Insulin aspart 50 injection and preparation method thereof

Abstract

The invention provides an insulin aspart 50 injection and a preparation method thereof, and belongs to the field of pharmaceutical preparations, the insulin aspart 50 injection comprises the following components: insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100,000 IU: (0.21-0.42 g): (16-20 g): (1.5-2 g): (1-2 g): (0.8-1 g): (1-1.5 g), and the pH value is 7.0-7.8. The preparation method is simple in preparation process, scientific and reasonable, and the preparation method is suitable for industrial production. The preparation method is simple and easy to operate, the prepared insulin aspart 50 injection has the advantages of high stability and good drug effect, the insulin aspart in the injection exists in two forms, one form is in a solution and plays a quick-acting role, and the other form is in a solution. One of the two insulin preparations is combined with protamine sulfate to form a precipitate, and has the time phase characteristic of medium-efficiency insulin, so that the insulin preparation has the action characteristics of two insulin preparations, great convenience is brought to diabetics, and the injection frequency and the pain and inconvenience caused by the injection frequency are reduced.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and specifically relates to an insulin aspart 50 injection and a method for preparing the insulin aspart 50 injection. Background Art

[0002] Diabetes is mainly divided into type 1 diabetes and type 2 diabetes. Type 1 diabetes is also called insulin-dependent diabetes. The cause is that the body's immune system attacks the beta cells that produce insulin in the body, which eventually leads to the inability to produce insulin in the body. Patients with type 1 diabetes need to continuously inject exogenous insulin to control blood sugar in the body. Type 2 diabetes is called non-insulin-dependent diabetes. The main cause is insulin resistance (that is, the cells no longer bind to insulin, which reduces the amount of glucose that enters the cells to participate in heat generation and increases the amount of glucose left in the blood). Patients with type 2 diabetes can usually take oral hypoglycemic drugs to help control blood sugar in the body. However, studies have shown that for patients with type 2 diabetes, as long as blood sugar rises to a level sufficient to diagnose diabetes, insufficient insulin secretion becomes the main contradiction. Therefore, almost all patients with type 2 diabetes need to use exogenous insulin to treat and control blood sugar during the course of the disease. In other words, insulin treatment is almost the most basic and important means for all diabetic patients to control blood sugar.

[0003] According to the source, medicinal insulin is mainly divided into: 1) animal insulin, such as bovine insulin (extracted from bovine pancreas, there are three amino acids in the molecular structure that are different from human insulin, the efficacy is slightly worse, and it is more prone to allergies or insulin resistance), porcine insulin (extracted from porcine pancreas, there is only one amino acid in the molecule that is different from human insulin, so the efficacy is better than bovine insulin and the side effects are also less than bovine insulin); 2) human insulin, such as semi-biosynthetic human insulin (porcine insulin is enzymatically converted to convert the 30th position of the B chain of alanine Ala into human threonine Thr) and recombinant human insulin; 3) insulin analogs.

[0004] According to the duration of action, insulin can be divided into: 1) Short-acting insulin: the most commonly used regular insulin, a colorless transparent liquid, takes effect 20 to 30 minutes after subcutaneous injection, has a peak effect of 2 to 4 hours, and lasts for 5 to 8 hours; 2) Intermediate-acting insulin: also called low-protamine zinc insulin, a milky white turbid liquid, takes effect 1.5 to 4 hours, has a peak effect of 6 to 10 hours, and lasts for about 12 to 14 hours; 3) Long-acting insulin: also called protamine zinc insulin, also a milky white turbid liquid, has a super-effective time of 3 to 4 hours, a peak effect of 14 to 20 hours, and lasts for about 24 to 36 hours; 4) Premixed insulin (biphasic insulin): short-acting insulin preparations and intermediate-acting insulin preparations are mixed in different proportions to produce premixed insulins with an onset time and duration of action between the two, such as protamine recombinant human insulin injection (premixed 30R), protamine recombinant human insulin injection (premixed 50R), aspart insulin 30 injection, and aspart insulin 50 injection.

