Multi-active tablets for treatment and control of severe chronic pain and methods for preparing the same

Abstract

To provide a stable, immediate release pharmaceutical composition comprising cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib, useful for the relief of pain having chronic neuropathic and nociceptive components, e.g., acute and recurrent painful neuropathy; and to provide a method for preparing the same.SOLUTION: The present invention relates to a simple and optimized method that allows the combined manufacture of five active substances: cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib in a single solid, stable, immediate release pharmaceutical form for pain. The combination use of drugs acting at different levels provides a higher analgesic effect and allows the use of lower doses, reducing the risk of side effects. In this respect, the combination of B vitamins with pregabalin and celecoxib is thought to show a higher analgesic activity due to their complementary mechanisms of action.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present invention relates to medicinal chemistry for the manufacture of medicines, particularly those focused on the control of chronic pain having neuropathic and nociceptive components. [Background technology]

[0002] To date, there is no technology available that provides synergistic alternative compositions of a neuropathic predominant analgesic such as pregabalin, a nociceptive predominant analgesic such as celecoxib, and their combination with B vitamins (particularly vitamin B12 and / or vitamin B1 and / or vitamin B6) in the same dosage unit for the treatment of pain.

[0003] Non-patent literature 1 by Reyes-Garcia G. et al., "Oral Administration of B Vitamins Increases the Antiallodynic Effect of Gabapentin in the Rat;" (Proc. West Pharmacol.Soc 47, published in 2004), describes a study evaluating the synergistic interaction between gabapentin and vitamin components consisting of vitamins B1, B6, B12 or a mixture thereof in a neuropathic pain model. The study results showed that oral administration of B vitamins moderately reduced tactile allodynia in a dose-dependent manner, and that combined administration of gabapentin / vitamin B significantly reduced tactile allodynia in a dose-dependent manner, and that combined administration of gabapentin / vitamin B reduced tactile allodynia at an effective dose of 50ED50. 50 It was shown that 100 mg / kg / day of tactile allodynia was associated with a significant dose-dependent reduction in tactile allodynia, lower than the theoretical additive dose.

[0004] Patent document 1 (WO 2009 / 046801 dated April 16, 2009) refers to a pharmaceutical composition for the treatment of neuropathic pain comprising the vitamin B1 derivative "benfotiamine" and an analgesic drug (pregabalin), and it has been shown that the synergistic interaction of the combination is significantly greater than that recorded for combinations of gabapentin, diclofenac, dexamethasone or ketorolac with B vitamins.

[0005] Non-patent literature 2 by MIXCOATL-ZECUATL T. et al., "Synergistic Antiallodynic Interaction between Gabapentin or Carbamazepine and either Benfotiamine or Cyanocobalamin in Neuropathic Rats;" (Methods Find Exp Clin. Pharmacol. 30 (6), published in 2008), reports a synergistic interaction in a composition containing gabapentin or carbamazepine and vitamin B12 "cyanocobalamin" or the B1 derivative "benfotiamine" as a treatment for neuropathic pain.

[0006] Non-patent literature 3 by REYES-GARCIA G. et al., "Analgesic Effect of B Vitamins in Formalin-Induced Inflammatory Pain;" (Proc. West. Pharmacol. Soc. 44, published in 2001), describes a study evaluating the analgesic effect of vitamins B1, B6, B12, or combinations of these for the treatment of inflammatory pain.

[0007] Non-patent literature 4 by Romano CL, Romano D, Bonora C, and Mineo G., "Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain" (J Orthop Traumatol. 2009 Dec;10(4):185-91), describes the effectiveness of combination therapy of celecoxib and pregabalin for chronic low-back pain. It concludes that combination therapy of celecoxib and pregabalin for chronic low-back pain is more effective than monotherapy with similar side effects.

[0008] Patent Document 2 (Mexican Patent Publication No. 2011 / 013989) describes an invention relating to a pharmaceutical combination drug containing pregabalin (150 mg), cyanocobalamin (250 mg, vitamin B12), thiamine hydrochloride (100 mg, vitamin B1) and pyridoxine hydrochloride (50 mg, vitamin B6) as a therapeutic drug for neuropathic pain. The incidence of peripheral neuropathy is not known with certainty. However, the worldwide prevalence is estimated to range from 25% to 8% of the population, and it can occur at any age in both sexes, although symptoms such as frequency, quality and intensity of pain vary from person to person. According to the Mexican Ministry of Health, there are approximately 7 million people suffering from neuropathic pain, and global statistics indicate that approximately 7% of the population suffers from neuropathic pain.

[0009] Patent document 3 (Mexican Patent No. 292254) discloses administering to a mammal a combination of at least one ligand for the calcium channel subunit α2δ and a nonsteroidal anti-inflammatory drug (NSAID). The combination results in a marked and potent inhibition of the micturition reflex, superior to that obtained by treatment with the ligand α2δ or NSAIDs alone. The combination of the ligand α2δ and the NSAIDs is useful for the treatment of lower urinary tract disorders and related conditions. Preferred ligands α2δ are gabapentin and pregabalin. Preferred NSAIDs are celecoxib, diclofenac, diflunisal, flurbiprofen, naproxen, nimesulide or sulindac.

[0010] Patent document 4 (Mexican Patent Application No. 2004 / 008175) refers to a combination consisting of a selective COX-2 inhibitor or a pharma- ceutically acceptable salt thereof, a ligand α2δ or a pharma- ceutically acceptable salt thereof, and valdecoxib. Examples of selective COX-2 inhibitors include valdecoxib, lefocoxib, and celecoxib, and examples of ligand α2δ include gabapentin, pregabalin, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)acetic acid, and 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride. These combinations are useful for the treatment of certain conditions, including certain diseases such as joint damage, inflammation, pain, and arthritis.

