A pharmaceutical composition for reducing blood sugar, a pharmaceutical preparation and a preparation method of the preparation

Abstract

The present invention belongs to the technical field of hypoglycemic drugs, and specifically relates to a hypoglycemic pharmaceutical composition, a pharmaceutical preparation and a preparation method thereof. The hypoglycemic pharmaceutical composition and the pharmaceutical preparation comprise metformin hydrochloride, as well as a mixed granule of bitter melon extract and microcrystalline cellulose. The preparation method of the hypoglycemic pharmaceutical preparation comprises the following steps: Step 1, preparing a mixed granule of bitter melon extract and microcrystalline cellulose; Step 2, treating metformin hydrochloride and excipients for standby; Step 3, premixing the raw and auxiliary materials in Step 1 and Step 2; Step 4, sieving and sizing the powder premixed in Step 3; Step 5, adding a lubricant to the sized powder in Step 4 for total mixing; Step 6, tabletting and packaging the granules after total mixing in Step 5. By using the pharmaceutical composition or the pharmaceutical preparation of the present invention, it is possible to prevent and treat diabetes while reducing the incidence of gastrointestinal reactions caused by metformin hydrochloride.

Description

Technical Field

[0001] The present invention belongs to the technical field of hypoglycemic drugs, and particularly relates to a hypoglycemic pharmaceutical composition, a pharmaceutical preparation and a preparation method of the preparation. Background Art

[0002] Diabetes mellitus is a group of metabolic disorder syndromes caused by absolute or relative insulin deficiency and reduced insulin sensitivity of target tissue cells, resulting in a series of disorders of proteins, fats, water and electrolytes, etc. Among them, hyperglycemia is the main sign. The main clinical manifestations of diabetes are polydipsia, polyuria, polyphagia and weight loss ("three more and one less"), as well as high blood sugar and glucose in urine (normal urine should not contain glucose). If diabetes is not effectively treated, it can cause damage to multiple systems of the body. Diabetes can be divided into type 1 diabetes and type 2 diabetes.

[0003] Type 1 diabetes, or type 1 diabetes mellitus, is a type of diabetes, also known as insulin-dependent diabetes mellitus. The symptoms of patients usually appear in children or adolescents. It may be an autoimmune disease. In this case, the body's immune system attacks the beta cells that produce insulin in the body, ultimately resulting in the inability to produce insulin in the body. Patients need to inject exogenous insulin to control blood sugar in the body. Factors related to type 1 diabetes are: 1. Autoimmune system defects: Because various autoantibodies can be detected in the blood of type 1 diabetes patients, such as glutamic acid decarboxylase antibody (GAD antibody), islet cell antibody (ICA antibody), etc. These abnormal autoantibodies can damage the B cells in the human pancreas that secrete insulin, making them unable to secrete insulin normally. 2. Genetic factors: Current research suggests that genetic defects are the basis for the onset of type 1 diabetes, and this genetic defect is manifested in the abnormal HLA antigen on the sixth pair of human chromosomes. 3. Viral infection may be an inducing factor: Many scientists suspect that viruses can also cause type 1 diabetes. This is because patients with type 1 diabetes often have a viral infection some time before the onset of the disease, and the "epidemic" of type 1 diabetes often appears after the viral epidemic. Viruses, such as those that cause mumps and rubella, and the Coxsackie virus family that can cause poliomyelitis, can all play a role in type 1 diabetes.

[0004] Type 2 diabetes (T2DM), formerly known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes, is a chronic metabolic disease that usually develops after the age of 35 to 40 and accounts for more than 90% of diabetes patients. The characteristics of patients include hyperglycemia, relative insulin deficiency, insulin resistance, etc. Common symptoms are polydipsia, frequent urination, and unexplained weight loss, and may also include polyphagia, fatigue, or soreness. Long-term complications caused by hyperglycemia include heart disease, stroke, and diabetic retinopathy, which may lead to blindness, kidney failure, and even amputation due to poor blood flow in the limbs. Diabetic ketoacidosis is a rare complication.

[0005] Metformin is an organic compound with the chemical formula C4H11N5 and is a first-line drug for the treatment of type 2 diabetes, especially for overweight patients. Its adverse reactions are as follows: 1. Gastrointestinal reactions: Gastrointestinal reactions are common adverse reactions of metformin, including diarrhea, nausea, vomiting, bloating, fatigue, indigestion, abdominal discomfort, etc. 2. Allergic reactions: Allergic reactions in the clinical use of metformin are extremely rare and are easily overlooked. 3. Hypoglycemia: Since metformin does not stimulate insulin release from pancreatic islet cells, it theoretically does not cause hypoglycemia. However, the absorption of intestinal glucose is inhibited and the uptake of glucose by peripheral tissues increases, resulting in the occurrence of fasting hypoglycemia. For patients with impaired liver and kidney function or elderly patients, the drug is likely to accumulate in the body and finally cause hypoglycemia. 4. Liver damage: Liver damage caused by metformin is relatively rare. It has been reported that metformin can induce liver function damage in hepatitis B patients. In addition, it can also cause abnormal elevation of alanine aminotransferase. 5. Lactic acidosis: Biguanide drugs can increase anaerobic glycolysis of glucose, inhibit the utilization of lactate by the liver and muscles, and inhibit gluconeogenesis, thus increasing the risk of lactic acidosis. Lactic acidosis is the most serious adverse reaction of metformin. Although the incidence rate is extremely low, the mortality rate is as high as 50%. 6. Neuropsychiatric abnormalities: Neuropsychiatric abnormalities caused by metformin are rare adverse reactions discovered in recent years. 7. Hematological system damage: The application of metformin can increase the risk of vitamin B12 deficiency. Early clinical symptoms caused by vitamin B12 deficiency include paresthesia, numbness, slow reaction, impaired memory function, and cognitive dysfunction, etc. Summary of the Invention

[0006] In order to solve the problems in the prior art, the present invention provides a hypoglycemic pharmaceutical composition, a pharmaceutical preparation, and a preparation method thereof, aiming to achieve the prevention and treatment of diabetes while reducing the incidence rate of gastrointestinal reactions caused by metformin hydrochloride.

