A combination containing dimethyl fumarate and esomeprazole.

Abstract

The present invention relates to a pharmaceutical combination containing dimethyl fumarate or its pharmaceutical salts with esomeprazole or one of its pharmaceutical salts, in crystalline form, and at least one filler.

Description

A combination containing dimethyl fumarate and esomeprazole. Field of Invention The present invention relates to the combination of dimethyl fumarate or its pharmaceutical salts with esomeprazole or its derivatives. a pharmaceutical combination containing a pharmaceutical salt, its crystalline form and at least one filler It is related to. Background of the Invention Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. Common Multiple sclerosis, also known as generalized encephalomyelitis, is a disease that affects the nerves in the brain and spinal cord. It is a demyelinating disease in which the insulating coverings of nerve cells are damaged. This damage affects the nerves. by disrupting the ability of parts of the system to communicate, physical, mental and sometimes psychiatric. It causes a wide variety of signs and symptoms, including various problems. MS has several types. It has different forms; new symptoms appear either as isolated attacks (recurrent forms) or over time. It manifests in developing (progressive) forms. Between attacks, symptoms are completely absent. It may disappear; however, permanent neurological problems frequently occur, especially as the disease progresses. Dimethyl fumarate, also known as DMF, is the dimethyl ester of fumaric acid and is used in multiple sclerosis (MS). It is an anti-inflammatory drug frequently used in treatment. Its molecular weight is 144.13, and its chemical composition is... Its structure is shown in formula I: Formula I Dimethyl fumarate is a white to off-white powder that is highly soluble in water. Esomeprazole magnesium is a proton pump used in the treatment of acid-related diseases. It is an inhibitor. Esomeprazole is a magnesium weak base and is released into its active form in a highly acidic environment. It transforms. Gastric acid is produced by the specific inhibition of H+ / K+-ATPase in gastric parietal cells. It suppresses secretion. Specifically, by acting on the proton pump, esomeprazole Magnesium blocks the final step in acid production, thereby reducing gastric acidity. 2 Esomeprazole magnesium is the S-isomer of omeprazole, which is a mixture of S- and R-isomers. The chemical name of esomeprazole is 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl) Its chemical structure is shown in Formula II, which is [methyl]sulfinyl]benzimidazole. Formula II Esomeprazole magnesium is susceptible to degradation and transformation in acidic environments. In acidic environments... It degrades rapidly, but exhibits acceptable stability under alkaline conditions. Esomeprazole magnesium pellet tablets and pellet capsules are sold under the brand name NEXIUM. It is marketed and the recommended dose is 20 mg to 40 mg esomeprazole magnesium per day (a tablet). Patients with multiple sclerosis (MS) frequently suffer from gastrointestinal symptoms. Gastrointestinal events are a symptom of extended-onset surgery, an approved treatment for relapsing-remitting multiple sclerosis. Common adverse events associated with released dimethyl fumarate include relapsing-remitting multiple sclerosis. Strategies for monitoring and managing the known adverse event profile of treatments, patient outcomes It is key to optimizing. Delayed-release dimethyl fumarate, in clinical trials, reduced flushing. and has been associated with an increased risk of gastrointestinal adverse events. Dimethyl fumarate clinical During their studies, flushing or pharmacological reactions associated with delayed-release dimethyl fumarate were not observed. gastrointestinal adverse events serious enough or bothersome to require intervention Various symptomatic treatments were used in the patients who presented. Combination therapies are available for multiple sclerosis, but they can alleviate gastrointestinal symptoms. There is no combination therapy that will reduce it. Therefore, in patients with multiple sclerosis developing a formulation containing an active agent to reduce gastrointestinal symptoms It is needed. We found that the combined use of dimethyl fumarate and esomeprazole yielded effective results. This In this invention, combining two molecules in a single dosage form improves patient compliance. This 3 According to the invention, using each drug in combination at lower doses reduces the total dose. will reduce it. These are advantageous for the patients being treated. Also, for this combination Eliminates content homogeneity and solubility profile problems encountered during formulation development. We developed a formulation with the desired stability and dissolution profile to remove it. Detailed Description of the Invention The main purpose of this invention is to treat multiple sclerosis and / or gastrointestinal symptoms. Dimethyl fumarate and, which have a synergistic effect and a desired dissolution profile, are used for this purpose. The goal is to provide a stable pharmaceutical combination containing esomeprazole. Another objective of the present invention is patient compliance with dimethyl fumarate and esomeprazole. The goal is to provide a high-performance combination. Another objective of the present invention is to produce dimethyl fumarate and esomeprazole with the desired stability. The goal is to provide a combination that includes. The term "combination" refers to a combination of drugs administered together, when the drugs in question are used separately in a way that reduces the effectiveness of the combination of those drugs. This means that a combined effect is achieved that is greater than the sum of its individual effects. The term "esomeprazole" used throughout the specification refers not only to esomeprazole, but also to the same substance. other pharmaceutically acceptable salts at the time, pharmaceutically acceptable to their solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable also refers to its viable polymorphs and pharmaceutically acceptable prodrugs. It is located. Our combination includes dimethyl fumarate and the reasons why dimethyl fumarate is used in the treatment of multiple sclerosis. It treats heartburn and other conditions caused by too much stomach acid. We used esomeprazole to treat this. By using these two active agents in the same tablet, we achieved a high patient volume. A stable combination has been obtained with its compatibility. In addition, our combination includes dimethyl fumarate. The weight ratio of esomeprazole is high, while the weight ratio of esomeprazole is low. These two active ingredients in a single dosage. When combined in this form, it causes homogeneity problems. Active ingredients the presence of homogeneity and fluidity problems in the formulation and the desired dissolution It is very important that it provides a profile. When filler material is used in the ratios indicated below: We observed that the homogeneity and fluidity were very good. Thus, the desired dissolution profile was obtained. We did. According to a definition of the present invention, the pharmaceutical combination