[0011] Patent document 5 (Mexican Patent No. 336979) relates to pharmaceutical combinations of two antiepileptic drugs and of an antiepileptic drug with a B vitamin, where the antiepileptic drug is selected from pregabalin and / or oxcarbazepine and the vitamin is selected from vitamin B1 and vitamin B12, as well as pharmaceutical compositions comprising such combinations and the use of such compositions for the treatment of neuropathic pain (NP).

[0012] Patent document 6 (WO 2021 / 111149) relates to a process for preparing a composition in the form of particles of a certain weight, number and volume (10 nm and 700 pm) consisting of a solid core and successive discrete layers, which process includes the steps of applying an initial layer of coating material to said solid core by gas deposition techniques, discharging the coated particles from a gas deposition reactor, then stirring the coated particles to dissociate them, and finally reapplying an additional layer of coating material to the dissociated particles. The core consists of a biologically active agent, for example a ligand α2δ (pregabalin), a nonsteroidal anti-inflammatory drug (NSAID), a vitamin, or a mixture thereof. This document mentions the possibility of producing a composition comprising a ligand α2δ (pregabalin), a nonsteroidal anti-inflammatory drug, and a vitamin, but does not teach or describe that the nonsteroidal anti-inflammatory drug can be an active ingredient such as celecoxib, nor the type or types of vitamins suitable for the combination.

[0013] Furthermore, a search for different active ingredients such as cyanocobalamin / pyridoxine / thiamine, either separately or in combination, resulted in patent document 7 (Mexican Patent No. 293045) protecting the combination meloxicam / cyanocobalamin / pyridoxine / thiamine. Searching for patents relating to combinations of pregabalin with other active substances also resulted in patent document 8 (Mexican Patent No. 360289) protecting the use of a combination of pregabalin and tapentadol, characterized in having a sustained release active ingredient (tapentadol) and at least one pharma- ceutically acceptable carrier, and a second active agent, the second active agent being pregabalin, which is in a sustained (controlled) or delayed release form.

[0014] With regard to celecoxib, patent document 9 (Mexican Patent No. 366118) of More Pharma Corporation S. de RL de CV claims a synergistic pharmaceutical composition for oral administration for the treatment of inflammatory pain, consisting of 357 mg of paracetamol and 50-75 mg of celecoxib. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. 2009 / 046801 Brochure [Patent Document 2] Mexican Patent Publication No. 2011 / 013989 [Patent Document 3] Mexican Patent No. 292254 [Patent Document 4] Mexican Patent Application No. 2004 / 008175 [Patent Document 5] Mexican Patent No. 336979 [Patent Document 6] International Publication No. 2021 / 111149 Brochure [Patent Document 7] Mexican Patent No. 293045 [Patent Document 8] Mexican Patent No. 360289 [Patent Document 9] Mexican Patent No. 366118 [Non-patent literature]

[0016] [Non-Patent Document 1] REYES-GARCIA G. ET AL., “Oral Administration of B Vitamins Increases the Antiallodynic Effect of Gabapentin in the Rat;” Proc. West Pharmacol. Soc. 47; published in 2004 [Non-Patent Document 2] MIXCOATL-ZECUATL T. ET AL., “Synergistic Antiallodynic Interaction between Gabapentin or Carbamazepine and either Benfotiamine or Cyanocobalamin in Neuropathic Rats;” Methods Find Exp Clin. Pharmacol. 30 (6), published in 2008 [Non-Patent Document 3] REYES-GARCIA G. ET AL., “Analgesic Effect of B Vitamins in Formalin-Induced Inflammatory Pain;” Proc. West. Pharmacol. Soc. 44, published in 2001 [Non-Patent Document 4] Romano CL, Romano D, Bonora C, Mineo G. “Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain” J Orthop Traumatol. 2009 Dec;10(4):185-91 Summary of the Invention [Problem to be solved by the invention]

[0017] There are no patent documents in the technical patent information on the oral combination of cyanocobalamin / pyridoxine / thiamine / pregabalin / celecoxib, therefore, it is certain that the combination of the above five active substances has a high degree of technological innovation for the treatment and control of chronic neuropathic and nociceptive pain.

[0018] Thus, heretofore, a stable, immediate release, fixed dose combination has not been formulated for the production of a pharmaceutical product consisting of cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib useful for the relief of pain having chronic neuropathic and nociceptive components, e.g., acute and recurrent painful neuropathy. [Means for solving the problem]

[0019] The present invention relates to a combined pharmaceutical composition comprising cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib in the dosages of 0.5mg / 50mg / 100mg / 150mg / 200mg, respectively, and a pharma- ceutically acceptable carrier in a single solid stable immediate release pharmaceutical form.

[0020] The pharma- ceutically acceptable carrier is selected from the group consisting of surfactants and / or humectants, diluents, solubilizers, binders, disintegrants, dyes, alkalizing agents, lubricants and solvents.

[0021] In one embodiment, the preferred pharmaceutical form is a tablet.

[0022] The present invention also relates to a simply optimized process that allows the combined preparation of fixed doses of five active substances: cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib, as well as a pharma- ceutically acceptable carrier, in a single solid, stable, immediate release pharmaceutical form for the treatment of pain.