[0005] The invention patent with authorization announcement number: CN101035557B provides a method for preparing aspart insulin 50 / 30 injection. In this method, disodium hydrogen phosphate dihydrate, sodium chloride, phenol, meta-cresol, glycerol and sodium hydroxide are mixed to form solution I, and then sodium chloride, meta-cresol, phenol, glycerol, protamine sulfate, AspB28 human insulin, hydrochloric acid and zinc chloride are mixed to form solution II. Finally, solution I and solution II are mixed to prepare aspart insulin injection. However, the preparation prepared by this method has the problem of uneven crystal form, and the stability of the preparation is insufficient and the efficacy is unstable. Summary of the invention

[0006] Based on the above problems in the prior art, the present invention provides an insulin aspart 50 injection, which includes insulin aspart, protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride and disodium hydrogen phosphate.

[0007] In the present invention, "insulin" includes:

[0008] Animal insulin, such as bovine insulin and porcine insulin;

[0009] Human insulin, such as semi-biosynthetic human insulin and recombinant human insulin;

[0010] Insulin analogs, such as insulin glargine, insulin aspart, and insulin degludec.

[0011] The "biphasic" in "biphasic insulin" means that this product contains two types of insulin with different onset times and duration of action, some of which are soluble insulin (rapid-acting) and some of which are low-protamine zinc insulin (intermediate-acting). For example, 30 / 70 means that 30% of the insulin injection is rapid-acting insulin and 70% is intermediate-acting insulin.

[0012] "Insulin Aspart 50 Injection" means: it contains 50% soluble insulin aspart and 50% intermediate-acting insulin aspart, with a faster onset of action and a more moderate duration of action.

[0013] Preferably, the insulin aspart 50 injection comprises the following ingredients in the following proportions:

[0014] Insulin Aspart: Protamine Sulfate: Glycerol: Meta-cresol: Phenol: Sodium Chloride: Disodium Hydrogen Phosphate = 100000 IU: 0.21-0.42 g: 16-20 g: 1.5-2 g: 1-2 g: 0.8-1 g: 1-1.5 g, pH value is 7.0-7.8.

[0015] Preferably, the insulin aspart 50 injection comprises the following ingredients in the following proportions:

[0016] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.21g: 16g: 1.5g: 1g: 0.8g: 1g.

[0017] Preferably, the insulin aspart 50 injection comprises the following ingredients in the following proportions:

[0018] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.31g: 18g: 1.75g: 1.5g: 0.9g: 1.25g.

[0019] Preferably, the insulin aspart 50 injection comprises the following ingredients in the following proportions:

[0020] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.42g: 20g: 2g: 2g: 1g: 1.5g.

[0021] The present invention also provides a method for preparing insulin aspart 50 injection, which comprises firstly mixing and dissolving insulin aspart, protamine sulfate, glycerol, meta-cresol, phenol and sodium chloride to prepare liquid A, then dissolving disodium hydrogen phosphate to prepare liquid B, and finally mixing and stirring liquid A and liquid B to obtain a suspension, which is a finished product, and comprises the following detailed steps:

[0022] Step S1, taking glycerol, m-cresol, phenol and sodium chloride, mixing and dissolving them with water for injection, then adding insulin aspart, adding hydrochloric acid solution while stirring until the insulin aspart is completely dissolved, then adding protamine sulfate, stirring evenly, and then making up the volume to 50% of the total amount with water for injection, adjusting the pH to 3.0-3.4, and filtering with a 0.22 um filter membrane to obtain liquid A;

[0023] Step S2, taking disodium hydrogen phosphate, dissolving it with water for injection and making up the volume to 50% of the total amount, adjusting the pH so that the pH after mixing equal volumes of solution A and solution B is 7.0-7.8, filtering with a 0.22 um filter membrane to obtain solution B;

[0024] Step S3, mixing liquid A and liquid B, stirring evenly to obtain a suspension.

[0025] The ratio of aspart insulin to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride and disodium hydrogen phosphate is 100000 IU: 0.21-0.42 g: 16-20 g: 1.5-2 g: 1-2 g: 0.8-1 g: 1-1.5 g.

[0026] The ratio of insulin aspart to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride and disodium hydrogen phosphate is 100000 IU: 0.21 g: 16 g: 1.5 g: 1 g: 0.8 g: 1 g;

[0027] or the ratio of insulin aspart to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride, and disodium hydrogen phosphate is 100,000 IU: 0.31 g: 18 g: 1.75 g: 1.5 g: 0.9 g: 1.25 g;

[0028] Or the ratio of aspart insulin to protamine sulfate, glycerol, m-cresol, phenol, sodium chloride, and disodium hydrogen phosphate is 100,000 IU: 0.42 g: 20 g: 2 g: 2 g: 1 g: 1.5 g.