includes: - dimethyl fumarate or its pharmaceutical salts, 4 - esomeprazole or its pharmaceutical salt, crystalline form, - at least one filler, where the amount of filler is the total amount of the combination It is between 5.0% and 25% by weight. According to one regulation of this invention, the amount of dimethyl fumarate or its pharmaceutical salts It is between 40.0% and 60.0% of the total combination by weight. According to one arrangement of this invention, the amount of esomeprazole is a percentage of the total combination by weight. It is between 1.0% and 15.0%. Suitable fillers include microcrystalline cellulose, lactose, starch, sucrose, talc, and ammonium alginate. calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose acetate, erythritol, ethyl cellulose, fructose, glyceryl palmitostearate, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, Polymethacrylates, sodium chloride, sorbitol, sugar spheres, gum tragacanth, trehalose, polysorbate 80, xylitol or selected from the group containing mixtures of these. According to this arrangement of the present invention, the fillers are microcrystalline cellulose, lactose, It is starch, sucrose, or a mixture of both. According to this arrangement of the present invention, the combination also includes binders, distributors, pharmaceuticals selected from the group consisting of sliders, glidants or mixtures thereof It contains at least one acceptable excipient. Suitable binders include low-substitution hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, agar, alginates, carbomers, cellulose acetate phthalate, chitosan, starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethyl cellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, maltodextrin, methylcellulose, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminum hydroxide, stearic acid, polyoxyethylene alkyl ethers or mixtures thereof They are selected from the group. According to this arrangement of the invention, the binder is low-substitution hydroxypropyl cellulose, It is hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, or a mixture thereof. According to this arrangement of the present invention, the amount of binder is a percentage of the total combination by weight. It is between 0.1% and 10.0%. 5 Suitable dispersants include cross-linked carboxymethyl cellulose (croscarmellose sodium) and sodium starch. glycolate, crospovidon, low-substitution hydroxypropyl cellulose, starch, calcium carboxymethyl cellulose, pregelatinized starch, docusate sodium, guar gum, sodium alginate, alginic acid acid, magnesium aluminum silica, poloxamer, sodium glycine carbonate or any of these. It is selected from the group that includes the mixtures. According to a regulation of the present invention, the dispersing croscarmellose sodium is sodium starch. It is glycolate, crospovidon, or a mixture thereof. According to one arrangement of this invention, the dispersant quantity is 0.1% by weight of the total combination. It is between 8.0%. Suitable lubricants or glidants include sodium stearyl fumarate, magnesium stearate, and colloidal silicone. dioxide, talc, calcium stearate, zinc stearate, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, sodium lauryl sulfate or any of these It is selected from the group that includes the mixtures. According to one arrangement of the present invention, the amount of slider or glidant is the total combination It is between 0.02% and 6.0% by weight. According to an arrangement of the present invention, the glidant or lubricant is sodium stearyl fumarate. These are magnesium stearate, colloidal silicon dioxide, talc, or a mixture thereof. According to one arrangement of this invention, the modified release dosage form includes controlled release, sustained release, from the group that includes delayed-release, extended-release, repeat-acting systems, or combinations thereof. is selected. According to one arrangement of the present invention, the pharmaceutical combination is administered orally. Pharmaceutical combination tablets, capsules, strips, syrups, powders, lozenges, sachets, effervescent compounds, pills, coated bead systems, granules, microspheres, coated tablets, films, orally applied films, solutions, solids, suspensions or emulsions It is in this form. According to another arrangement of the present invention, the pharmaceutical combination is in the form of a tablet. According to another arrangement of this invention, tablets containing dimethyl fumarate and esomeprazole must be at least It contains a coating. According to another arrangement of the present invention, the coating contains coating materials. 6 Suitable coating agents include triethyl citrate, hydroxypropyl methylcellulose, polymethacrylates, and polyvinyl. alcohol, polyethylene glycol, ethyl cellulose dispersions (Surelease®), polyvinylpyrrolidone, all types Opadry® contains pigments, dyes, titanium dioxide, iron oxide or mixtures thereof. They are selected from the group. According to one arrangement of the present invention, the coating agent is triethyl citrate. The present invention is an extended-release formulation. This combination is what makes it an extended-release. The enteric polymers used in the coating are a key feature. This helps to reduce gastrointestinal risks. It has also helped to reduce it. Dimethyl fumarate is a sensitive active ingredient. There are sublimation problems. Therefore, enteric A coated layer was used. This provided the desired delayed dissolution profile and also It helped to ensure the stability of the formulation. According to one arrangement of the present invention, the coating also contains enteric polymers. Suitable enteric polymer methacrylic acid and methyl methacrylate copolymer (1:2), methacrylic acid and methyl methacrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer (1:1), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and cellulose acetate phthalate It is selected from the group consisting of (CAP) or a mixture of these. According to one arrangement of this invention, the enteric polymer is methacrylic acid and methyl methacrylate. copolymer (1:2) or methacrylic acid and methyl methacrylate copolymer (1:1) or methacrylic acid-ethyl It is an acrylate copolymer (1:1) or a mixture thereof. According to a modification of the present invention, enteric polymer methacrylic acid and methyl methacrylate It is a copolymer (1:2). According to a modification of the present invention, enteric polymer methacrylic acid and methyl methacrylate It is a copolymer (1:1). According to one arrangement of the present invention, the enteric polymer is a methacrylic acid-ethyl acrylate copolymer. (1:1). According to this arrangement of the present invention, the coating amount is the weight of the total combination. It is between 10.0% and 20.0%. 7 Example 1; Components % by weight % by weight Dimethyl fumarate 52.9 40-60 Esomeprazole 8.9 1-15 Filler material 15.4 5-25 Connector 2.4 0.1-10 Distributor 2.6 0.1-8 Glidant 0.9 0.01-5 Slider 0.9 0.01-5 Tablet Weight 84 75-95 methacrylic acid and methyl methacrylate 7.7 1-15 copolymer [1:2] methacrylic acid and methyl methacrylate 3.7 0.1-8 copolymer [1:1] Methacrylic Acid - Ethyl Acrylate 3.7 0.1-8 Copolymer (1:1) Triethyl citrate 0.9 0.01-5 Enteric Coated Tablet Weight 100 100