[0023] In another embodiment of the present invention, the use of the active ingredients cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib is described for the manufacture of a medicament useful for the treatment and control of chronic pain with neuropathic and nociceptive components, such as acute and recurrent painful neuropathy, and the medicament is a single solid stable immediate release pharmaceutical form.The combined use of drugs that act at distinctly different levels provides a higher analgesic effect and can be used at lower doses, reducing the risk of side effects.In this respect, the combined use of vitamin B complex with pregabalin and celecoxib is believed to show a higher analgesic effect due to their complementary mechanisms of action. [Brief description of the drawings]

[0024] [Figure 1] Mean plasma concentrations and standard errors of pregabalin. T1: test drug celecoxib / pregabalin / vitamin B. T3: reference drug, pregabalin. [Diagram 2] Log-transformed mean plasma concentrations and standard errors of pregabalin. Original concentrations are μg / mL. T1: test drug, celecoxib / pregabalin / vitamin B. T3: reference drug, pregabalin. [Diagram 3] Mean plasma concentrations and standard errors of celecoxib. T1: Test drug celecoxib / pregabalin / vitamin B. T2: Reference drug celecoxib. [Figure 4] Log-transformed mean plasma concentrations and standard errors of celecoxib. Original concentrations are μg / mL. T1: Test drug celecoxib / pregabalin / vitamin B. T2: Reference drug celecoxib. [Diagram 5] Trend of Cyanocobalamin content results over 18 months under conditions of 30℃±2℃ / 75%RH±5%RH for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17, DFF2002-18. [Figure 6]Trend of pyridoxine hydrochloride content of product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18, after 18 months of use under conditions of 30℃±2℃ / 75%RH±5%RH. [Figure 7] Thiamine mononitrate content trend for Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17, DFF2002-18, after 18 months of use at 30°C±2°C / 75%RH±5%RH. [Figure 8] Trend of pregabalin content for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18, when used for 18 months under conditions of 30℃±2℃ / 75%RH±5%RH. [Figure 9] Trend of celecoxib content results over 18 months under conditions of 30℃±2℃ / 75%RH±5%RH for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18. [Figure 10] Trend of pyridoxine hydrochloride dissolution results over a period of 18 months under the conditions of 30℃±2℃ / 75%HR±5%HR for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18. [Figure 11]Dissolution trends of thiamine mononitrate for Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17, DFF2002-18 at 30°C±2°C / 75%RH±5%RH for a period of 18 months. [Figure 12] Trend of pregabalin dissolution results for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18, under conditions of 30℃±2℃ / 75%RH±5%RH for 18 months of use. [Figure 13] Trend of celecoxib dissolution results over a period of 18 months under conditions of 30°C±2°C / 75%RH±5%RH for product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The preparation of a pharmaceutical composition for oral administration consisting of a combination of cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib is described. This method allows for the preparation of a pharmaceutical composition that is easy to administer in one dose. The present invention relates to both the pharmaceutical composition and the preparation method for obtaining it.

[0026] The technical development included a series of evaluations to define the formulation and manufacturing process as follows: The formulation contains cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib in doses of 0.5mg / 50mg / 100mg / 150mg / 200mg, respectively, combined with pharmacologic acceptable excipients (see Table 1).

[0027] The technical complexity lies in the combination of five drugs with different rheological and solubility properties and pharma- ceutically acceptable excipients.

[0028] On the one hand, there are lipid-soluble drugs with poor flowability and high adhesion (celecoxib), and on the other hand, there are water-soluble drugs with poor flowability and low compressibility (pyridoxine, thiamine), which may compromise stability, absorption and release mechanisms.

[0029] [Cyanocobalamin] Simplified formula: C 63 H 88 CoN 14 O 14 P Description: Dark red crystals or red amorphous powder. The anhydrous form is hygroscopic. pH: 6.0 (1g / L at 20℃) pKa: 1.82 Solubility: Soluble in alcohol, slightly soluble in water, practically insoluble in acetone, chloroform, and diethyl ether. 12g / L

[0030] [Pyridoxine] Simplified formula: C 8 H 11 NO 3 O-HCl Overview: A white or almost white crystalline powder that is stable in air and decomposes slowly in light. pKa: 9.4 Solubility: Freely soluble in water, slightly soluble in alcohol, practically insoluble in diethyl ether.

[0031] [Thiamine] Simplified formula: C 12 H 17 N 5 O 4 S Overview: White or almost white crystalline powder or small colorless crystals. pKa: 15.5 Solubility: Soluble in hot water, slightly soluble in water, slightly soluble in ethanol and methanol, very slightly soluble in chloroform, practically insoluble in diethyl ether.

[0032] [Pregabalin] Simplified formula: C 8 H 17 NO 2 Description: White crystals with no distinctive odor or taste. Solubility: 11.3g / L Biopharmaceutical classification: Category I, highly permeable, highly soluble.

[0033] [Celecoxib] Simplified formula: C 17 H 14 F 3 N 3 O 2 S Description: White crystals with no distinctive odor or taste. Solubility: 3.3g / L Classification of biopharmaceuticals: Class II, highly permeable, poorly soluble.

[0034] Meanwhile, the ingredients of the formulation are selected based on their function and concentration and a series of tests are carried out, which are established in relation to the product behavior and ensure the proper functioning of the product.

[0035] [Surfactant / moisturizer] The surfactant or humectant is selected from the group consisting of poloxamer, polyoxyethylene castor oil derivative, benzalkonium chloride, benzethonium chloride, polyoxyethylene alkyl ether and polyoxyethylene sorbitan fatty acid ester, preferably sodium lauryl sulfate, which is added in the range of 1-25%. Sodium lauryl sulfate can be added in a concentration of 0.64%, which can moisten the insoluble drug, break the surface tension and achieve the solubilization effect.

[0036] [Binding agent] It is selected from the group consisting of all K grades of povidone and its derivatives, cellulose derivatives such as carbomer, hydroxypropylcellulose, carboxymethylcellulose, starch derivatives such as pregelatinized starch and corn starch, added in the range of 1-25%. The binder can also be polyvidone, preferably polyvidone K30, which can be added at a concentration of 3.27%, a high binding strength additive, which, by absorbing water during production, forms bonds between the particles of material to facilitate granulation of the ingredients of the formulation and improve the physical properties of the powder mixture such as compaction, particle size, density and flowability.