[0007] The technical problem solved by the present invention is achieved by the following technical solutions:

[0008] The present invention aims to provide a hypoglycemic pharmaceutical composition, comprising metformin hydrochloride, and a mixed granule of bitter melon extract and microcrystalline cellulose.

[0009] Through the above technical solutions, the inventors found during the research process that the mixed granule of bitter melon extract and microcrystalline cellulose can significantly reduce the dosage of metformin hydrochloride. This pharmaceutical composition can produce an obvious synergistic effect, is used for the prevention and treatment of diabetes, has a rapid onset, can also reduce the incidence of gastrointestinal reactions caused by metformin hydrochloride during use, and its disintegration time limit meets the requirements and is significantly better than using bitter melon extract alone.

[0010] Furthermore, the mass ratio of metformin hydrochloride to the mixed granule of bitter melon extract and microcrystalline cellulose is 1:0.5 - 1, and the mass ratio of bitter melon extract to microcrystalline cellulose in the mixed granule of bitter melon extract and microcrystalline cellulose is 1:1.2 - 1.5.

[0011] Through the above technical solutions, it was found during the research process that the dosage ratio relationship of metformin hydrochloride to the mixed granule of bitter melon extract and microcrystalline cellulose can greatly improve the disintegration performance of the orally disintegrating tablets of the present invention. At the same time, controlling the mass ratio of bitter melon extract to microcrystalline cellulose in the mixed granule of bitter melon extract and microcrystalline cellulose can further enhance the synergistic therapeutic effect of the three, reduce the side effects of metformin hydrochloride while having a good effect on hypoglycemia, improve the physical mechanism of diabetic patients during the healing process, and enhance the hypoglycemic effect.

[0012] The present invention also provides a hypoglycemic pharmaceutical preparation, comprising the above pharmaceutical composition and excipients. The excipients include fillers, flavoring agents, disintegrants, and lubricants. The filler is one or more of mannitol, microcrystalline cellulose, sorbitol, glucose, and starch; the flavoring agent is one or more of sucrose, aspartame, and stevioside; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone; the lubricant is one of magnesium stearate, talc powder, calcium stearate, and sodium stearyl fumarate.

[0013] Through the above technical solutions, in the mixed granule of metformin hydrochloride, bitter melon extract, and microcrystalline cellulose, by adding various preferably selected excipients, the various physical and chemical properties of the obtained preparation all meet the pharmaceutical requirements, and these excipients cooperate with the main raw materials to further enhance the pharmacological effect during hypoglycemia and reduce the adverse reactions during the treatment of diabetes.

[0014] Furthermore, the pharmaceutical preparation comprises the following raw and auxiliary materials in parts by weight: 20-25 parts of metformin hydrochloride, 16-25 parts of the mixed granules of balsam pear extract and microcrystalline cellulose, 20-25 parts of microcrystalline cellulose, 20-23 parts of croscarmellose sodium, 20-23 parts of crospovidone, 3-5 parts of sucrose, and 1.2-1.5 parts of magnesium stearate.

[0015] Through the above technical solution, different dosage ratios are adopted among the raw and auxiliary materials, which can further improve the medicinal effect on blood sugar reduction. After long-term tests, there are no significant changes in various indicators such as disintegration time limit, identification, content, related substances, and microbial limit. The quality of this preparation is stable and the increment of related substances is small. By specially treating the balsam pear concentrated solution, the increment of related substances within the shelf life can be significantly reduced, thereby improving the medicinal effect of the preparation and reducing side effects.

[0016] Furthermore, the preparation is an orally disintegrating tablet, chewable tablet, oral solution, oral tablet or capsule.

[0017] Through the above technical solution, the preparation is made into an orally disintegrating tablet, chewable tablet, oral solution, oral tablet or capsule. There will be no sticking phenomenon during the tabletting process. The product disintegrates rapidly and can be completely disintegrated within 20 seconds. The finished product has good stability and safety, and is worthy of market promotion and application.

[0018] The present invention also provides a preparation method of a blood sugar-lowering pharmaceutical preparation, which comprises the following steps:

[0019] Step 1, prepare the mixed granules of balsam pear extract and microcrystalline cellulose;

[0020] Step 2, treat metformin hydrochloride and auxiliary materials for standby;

[0021] Step 3, premix the raw and auxiliary materials in Step 1 and Step 2;

[0022] Step 4, sieve and size the powder premixed in Step 3;

[0023] Step 5, add lubricant to the sized powder in Step 4 and mix uniformly;

[0024] Step 6, tablet and package the granules after mixing uniformly in Step 5.

[0025] Through the above technical solution, the raw and auxiliary materials of the preparation are respectively prepared and treated, and then tableted after premixing, sizing and total mixing. The preparation method is simple, the medicinal performance effect among the raw and auxiliary materials is good, the blood sugar-lowering effect of the prepared preparation is improved, and the control effect on the adverse reactions caused by metformin hydrochloride is good, with low side effects.