[0029] The beneficial effects of the present invention are:

[0030] 1. In the present invention, aspart insulin exists in two forms, one in solution, exerting a rapid-acting effect; the other combined with protamine sulfate exists in a precipitate, having the phase characteristics of intermediate-acting insulin. Thus, it has the action characteristics of two insulin preparations, greatly facilitating diabetics, reducing the number of injections and the pain and inconvenience caused thereby.

[0031] 2. The preparation method of the present invention has a simple preparation process, is scientific and reasonable, and is easy to operate, and the prepared insulin aspart 50 injection has the advantages of high stability and good efficacy. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The present invention is a schematic flow chart of a method for preparing insulin aspart 50 injection. DETAILED DESCRIPTION

[0033] The technical solution of the present invention is described below in conjunction with the accompanying drawings and specific embodiments.

[0034] Embodiment 1:

[0035] As attached Figure 1 The method for preparing an insulin aspart 50 injection is shown, which firstly mixes and dissolves insulin aspart, protamine sulfate, glycerol, meta-cresol, phenol and sodium chloride to prepare liquid A, then dissolves disodium hydrogen phosphate to prepare liquid B, and finally mixes and stirs liquid A and liquid B to obtain a suspension, which is the finished product, and includes the following detailed steps:

[0036] Step S1, weigh 16g glycerol, 1.5g m-cresol, 1g phenol and 0.8g sodium chloride respectively, mix them in a container, add an appropriate amount of water for injection, stir until completely dissolved, then add 100000IU insulin aspart, add an appropriate amount of hydrochloric acid solution while stirring until the insulin aspart is completely dissolved, then add a protamine sulfate solution equivalent to 0.21g protamine sulfate, stir evenly, then dilute to 500ml with water for injection, adjust the pH to 3.0-3.4, filter with a 0.22um filter membrane, and obtain liquid A;

[0037] Step S2, take 1g of disodium hydrogen phosphate, dissolve it in water for injection and make the volume to 500ml, adjust the pH so that the pH after mixing equal volumes of solution A and solution B is 7.0, and filter it with a 0.22um filter membrane to obtain solution B;

[0038] Step S3, mixing equal volumes of liquid A and liquid B, stirring evenly, to obtain a suspension, namely the prepared insulin aspart 50 injection, which includes the following components in the following proportions:

[0039] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.21g: 16g: 1.5g: 1g: 0.8g: 1g.

[0040] Embodiment 2:

[0041] The difference between this embodiment and the first embodiment is that the ingredients of the insulin aspart 50 injection are prepared in different proportions. Specifically, the dosage in step S1 is: 18 g glycerol, 1.75 g m-cresol, 1.5 g phenol, 0.9 g sodium chloride, 100,000 IU insulin aspart and 0.31 g protamine sulfate. The dosage of disodium hydrogen phosphate in step S2 is 1.25 g. The pH of the mixture of liquid A and liquid B is 7.4. The mixture is stirred evenly to obtain a suspension, i.e., the prepared insulin aspart 50 injection, which includes the following ingredients in the following proportions:

[0042] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.31g: 18g: 1.75g: 1.5g: 0.9g: 1.25g.

[0043] Embodiment three:

[0044] The difference between this embodiment and the first embodiment is that the ingredients of the insulin aspart 50 injection are prepared in different proportions. Specifically, the dosage in step S1 is: 20 g glycerol, 2 g m-cresol, 2 g phenol, 1 g sodium chloride, 100,000 IU insulin aspart and 0.42 g protamine sulfate. The dosage of disodium hydrogen phosphate in step S2 is 1.5 g. The pH of the mixture of liquid A and liquid B is 7.8. The mixture is stirred evenly to obtain a suspension, i.e., the prepared insulin aspart 50 injection, which includes the following ingredients in the following proportions:

[0045] Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.42g: 20g: 2g: 2g: 1g: 1.5g.

[0046] The insulin aspart 50 injections prepared in the three examples were tested below.

[0047] Experiment 1: Verification of drug efficacy.