[0037] [Diluent] The diluent is selected from the group consisting of cellulose derivatives such as microcrystalline cellulose, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch and corn starch, and lactose such as anhydrous lactose, and is added in the range of 5 to 90%. Thus, the diluent can be microcrystalline cellulose, preferably silicified microcrystalline cellulose, which can be added in a concentration of 27.99%, and provides stability to each outer granule due to its improved compression properties in direct compression compared to conventional microcrystalline cellulose. The diluent is lactose, preferably lactose monohydrate, which can be added in a concentration of 16.33%, and is useful for poorly soluble drugs (celecoxib) because its good flow properties and particle size make the mixture more hydrophilic and do not present incompatibility problems with other components of the formulation.

[0038] [Disintegrant] The disintegrant may be selected from the group consisting of cellulose derivatives such as hydroxypropylcellulose, carboxymethylcellulose, microcrystalline cellulose, povidone derivatives such as crospovidone, plaston, starch derivatives such as pregelatinized starch, sodium starch glycolate, corn starch, etc., and is added in the range of 0.5-15%. The disintegrant may also be croscarmellose sodium, a white to off-white odorless powder, which may be added in a concentration of 4.08% to increase the disintegration rate of the tablet and thus improve the dissolution profile of the drug.

[0039] [lubricant] For example, the lubricant is selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearic acid derivatives such as stearyl fumarate, sulfated derivatives such as magnesium lauryl sulfate, magnesium lauryl sulfate, and talc, and is added in the range of 0.25 to 10%. The lubricant is preferably magnesium stearate, and can be added in a concentration of 0.41% to reduce friction during the compression process and prevent adhesion between different tools.

[0040] [dye] The β-carotene is selected from the group consisting of indigo carmine, iron oxide, sunset yellow FCF and titanium dioxide and is added in the range of 0.5 to 1.0% (DL50 (rat, oral), 10 g / kg). The dye is preferably Yellow No. 5, which can be added at a concentration of 0.31%, and its stable condition provides a pleasing color in combination with cyanocobalamin.

[0041] [Solubilizer] It is selected from the group consisting of different grades of polyethylene glycol, glyceryl behenate, microcrystalline wax and stearoyl polyoxyglyceride, and is added in the range of 5-10%. The solubilizer can also be a poloxamer, preferably poloxamer 188, which can be added in a concentration of 2.04%, and this poloxamer's emulsifying properties give it the solubilizing function.

[0042] [Alkalization] It is selected from the group consisting of sodium carbonate, calcium hydroxide, potassium hydrogen carbonate, potassium citrate, potassium hydroxide, sodium citrate dihydrate, and sodium hydroxide, and is added in the range of 10 to 50%. In addition, the alkalizing agent can be a hydrogen carbonate, preferably sodium hydrogen carbonate, and adding it at a concentration of 4.08% can increase the bioavailability of the drug in the body.

[0043] The choice of excipients was based on the physicochemical properties of the drugs: for celecoxib, improved rheological and adhesive properties, pH adjustment to improve inherent stability, and the creation of a microenvironment that promotes dissolution, thus improving bioavailability; for pregabalin and vitamins, improved rheological and compression properties ensured stability and solubility. do.

[0044] Once the drugs or active substances cyanocobalamin, pyridoxine, thiamine, pregabalin, and celecoxib were selected, fixed doses of 0.5 mg / 50 mg / 100 mg / 150 mg / 200 mg, respectively, and pharma- ceutically acceptable excipients for one dosage unit were defined.

[0045] The formulation chosen to administer the drug was "tablets", the most widely accepted formulation due to the accuracy of the dosage and ease of administration. Capsules are an alternative, however, capsule size is limited and does not allow for high drug concentrations. Tablets allow for a reduced powder volume, which makes them easier to handle and administer.

[0046] The manufacturing process of the pharmaceutical composition comprises the following steps: i. mixing the active ingredient celecoxib with pre-screened first diluent, disintegrant, binder, solubilizer and alkalizer for 10 minutes; ii. Wetting with purified water and granulating; iii. drying the granules obtained in the previous step until the moisture content is about 0.8% or less; iv. adding the active ingredient cyanocobalamin and a portion of the second diluent and mixing for 5 minutes; v. adding a portion of the second diluent and mixing for 5 minutes; vi. Repeating the previous step by adding a portion of the second diluent and mixing for 5 minutes; vii. adding solubilizer and mixing for 5 minutes; viii. adding the active ingredients pyridoxine, thiamine and pregabalin, and a portion of the second diluent; ix. adding a portion of the second diluent and mixing for 5 minutes; x. adding binder, surfactant / wetting agent and disintegrant and mixing for 5 minutes; xi. adding pre-sieved dyes and lubricants and mixing for 3 minutes; and xii. compressing the granules obtained in the previous step; Equipped with.

[0047] In a preferred embodiment, the process is as follows.

[0048] In step i., 50% of the total amount of disintegrants, 50% of the total amount of binders, and 50% of the total amount of solubilizers are mixed. In step iv., the portion of the second diluent is 5% of the total amount of the second diluent. In step v., the portion of the second diluent is 10% of the total amount of the second diluent. In step vi., the portion of the second diluent is 20% of the total amount of the second diluent. In step vii., the remaining 50% of the solubilizer is mixed. In step viii., 32.5% of the total amount of the second diluent is mixed. In step ix, the portion of the second diluent is 32.5% of the total amount of the second diluent. In step x, the remaining 50% of the binder and the remaining 50% of the disintegrant are mixed.

[0049] In a preferred embodiment, the pyridoxine is pyridoxine hydrochloride and the thymine is thymine mononitrate.

[0050] In non-limiting embodiments, the surfactants / wetting agents, binders, diluents, disintegrants, lubricants, dyes, solubilizers, and alkalinizers are selected from the options detailed above.