[0026] Further, the preparation of the mixed particles of bitter gourd extract and microcrystalline cellulose in Step 1 is as follows: Take fresh bitter gourd and place it in a container, and extract it twice. For the first extraction, use an ethanol solution with a volume fraction of 30% and a mass 25 times that of the bitter gourd at a temperature of 60°C for 1 - 1.5 hours. After the extraction is completed, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time, extract at a temperature of 60°C for 1 - 1.5 hours, filter, and collect the filtrate. Combine the two filtrates and concentrate them to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract and stir for 3 - 5 minutes at a rotation speed of 50 - 70 rpm / min, then let it stand for 24 - 36 hours, and take the supernatant for standby. Separately, take microcrystalline cellulose and add it to a fluidized bed as a substrate. Set the inlet air temperature of the fluidized bed at 70 - 90°C and the inlet air frequency at 35 - 40 Hz for preheating. When the material temperature reaches 50 - 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation. Set the spray pressure at 0.3 - 0.5 MPa and the liquid spraying rotation speed at 50 - 60 rpm / min. After the spraying is completed, obtain the mixed particles of bitter gourd extract and microcrystalline cellulose; the mass ratio of bitter gourd extract to microcrystalline cellulose is 1:1.2 - 1.5.

[0027] Through the above technical solution, the bitter gourd is extracted twice to obtain the bitter gourd extract, and then the bitter gourd extract and microcrystalline cellulose are spray granulated to obtain the mixed particles of the bitter gourd extract and microcrystalline cellulose after mixing. By controlling the mass ratio of the bitter gourd extract to microcrystalline cellulose in the mixed particles, the preparation method is simple, and the components that can reduce the side effects of metformin hydrochloride in bitter gourd and microcrystalline cellulose are fully utilized and integrated. Compared with using bitter gourd alone or replacing microcrystalline cellulose with other substances, the effects of the mixed particles of bitter gourd extract and microcrystalline cellulose in this application cannot be achieved, and the disintegration time limit of this application is significantly improved and shortened.

[0028] Further, in Step 2, the treatment of metformin hydrochloride and excipients is to pass metformin hydrochloride, microcrystalline cellulose, croscarmellose sodium, crospovidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0029] Through the above technical solution, the metformin hydrochloride and excipients are treated to screen out the qualified raw and auxiliary materials, providing high-quality raw and auxiliary materials for subsequent premixing and total mixing, and further improving the product quality of the preparation and the synergistic effect between the raw and auxiliary materials.

[0030] Further, in Step 3, the premixing is to place metformin hydrochloride microcrystals, microcrystalline cellulose, and sodium carboxymethylcellulose cross-linked in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20 to 30 minutes to obtain Premixed Powder 1 for standby; then mix the mixed granules of bitter gourd extract and microcrystalline cellulose with cross-linked polyvinylpyrrolidone and sucrose in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20 to 30 minutes to obtain Premixed Powder 2 for standby.

[0031] Through the above technical solution, the respective raw and auxiliary materials prepared for standby are separately mixed. Compared with the direct mixing method, the disintegration time limit of the obtained preparation is significantly shortened, from at least one minute originally to only about ten seconds, greatly improving the disintegration time limit of the preparation, enhancing the blood sugar lowering effect, and reducing the generation of side effects.

[0032] Further, the Premixed Powder 1 after granulation and the Premixed Powder 2 after granulation are placed in a three-dimensional motion mixer, and the formulated amount of magnesium stearate lubricant is added and mixed for 10 minutes to obtain the total mixed granules. Then, the total mixed granules are added to a rotary tablet press for tableting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet.

[0033] Through the above technical solution, all the raw and auxiliary materials are total mixed to obtain the total mixed granules, and finally tableting is carried out to obtain tablets. By strictly controlling the total mixing and tableting parameters, the overall quality of the preparation is improved, the blood sugar lowering effect is enhanced, and the finished product has good stability and safety after being made into a preparation, which is worthy of market promotion and application.

[0034] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0035] 1. Although the main component of the present invention, metformin hydrochloride, may cause an incidence of adverse reactions such as gastrointestinal reactions, when combined with the traditional Chinese medicine bitter gourd, on the one hand, the usage amount of the main drug metformin hydrochloride is reduced, and on the other hand, bitter gourd also has a blood sugar lowering effect. This pharmaceutical composition and pharmaceutical preparation can produce an obvious synergistic effect and is used for the prevention and treatment of diabetes; and it can significantly improve and reduce the adverse reaction rate of metformin hydrochloride.

[0036] 2. The pharmaceutical composition of the present invention is made into preparations such as orally disintegrating tablets. There will be no sticking phenomenon during the tableting process, the product disintegrates rapidly, and can be completely disintegrated within 20 seconds. The finished product has good stability and safety, and is worthy of market promotion and application.

[0037] 3. The preparation method of the pharmaceutical preparation of the present invention is simple. The raw and auxiliary materials of the preparation are separately prepared and processed, and then tableted after premixing, granulation, and total mixing. The medicinal performance effects between the raw and auxiliary materials are well integrated, improving the blood sugar lowering effect of the prepared preparation, and having a good control effect on the adverse reactions produced by metformin hydrochloride, with low side effects.

[0038] 4. In the preparation method of the present invention, the raw and auxiliary materials are separately mixed during premixing. Compared with direct mixing, the disintegration time limit of the obtained preparation is significantly shortened, from more than one minute originally to only about ten seconds, greatly improving the disintegration time limit of the preparation.