Claims

1- A pharmaceutical combination includes the following: - dimethyl fumarate or its pharmaceutical salts, - esomeprazole or its pharmaceutical salt, crystalline form, - minimum filler, where the amount of filler is the total combination It is between 5.0% and 25% by weight. 2- A pharmaceutical combination according to Claim 1, wherein dimethyl fumarate or a derivative thereof The amount of pharmaceutical salts is between 40.0% and 60.0% by weight of the total combination. It is among them. 3- According to claim 1, it is a pharmaceutical combination where the amount of esomeprazole is total. The combination's weight is between 1.0% and 15.0%. 4- According to claim 1, it is a pharmaceutical combination where the fillers are microcrystalline. cellulose, lactose, starch, sucrose, talc, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose acetate, erythritol, ethyl cellulose, fructose, glyceryl palmitostearate, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, Polymethacrylates, sodium chloride, sorbitol, sugar spheres, gum tragacanth, trehalose, polysorbate 80, It is selected from the group containing xylitol or mixtures thereof. 5- A pharmaceutical combination according to claim 1 or 4, where fillers are used. It is microcrystalline cellulose, lactose, starch, sucrose, or a mixture thereof. 6- A pharmaceutical combination according to claim 1, where the combination also includes binders, selected from a group consisting of dispersants, sliders, glidants or mixtures thereof. It contains at least one pharmaceutically acceptable excipient. 7- A pharmaceutical combination according to claim 6, where the binders are of low substitution. hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sugars, agar, alginates, carbomers, cellulose acetate phthalate, chitosan, starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, alumina hydroxide, stearic acid, polyoxyethylene-alkyl ethers or their derivatives It is selected from the group that includes the mixtures. 8- A pharmaceutical combination according to claim 6 or 7, where the binding agent is a low substitution. hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl 35 methylcellulose or a mixture thereof. 9 9- A pharmaceutical combination according to claim 6, where the distributors are cross-linked. carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, crospovidon Selected from the group containing low-substitution hydroxypropyl cellulose, starch, calcium carboxymethyl cellulose, pregelatinized starch, docusate sodium, guar gum, sodium alginate, alginic acid, magnesium aluminum silica, poloxamer, sodium glycine It is carbonate or a mixture thereof. 10- A pharmaceutical combination according to claim 6 or 9, where the distributor is croscarmellose. sodium, sodium starch glycolate, crospovidon, or a mixture thereof. 11- A pharmaceutical combination according to claim 6, where the lubricants or glidants are stearyl. fumarate, magnesium stearate, colloidal silicon dioxide, talc, calcium stearate, zinc stearate, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium from the group containing benzoate, polyethylene glycol, sodium lauryl sulfate or mixtures thereof is selected. 12- A pharmaceutical combination according to claim 6 or 11, where the lubricant or glidant sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, talc, or any of these. It is a mixture.