[0051] In a preferred embodiment, the surfactant / wetting agent is sodium lauryl sulfate, the first diluent is lactose monohydrate, the solubilizer is poloxamer, the binder is polyvidone, the disintegrant is croscarmellose sodium, the second diluent is microcrystalline cellulose, the dye is Yellow No. 5, the alkalinizer is sodium bicarbonate, and the lubricant is magnesium stearate.

[0052] The process of the present invention, which allows obtaining a single product combining dosages of cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib, represents a series of significant technical challenges due to the differences in the physicochemical properties and dosages of each active ingredient, in order to ensure a stable product is obtained.

[0053] In another aspect of the present invention, there is provided a method for the treatment and control of chronic pain, comprising administering to a patient in need thereof a composition according to the present invention. In a preferred embodiment, the pain is painful, acute and recurrent neuropathic. EXAMPLES

[0054] Example 1 Preparation of pharmaceutical compositions according to embodiments of the present invention.

[0055] The pharmaceutical compositions were prepared according to the qualitative-quantitative formulas set forth in Table 1.

[0056] [Table 1]

[0057] To prepare the pharmaceutical compositions described in Table 1, the process followed consisted of the following:

[0058] i. Celecoxib (active ingredient), lactose monohydrate (diluent), 50.0% croscarmellose sodium (disintegrant), 50.0% polyvidone K30 (binder), 50% poloxamer 188 (solubilizer) and sodium bicarbonate (alkalinizer) were sieved through a 0.157 cm mesh (0.062 inch). ii. The sieve fraction from step No. 1 was added to the mixer and mixed for 10 minutes. iii. The mixture of step No. 2 was added to a granulator and granulated by wetting with purified water. iv. In a granulator, the granules obtained from step no. 3 were dried to a humidity of less than 0.8%. v. The granules obtained in step No. 4 were subjected to a size reduction operation using a 0.127 cm mesh (0.050 inch). vi. Cyanocobalamin (active ingredient) and 5.0% silicified microcrystalline cellulose (diluent) were added to the diffusion mixer. Mixed for 5 minutes. vii. 10% silicified microcrystalline cellulose (diluent) was added to the diffusion mixer in step No. 6. Mixed for 5 minutes. viii. 20% silicified microcrystalline cellulose (diluent) was added to the diffusion mixer in step No. 7. Mixed for 5 minutes. ix. 50% Poloxamer 188 (solubilizer) was added to the diffusion mixer in step No. 8. Mixed for 5 minutes. x. The following ingredients were added to the diffusion mixer in step No. 9: Pyridoxine Hydrochloride (active ingredient), Thiamine Mononitrate (active ingredient), Pregabalin (active ingredient) and 32.5% silicified microcrystalline cellulose (diluent). Mixed for 5 minutes. xi. 32.5% silicified microcrystalline cellulose (diluent) was added to the diffusion mixer in step number 10. This was mixed for 5 minutes. xii. A material of Polyvinyl Chloride K30 (binder) 50.0%, Sodium Lauryl Sulfate (surfactant / wetting agent) and Croscarmellose Sodium (disintegrant) 50.0% was sieved through a 0.157 cm mesh (0.062 inch). xiii. Sieve fractions from step No. 5 and No. 12 were added to the diffusion mixer and mixed for 5 minutes. xiv. Screen through 0.157 mesh (0.062 inch) and add Yellow No. 5 (color) and magnesium stearate (lubricant). xv. The mixture from step No. 13 and the sieve from step No. 14 were added to the diffusion mixer and mixed for 3 minutes. xvi. The granules are capable of producing tablets with good mechanical properties. Thus, the final powder blend was compressed to 1225 mg ± 61 mg with a hardness of 14.0 Kp or less and a disintegration time of 30 minutes or less.

[0059] In this way, manufacturing was carried out taking into account the physicochemical properties of the drugs, and for celecoxib, the rheological properties and adhesion were improved, while for the other active ingredients, the rheological properties and compression properties were improved, ensuring stability and solubility.

[0060] (Example 2) Comparative bioavailability clinical trial A pharmacokinetic non-interaction study of celecoxib 200mg / pregabalin 150mg / vitamin B (healthy subjects, both sexes, single dose in fasting state, individual or combined administration)

[0061] In this study, we compared the pharmacokinetic profile (C ) of a single dose of Laboratorios Silanes SAde CV celecoxib 200 mg / pregabalin 150 mg / vitamin B combination (tablet, test drug) versus each component administered separately (celecoxib 200 mg, pregabalin 150 mg, reference drug). max , AUC 0-t , AUC 0-∞ , t max , K e , t 1 / 2 ) were compared under fasting conditions in healthy men and women to clarify the non-pharmacokinetic interactions of the combination drug and to determine whether the 90% confidence intervals of the test drug and the reference drug were C max and AUC 0-t We checked whether the values ​​were within the range of 80 to 120%.

[0062] The study was an open, longitudinal, prospective, 3x6x3 design, randomized, single-dose, three treatment, three period, six sequences under fasting conditions, with a one-week (07 days) washout period between each period in a healthy Mexican female and male population.

[0063] [Table 2]

[0064] The study was started with 42 study subjects and ended with 41 female (27) and male (14) study subjects. Due to the COVID-19 health emergency, the 42 study subjects were divided into two hospitalized groups: 22 in group 1 and 20 in group 2. After at least 10 hours of fasting, blood was drawn at 0.00 hours and administered orally at room temperature with 250 mL of water, as a single dose of the test or reference drug (celecoxib 200 mg capsule or pregabalin 150 mg capsule), according to the pre-randomization. After administration of the corresponding drug, 17 additional samples were collected at 0.50, 0.75, 1.00, 1.33, 1.66, 2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00, 14.00, 24.00, 36.00, and 48.00 hours post-dose.

[0065] The quantitative analytical method for celecoxib and pregabalin in plasma was developed and validated according to the parameters of NOM-177-SSA1-2013, with storage conditions of plasma samples at -65°C ± 15°C, and according to the state of the art well known to experts in this field. The analysis of the samples proved that the method was linear, reproducible, accurate and specific.