[0039] 5. The pharmaceutical composition and pharmaceutical preparation of the present invention use the mixed particles of bitter melon extract and microcrystalline cellulose. Compared with using bitter melon alone or replacing microcrystalline cellulose with other substances, the effects of the mixed particles of bitter melon extract and microcrystalline cellulose in this application cannot be achieved. The disintegration time limit is significantly improved and shortened in this application, and the improvement effect on the adverse reactions caused by metformin hydrochloride is significant.

[0040] The above description is only an overview of the technical solution of the present invention. In order to be able to more clearly understand the technical means of the present invention, it can be implemented according to the content of the specification. And in order to make the above content, its purpose, features and advantages of the present invention more obvious and understandable, the following specific embodiments of the present invention are specifically given. Specific Embodiments

[0041] The following examples are only used to illustrate and explain the present invention exemplarily, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0042] In addition, unless otherwise specifically stated, various raw materials, reagents, instruments and equipment used in the present invention can be obtained through market purchase or prepared by existing methods.

[0043] A hypoglycemic pharmaceutical composition includes metformin hydrochloride and a mixture of bitter melon extract and microcrystalline cellulose. The mass ratio of metformin hydrochloride to the mixture of bitter melon extract and microcrystalline cellulose is 1:0.5 - 1, and further preferably the ratio of the two is 1:0.8 - 1. In the mixed particles of bitter melon extract and microcrystalline cellulose, the mass ratio of bitter melon extract to microcrystalline cellulose is 1:1.2 - 1.5.

[0044] A hypoglycemic pharmaceutical composition of the present invention can be prepared into oral disintegrating tablets, chewable tablets, oral solutions, oral tablets, capsules and other preparations for taking.

[0045] A hypoglycemic pharmaceutical preparation takes the mixed particles of metformin hydrochloride, bitter melon extract and microcrystalline cellulose as the main components, and also includes fillers, flavoring agents, disintegrants, lubricants acceptable in pharmacy.

[0046] Among them, the filler is one or more of mannitol, microcrystalline cellulose, sorbitol, glucose, and starch; the flavoring agent is one or more of sucrose, aspartame, and stevioside; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone; the lubricant is one of magnesium stearate, talc powder, calcium stearate, and sodium stearyl fumarate.

[0047] As a further preference, a hypoglycemic pharmaceutical preparation comprises the following raw and auxiliary materials in parts by weight: 20 - 25 parts of metformin hydrochloride, 16 - 25 parts of the mixed granules of bitter gourd extract and microcrystalline cellulose, 20 - 25 parts of microcrystalline cellulose, 20 - 23 parts of cross-linked carboxymethyl cellulose sodium, 20 - 23 parts of cross-linked polyvinylpyrrolidone, 3 - 5 parts of sucrose, and 1.2 - 1.5 parts of magnesium stearate.

[0048] Taking the orally disintegrating tablet as an example, the preparation method of the hypoglycemic pharmaceutical preparation of the present application will be described in detail.

[0049] Example 1

[0050] Prescription: 20 parts of metformin hydrochloride, 20 parts of the mixed granules of bitter gourd extract and microcrystalline cellulose, 20 parts of microcrystalline cellulose, 20 parts of cross-linked carboxymethyl cellulose sodium, 20 parts of cross-linked polyvinylpyrrolidone, 5 parts of sucrose, and 1.25 parts of magnesium stearate.

[0051] Preparation method:

[0052] 1. Preparation of the mixed granules of bitter gourd extract and microcrystalline cellulose:

[0053] Take fresh bitter gourd and place it in a suitable container, extract twice. For the first time, use an ethanol solution with a volume fraction of 30% and 25 times the mass of the bitter gourd for extraction, the extraction temperature is 60°C, and the extraction time is 1.5 h. After the extraction is completed, filter and collect the filtrate for standby; take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time for extraction, the extraction temperature is 60°C, and the extraction time is 1.5 h, filter and collect the filtrate. Combine the two filtrates and concentrate them to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract, stir at a rotation speed of 60 rpm / min for 5 minutes, then let it stand for 30 hours, and take the supernatant for standby; separately take microcrystalline cellulose and add it to the fluidized bed as a substrate, set the inlet air temperature of the fluidized bed to 80°C and the inlet air frequency to 40 Hz for preheating. When the material temperature reaches 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation, set the spray pressure to 0.4 MPa and the liquid spraying rotation speed to 55 rpm / min. After the spraying is completed, obtain the mixed granules of bitter gourd extract and microcrystalline cellulose; the mass ratio of bitter gourd extract to microcrystalline cellulose is 1:1.3.

[0054] 2. Pretreatment of raw and auxiliary materials: Metformin hydrochloride, microcrystalline cellulose, croscarmellose sodium, crospovidone, sucrose, and magnesium stearate were each passed through a 100-mesh sieve and reserved for use.

