Empagliflozin tablet and preparation process thereof

Abstract

The tablet comprises the following components in parts by mass: 5 parts of an active component empagliflozin, 20-30 parts of an auxiliary material, 45-75 parts of a filling agent, 5-8 parts of an adhesive, 1-3 parts of a disintegrating agent, 0.5-2 parts of a lubricant and 1-5 parts of a coating agent, the auxiliary material, the adhesive, the disintegrating agent and the lubricant are all compositions, the auxiliary material is a composition of Omega-3 fatty acid and cholecalciferol, and the coating agent is a composition of Cholecalciferol, Cholecalciferol, Cholecalciferol, Cholecalciferol, Cholecalciferol, Cholecalciferol and Cholecalciferol. And preparing the tablet by a wet method. The empagliflozin tablet has the beneficial effects that the prepared tablet product is good in stability and high in drug release control capability, the side effect of empagliflozin can be effectively reduced through cooperation of empagliflozin and auxiliary materials, and meanwhile, other complications of diabetes mellitus can be prevented and relieved to a certain extent.

Description

Technical Field

[0001] The present invention relates to the technical field related to pharmaceutical preparations, and in particular to an empagliflozin tablet and a preparation process thereof. Background Art

[0002] Diabetes is a complex disease with multiple causes. It is a complex disease caused by glucose, protein and lipid metabolism disorders due to insulin deficiency or increase in hormones that antagonize insulin, or insulin cannot play a normal physiological role in target cells. It is characterized by abnormal increase in glucose concentration in the blood circulation and high urine sugar and blood sugar, and the typical "three more and one less" symptoms appear, that is, eating more, urinating more, eating more and losing weight, accompanied by fatigue and weakness. In severe cases, ketoacidosis and hyperosmolar diabetic coma may occur, and it is easy to be combined with multiple infections. As the course of the disease prolongs, its metabolic disorder can lead to chronic lesions of tissues and organs such as eyes, kidneys, nerves, blood vessels and heart. If it is not treated promptly and appropriately, heart disease, cerebrovascular disease, renal failure, blindness, lower limb necrosis and other conditions may occur, becoming the main cause of disability and death.

[0003] Diabetes is considered to be a disease in which abnormal sugar metabolism leads to high blood sugar due to some reasons, and various complications are caused by the high blood sugar. Therefore, it is obvious that controlling blood sugar is important for the treatment of diabetes. In order to improve blood sugar levels, insulin preparations, biguanides, sulfonylurea preparations, thiazolidinediones, etc. are used today. However, insulin preparations are difficult to administer, and although biguanides have been gradually valued recently, they are still difficult to use because they are easy to cause lactic acidosis. In addition, sulfonylurea preparations burden the pancreatic islet β cells that secrete insulin, so they are not suitable for long-term use. Thiazolidinediones are the only drugs that can improve insulin resistance, but there are also many patients who do not respond to them, and there are also problems such as weight gain. Therefore, the hypoglycemic agents currently used are still insufficient as therapeutic drugs for diabetes.

[0004] Empagliflozin belongs to the SGLT2 inhibitor class of drugs, which directly targets glucose. Its mechanism of action is independent of B cell function and insulin resistance. It is used to treat adult patients with type 2 diabetes who have not achieved adequate blood sugar control with diet and exercise, in order to improve blood sugar control. Sodium glucose cotransporter 2 (SGLT-2) is the main transporter that reabsorbs glucose from the glomerular filtrate into the blood circulation. Empagliflozin reduces glucose reabsorption in the kidneys, lowers the renal glucose threshold, and promotes glucose excretion from the urine. Empagliflozin is a new type of gliflozin drug developed, produced and sold in cooperation between Boehringer Ingelheim and Eli Lilly. Boehringer Ingelheim told the Economic Daily-China Economic Net reporter that the global sales of empagliflozin in 2017 were 1.01 billion euros, an increase of 135.7% over 2016. The drug has shown great clinical demand for its use. However, due to the unique chemical structure and properties of this drug, its solubility is low, resulting in unsatisfactory bioavailability, especially the reduction of Cmax and AUC after meals. In addition, its chemical stability is poor, the content of related impurities increases during the preparation process, and the stability deteriorates during the storage period of the preparation. If the preparation process technology problems cannot be well solved, it will be difficult to obtain a stable product, achieve high bioavailability of the preparation, and achieve large-scale clinical promotion.

