CN116999398A - An oral composition - Google Patents

Abstract

In view of the existing problems, the present invention provides an oral composition, the oral composition includes active ingredients and soybean oil, the active ingredients include metformin and/or phenformin eicosapentaenoate, the The active ingredients and soybean oil synergistically reduce blood sugar and can significantly improve the blood sugar-lowering effect of the active ingredients.

Description

An oral composition

Technical field

The present invention belongs to the field of diabetes treatment, and specifically relates to an oral composition.

Background technique

Diabetes is a chronic metabolic disease that seriously threatens global health. The ninth edition of the IDF shows that 463 million adults currently have diabetes. If adequate response measures are not taken, the number of people with diabetes worldwide will reach 578 million by 2030, and will jump to a staggering 700 million by 2045.

Biguanide compounds are important drugs for the treatment of diabetes. Common biguanide compounds include metformin and phenformin. Their mechanism of action is to reduce the production of liver glycogen, inhibit the absorption of glucose in the intestine, and increase the peripheral resistance to glucose absorption and Utilization, which improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Metformin is a first-line drug and a basic drug in drug combinations for controlling hyperglycemia in patients with T2DM, and is recommended by diabetes treatment guidelines in many countries around the world. The 2020 version of China’s Guidelines for the Prevention and Treatment of Type 2 Diabetes points out that metformin is currently the most commonly used hypoglycemic drug and has a variety of potential benefits beyond hypoglycemic effects (such as the treatment of cardiovascular disease, cardiovascular complications of diabetes, etc.) and does not increase hypoglycemia. risk. If there are no contraindications, metformin should remain in the diabetes treatment regimen.

Metformin can be used for type 2 diabetes where diet control and physical exercise alone are ineffective in controlling blood sugar. It can also be used in combination with sulfonylureas or insulin. The chemical formula of metformin is:

Therefore, it has always been a pursuit of those skilled in the art to improve the therapeutic effect of metformin's eicosapentaenoate.

Contents of the invention

1. Problems to be solved

In view of the existing problems, the present invention provides an oral composition, the oral composition includes active ingredients and soybean oil, the active ingredients include metformin and/or phenformin eicosapentaenoate, the The active ingredients and soybean oil synergistically reduce blood sugar and can significantly improve the blood sugar-lowering effect of the active ingredients.

2. Technical solutions

In order to solve the above problems, the present invention adopts the following technical solutions.

A first aspect of the invention provides an oral composition comprising an active ingredient comprising metformin and/or an eicosapentaenoate salt of phenformin and soybean oil.

Preferably, the weight ratio of the active ingredient to soybean oil is 100: (50-1000), preferably 100: (50-400), preferably 100: (400-1000).

Preferably, the weight of the active ingredient and soybean oil is

Active ingredient 100mg

Soybean oil 50mg

or

Active ingredient 100mg

Soybean oil 400mg

or

Active ingredient 100mg

Soybean oil 1000mg.

In a second aspect, the present invention provides a pharmaceutical preparation, which includes any one of the above oral compositions and pharmaceutical excipients.

Preferably, the pharmaceutical excipients include binders, disintegrants or lubricants. Preferably, the pharmaceutical excipients also include diluents, emulsifiers, solubilizers, colorants, fragrances or sweeteners.

Preferably, the weight ratio of the binder, lubricant and disintegrant is:

Adhesive 0～4

Lubricant 0～20

Disintegrant 0～6

or

Adhesive 0～3

Lubricant 0～10

Disintegrant 0～3

or

Adhesive 3～4

Lubricant 10～20

Disintegrant 3～6.

Preferably, the binder is selected from one or more of starch slurry, gelatin solution, sucrose solution, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. Several, preferably, the disintegrant is selected from sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium or cross-linked polyvinylpyrrolidone. Or several, preferably, the lubricant is selected from talc, micronized silica gel, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, stearic acid, calcium stearate or magnesium stearate. one or several kinds.

