Coated stable solid pharmaceutical compositions of opioid analgesics for pain and antiepileptic drugs

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 pharmaceutical combination compositions for treating and controlling pain. [Background technology]

[0002] Neuropathic analgesia, as defined by the International Association for the Study of Pain Relief (IASP), is pain that occurs as a direct result of an injury or disease that affects 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 IASP, although many effective medications and guidelines are available for the treatment of neuropathic pain, they are not commonly used in US and Western trials, suggesting that many cases go untreated or untreated.

[0005] For example, tramadol, designated (1R,2R)-2-[(dimethylamino)methyl]-1-(3-mexitophenyl)cyclohex-1-ol, represented by formula I, is a synthetic codeine analogue and is a centrally acting analgesic that possesses 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 administration of 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 various animal models and in healthy volunteers with experimentally induced pain, and oral tramadol also exhibits 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. Serious side effects 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 can lead to addiction. High doses of tramadol are known to be more likely to cause side effects. Intentional and accidental overdoses of tramadol can lead to respiratory arrest and acute liver failure, and several fatal cases have been reported. However, in these cases, liver damage may have resulted from shock, hypoxia, or ischemia secondary to respiratory arrest. Liver damage from tramadol overdose 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. This drug belongs to the neuromodulatory group and has a better pharmacokinetic profile than previous drugs. It is also a GABA analogue, but does not exert all of the GABAergic effects. Pregabalin also has an analgesic effect due to its ability to bind to the alpha-2-delta protein subunit of voltage-gated calcium channels in 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, including blurred or double vision, hives, blisters, swelling of the face, arms, hands, and 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] To avoid the most common side effects and those caused by high-dose 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 pharmaceutically acceptable analgesic and a GABA agonist, such as gamma-vinyl GABA, to reduce or inhibit the addictive side effects of the analgesic. The document does not mention or explain the synergistic effect of combining an analgesic and a GABA agent. More recently, Patent Document 2 discusses the sustained-release formulation of an opioid and a GABA analog in separate 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 saturated peak, which differs from pregabalin, which is rapidly absorbed into the blood.

[0012] As another example of a 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, with the latter at a concentration of 15 to 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 a gamma-aminobutyric acid (GABA) analog with an opioid-type analgesic, the former being pregabalin and the latter being tramadol. However, this application neither claims nor describes a method for overcoming stability issues and combining the two drugs without affecting the bioavailability and dissolution of both compounds. Patent Document 7 also describes a synergistic pharmaceutical combination containing tramadol hydrochloride and pregabalin in a 1:1.5 and 1:2.5 w / w ratio, together with pharmaceutically acceptable excipients, and the synergistic combination is in oral or parenteral form. The present invention also relates to a method for treating neuropathic pain, particularly a synergistic pharmaceutical combination for use in the treatment of neuropathic analgesia, which may be of central or peripheral type. However, this document does not address the pharmacological problem of combining 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 an Acute Model of Analgesia" presents an antinociception study of pregabalin and tramadol, concluding 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 conducted in which a starting dose of combinations of tramadol and duloxetine (30 mg / 75 mg) or tramadol and pregabalin (30 mg / 75 mg) was compared with a placebo and an initial daily dose of 100 mg of tramadol. Each drug was administered separately. There are other problems with the development of formulations related to these analgesic therapeutics. Patent Document 8 points out problems with pregabalin formulations due to external factors such as humidity. This problem is solved by adding large amounts of colloidal silicon dioxide. This patent also states that capsules are the preferred formulation form because tablet formulation requires multiple steps.