[0005] Patent CN104623684A uses mannitol, and obtains a composition of empagliflozin and mannitol by melting, stirring, and cooling; Patent CN111214450B uses a combination of poloxamer and mannitol as a drug carrier, and disperses empagliflozin in the carrier material by heating and melting. This type of technology has high requirements for equipment and parameter control, such as the need for excessively high temperature melting and vigorous stirring, and also has high safety requirements for operators.

[0006] Patent CN110946832A discloses that empagliflozin is reacted with β-cyclodextrin in a certain proportion in water or aqueous ethanol medium to prepare an inclusion compound. Patent CN105456211A prepares an inclusion compound by grinding and mixing empagliflozin with succinic acid and avocado oil, and then mixing with hydroxypropyl-β-cyclodextrin and methacrylic acid. However, the key excipients involved in the two technologies are divided into β-cyclodextrin or hydroxypropyl-β-cyclodextrin. These two excipients will be converted into glucose in the body, and relevant data show that they have certain nephrotoxicity and are not suitable for long-term use by diabetic patients, and cannot completely overcome the safety issues of the drug.

[0007] Patent CN106692069A discloses that empagliflozin and povidone are dissolved in an organic solvent and a solid dispersion is prepared by solvent evaporation or spray drying. This method requires evaporation or spray drying equipment that is not common in the pharmaceutical industry and is difficult to expand in batches. Organic solvents are required in the process, which not only poses a production safety hazard, but also is not in line with the trend of environmental friendliness.

[0008] In addition, empagliflozin has many side effects. SGLT-2 inhibitors can increase urine sugar and increase the sugar content in urine, which may provide a breeding ground for bacteria and increase the risk of urinary tract infection. There are also ketoacidosis, hypoglycemia (hypoglycemia), increased urine sugar and polyuria, decreased blood volume and hypotension, skin reactions, urinary tract infection, and bone-related risks. Summary of the invention

[0009] In view of the above-mentioned side effects of empagliflozin and the shortcomings of the tablet preparation process, the present invention aims to provide a more efficient empagliflozin tablet with fewer side effects and an environmentally friendly, low-cost tablet preparation process that is easy to implement in large quantities in industry, so as to obtain a simple and easy industrial production of empagliflozin tablets with good stability, high efficiency and few side effects.

[0010] The technical solution of the present invention is as follows: An empagliflozin tablet, comprising the following components in parts by mass: The active ingredient empagliflozin is 5 parts, excipients are 20-30 parts, fillers are 40-75 parts, binders are 5-8 parts, disintegrants are 1-3 parts, lubricants are 0.5-2 parts and coating agents are 1-5 parts.

[0011] Furthermore, the auxiliary material is a composition of Omega-3 fatty acids and cholecalciferol, and the mass ratio of Omega-3 fatty acids to cholecalciferol (vitamin D3) is mg / μg = 2 to 3:1. Omega-3 is part of the polyunsaturated fatty acid (PUFA) family. They are essential fatty acids (EFA) and can be decomposed into α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The combination of Omega-3 fatty acids and vitamin D3 helps to maintain the normal function of the cardiovascular system, bone health, immune system support, anti-inflammatory effects and other aspects.

[0012] Furthermore, the filler is one of microcrystalline cellulose, lactose or pregelatinized starch.

[0013] Furthermore, the adhesive is a composition of gelatin and one or more of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone, and the mass ratio of gelatin: sodium carboxymethyl cellulose or hydroxypropyl methylcellulose or polyvinyl pyrrolidone is 3:1.

[0014] Furthermore, the disintegrant is a composition of hydroxymicrocrystalline cellulose and hypromellose, and the molar ratio of the hydroxymicrocrystalline cellulose to the hypromellose is 1:2.

[0015] Furthermore, the lubricant is a composition of magnesium stearate and silicon dioxide, wherein the molar ratio of magnesium stearate to silicon dioxide is 10:1.

[0016] Furthermore, the coating agent is chitosan.

[0017] The process for preparing tablets according to the above formulation comprises the following steps: S1. Material preparation Prepare empagliflozin, auxiliary material omega-3 fatty acid and cholecalciferol composition, filler (microcrystalline cellulose, lactose or pregelatinized starch, etc.), binder (mix evenly), disintegrant (mix evenly), lubricant (mix evenly), coating agent, etc.; S2. Material Mixing The active ingredients of empagliflozin, the composition of omega-3 fatty acids and cholecalciferol and the filler (microcrystalline cellulose, starch, lactose or pregelatinized starch) are mixed uniformly according to proportion; S3. Preparation of adhesive A colloidal solution is prepared by dissolving a combination of gelatin and one or more of sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone in pure water in a certain proportion, and adjusting the amount of water according to the actual situation within a range of 10 to 20% by mass of the adhesive. S4. Mix again Add the drug and excipients obtained in step S2 to the prepared colloidal solution and mix evenly to ensure that the mixture has the desired consistency and adhesion; S5. Filling the mixture into a pharmaceutical machine or mold for tableting operation; S6. Drying and molding The material obtained in the previous step is heated and dried to obtain a formed tablet, the drying temperature is 50-60°C; S7. Coating operation Prepare the coating solution, and the tablets are evenly coated with the coating solution through a rotating bed or a sprayer. After the coating solution forms a uniform film on the surface of the tablets, it is dried and solidified at a drying temperature of 50-60°C; S8.Quality Inspection The obtained tablets are quality tested, and qualified tablet preparations are screened out for further packaging and molding.