[0055] 3. Premixing: Metformin hydrochloride microcrystals, microcrystalline cellulose, and croscarmellose sodium were placed in a high-efficiency wet granulator, and low-speed stirring was started for 25 minutes of premixing to obtain Premixed Powder 1, which was reserved for use; then the mixed granules of bitter melon extract and microcrystalline cellulose, crospovidone, and sucrose were mixed in a high-efficiency wet granulator, and low-speed stirring was started for 25 minutes of premixing to obtain Premixed Powder 2, which was reserved for use;

[0056] 4. Granule sizing: Premixed Powder 1 and Premixed Powder 2 were each passed through an 18-mesh sieve, and the sized granules were collected and reserved for use;

[0057] 5. Total mixing: Premixed Powder 1 after granule sizing and Premixed Powder 2 after granule sizing were placed in a three-dimensional motion mixer, and the formulated amount of magnesium stearate was added and mixed for 15 minutes to obtain the total mixed granules;

[0058] 6. Tabletting: The total mixed granules were added to a rotary tabletting machine for tabletting, with a hardness of 3.5 kg and a tablet weight of 320 mg / tablet, and the tablets were obtained by tabletting.

[0059] 7. Aluminum packaging: Packed into 12 tablets / board or 18 tablets / board;

[0060] 8. Outer packaging: Outer packaged into 3 boards / box.

[0061] Example 2

[0062] Prescription: 23 parts of metformin hydrochloride, 21 parts of the mixed granules of bitter melon extract and microcrystalline cellulose, 21 parts of microcrystalline cellulose, 21 parts of croscarmellose sodium, 21 parts of crospovidone, 5 parts of sucrose, 1.3 parts of magnesium stearate

[0063] Preparation method:

[0064] 1. Preparation of the mixed granules of bitter melon extract and microcrystalline cellulose:

[0065] Take fresh bitter gourd and place it in a suitable container for extraction twice. For the first extraction, use an ethanol solution with a volume fraction of 30% and a mass 20 times that of the bitter gourd at a temperature of 60°C for 1 hour. After the extraction is completed, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time, extract at a temperature of 60°C for 1 hour, filter, and collect the filtrate. Combine the two filtrates and concentrate to an extract with a relative density of 1.25 at 60°C. Add purified water to the extract and stir for 4 minutes at a rotation speed of 55 rpm / min, then let it stand for 24 hours, and take the supernatant for standby. Separately, add microcrystalline cellulose to the fluidized bed as the substrate, set the inlet air temperature of the fluidized bed at 70°C and the inlet air frequency at 35 Hz for preheating. When the material temperature reaches 50°C, spray the above-prepared supernatant into the fluidized bed for spray granulation, set the spray pressure at 0.3 MPa and the liquid spraying rotation speed at 50 rpm / min. After the spraying is completed, obtain the mixed particles of bitter gourd extract and microcrystalline cellulose; the mass ratio of the bitter gourd extract to microcrystalline cellulose is 1:1.2.

[0066] 2. Pretreatment of raw and auxiliary materials: Pass metformin hydrochloride, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0067] 3. Premixing: Place metformin hydrochloride microcrystals, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20 minutes to obtain premixed powder 1 for standby; then place the mixed particles of bitter gourd extract and microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and sucrose in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20 minutes to obtain premixed powder 2 for standby;

[0068] 4. Granule screening: Pass premixed powder 1 and premixed powder 2 through an 18-mesh sieve respectively, collect the granulated particles for standby;

[0069] 5. Total mixing: Place the granulated premixed powder 1 and the granulated premixed powder 2 in a three-dimensional motion mixer, add the formulated amount of magnesium stearate, and mix for 10 minutes to obtain the total mixed granules;

[0070] 6. Tabletting: Add the total mixed granules to a rotary tablet press for tabletting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet, and the tablets are obtained.

[0071] 7. Aluminum packaging: Pack into 12 tablets / board or 18 tablets / board;

[0072] 8. Outer packaging: Outer package into 3 boards / box.

[0073] Example 3

[0074] Prescription: 25 parts of metformin hydrochloride, 25 parts of the mixed granules of bitter melon extract and microcrystalline cellulose, 25 parts of microcrystalline cellulose, 23 parts of croscarmellose sodium, 23 parts of crospovidone, 5 parts of sucrose, 1.5 parts of magnesium stearate

[0075] Preparation method:

[0076] 1. Preparation of the mixed granules of bitter melon extract and microcrystalline cellulose:

[0077] Take fresh bitter melon and place it in a suitable container for extraction twice. For the first time, extract with an ethanol solution with a volume fraction of 30% and 30 times the mass of the bitter melon at a temperature of 60°C for 1.5 hours. After the extraction is completed, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time, extract at a temperature of 60°C for 1.5 hours, filter, collect the filtrate, combine the two filtrates, and concentrate to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract, stir at a speed of 70 rpm / min for 5 minutes, then let it stand for 36 hours, and take the supernatant for standby. Separately take microcrystalline cellulose and add it to the fluidized bed as the substrate. Set the inlet air temperature of the fluidized bed at 90°C and the inlet air frequency at 40 Hz for preheating. When the material temperature reaches 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation. Set the spray pressure at 0.5 MPa and the liquid spraying speed at 60 rpm / min. After the spraying is completed, obtain the mixed granules of bitter melon extract and microcrystalline cellulose; the mass ratio of the bitter melon extract to microcrystalline cellulose is 1:1.5.

[0078] 2. Pretreatment of raw and auxiliary materials: Pass metformin hydrochloride, microcrystalline cellulose, croscarmellose sodium, crospovidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0079] 3. Premixing: Place metformin hydrochloride microcrystals, microcrystalline cellulose, and croscarmellose sodium in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder 1 for standby; then place the mixed granules of bitter melon extract and microcrystalline cellulose, crospovidone, and sucrose in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder 2 for standby;

[0080] 4. Granule screening: Pass premixed powder 1 and premixed powder 2 through an 18-mesh sieve respectively, collect the granulated particles for standby;

[0081] 5. Total mixing: Place the granulated premixed powder 1 and the granulated premixed powder 2 in a three-dimensional motion mixer, add the formulated amount of magnesium stearate, and mix for 10 minutes to obtain the total mixed granules;

[0082] 6. Tabletting: Add the granulated mixture for overall blending into a rotary tabletting machine for tabletting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet. The tablets are obtained upon tabletting.