[0066] A total of 25 adverse events were considered to be related to the celecoxib / pregabalin / vitamin B treatment (20 dizziness, 2 visual disturbances, 1 nausea, and 2 paresthesia), and a total of 16 adverse events were considered to be related to the pregabalin treatment (13 dizziness, 1 headache, 1 visual disturbance, and 1 paresthesia). All adverse events were classified as nonsevere, 44 of 45 events were classified as mild in severity, and only one event was classified as moderate. All adverse events were resolved without new complications or sequelae.

[0067] The mean values ​​of the pharmacokinetic parameters (Tables 3-4), respective arithmetic means, standard deviations, coefficients of variation, geometric means, minimum values, medians, and maximum values ​​of the pharmacokinetic parameters estimated from the sampling of the treatment regimens were as follows:

[0068] Table 3. Descriptive statistics of pregabalin pharmacokinetic parameters in 41 study subjects [Table 3]

[0069] Table 4. Descriptive statistics of celecoxib pharmacokinetic parameters for 41 subjects [Table 4]

[0070] [90% confidence interval for pregabalin, 41 patients] C max , A.B.C. 0-t and A.B.C. 0-∞ The 90% confidence interval for the log transformation of is within the range of 80–125% cited in the protocol. Therefore, the null hypothesis of no bioavailability can be rejected (Tables 5–6).

[0071] [Table 5]

[0072] [90% CI for celecoxib in 41 patients] C max and A.B.C. 0-t The 90% confidence interval for the logarithmic transformation of is not within the range of 80-125%. However, ABC 0-∞ If is within the range stated in the protocol, the null hypothesis of unequal bioavailability cannot be rejected.

[0073] [Table 6]

[0074] Graphs of the mean plasma concentrations of pregabalin in the 41 subjects are shown in Figures 1 and 2, and graphs of the mean plasma concentrations of celecoxib in the 41 subjects are shown in Figures 3 and 4.

[0075] [Statistical conclusion] In a comparative bioavailability study comparing a fixed combination of celecoxib / pregabalin / vitamin B with pregabalin alone, the pharmacokinetic parameter C max , A.B.C. 0-t , A.B.C. 0-∞ The IC90 estimated from the logarithmic transformation of is in the range of 80–125% quoted in the protocol. Similarly, the parameter C max , A.B.C. 0-t , A.B.C. 0-∞ The P values ​​of t1 and t2 in the two-tailed t-test for the above were less than 0.05, and the null hypothesis that the bioavailability of the evaluated substances was not equivalent could be rejected. When the celecoxib-pregabalin-vitamin B 200mg / 150mg combination tablet manufactured by Laboratorios Silanes SA de CV was administered, the bioavailability was equivalent to that of pregabalin 150mg alone, so the absorption rate and amount of pregabalin were not affected.

[0076] The pharmacokinetic parameter C was compared between the celecoxib component of the fixed combination of celecoxib / pregabalin / vitamin B1 and celecoxib alone. max , A.B.C. 0-t The 90% confidence interval (CI90) estimated from the logarithmic transformation of was not within the range of 80–125% cited in the protocol, and the pharmacokinetic parameter ln(AUC 0-∞ ) is within that range. Similarly, the pharmacokinetic parameter C max , A.B.C. 0-t The P value of the two-tailed t-test for t1 was less than 0.05. However, the P value of the two-tailed Schuirmann t-test for the same parameters for t2 was greater than 0.05, and the null hypothesis of unequal bioavailability could not be rejected.

[0077] Therefore, from a statistical point of view, it was concluded that there is an interaction between the components of the formulation of Laboratorios Silanes' celecoxib / pregabalin / vitamin B combination 200mg / 150mg / vitamin B12 500μg / vitamin B1 100mg / vitamin B6 50mg. max and A.B.C. 0-t The bioavailability, expressed as C, was not comparable to that observed for the individual reference drug celecoxib 200 mg capsules (Celebrex®), and the fixed combination exhibited a higher absorption rate (C max ) and quantity (ABC 0-t However, the bioavailability of C max and A.B.C. 0-t values ​​of 938.6 ± 301.7 ng / mL and 7047.13 ± 2135.1 ng / mL * Considering h, it is comparable to values ​​reported for the reference drugs in the literature (Table 7).

[0078] [Table 7]

[0079] A.B.C. 0-∞was initially referred to as descriptive. However, the results obtained in this study (7144.894 ng / mL * h) were within the evaluation interval and were comparable to the results observed with the reference drug.

[0080] However, by excluding extreme values ​​(NOM-177-SSA1-2013) with an absolute residual value of more than 2 from the statistical analysis, ln(ABC 0-t ) and ln(ABC 0-∞ ) remains in the range of 80-125% quoted in the protocol.

[0081] In addition, pregabalin does not induce or inhibit hepatic enzymes, which are the main metabolic pathways of celecoxib, and this is thought to be why these results were obtained. The observed results may be explained by the difference in the formulation of the fixed combination (tablets) and the reference drug (capsules). The bioavailability (C max , A.B.C. 0-t , A.B.C. 0-∞ ) was confirmed to be statistically equivalent to the reference drug, pregabalin capsules 150 mg (Lyrica (registered trademark)), supporting the absence of drug-drug interactions.

[0082] Finally, since no serious adverse events occurred, the authors concluded that celecoxib / pregabalin / vitamin B 200 mg / 150 mg tablets manufactured by Laboratorios Silanes SA de CV are safe for administration to humans.

