A tablet combination comprising dimethyl fumarate and omeprazole

Abstract

The present invention relates to a pharmaceutical tablet combination comprising dimethyl fumarate or pharmaceutical salts thereof and omeprazole or pharmaceutical salts, crystalline form thereof and at least one enteric polymer, wherein enteric polymers in a coating.

Description

A tablet combination containing dimethyl fumarate and omeprazole. Field of Invention This invention relates to dimethyl fumarate or its pharmaceutical salts and omeprazole or its pharmaceutical salts. with a combination of salts, crystalline form and a pharmaceutical tablet containing at least one enteric polymer This is related to the fact that enteric polymers are contained within a coating. Background of the Invention Multiple sclerosis (MS) is the most common autoimmune disease affecting the central nervous system. Common Multiple sclerosis, also known as encephalomyelitis disseminata, is a disease affecting 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. Multiple sclerosis (MS) causes a wide range of signs and symptoms, including various forms of MS. There are new symptoms, either in isolated attacks (recurrent forms) or developing over time. It appears in (progressive forms). Symptoms may completely disappear 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. Omeprazole reverses H+ / K+ ATPase (proton pump) activity on the secretory surface of gastric parietal cells. A substituted benzimidazole, 6-, reduces gastric acid production by irreversibly inhibiting it. It is methoxy-2-[[(4methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Omeprazole As shown in formula II; 2 Formula II The proton pump is directly responsible for the release of H+ ions into the gastric lumen. Omeprazole inhibits the proton pump, thereby affecting the gastric system of mammals. It regulates the final step of hydrogen ion production in the acid secretion pathway. Omeprazole and other proton pump inhibitors (PPIs) are used for gastritis and gastroesophageal reflux disease. (GERD), dyspepsia, peptic ulcer disease, laryngopharyngeal reflux, gastric and duodenal ulcers, and acid production through proton pump inhibition, such as in Zollinger-Ellison syndrome It is used to treat a number of conditions that require reduction. 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 omeprazole yields effective results. This In this invention, combining two molecules in a single dosage form improves patient compliance. This According to the invention, using each drug in combination at lower doses reduces the total dose. This will reduce it. These are advantageous for the patients being treated. 3 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 aim is to provide a stable pharmaceutical tablet combination containing omeprazole. Another aim of the present invention is to develop a highly compliant solution containing dimethyl fumarate and omeprazole. It is to provide a combination. Another objective of the present invention is to achieve the desired stability with dimethyl fumarate and omeprazole. The goal is to provide a combination that has something. 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. 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 omeprazole to achieve this. Patient compliance was improved by using these two active agents in the same tablet. A high concentration of combination was obtained. Furthermore, dimethyl fumarate and omeprazole were used in an acidic environment. Because one is unstable and the other stable in alkaline to neutral environments, these two active ingredients are often used in acid. It should be used in tablets or capsules provided with a durable coating. This When the combination is coated with enteric polymers, it becomes a combination with high stability. We obtained this. In addition, the polymers provide excellent controlled release properties, thus enabling effective treatment. We obtained the desired dissolution profile. According to a definition of the present invention, the pharmaceutical tablet combination includes: - dimethyl fumarate or its pharmaceutical salts, - omeprazole or its pharmaceutical salts, in their crystalline form, - at least one enteric polymer, where the enteric polymers are contained within a coating. According to one regulation of this invention, the amount of dimethyl fumarate or its pharmaceutical salts It is between 40.0% and 70.0% of the total combination by weight. According to an arrangement of the present invention, the amount of omeprazole is a percentage of the total combination by weight. It is between 1.0% and 15.0%. 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. 4 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 combination also includes fillers, binders, containing dispersants, lubricants, glidants, coating agents or mixtures thereof It contains at least one pharmaceutically acceptable excipient selected from the group. 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 amount of fillers is a percentage of the total combination. It is between 5.0% and 25.0% by weight. 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 5 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%. 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, magnesium aluminum silica, poloxamer, sodium glycine carbonate or mixtures thereof It is selected from the group that includes. 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 10.0% 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 coating also 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. Selected from the group. 6 According to one arrangement of the present invention, the film coating agent is triethyl citrate. According to this arrangement of the present invention, the total coating amount is the total combination's It is between 10.0% and 20.0% by weight. Example 1; Components (by weight %) (by weight %) Dimethyl fumarate 55.3 40-70 Omeprazole 4.6 1-15 Filler material 16.2 5-25 Connector 2.5 0.1-10 Distributor 2.8 0.1-8 Glidant 0.9 0.01-5 Slider 0.9 0.01-5 Tablet Weight 82.2 70-92 methacrylic acid and methyl methacrylate 8.1 1-15 copolymer [1:2] methacrylic acid and methyl methacrylate 3.9 0.1-8 copolymer [1:1] Methacrylic Acid-Ethyl Acrylate Copolymer 3.9 0.1-8 (1:1) Triethyl citrate 0.9 0.01-5 Enteric Coated Tablet Weight 100 100