[0015] However, this patent does not address or suggest how to formulate a second drug, such as tramadol, or how to solve the problem of administering high drug concentrations due to limited capsule size without affecting dissolution, bioavailability, or stability. Patent Document 9 claims a composition that is sugar-free, lactose-free, and contains fewer amino acids, and is formulated in the presence of water. It does not mention any special coating system, and the composition is not protected from external factors such as light, humidity, and temperature that could affect release, which could lead to various storage issues. Patent Document 10 claims a sustained-release pregabalin composition with a special coating system. Patent Document 11 also mentions the addition of coatings or gelling components that can delay drug release. Furthermore, Patent Document 12 seeks to protect three supplement coating systems that provide 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 Liver 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] Furthermore, the current state of the art has not yet addressed the problem of finding a combination of both drugs for pain treatment and management that achieves synergistic effects, improves bioavailability, solubility, and stability, and reduces side effects when administered to patients, while maintaining a low dose. This lack of solutions or alternatives has resulted in longer therapeutic effects and the need for higher doses. Furthermore, there are issues with synergistic effects and increased side effects when combining high doses of tramadol and pregabalin, as well as technical challenges in 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 treating neuropathic pain, preferably acute neuropathic pain, comprising tramadol and pregabalin, or pharmaceutically acceptable salts thereof, which allows for analgesic effect and a reduction in adverse events by reducing the 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] The excipients that make up the composition and that give it essential characteristics 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 incorporating water as a solvent into a formulation medium that minimizes contact with the tablet surface and does not affect the absorption of two moisture- and light-sensitive drugs, and furthermore, the composition employs a light-protective coating, so that the release of both drugs is not affected. [Brief explanation 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 2.0% or less within the sampling time. [Figure 2] Figure 1 shows a comparison of tramadol dissolution profiles for the reference drug (tramadol HCl 50 mg / pregabalin 150 mg) and the test drug (tramadol HCl 50 mg / pregabalin 75 mg), both lots from Laboratorios Silanes SA de CV. DETAILED DESCRIPTION OF THE INVENTION

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

[0029] definition Pharmaceutically acceptable salts: The term "pharmaceutically acceptable salts" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and 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, ethylesinamine, 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 pregabalin tosylate hydrochloride, derived from sulfuric acid, have been synthesized and are described in WO 2009 / 080365, "Pregabalin Salts." The acid anion is assumed to be nontoxic 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 pharmaceutically acceptable forms of pregabalin and / or tramadol, including pharmaceutically 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 to somatosensory systems. This type of pain is caused by various 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 that has synergistic effects and improved stability while maintaining the solubility and bioavailability of an opioid analgesic and an antiepileptic / analgesic, and can be administered as a therapeutic agent to treat pain, the target pain being neuropathic pain, preferably acute neuropathic pain.

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

[0038] The combination of tramadol and pregabalin has been shown to have antinociceptive effects in animal models and to reduce tramadol's adverse events, 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 single agents (Suthakaran 2017).

[0039] The combination of tramadol and pregabalin presents a series of significant technical challenges due to the physicochemical properties of the drugs. The appropriate selection of excipients and manufacturing conditions plays a key role in the development of pharmaceutical compositions, as it is related to the rate of drug release and absorption in the body. This composition thus overcomes the technical challenge of placing both moisture- and light-sensitive drugs in a formulation medium that does not affect absorption by incorporating water as a solvent, as contact with the tablet surface is minimized. Furthermore, the composition is coated with a protective coating against 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 pharmaceutically acceptable salt thereof, in a dose of 50-150 mg tramadol and 50-150 mg pregabalin, preferably in a lower dose such as 50-100 mg tramadol or one of its pharmaceutically acceptable salts, and 75-150 mg pregabalin or one of its pharmaceutically acceptable salts, together with at least one pharmaceutically acceptable excipient.

[0041] The solid pharmaceutical composition can be found as a tablet, monolayer tablet, granule, caplet, lozenge or pill, preferably in the form of a tablet or 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, making it the most widely accepted dosage form and allowing for the administration of high concentrations of drugs. Tablets allow for a reduced powder volume, making them easier to handle and administer.

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

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

[0045] Examples of pharmaceutically acceptable diluents include cellulose derivatives such as microcrystalline cellulose PH102, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch and corn starch, and mannitol, xylitol, maltitol, lactitol, sorbitol, sucrose or combinations thereof. The most preferred diluent in this invention is PH102 microcrystalline cellulose. The diluent is preferably present at a concentration of 5 to 90% by weight.