[0083] Example 3: Stability of pharmaceutical compositions Long-term stability conditions for the product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets

[0084] This test is based on the Mexican official standard NOM-073-SSA1-2015, Stability of drugs and medicaments, Mexican Official Standard NOM-059-SSA1-2015, No. 11, containing requirements for good practice in analytical laboratories, was implemented based on the guidelines established by the WHO Expert Committee on Specifications for Pharmaceutical Preparations Forthy Third Report, WHO.

[0085] The stability of the product cyanocobalamin-pyridoxine hydrochloride-thiamine mononitrate-pregabalin-celecoxib 0.5 mg / 50 mg / 100 mg / 150 mg / 200 mg tablets, batches DFF2002-16, DFF2002-17 and DFF2002-18 (Laboratorios Silanes SA de CV) was evaluated under long-term stability conditions in climatic zone IVB (30°C ± 2°C / 75% ± 5% RH) for a period of 18 months.

[0086] The batch size is · DFF2002-16: 25,000 tablets packed into cold-formed aluminium blisters of 176μm / 25μm aluminium foil. · DFF2002-17: 25,000 tablets packed into cold-formed aluminium blisters of 176μm / 25μm aluminium foil. · DFF2002-18: 25,000 tablets packed into cold-formed aluminium blisters of 176μm / 25μm aluminium foil.

[0087] The analysis parameters are: ·Contents Cyanocobalamin content Pyridoxine Hydrochloride Content Thiamine nitrate content Pregabalin content Celecoxib content Pyridoxine hydrochloride solution Thiamine mononitrate solution Pregabalin solution Celecoxib solution Organic impurities Celecoxib Related substance: Pregabalin Microbial limits ·Moisture content ·hardness

[0088] The results are presented below in Tables 8-10. All batches demonstrated that the chemical and physical properties remained within established specifications, thereby ensuring quality, efficacy and safety.

[0089] Table 8. Stability of product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batch DFF2002-16 over 18 months (30°C ±2°C / 75% ±5% RH) [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0090] Table 9. Stability of product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batch DFF2002-17 over 18 months (30°C ±2°C / 75% ±5% RH). [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0091] Table 10. Stability of product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets, batch DFF2002-18 over 18 months (30°C ±2°C / 75% ±5% RH) [Table 10-1] [Table 10-2] [Table 10-3] [Table 10-4]

[0092] The product Cyanocobalamin-Pyridoxine Hydrochloride-Thiamine Mononitrate-Pregabalin-Celecoxib 0.5mg / 50mg / 100mg / 150mg / 200mg tablets was carried out in three pilot batches, packaged in cold-formed aluminum blisters 176μm / aluminum foil 25μm in cardboard boxes, batches DFF2002-16, DFF2002-17 and DFF2002-18 were subjected to long-term stability conditions (18 months) in climate zone IVB (30℃±2℃ / 75%±5%RH), and the stability was met and the chemical and physical properties were maintained within the specifications set for this product, ensuring its quality, efficacy and safety. The trends of the content of the active ingredient and the dissolution results are also shown (Figures 5-13).

[0093] To achieve sufficient bioavailability of celecoxib, clarification of the manufacturing process and selection of excipients are important, and an alkaline microenvironment using sodium bicarbonate is required to control the pH of the pharmaceutical formulation so that the gastric environment does not affect absorption.

[0094] For the manufacture of a medicament comprising the drugs or active substances cyanocobalamin, pyridoxine hydrochloride, thiamine mononitrate, pregabalin and celecoxib, and pharma- ceutically acceptable excipients, by compounding into a single stable and immediate release pharmaceutical form, greater analgesic efficacy at reduced dosages and reduced side effects can be obtained in the treatment and control of pain having neuropathic and nociceptive components, for example, where the neuropathic pain is acute, painful and recurrent.

[0095] [Advantages and Industrial Applicability of the Invention] The present invention relates to a simple and optimized method that allows the combination of five active substances, cyanocobalamin, pyridoxine hydrochloride, thiamine mononitrate, pregabalin and celecoxib, in the form of a single solid, stable immediate release pain medication. The combination of drugs acting at different levels provides a higher analgesic effect and allows the use of lower doses, reducing the risk of side effects. In this respect, the combination of B vitamins with pregabalin and celecoxib is believed to show higher analgesic activity due to their complementary mechanisms of action.

[0096] Thus, for the manufacture of a medicine containing the drugs or active substances cyanocobalamin, pyridoxine hydrochloride, thiamine mononitrate, pregabalin and celecoxib, combined in a single stable and immediate release pharmaceutical form, would be useful in the treatment and control of various pathologies presenting with pain having neuropathic and nociceptive components.

[0097] On the other hand, the method for obtaining the pharmaceutical composition of the present invention allows to obtain a single product combining the doses of cyanocobalamin, pyridoxine hydrochloride, thiamine mononitrate, pregabalin and celecoxib, which, due to the differences in the physicochemical properties and dosages of each active substance, implies a series of important technical challenges to ensure that a stable product is obtained. Importantly, if one of the unit operations is missing or its sequence is changed in the manufacturing process, a stable product is not obtained and does not comply with the established quality characteristics.

Claims

1. A pharmaceutical composition comprising cyanocobalamin, pyridoxine, thiamine, pregabalin and celecoxib, said pharmaceutical composition being in a single solid immediate release pharmaceutical form.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical form is a tablet.

3. 10. The pharmaceutical composition of claim 1, comprising 0.5 mg cyanocobalamin, 50 mg pyridoxine, 100 mg thiamine, 150 mg pregabalin, and 200 mg celecoxib.

4. 2. The pharmaceutical composition according to claim 1, further comprising at least one pharmaceutically acceptable excipient selected from the group consisting of a surfactant and / or humectant, a diluent, a solubilizer, a binder, a disintegrant, a dye, an alkalizing agent, a lubricant, and a solvent.