[0083] 7. Aluminum packaging: Packaged into 12 tablets / plate or 18 tablets / plate;

[0084] 8. Outer packaging: The outer packaging is packed into 3 plates / box.

[0085] Test Example 1: Conduct a long-term stability test on the products prepared in Examples 1, 2, and 3

[0086] 1. Test method: Refer to the stability test inspection in the second part of the "Chinese Pharmacopoeia" (2015 edition)

[0087] 2. Test conditions:

[0088] Long-term test temperature: 25 ± 2 °C;

[0089] Long-term test humidity: RH60% ± 10%

[0090] Long-term test inspection time: 0, 3, 6, 9, 12, 18, 24 months

[0091] 3. Test results:

[0092] The stability record of the long-term test is shown in Table 1:

[0093] Table 1 Long-term test results

[0094]

[0095]

[0096] Remarks: "--" indicates that the detection was not carried out.

[0097] The long-term test shows that for the products of Examples 1, 2, and 3 of this product, there are no significant changes in various indicators such as appearance, disintegration time limit, identification, content, related substances, and microbial limit after 24 months of long-term test. And the maximum increase in related substances after 24 months of long-term is only 0.07% (sample of Example 3), with a small increase. Therefore, the quality of this product is stable after 24 months of long-term test. The content increase of Example 3 reaches 3.9%, with a large increase. Therefore, the present invention selects to specially treat the bitter gourd concentrated liquid, which can significantly reduce the increase of related substances during the shelf life; In summary, the products (Examples 1, 2, and 3) prepared by the present invention are stable in quality during the storage period and can last up to 24 months.

[0098] Test Example 2: Conduct a comparative test on gastrointestinal reactions of the products prepared in Examples 1, 2, and 3

[0099] 1. Test purpose:

[0100] To study that the combined use of metformin and bitter gourd has less side effects on gastrointestinal reactions

[0101] 2. Test method:

[0102] Select 1000 diabetic patients and use the form of questionnaire survey to compare the gastrointestinal reactions caused by metformin hydrochloride and the gastrointestinal reactions caused by the combined use of metformin hydrochloride and bitter gourd extract.

[0103] 3. Test conditions:

[0104] Test investigation time: 180 days (90 days of using metformin hydrochloride alone, 90 days of using the combination of metformin hydrochloride and bitter gourd extract)

[0105] 3. Test results:

[0106] The results of the incidence of gastrointestinal reactions in the test are shown in Table 2:

[0107] Table 2 Results of the incidence of gastrointestinal reactions

[0108] Experimental conditions Metformin hydrochloride alone Combined use of metformin hydrochloride and bitter gourd extract Diarrhea 1.3％ 0.4％ Nausea 2.5％ 0.3％ Vomiting 0.6％ 0.1％ Abdominal distension 3.2％ 0.4％ Dyspepsia 1.2％ 0.2％ Abdominal discomfort 6.4％ 0.5％

[0109] The comparative experiment of gastrointestinal reactions shows that: the results of the incidence of gastrointestinal reactions show that when using metformin hydrochloride alone, among 1000 diabetic patients, the total incidence of gastrointestinal reactions in 90 days is 15.2%. After adding bitter gourd extract in the latter 90 days, the incidence of adverse gastrointestinal reactions is 1.9%, and the incidence of adverse reactions is reduced by 13.3%. In summary, the combined use of metformin hydrochloride and bitter gourd extract in the present invention can reduce the incidence of adverse gastrointestinal reactions, which is a feasible solution.

[0110] Change different mixing methods, material granulation and materials, and conduct disintegration comparative tests

[0111] Comparative Example 1:

[0112] Prescription: 24 parts of metformin hydrochloride, 24 parts of the mixed granules of bitter gourd and microcrystalline cellulose, 24 parts of microcrystalline cellulose, 23 parts of cross-linked carboxymethylcellulose sodium, 23 parts of cross-linked polyvinylpyrrolidone, 5 parts of sucrose, 1.5 parts of magnesium stearate

[0113] Preparation method:

[0114] 1. Preparation of the mixed granules of bitter gourd extract and microcrystalline cellulose:

[0115] Take fresh bitter gourd and place it in a suitable container for extraction twice. For the first extraction, use an ethanol solution with a volume fraction of 30% and a mass 30 times that of the bitter gourd at a temperature of 60°C for 1.5 hours. After the extraction is completed, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time, extract at a temperature of 60°C for 1.5 hours, filter, and collect the filtrate. Combine the two filtrates and concentrate to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract and stir at a speed of 70 rpm / min for 5 minutes, then let it stand for 36 hours. Take the supernatant for standby. Separately, add microcrystalline cellulose to the fluidized bed as a substrate, preheat it with an inlet air temperature of 90°C and an inlet air frequency of 40 Hz. When the material temperature reaches 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation, set the spray pressure to 0.5 MPa and the liquid spraying speed to 60 rpm / min. After the spraying is completed, obtain the mixed particles of bitter gourd extract and microcrystalline cellulose; the mass ratio of the bitter gourd extract to microcrystalline cellulose is 1:1.5.