[0046] Pharmaceutically acceptable disintegrants include, but are not limited to, cellulose derivatives such as croscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, and microcrystalline cellulose; povidone derivatives such as crospovidone; and starch derivatives such as pregelatinized starch, sodium starch glycolate, and cornstarch. The disintegrant may be present in an amount of 0.5 to 15% by weight, preferably 0.5 to 3% by weight. The most preferred disintegrant in this embodiment is croscarmellose sodium.

[0047] Examples of pharmaceutically 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 to 10% by weight, preferably 0.8 to 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 combining both moisture- and light-sensitive drugs in a formulation medium that minimizes contact with the tablet surface through the incorporation of water as a solvent. Furthermore, the composition is coated with a light-protective coating system, which enhances stability while not affecting the release of the two drugs. Tramadol and pregabalin are known to be light- and moisture-sensitive drugs. Therefore, to date, no drug has been able to combine these two drugs in a single formulation without these effects. We have successfully developed a process that minimizes water-drug contact. To achieve this, we selected a core (uncoated tablet) process using 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 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 ingredients 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 a cellulose derivative such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, a polyvinyl derivative such as polyvinyl alcohol, polyethylene glycol, all K value The povidone derivative is selected from and their derivatives. Preferably, the concentration of hydroxypropyl cellulose is 0.5-6% by weight, most preferably 2.5-3.5% by weight. Preferably, no alcohol-based vehicle is used for coating; 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 solvent with the surface of the solid dosage form or tablet, ensuring film incorporation into the final dosage form.

[0052] The composition of this embodiment further includes, but is not limited to, 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), and magnesium derivatives (magnesium carbonate, magnesium silicate) as absorbents for residual water from tablets. A preferred absorbent is amorphous magnesium aluminum metasilicate at a concentration of 0.5 to 90% by weight, most preferably 1 to 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 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 pharmaceutical combination described above includes a comparison between both concentrations to demonstrate bioimmunity. [Example]

[0056] Example 1. Tablet manufacturing process The pharmaceutical composition of this embodiment is manufactured by selecting unit operations, their sequence, and duration to control different physicochemical properties of the drug. This process avoids prolonged contact between water and the drug and also ensures a light barrier by selecting appropriate coating components and ideal temperatures. The unit operations include sieving, blending, and compression.

[0057] Meanwhile, temperature is crucial in any coating step to ensure that the film adheres to the core surface. Typically, for this type of hydroxypropyl cellulose-based system, a temperature of 40°C to 45°C is used. In this embodiment, the coating process could be carried out at a core temperature in the range of 45°C to 50°C, with the goal of adhering the film to the core surface and reducing contact with water. In this way, the inclusion of a coating suspension maintains product stability during the coating process and protects it from light at the end of the process. Some steps in the manufacturing method for tablets (caplet form) of this embodiment containing tramadol and / or pregabalin or pharmaceutically acceptable salts thereof are shown below, but are not limited to these: 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 sieving material 1, sieving material 2 and disintegrant for 5 minutes (mixture 33). 4. Sift the lubricant and mix the powder from 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 may be in the form of a tablet, a monolayer tablet, a granule, a caplet, a lozenge, a pill, or the like. 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 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 is 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 a 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, and pills, and is preferably in the form of a tablet or pill.

[0067] Example 5. Stability test Stability studies were carried out in accordance with current regulations on three batches of the pharmaceutical compositions described in Example 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 profiles (C max and AUC) were compared in healthy male and female subjects under fasting conditions to confirm the absence of drug interactions.

[0071] Pharmacokinetic parameters of the combination of pregabalin and tramadol after single oral administration C max ,AUC,T max ,Ke,and T 1 / 2 The study characterized pregabalin 150 mg / tramadol 50 mg tablets (Treatment C, Laboratorios Silanes study drug) compared with each component administered separately. Pregabalin 150 mg capsules (Treatment A, regulatory reference drug) or tramadol 50 mg capsules (Treatment B, regulatory reference drug) were used as reference drugs, and the study was conducted in healthy male and female subjects under fasting conditions.