Preferably, the pharmaceutical preparation is in the form of tablets, capsules, powders, granules, capsules, pills, suppositories, ointments, gels, aerosols, films, syrups, emulsions, suspensions or injection.

In a third aspect, the present invention provides an oral composition as described in any one of the above, and a pharmaceutical preparation as described in any of the above for preparation, treatment or prevention of hyperglycemia, type 2 diabetes, type 1 diabetes, obesity, Impaired glucose tolerance, diabetes with non-alcoholic fatty liver disease, diabetic cardiovascular disease, cardiovascular disease or non-alcoholic fatty liver disease.

3. Beneficial effects

Compared with the existing technology, the beneficial effects of the present invention are:

(1) The oral composition of the present invention can significantly improve the hypoglycemic effect of eicosapentaenoate of metformin and/or phenformin.

Detailed ways

A first aspect of the invention provides an oral composition comprising an active ingredient comprising metformin and/or an eicosapentaenoate salt of phenformin and soybean oil.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:50.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:55.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:60.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:65.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:70.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:75.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:80.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:85.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:90.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:95.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:100.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:110.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:120.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:130.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:150.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:170.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:190.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:200.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:220.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:230.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:240.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:250.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:270.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:300.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:310.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:320.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:350.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:370.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:390.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:400.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:430.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:450.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:470.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:480.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:500.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:520.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:550.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:600.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:650.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:700.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:750.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:800.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:850.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:900.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:950.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:1000.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:2000.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:3000.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:4000.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:5000.

In one embodiment, the weight ratio of the active ingredient to soybean oil is 100:6000.

In one embodiment, the active ingredient weight is 5 mg/dose.

In one embodiment, the active ingredient weight is 10 mg/dose.

In one embodiment, the active ingredient weight is 20 mg/dose.

In one embodiment, the active ingredient weight is 30 mg/dose.

In one embodiment, the active ingredient weight is 40 mg/dose.

In one embodiment, the active ingredient weight is 50 mg/dose.

In one embodiment, the active ingredient weight is 70 mg/dose.

In one embodiment, the active ingredient weight is 100 mg/dose.

In one embodiment, the active ingredient weight is 130 mg/dose.

In one embodiment, the active ingredient weight is 200 mg/dose.

In one embodiment, the active ingredient weight is 250 mg/dose.

In one embodiment, the active ingredient weight is 300 mg/dose.

In one embodiment, the active ingredient weight is 400 mg/dose.

In one embodiment, the active ingredient weight is 500 mg/dose.

In one embodiment, the active ingredient weight is 600 mg/dose.

In one embodiment, the active ingredient weight is 700 mg/dose.

In one embodiment, the active ingredient weight is 800 mg/dose.

In one embodiment, the active ingredient weight is 900 mg/dose.

In one embodiment, the active ingredient weight is 1000 mg/dose.

In one embodiment, the active ingredient weight is 1100 mg/dose.

In one embodiment, the active ingredient weight is 1200 mg/dose.

In one embodiment, the active ingredient weight is 1300 mg/dose.

In one embodiment, the active ingredient weight is 1400 mg/dose.

In one embodiment, the active ingredient weight is 1500 mg/dose.

In one embodiment, the active ingredient weight is 1600 mg/dose.

In one embodiment, the active ingredient weight is 1700 mg/dose.

In one embodiment, the active ingredient weight is 1800 mg/dose.

In one embodiment, the active ingredient weight is 2000 mg/dose.

In one embodiment, the weight of the active ingredient and soybean oil is

Active ingredient 100mg

Soybean oil 50mg

or

Active ingredient 100mg

Soybean oil 400mg

or

Active ingredient 100mg

Soybean oil 1000mg.

In a second aspect, the present invention provides a pharmaceutical preparation, which includes any one of the above oral compositions and pharmaceutical excipients.

In one embodiment, the pharmaceutical excipients include binders, disintegrants or lubricants. Preferably, the pharmaceutical excipients also include diluents, emulsifiers, solubilizers, colorants, fragrances or sweeteners. agent.