[0116] 2. Pretreatment of raw and auxiliary materials: Pass metformin hydrochloride, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0117] 3. Premixing: Mix metformin hydrochloride microcrystals, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, the mixed particles of bitter gourd and microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and sucrose in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder for standby;

[0118] 4. Granule screening: Pass the premixed powder through an 18-mesh sieve, collect the granules after screening for standby;

[0119] 5. Total mixing: Place the premixed powder after granule screening in a three-dimensional motion mixer, add the formulated amount of magnesium stearate, and mix for 10 minutes to obtain the total mixed granules;

[0120] 6. Tabletting: Add the total mixed granules to a rotary tabletting machine for tabletting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet. The tablets are obtained after tabletting.

[0121] 7. Aluminum packaging: Pack into 12 tablets / board or 18 tablets / board;

[0122] 8. Outer packaging: Pack the outer packaging into 3 boards / box.

[0123] Comparative Example 2:

[0124] Prescription: 22 parts of metformin hydrochloride, 25 parts of bitter gourd granules, 45 parts of microcrystalline cellulose, 23 parts of cross-linked carboxymethyl cellulose sodium, 23 parts of cross-linked polyvinylpyrrolidone, 5 parts of sucrose, 1.5 parts of magnesium stearate

[0125] Preparation method:

[0126] 1. Preparation of bitter gourd granules:

[0127] Take fresh bitter gourd and place it in a suitable container, and extract it twice. For the first time, extract it with an ethanol solution with a volume fraction of 30% and 30 times the mass of the bitter gourd at a temperature of 60°C for 1.5 hours. After the extraction is completed, filter and collect the filtrate for standby; take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first time, extract it at a temperature of 60°C for 1.5 hours, filter and collect the filtrate, combine the two filtrates, and concentrate them to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract, stir it at a speed of 70 rpm / min for 5 minutes, then let it stand for 36 hours, take the supernatant for standby; set the inlet air temperature of the fluidized bed to 90°C and the inlet air frequency to 40 Hz for preheating. When the material temperature reaches 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation. Set the spray pressure to 0.5 MPa and the liquid spraying speed to 60 rpm / min. After the spraying is completed, obtain the bitter gourd granules for standby.

[0128] 2. Pretreatment of raw and auxiliary materials: Pass metformin hydrochloride, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0129] 3. Premixing: Place metformin hydrochloride microcrystals, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder 1 for standby; then mix the bitter gourd granules and cross-linked polyvinylpyrrolidone in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder 2 for standby;

[0130] 4. Granule screening: Pass premixed powder 1 and premixed powder 2 through an 18-mesh sieve respectively, and collect the granules after granule screening for standby;

[0131] 5. Total mixing: Place the premixed powder 1 after granule screening and the premixed powder 2 after granule screening in a three-dimensional motion mixer, add the formulated amount of magnesium stearate, and mix for 10 minutes to obtain the total mixed granules;

[0132] 6. Tabletting: Add the total mixed granules to a rotary tabletting machine for tabletting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet. After tabletting, it is obtained.

[0133] 7. Aluminum packaging: Pack into 12 tablets / board or 18 tablets / board;

[0134] 8. Outer packaging: The outer packaging is packed into 3 boards / box.

[0135] Comparative Example 3:

[0136] Prescription: 20 parts of metformin hydrochloride, 25 parts of mixed granules of bitter gourd and lactose, 25 parts of lactose, 22 parts of croscarmellose sodium, 22 parts of crospovidone, 3 parts of sucrose, 1.5 parts of magnesium stearate

[0137] Preparation method:

[0138] 1. Preparation of mixed granules of bitter gourd and lactose:

[0139] Take fresh bitter gourd and place it in a suitable container for extraction twice. For the first extraction, use an ethanol solution with a volume fraction of 30% and a mass 30 times that of the bitter gourd at a temperature of 60°C for 1.5 hours. After the extraction is completed, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first extraction, extract at a temperature of 60°C for 1.5 hours, filter, and collect the filtrate. Combine the two filtrates and concentrate to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract and stir at a speed of 70 rpm / min for 5 minutes, then let it stand for 36 hours and take the supernatant for standby. Separately take lactose and add it to the fluidized bed as the substrate. Set the inlet air temperature of the fluidized bed to 90°C and the inlet air frequency to 40 Hz for preheating. When the material temperature reaches 60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation. Set the spray pressure to 0.5 MPa and the liquid spraying speed to 60 rpm / min. After the spraying is completed, obtain the mixed granules of bitter gourd and lactose; the mass ratio of the bitter gourd to microcrystalline cellulose is 1:1.5.

[0140] 2. Pretreatment of raw and auxiliary materials: Pass metformin hydrochloride, lactose, croscarmellose sodium, crospovidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

[0141] 3. Premixing: Place metformin hydrochloride, lactose, croscarmellose sodium, the mixed granules of bitter gourd and microcrystalline cellulose, and crospovidone in a high-efficiency wet granulator, start stirring at a low speed, and premix for 30 minutes to obtain premixed powder 2 for standby;

[0142] 4. Granule sizing: Pass premixed powder 1 and premixed powder 2 through an 18-mesh sieve respectively, collect the sized granules for standby;

[0143] 5. Total mixing: Place the sized premixed powder 1 and the sized premixed powder 2 in a three-dimensional motion mixer, add the formulated amount of magnesium stearate, and mix for 10 minutes to obtain the total mixed granules;

[0144] 6. Tabletting: Add the total mixed granules to a rotary tabletting machine for tabletting, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet. After tabletting, the tablets are obtained.