[0072] The single dose frequency was established after a single dose of the formulation.

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

[0074] Sampling times: 18 samples were collected 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 an 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 , ABC 0-t ,ABC 0-∞ Results of statistical tests applied to the comparison of pregabalin tablets with tramadol tablets and each component administered individually: Pregabalin capsules or tramadol capsules were administered to healthy subjects in the fasting state.

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

[0078] [Table 6]

[0079] [Table 7]

[0080] Example 7. Dissolution test Dissolution testing (in vitro testing) is 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 testing lies in: a) A guide for the development of new formulations during product development, which allows for the evaluation of possible excipient or manufacturing process interference with drug release. b) Process Control and Quality Assurance: Helps ensure the continued quality of the product and its optimization after changes in manufacturing, formulation, production site and process scale. c) In vivo developmental indicators: These are indicators of bioavailability and allow for 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 tested.

[0082] Quantitation of pregabalin in this study was performed using a previously validated method based on the Mexican Official Standard NOM-177-SSAA-2013. The method was performed using high-performance liquid chromatography coupled to a UV-Vis detector at 210 nm, with nominal concentrations ranging from 16.6 to 99.6 mcg / mL. Samples were collected at 10, 15, 20, 30, and 45 minutes. The dissolution medium used was 0.06 N hydrochloric acid solution.

[0083] Similarly, the quantification of tramadol hydrochloride was validated according to the Mexican Official Standard NOM-177-SSAA-2013. The method was performed using high-resolution liquid chromatography coupled to a UV-Vis detector at 270 nm, with nominal concentrations ranging from 11.1 to 66.6 mcg / mL, and samples were collected at 10, 15, 20, 25, and 30 minutes. The dissolution medium used was 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 minutes (Figures 1 and 2).

[0085] Under the evaluation conditions, the coefficient of variation for the percentage of dissolved drug for both tramadol hydrochloride and pregabalin was less than 20% at the first sampling time and less than 10% at subsequent sampling times. The percentage of tramadol hydrochloride and pregabalin in the dissolution medium for both the reference and test drugs exceeded 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. Values of the similarity factor, f2, were reported to be 96.2 for tramadol hydrochloride and 85.0 for pregabalin. [Industrial Applicability]

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

[0087] The present invention relates to a stable immediate release combination pharmaceutical composition in which an opioid analgesic, such as tramadol, is combined with an antiepileptic / analgesic, such as pregabalin, which is useful for the treatment and control of pain, such as neuropathic pain and / or acute neuropathic pain, by maintaining the synergistic drug effects at low doses while maintaining the solubility and bioavailability of the composition without losing therapeutic efficacy once administered, as demonstrated by the pharmacokinetic bioavailability after administration of the composition of the present invention and a reference oral formulation.

Claims

1. a combination of 50 mg to 150 mg of tramadol or a pharmaceutically acceptable salt thereof and 50 mg to 150 mg of pregabalin or a pharmaceutically acceptable salt thereof; a photoprotective coating system that improves stability without altering solubility and bioavailability; at least one pharmaceutically 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 pharmaceutically acceptable salt thereof is 50 mg to 150 mg, and the concentration of pregabalin or a pharmaceutically acceptable salt thereof is 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 a combination thereof.

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

5. The pharmaceutical composition of claim 1 or 2, wherein the disintegrant is selected from croscarmellose, hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, crospovidone, pregelatinized starch, sodium starch glycolate or corn starch.

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

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

8. The pharmaceutical composition of claim 1 or 2, wherein the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearyl fumarate, talc or magnesium lauryl sulfate.

9. 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% by weight 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. 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 described in claim 12, wherein the absorbent is contained in an amount of 1% by weight 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 described in claim 14, wherein the concentration of the coating system is 2.5% by weight 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, lozenge, or capsule.

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

18. The pharmaceutical composition described in claim 16, which is in the form of a caplet 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 described in claim 20, wherein the pain is neuropathic pain.

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

Images