In one embodiment, the weight ratio of the binder, lubricant and disintegrant is:

Adhesive 0～4

Lubricant 0～20

Disintegrant 0～6

or

Adhesive 0～3

Lubricant 0～10

Disintegrant 0～3

or

Adhesive 3～4

Lubricant 10～20

Disintegrant 3～6.

In one embodiment, the binder is selected from starch slurry, gelatin solution, sucrose solution, polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. One or more, preferably, the disintegrant is selected from sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium or cross-linked polyvinylpyrrolidone One or more, preferably, the lubricant is selected from talc, micronized silica gel, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, stearic acid, calcium stearate or stearin One or more of the magnesium phosphates.

In one embodiment, the pharmaceutical preparation is in the form of tablets, capsules, powders, granules, capsules, pills, suppositories, ointments, gels, aerosols, films, syrups, emulsions, mixtures, etc. Suspension or injection.

In a third aspect, the present invention provides an oral composition as described in any one of the above, and a pharmaceutical preparation as described in any of the above for preparation, treatment or prevention of hyperglycemia, type 2 diabetes, type 1 diabetes, obesity, Impaired glucose tolerance, diabetes with non-alcoholic fatty liver disease, diabetic cardiovascular disease, cardiovascular disease or non-alcoholic fatty liver disease.

Example 1

Preparation of metformin eicosapentaenoate

The structure of eicosapentaenoic acid is as follows

Dissolve commercially available metformin hydrochloride with 1mo/L sodium hydroxide aqueous solution, stir for half an hour, add ethanol, spin off the solvent, then add ethanol, filter to remove sodium chloride, and spin evaporate the filtrate to obtain metformin free base.

Weigh 1 mol of metformin free base, add an appropriate amount of acetonitrile to dissolve it, filter to remove sodium chloride, slowly add 0.9 mol of eicosapentaenoic acid solution (dissolved in acetonitrile) to the filtrate, stir, and cool to 0~5°C. , filtered under nitrogen protection and protected from light to obtain a light brown solid, which is metformin eicosapentaenoate.

Example 2

Preparation of pharmaceutical compositions

Prescription (1000 tablets)

Raw materials Prescription quantity (g) metformin eicosapentaenoate 100 Soybean oil 50 Polyvinylpyrrolidone 3 Magnesium Lauryl Sulfate 10 sodium carboxymethyl starch 6

Weigh each raw and auxiliary material according to the above prescription, pass 100g of metformin eicosapentaenoate through an 80 mesh sieve, add 6g of sodium carboxymethyl starch and mix, add 50g of soybean oil and a 3% polyvinylpyrrolidone aqueous solution ( 3g polyvinylpyrrolidone and purified water), stir evenly, sieve, and granulate. After granulation, place it in a hot air circulation oven, dry at 50°C for 0.5 hours, pass through a 14-mesh sieve, and granulate. Then, add it to a three-dimensional mixer, add 10g of magnesium lauryl sulfate, 50 rpm, mix for 1 hour, finish mixing, and press into tablets to obtain a metformin eicosapentaenoate soybean oil composition.

Example 3

Preparation of pharmaceutical compositions

Prescription (1000 capsules)

Weigh each raw and auxiliary material according to the above prescription, pass 100g of metformin eicosapentaenoate through an 80 mesh sieve, add 400g of soybean oil and stir evenly. After mixing is completed, put it into a capsule to obtain metformin eicosapentaenoate. Soybean oil composition.