[0018] The beneficial effects of the present invention are: 1. The empagliflozin oral tablets of the present invention have good stability, good storage stability, the dosage can be precisely controlled, the medication is safe, and the bioavailability is high. 2. The preparation process of the empagliflozin oral tablets of the present invention does not require the use of special and expensive equipment, the process is robust, environmentally friendly and pollution-free, and is suitable for large-scale industrial production, solving the problems of high manufacturing costs and poor clinical medication safety and bioavailability; 3. The excipients of the present invention are Omega-3 fatty acids and cholecalciferol, which effectively reduce the side effects of empagliflozin, play a certain positive role in diabetes itself, and the synergistic effect with empagliflozin makes full use of the blood sugar lowering ability and efficacy of the tablets, while preventing and alleviating other complications of diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] none DETAILED DESCRIPTION

[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0021] Prepare tablets according to the recipe Formula: 5 parts of active ingredient empagliflozin, 20-30 parts of excipients, 32-40 parts of fillers, 5-8 parts of binders, 1-3 parts of disintegrants, 0.5-2 parts of lubricants and 1-5 parts of coating agents, with a total of 100 parts by mass.

[0022] The specific process steps are as follows: S1. Material preparation Prepare empagliflozin, auxiliary material omega-3 fatty acid and cholecalciferol composition, filler (microcrystalline cellulose, lactose or pregelatinized starch, etc.), binder (mix evenly), disintegrant (mix evenly), lubricant (mix evenly), coating agent, etc.; S2. Material Mixing The active components of empagliflozin, omega-3 fatty acids and cholecalciferol composition and fillers (microcrystalline cellulose, starch, lactose or pregelatinized starch) are mixed uniformly according to proportion; S3. Preparation of adhesive A colloidal solution is prepared by dissolving a combination of gelatin and one or more of sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone in pure water in a certain proportion, and adjusting the amount of water according to the actual situation within a range of 10 to 20% by mass of the adhesive. S4. Mix again Add the drug and excipients obtained in step S2 to the prepared colloidal solution and mix evenly to ensure that the mixture has the desired consistency and adhesion; S5. Filling the mixture into a pharmaceutical machine or mold for tableting operation; S6. Drying and molding The material obtained in the previous step is heated and dried to obtain a formed tablet, the drying temperature is 50-60°C; S7. Coating operation Prepare the coating solution, and the tablets are evenly coated with the coating solution through a rotating bed or a sprayer. After the coating solution forms a uniform film on the surface of the tablets, it is dried and solidified at a drying temperature of 50-60°C; S8.Quality Inspection The obtained tablets are quality tested, and qualified tablet preparations are screened out for further packaging and molding.

[0023] The molar ratio of omega-3 fatty acids to cholecalciferol is 2:1 (mg / μg), the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: sodium carboxymethyl cellulose or hydroxypropyl methylcellulose or polyvinyl pyrrolidone = 3:1.

[0024] Components Mass Empagliflozin 5 Excipients 20 Fillers 72.5 Adhesives 5 Disintegrant (hydroxy microcrystalline cellulose: hypromellose = 1:2) 1 Lubricant (magnesium stearate: silicon dioxide = 10:1) 0.5 Coating agent (chitosan) 1 The molar ratio of omega-3 fatty acids to cholecalciferol is 2:1 (mg / μg), the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: sodium carboxymethyl cellulose or hydroxypropyl methylcellulose or polyvinyl pyrrolidone = 3:1.

[0025] Components Mass Empagliflozin 5 Excipients 30 Fillers 45 Adhesives 8 Disintegrants 5 Lubricants 2 Coating agent 5 The molar ratio of omega-3 fatty acids to cholecalciferol is 2:1 (mg / μg), the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: sodium carboxymethyl cellulose = 3:1.