Claims

1. A combination of pharmaceutical tablets includes the following: - dimethyl fumarate or its pharmaceutical salts, - omeprazole or its pharmaceutical salts, in their crystalline form - at least one enteric polymer, where the enteric polymers are contained within a coating.

2. A pharmaceutical tablet combination according to claim 1, wherein dimethyl fumarate or The amount of its pharmaceutical salts is between 40.0% and 70.0% by weight of the total combination. It is among them.

3. According to claim 1, it is a pharmaceutical tablet combination where the total amount of omeprazole is... The combination's weight is between 1.0% and 15.0%.

4. A combination of pharmaceutical tablets according to claim 1, containing enteric polymers. copolymer of methacrylic acid and methyl methacrylate (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 It is phthalate (CAP) or a mixture thereof.

5. A combination of pharmaceutical tablets according to claim 1 or 4, wherein enteric polymer methacrylic acid and methyl methacrylate copolymer (1:2) or methacrylic acid and methyl methacrylate copolymer (1:1) or methacrylic acid-ethyl acrylate copolymer (1:1) or any of these It is a mixture.

6. A combination of pharmaceutical tablets according to Claim 1, which also includes fillers, binders, dispersants, lubricants, glidants, coating agents or any of these at least one pharmaceutically acceptable substance selected from the group of mixtures Contains excipients.

7. A combination of pharmaceutical tablets according to claim 6, where fillers are used. 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 is selected from the group containing xylitol or mixtures thereof.

8. A combination of pharmaceutical tablets according to claim 6 or 7, where fillers are used. It is microcrystalline cellulose, lactose, starch, sucrose, or a mixture thereof.

9. A combination of pharmaceutical tablets according to claim 6, where the binders are low. substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl 35 methylcellulose, carboxymethylcellulose sodium, sugars, agar, alginates, carbomers, cellulose acetate phthalate, chitosan, starch, starch mucilage, acacia mucilage, dextrates, 8 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.

10. A combination of pharmaceutical tablets according to claim 6 or 9, where binding is low. substituted hydroxypropyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl It is methylcellulose or a mixture thereof.

11. A combination of pharmaceutical tablets according to claim 6, where the distributors are cross-linked. carboxymethyl cellulose (croscarmellose sodium), sodium starch glycolate, crospovidon, 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.

12. A combination of pharmaceutical tablets according to claim 6 or 11, where the distributor is... Croscarmellose sodium, sodium starch glycolate, crospovidon, or a mixture thereof.

13. A combination of pharmaceutical tablets according to claim 6, whereby sliders or Glidants include sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, and 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.

14. A combination of pharmaceutical tablets according to claim 6 or 13, where a slider or glidant sodium stearyl fumarate, magnesium stearate, colloidal silicon dioxide, talc or It is a mixture of these.