Example 4

Preparation of pharmaceutical compositions

Prescription (1000 tablets)

Raw materials Prescription quantity (g) metformin eicosapentaenoate 100 Soybean oil 1000 Polyvinylpyrrolidone 4 Magnesium stearate 20 sodium carboxymethyl starch 3

Weigh each raw and auxiliary material according to the above prescription, pass 100g of metformin eicosapentaenoate through an 80 mesh sieve, add 3g of sodium carboxymethyl starch and mix, add 1000g of soybean oil and a 5% polyvinylpyrrolidone aqueous solution ( 4g polyvinylpyrrolidone and purified water), stir evenly, sieve, and granulate. After granulation, place it in a hot air circulation oven, dry at 60°C for 1 hour, pass through a 14-mesh sieve, and granulate. , add to the three-dimensional mixer, add 20g magnesium stearate, 50 rpm, mix for 1 hour, after mixing is completed, press into tablets to obtain a metformin eicosapentaenoate soybean oil composition.

Example 5

Animal experiment

experimental method:

Establishment of diabetic model mice:

70 rats were fasted for 6 hours. Each rat was intraperitoneally injected with streptozotocin at a dose of 40 mg/kg once a day. At the same time, they were fed high-fat feed. Fasting blood glucose and fasting blood glucose were measured with a Roche blood glucose meter. Greater than 11.1mmol/L is considered as successful modeling. The model mice were randomly divided into 6 groups, with 10 mice in each group. Another 10 rats without modeling were selected as normal control group.

Experimental grouping:

Normal control group: 10 normal rats without modeling, injected with normal saline subcutaneously;

Model control group: 10 model mice, injected subcutaneously with normal saline;

Drug group:

The pharmaceutical compositions prepared in Examples 1-4 were administered to each group. Before each group was administered the drug, fasting blood glucose was measured with a blood glucose meter. After each group was administered the corresponding drug, each group drank water freely and continued to feed high-fat feed, and was administered on the 10th day. After trimming the tail, blood was collected, and the blood glucose of each rat was measured with a blood glucose meter. The average blood glucose value of the 10 rats in the corresponding group was obtained. The specific dosage regimen is as follows:

Group A: 10 model rats were administered the pharmaceutical composition prepared in Example 2 at 20 mg/kg rat body weight once a day for 10 consecutive days;

Group B: 10 model rats were administered the pharmaceutical composition prepared in Example 3 at 20 mg/kg rat body weight once a day for 10 consecutive days;

Group C: 10 model rats were administered the pharmaceutical composition prepared in Example 4 at 20 mg/kg rat body weight once a day for 10 consecutive days;

Group D: 10 model rats were administered 20 mg/kg rat body weight of metformin eicosapentaenoate prepared in Example 1 once a day for 10 consecutive days;

Group E: 10 model rats were administered commercially available soybean oil at a dose of 20 mg/kg rat body weight once a day for 10 consecutive days.

The experimental results are as follows

time/group Group A Group B Group C 0d 18.3±3.1 17.2±3.2 17.0±3.7 10d 7.1±1.5 6.7±3.4 7.5±2.3

time/group Group D Group E normal control group model control group 0d 18.6±2.0 17.5±2.6 5.2±2.2 18.3±3.1 10d 10.3±1.9 18.3±2.0 6.0±2.4 19.0±2.5

Among them, compared with the normal control group and the model control group, P<0.01, indicating that the diabetes modeling was successful.

There was no significant difference between group E and the model control group, indicating that soybean oil alone had poor hypoglycemic effect.

Compared with the model control group, P<0.01 in group A, group B, group C, and group D.

Compared with group D, group A, group B, group C, P<0.05.

Therefore, the combined use of metformin eicosapentaenoate and soybean oil can achieve significant hypoglycemic effects and play a synergistic effect.