[0145] 7. Aluminum packaging: Packed into 12 tablets / plate or 18 tablets / plate;

[0146] 8. Outer packaging: Packed into 3 plates / box.

[0147] The disintegration time limit test results of the products obtained from Comparative Examples 1-3 are shown in Table 3:

[0148] Table 3 Disintegration time limit

[0149] Experimental samples Disintegration time limit Comparative example 1 59s Comparative example 2 126s Comparative example 3 123s

[0150] The disintegration time limit shows that in Comparative Example 1, its mixing method was changed to a direct mixing method. The inventor found that the disintegration time limit was significantly prolonged, which was not conducive to the disintegration of the orally disintegrating tablets; in Comparative Example 2, the material granulation was changed, and bitter gourd was separately made into bitter gourd granules. It was found that the disintegration time limit was 126 s, which did not meet the disintegration time limit of the orally disintegrating tablets; in Comparative Example 3, the composition of the excipients was changed, and microcrystalline cellulose was replaced with lactose. It was found that the disintegration time limit was 123 s, which did not meet the disintegration time limit of the orally disintegrating tablets.

[0151] The serial numbers of the above embodiments of the present invention are only for description and do not represent the advantages or disadvantages of the embodiments.

[0152] The above embodiments of the present invention have been described, but the present invention is not limited to the above specific embodiments. The above specific embodiments are only illustrative and not restrictive. Under the inspiration of the present invention, those of ordinary skill in the art can also make many forms without departing from the spirit and scope protected by the claims of the present invention. These all belong to the protection scope of the present invention.

Claims

1. A pharmaceutical composition for reducing blood sugar, characterized in that, It is made from the following raw and auxiliary materials in parts by weight: 20-25 parts of metformin hydrochloride, 16-25 parts of the mixed granules of bitter gourd extract and microcrystalline cellulose, 20-25 parts of microcrystalline cellulose, 20-23 parts of cross-linked carboxymethyl cellulose sodium, 20-23 parts of cross-linked polyvinylpyrrolidone, 3-5 parts of sucrose, and 1.2-1.5 parts of magnesium stearate; The mass ratio of metformin hydrochloride to the mixed granules of bitter gourd extract and microcrystalline cellulose is 1:0.5-1; The preparation method of the pharmaceutical composition comprises the following steps: Step 1, prepare the mixed granules of bitter gourd extract and microcrystalline cellulose: Place fresh bitter gourd in a container and extract twice. For the first extraction, use an ethanol solution with a volume fraction of 30% and a mass 25 times that of the bitter gourd at a extraction temperature of 60°C for 1-1.5 hours. After the extraction, filter and collect the filtrate for standby. Take the filter cake after the first extraction, add an ethanol solution with a volume fraction of 50% with the same mass as the first extraction, extract at a temperature of 60°C for 1-1.5 hours, filter, and collect the filtrate. Combine the two filtrates and concentrate to an extract with a relative density of 1.30 at 60°C. Add purified water to the extract, stir at a speed of 50-70 rpm / min for 3-5 minutes, then let it stand for 24-36 hours, and take the supernatant for standby. Separately, add microcrystalline cellulose to a fluidized bed as a substrate, preheat it with an inlet air temperature of 70-90°C and an inlet air frequency of 35-40 Hz. When the material temperature reaches 50-60°C, spray the above-prepared supernatant into the fluidized bed for spray granulation, set the spray pressure at 0.3-0.5 MPa and the liquid spraying speed at 50-60 rpm / min. After the spraying is completed, obtain the mixed granules of bitter gourd extract and microcrystalline cellulose; the mass ratio of bitter gourd extract to microcrystalline cellulose is 1:1.2-1.5; Step 2, treat metformin hydrochloride and auxiliary materials for standby: Step 3, premix the raw and auxiliary materials in Step 1 and Step 2: Place metformin hydrochloride microcrystals, microcrystalline cellulose, and cross-linked carboxymethyl cellulose sodium in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20-30 minutes to obtain premixed powder 1 for standby. Then, place the mixed granules of bitter gourd extract and microcrystalline cellulose, cross-linked polyvinylpyrrolidone, and sucrose in a high-efficiency wet granulator, start stirring at a low speed, and premix for 20-30 minutes to obtain premixed powder 2 for standby; Step 4, sieve and size the powder premixed in Step 3; Step 5, add lubricant for total mixing in the sized powder in Step 4: Place the sized premixed powder 1 and the sized premixed powder 2 in a three-dimensional motion mixer, add the formulated amount of magnesium stearate lubricant, and mix for 10-15 minutes to obtain total mixed granules.

2. The pharmaceutical composition for reducing blood sugar according to claim 1, wherein: The treatment of metformin hydrochloride and auxiliary materials in Step 2 is to pass metformin hydrochloride, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sucrose, and magnesium stearate through a 100-mesh sieve respectively for standby.

3. A pharmaceutical preparation for reducing blood sugar, characterized in that: It is prepared by using the hypoglycemic pharmaceutical composition described in Claim 1 or 2.

4. The pharmaceutical preparation for reducing blood sugar according to claim 3, wherein: The preparation is an oral solution, tablet, or capsule.

5. The pharmaceutical preparation for reducing blood sugar according to claim 4, wherein: The pharmaceutical preparation is an orally disintegrating tablet. The preparation method of the orally disintegrating tablet further includes adding the total mixed granules to a rotary tablet press for tableting after obtaining the total mixed granules, with a hardness of 3.5 kg and a tablet weight of 310 mg / tablet.

Images