceutical composition of claim 21, wherein the neuropathic pain is acute neuropathic pain.

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