Claims (10)

1. Oral composition, characterized in that, the oral composition includes an active ingredient and soybean oil, the active ingredient includes metformin and/or phenformin eicosapentaenoic acid salt, the active ingredient and soybean oil The weight ratio is 100: (50～1000). 2. The oral composition according to claim 1, wherein the weight ratio of the active ingredient to soybean oil is 100: (50-400), preferably 100: (400-1000). 3. Oral composition according to claim 1, characterized in that the weight of the active ingredient and soybean oil is Active ingredient 100mg Soybean oil 50mg or Active ingredient 100mg Soybean oil 400mg or Active ingredient 100mg Soybean oil 1000mg. 4. Pharmaceutical preparation, characterized in that the pharmaceutical preparation includes the oral composition of any one of claims 1-3 and pharmaceutical excipients. 5. The pharmaceutical preparation according to claim 4, characterized in that the pharmaceutical auxiliary materials include a binder, a disintegrant or a lubricant. Preferably, the pharmaceutical auxiliary materials further include a diluent, an emulsifier, a lubricant and a lubricant. Solvents, colorants, fragrances or sweeteners. 6. The pharmaceutical preparation according to claim 5, wherein the binder is selected from the group consisting of starch slurry, gelatin solution, sucrose solution, polyvinylpyrrolidone, methylcellulose, ethylcellulose, and hydroxypropyl fiber. One or more types of cellulose or hydroxypropyl methylcellulose. Preferably, the disintegrant is selected from sodium carboxymethyl starch, dry starch, low-substituted hydroxypropyl cellulose, and cross-linked carboxymethyl cellulose. One or more of sodium or cross-linked polyvinylpyrrolidone. Preferably, the lubricant is selected from talc, micronized silica gel, magnesium lauryl sulfate, polyethylene glycol, magnesium lauryl sulfate, hard One or more of fatty acid, calcium stearate or magnesium stearate. 7. The pharmaceutical preparation according to any one of claims 4-6, characterized in that the dosage form of the pharmaceutical preparation is tablet, capsule, powder, granule, capsule, pill, suppository, ointment, gel agents, aerosols, films, syrups, emulsions, suspensions or injections. 8. The pharmaceutical preparation according to any one of claims 4 to 7, characterized in that the pharmaceutical preparation further includes a second active ingredient, and the second active ingredient is a hypoglycemic drug. Preferably, the second active ingredient is a hypoglycemic drug. Active ingredients include insulin, insulin analogs, glycosidase inhibitors, dipeptidyl peptidase IV inhibitors, glucagon-like peptide-1 receptor agonists, sodium-dependent glucose transporter-2 inhibitors, sulfonylureas Any one or a combination of compounds or thiazolidinedione compounds. Preferably, the insulin includes porcine insulin, human insulin or recombinant human insulin. Preferably, the insulin analogues include insulin lispro, insulin aspart, glycerol, Insulin protamine or insulin detemir, preferably, the glycosidase inhibitor includes acarbose, voglibose or miglitol, preferably, the dipeptidyl peptidase IV inhibitor includes sitaglitol Vildagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, gemagliptin or texagliptin, preferably, the glucagon-like peptide-1 receptor agonist includes Exenatide, belaglutide, liraglutide, loxenatide, semaglutide, albiglutide or dulaglutide, preferably, the sodium-dependent glucose transporter-2 inhibitor Including canagliflozin, dapagliflozin, empagliflozin, empagliflozin, rupagliflozin or togliflozin, preferably, the sulfonylurea compound includes glyburide, glimepiride , gliclazide, glipizide or gliflozin. Preferably, the thiazolidinedione compound includes rosiglitazone, troglitazone, ciglitazone or pioglitazone. 9. The oral composition according to any one of claims 1 to 3 is suitable for use in the treatment or prevention of hyperglycemia, type 2 diabetes, type 1 diabetes, obesity, impaired glucose tolerance, hyperlipidemia, and diabetes with non-alcoholic Fatty liver disease, diabetic cardiovascular disease, cardiovascular disease or non-alcoholic fatty liver disease drug use. 10. The pharmaceutical preparation according to any one of claims 4 to 9 is used for the treatment or prevention of hyperglycemia, type 2 diabetes, type 1 diabetes, obesity, impaired glucose tolerance, hyperlipidemia, and diabetes with non-alcoholic fat. Applications in liver, diabetic cardiovascular disease, cardiovascular disease or non-alcoholic fatty liver disease medications.