[0026] Components Mass Empagliflozin 5 Excipients 20 Fillers 55 Adhesives 5 Disintegrants 1 Lubricants 0.5 Coating agent 1 The mass ratio of omega-3 fatty acids to cholecalciferol is 2:1 (mg / μg), the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: sodium carboxymethyl cellulose = 3:1.

[0027] Components Mass Empagliflozin 5 Excipients 30 Fillers 57.5 Adhesives 5 Disintegrants 1 Lubricants 0.5 Coating agent 1 The molar ratio of omega-3 fatty acids to cholecalciferol is 3:1, the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: sodium carboxymethyl cellulose = 3:1.

[0028] Components Mass Empagliflozin 5 Excipients 20 Fillers 72.5 Adhesives 5 Disintegrant (hydroxy microcrystalline cellulose: hypromellose = 1:2) 1 Lubricant (magnesium stearate: silicon dioxide = 10:1) 0.5 The molar ratio of omega-3 fatty acids to cholecalciferol is 2:1 (mg / μg), the filler is microcrystalline cellulose, and the mass ratio of the binder is gelatin: polyvinyl pyrrolidone = 3:1.

[0029] Components Mass Empagliflozin 5 Excipients 20 Fillers 72.5 Adhesives 5 Disintegrant (hydroxy microcrystalline cellulose: hypromellose = 1:2) 1 Lubricant (magnesium stearate: silicon dioxide = 10:1) 0.5 It will be apparent to those skilled in the art that the invention is not limited to the details of the exemplary embodiments described above and that the invention can be implemented in other specific forms without departing from the spirit or essential features of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations within the meaning and scope of the equivalent elements of the claims be included in the invention. Any marking in a claim should not be considered as limiting the claim to which it relates.

[0030] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. An empagliflozin tablet, characterized in that The tablet comprises the following components in parts by weight: The active ingredient empagliflozin 5 parts, excipients 20-30 parts, fillers 32-40 parts, binders 5-8 parts, disintegrants 1-3 parts, lubricants 0.5-2 parts and coating agents 1-5 parts, the excipients, binders, disintegrants and lubricants are all compositions, and the excipients are compositions of omega-3 fatty acids and cholecalciferol.

2. The empagliflozin tablet according to claim 1, characterized in that: The mass ratio of the omega-3 fatty acids to cholecalciferol is mg / μg=2-3:

1.

3. The empagliflozin tablet according to claim 1, characterized in that: The filler is one of microcrystalline cellulose, lactose or pregelatinized starch.

4. The empagliflozin tablet according to claim 1, characterized in that: The adhesive is a composition of gelatin and one or more of sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone, and the mass ratio of gelatin: sodium carboxymethyl cellulose or hydroxypropyl methylcellulose or polyvinyl pyrrolidone is 3:

1.

5. The empagliflozin tablet according to claim 1, characterized in that: The disintegrant is a composition of hydroxy microcrystalline cellulose and hypromellose, and the molar ratio of the hydroxy microcrystalline cellulose to the hypromellose is 1:

2.

6. The empagliflozin tablet according to claim 1, characterized in that: The lubricant is a composition of magnesium stearate and silicon dioxide, wherein the molar ratio of magnesium stearate to silicon dioxide is 10:

1.

7. The empagliflozin tablet according to claim 1, characterized in that: The coating agent is chitosan.

8. The process for preparing the empagliflozin tablet according to claims 1 to 7, characterized in that The following steps are involved: S1. Material preparation Prepare empagliflozin, auxiliary material omega-3 fatty acid and cholecalciferol composition, filler (microcrystalline cellulose, lactose or pregelatinized starch, etc.), binder, disintegrant, lubricant, coating agent, etc.; S2. Material Mixing The active components of empagliflozin, omega-3 fatty acids and cholecalciferol composition and fillers (microcrystalline cellulose, starch, lactose or pregelatinized starch) are mixed uniformly according to proportion; S3. Preparation of adhesive A colloidal solution is prepared by dissolving gelatin and a combination of one or more substances selected from sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinyl pyrrolidone in pure water in a certain proportion; S4. Mix again Add the drug and excipients obtained in step S2 to the prepared colloidal solution and mix evenly to ensure that the mixture has the desired consistency and adhesion; S5. Filling the mixture into a pharmaceutical machine or mold for tableting operation; S6. Drying and molding The material obtained in the previous step is heated and dried to obtain a formed tablet; S7. Coating operation Prepare the coating solution, and the tablets are evenly coated with the coating solution through a rotating bed or a sprayer. After the coating solution forms a uniform film on the surface of the tablets, it is dried and solidified; S8. Quality Inspection The obtained tablets were subjected to quality inspection.