5. 5. The pharmaceutical composition of claim 4, wherein the surfactant and / or humectant is selected from the group consisting of sodium lauryl sulfate, poloxamer, castor oil derivatives, polyoxyethylene, benzalkonium chloride, benzethonium chloride, polyoxyethylene alkyl ethers, and polyoxyethylene sorbitan fatty acid esters.

6. 5. The pharmaceutical composition of claim 4, wherein the binder is selected from the group consisting of all K grades of povidone and their derivatives, cellulose derivatives such as carbomer, hydroxypropyl cellulose, carboxymethyl cellulose, and starch derivatives such as pregelatinized starch and corn starch.

7. 5. The pharmaceutical composition of claim 4, wherein the diluent is selected from the group consisting of cellulose derivatives such as microcrystalline cellulose, phosphate derivatives such as dibasic calcium phosphate, starch derivatives such as pregelatinized starch, corn starch, and lactose such as anhydrous lactose.

8. 5. The pharmaceutical composition according to claim 4, wherein the disintegrant is selected from the group consisting of cellulose derivatives such as hydroxypropyl cellulose, carboxymethyl cellulose, microcrystalline cellulose, and croscarmellose sodium; povidone derivatives such as crospovidone and plaston; and starch derivatives such as pregelatinized starch, sodium starch glycolate, and corn starch.

9. 5. The pharmaceutical composition of claim 4, wherein the lubricant is selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, monostearate, stearic acid derivatives such as stearyl fumarate, magnesium lauryl sulfate, sulfated derivatives such as magnesium lauryl sulfate, and talc.

10. 5. The pharmaceutical composition of claim 4, wherein the dye is selected from the group consisting of β-carotene, indigo carmine, iron oxide, Sunset Yellow FCF, Yellow No. 5, and titanium dioxide.

11. 5. The pharmaceutical composition of claim 4, wherein the solubilizer is selected from the group consisting of various grades of polyethylene glycol, glyceryl behenate, microcrystalline wax, stearoyl polyoxyglyceride and poloxamer.

12. 5. The pharmaceutical composition of claim 4, wherein the alkalinizing agent is selected from the group consisting of sodium carbonate, calcium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium citrate, potassium hydroxide, sodium citrate dihydrate, and sodium hydroxide.

13. 5. The pharmaceutical composition of claim 4, wherein the surfactant and / or humectant is sodium lauryl sulfate, the binder is polyvidone, the diluent is selected from the group consisting of lactose and / or microcrystalline cellulose, the disintegrant is croscarmellose sodium, the alkalinizing agent is bicarbonate, the lubricant is stearate, the solubilizer is poloxamer, the dye is Yellow No. 5, and the solvent is water.

14. 2. The pharmaceutical composition of claim 1, - 0.50 mg of cyanocobalamin as the active ingredient - Active ingredient: pyridoxine 50.00 mg - Active ingredient: thiamine 100.00 mg - 150.00 mg of pregabalin as the active ingredient, - 200.00 mg of celecoxib as the active ingredient, 7.80 mg sodium lauryl sulfate as a surfactant / wetting agent, 200.00 mg of lactose monohydrate as a first diluent; 25.00 mg of poloxamer as a solubilizer, 40.00 mg of povidone as a binder; Croscarmellose sodium 50.00 mg as a disintegrant 342.90 mg microcrystalline cellulose as a second diluent, 3.80 mg of sodium bicarbonate as an alkaline agent 5.00 mg magnesium stearate as a lubricant, and 0.068 mL of purified water as a solvent A pharmaceutical composition comprising:

15. A method for producing the pharmaceutical composition according to any one of claims 1 to 14, comprising: i. Mixing the active ingredient celecoxib with the pre-screened first diluent, disintegrant, binder, solubilizer and alkalizer for 10 minutes; ii. Wetting with purified water and granulating; iii) drying the granules obtained in the previous step until the moisture content is 0.8% or less; iv. Adding and mixing the active ingredient cyanocobalamin and a portion of the second diluent; v. adding a portion of the second diluent and mixing for 5 minutes; vi) repeating the previous step by adding a portion of the second diluent and mixing for 5 minutes; vii. adding a solubilizer and mixing for 5 minutes; viii. adding the active ingredients pyridoxine, thiamine, and pregabalin and a portion of the second diluent; ix. adding a portion of the second diluent and mixing for 5 minutes; x. Adding binder, surfactant / wetting agent and disintegrant and mixing for 5 minutes; xi. adding dye and lubricant and mixing for 3 minutes; xii. compressing the granules obtained in the previous step; A method for producing a pharmaceutical composition, comprising:

16. The manufacturing method according to claim 15, In step i, mixing 50% of the total amount of the disintegrants, 50% of the total amount of the binders, and 50% of the total amount of the solubilizers; In step iv, the portion of the second diluent is 5% of the total amount of the second diluent; In step v, the portion of the second diluent is 10% of the total amount of the second diluent; In step vi, the portion of the second diluent is 20% of the total amount of the second diluent; In step vii, mixing the remaining 50% of the solubilizer; In step viii, 32.5% of the total amount of the second diluent is mixed; In step ix, the portion of the second diluent is 32.5% of the total amount of the second diluent; In step x, the remaining 50% of the binder and the remaining 50% of the disintegrant are mixed. Manufacturing method.

17. 16. The process of claim 15, wherein the surfactant / wetting agent is sodium lauryl sulfate, the first diluent is lactose monohydrate, the solubilizing agent is poloxamer, the binder is polyvidone, the disintegrating agent is croscarmellose sodium, the second diluent is microcrystalline cellulose, the color is Yellow No. 5, the alkalizing agent is sodium bicarbonate, and the lubricant is magnesium stearate.

18. 16. The method of claim 15, wherein the pharmaceutical composition is a tablet.

19. A composition according to any one of claims 1 to 14 for use in the treatment and control of chronic pain.

20. 20. The composition for use according to claim 19, wherein the pain is acute and recurrent painful neuropathy.

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