A combination comprising dimethyl fumarate and dexlansoprazole

Abstract

The present invention relates to a pharmaceutical combination comprising dimethyl fumarate or pharmaceutical salts thereof and dexlansoprazole or a pharmaceutical salt, crystalline form thereof and at least one filler.

Description

A combination containing dimethyl fumarate and dexlansoprazole. Field of invention The present invention relates to the combination of dimethyl fumarate or its pharmaceutical salts with dexlansoprazole 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 in isolated attacks (recurrent forms) or It develops over time (progressive forms). Symptoms may disappear completely between attacks; 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 1 Dimethyl fumarate is a white to off-white powder that is highly soluble in water. Dexlansoprazole is a proton pump inhibitor that reduces gastric acid secretion. Its active ingredient is... It is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}sulfinyl]-1H-benzimidazole. Dexlansoprazole is a racemic mixture containing both R- and S-enantiomers. It is the R-enantiomer of lansoprazole. The empirical formula of dexlansoprazole is CHFNO₃S and 16 14 3 3 22 It has a molecular weight of 369.36. The chemical structure of dexlansoprazole is given by formula II. It has been shown: Formula II Dexlansoprazole is a white to off-white crystalline powder that melts at 140°C. Dimethylformamide is freely soluble in methanol, dichloromethane, ethanol, and ethyl acetate; Soluble in acetonitrile; slightly soluble in ether; very slightly soluble in water; and practically soluble in water. It is insoluble in hexane. Dexlansoprazole is stable when exposed to light. Dexlansoprazole It is more stable in neutral and alkaline conditions than in acidic conditions. 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 that are serious or bothersome enough 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 dexlansoprazole yielded effective results. This innovation combines two molecules in a single dosage form, improving patient compliance. According to the current invention, using each drug in combination at lower doses results in a total... This will reduce the dose. These are advantageous for the patients being treated. Also, 3 for this combination. Eliminates content uniformity and dissolution profile issues 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 dexlansoprazole. The other objective of the present invention is to develop dimethyl fumarate and dexlansoprazole containing highly compliant patient-adherent formulations. It is to provide a combination. Another objective of the present invention is to obtain dimethyl fumarate with the desired stability and The goal is to provide a combination containing dexlansoprazole. The term "combination" refers to medications administered together when the same drugs are used separately. This means achieving a combined effect that is greater than the sum of their individual effects. 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 dexlansoprazole to achieve this. By using these two active ingredients in the same tablet, A stable combination with high patient compliance has been achieved. Furthermore, the two active ingredients... It has different ratios in the formulation. Dimethyl fumarate is used in high proportions. The amount of dexlansoprazole is low. When these two active ingredients are combined in a single dosage form... This causes homogeneity problems. However, the following ratios of filler material are used: We observed that the homogeneity was very good when used. 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, - dexlansoprazole or a pharmaceutical salt, its crystalline form - at least one filler, where the amount of filler is the total amount of the combination It is between 5.0% and 25.0% 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 a regulation of the present invention, the amount of dexlansoprazole is a percentage of the total combination. It is between 5.0% and 20.0% by weight. 4 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 ranges from 0.1% to 10.0%. 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. 5 According to one arrangement of this invention, the dispersant quantity is 0.1% by weight of the total combination. It is between 5.0% and 5.0%. Suitable lubricants or glidants include sodium stearyl fumarate, magnesium stearate, and colloidal silicone. sodium 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 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 a tablet. It is in this form. According to another arrangement of this invention, the tablet containing dimethyl fumarate and dexlansoprazole is the most... It contains a small amount of coating. According to another arrangement of the present invention, the coating includes coating materials. 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. 6 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; Contents (by weight %) (by weight %) Dimethyl fumarate 50.6 40-60 Dexlansoprazole 12.7 5-20 Filler Material 14.9 5-25 Connector 2.3 0.1-10 Distributor 2.5 0.1-5 Glidant 0.8 0.01-3 Slider 0.8 0.01-3 Tablet Weight 84.6 80-90 methacrylic acid and methyl methacrylate 7.4 1-15 copolymer [1:2] methacrylic acid and methyl methacrylate 3.6 0.5-8 copolymer [1:1] Methacrylic Acid-Ethyl Acrylate Copolymer 3.6 0.5-8 (1:1) Triethyl citrate 0.8 0.01-3 Enteric Coated Tablet Weight 100 100

Claims

1. A pharmaceutical combination includes the following: - dimethyl fumarate or its pharmaceutical salts, - dexlansoprazole or its pharmaceutical salt, crystalline form, - at least one filler, where the amount of filler is the total amount of the combination It ranges from 5.0% to 25.0% 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. Pharmaceutical combination according to claim 1, where the amount of dexlansoprazole is total. The combination contains between 5.0% and 20.0% by weight.

4. Pharmaceutical combination according to claim 1, 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. Pharmaceutical combination according to claim 1 or 4, where fillers 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 linkers 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, ethyl cellulose, glyceryl behenate, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl starch, magnesium aluminum silicate, maltodextrin, methylcellulose, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminum hydroxide, stearic acid, polyoxyethylene alkyl ethers or mixtures thereof The groups containing are selected.

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. A pharmaceutical combination according to claim 6, where the distributors are cross-linked. carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, crospovidon, 9 low substituted hydroxypropyl cellulose, starch, calcium carboxymethyl cellulose, pre- gelatinized starch, docusate sodium, guar gum, sodium alginate, alginic acid, magnesium aluminum silica, poloxamer, sodium glycine carbonate or any of these It is selected from the group that includes the mixtures.

10. A pharmaceutical combination according to claim 6 or 9, where the distributors are croscarmellose. sodium, sodium starch glycolate, crospovidon, or a mixture thereof.

11. A pharmaceutical combination according to claim 6, where there are sliders or glidants. sodium stearyl fumarate, magnesium stearate, colloidal silicon 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.

12. A pharmaceutical combination according to claim 6 or 11, where a slider or glidant sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, talc, or any of these. It is a mixture. 35