[0048] Experimental subjects: Healthy Beagle dogs

[0049] Experimental method: Using a random cross-administration scheme, 6 healthy Beagle dogs were subcutaneously injected with the same dose of short-acting insulin, intermediate-acting insulin, and insulin aspart 50 injection prepared in Examples 1 to 3, and dynamic blood samples were collected within 24 hours as designed. The blood glucose level of the animals was measured using a Roche blood glucose meter, and the relevant data were recorded as follows:

[0050]

[0051]

[0052] It can be seen from the above efficacy data that the onset time of the aspart insulin 50 injection provided by the present invention is shorter than that of conventional short-acting insulin, the time to reach the peak of action is shorter than that of short-acting insulin, the duration of action is longer than that of short-acting insulin and slightly shorter than that of intermediate-acting insulin, and it has the advantages of short onset time and long duration.

[0053] Test 2: Stability verification.

[0054] Generally, insulin preparations need to be stored in a refrigerator at 2-8°C. According to the current pharmacopoeia requirements, they need to be verified by destructive testing (influencing factor testing) within 28 days. The test data are shown below.

[0055] The insulin aspart 50 injection prepared in Examples 1 to 3 was placed under high temperature and light conditions for 30 days, and samples were taken for testing at 0, 7, 14 and 28 days, respectively. The test results are as follows:

[0056] Table 1: Stability data of insulin aspart 50 injection in Example 1

[0057]

[0058] Table 2: Stability data of insulin aspart 50 injection in Example 2

[0059]

[0060] Table 3: Stability data of insulin aspart 50 injection in Example 3

[0061]

[0062] From the above stability data, it can be seen that the content of the active ingredient (soluble insulin aspart) in the insulin aspart 50 injection prepared in the example is almost unchanged when placed for up to 28 days under high temperature (40±2°C) or light (4500±500lx) conditions, and the changes in the contents of other related impurities are also far better than the requirements of relevant drug quality standards, which proves that the drug prepared by the method of the present invention has very excellent stability and fully meets the requirements of relevant drug quality standards.

[0063] The present invention provides the above embodiments only to illustrate rather than limit the technical solutions of the present invention. Although the above embodiments describe the present invention in detail, relevant technical personnel in the field should understand that the present invention can be modified or equivalently replaced, but any modification and partial replacement that does not depart from the spirit and scope of the present invention should be included in the scope of the claims of the present invention.

Claims

1. An insulin aspart 50 injection, characterized in that: It includes insulin aspart, protamine sulfate, glycerol, m-cresol, phenol, sodium chloride, and disodium hydrogen phosphate.

2. The insulin aspart 50 injection according to claim 1, characterized in that: It includes the following ingredients in the following proportions: Insulin Aspart: Protamine Sulfate: Glycerol: Meta-cresol: Phenol: Sodium Chloride: Disodium Hydrogen Phosphate = 100000 IU: 0.21-0.42 g: 16-20 g: 1.5-2 g: 1-2 g: 0.8-1 g: 1-1.5 g, pH value is 7.0-7.

8.

3. The insulin aspart 50 injection according to claim 2, characterized in that: It includes the following ingredients in the following proportions: Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.21g: 16g: 1.5g: 1g: 0.8g: 1g.

4. The insulin aspart 50 injection according to claim 2, characterized in that: It includes the following ingredients in the following proportions: Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.31g: 18g: 1.75g: 1.5g: 0.9g: 1.25g.

5. The insulin aspart 50 injection according to claim 2, characterized in that: It includes the following ingredients in the following proportions: Insulin aspart: protamine sulfate: glycerol: m-cresol: phenol: sodium chloride: disodium hydrogen phosphate = 100000 IU: 0.42g: 20g: 2g: 2g: 1g: 1.5g.

6. A method for preparing insulin aspart 50 injection, characterized in that: First, insulin aspart, protamine sulfate, glycerol, meta-cresol, phenol and sodium chloride are mixed and dissolved to prepare liquid A, then disodium hydrogen phosphate is dissolved to prepare liquid B, and finally liquid A and liquid B are mixed and stirred to obtain a suspension, which is the finished product.

7. The method for preparing insulin aspart 50 injection according to claim 6, characterized in that: It includes the following detailed steps: Step S1, taking glycerol, m-cresol, phenol and sodium chloride, mixing and dissolving them with water for injection, then adding insulin aspart, adding hydrochloric acid solution while stirring until the insulin aspart is completely dissolved, then adding protamine sulfate, stirring evenly, and then making up the volume to 50% of the total amount with water for injection, adjusting the pH to 3.0-3.4, and filtering with a 0.22 um filter membrane to obtain liquid A; Step S2, taking disodium hydrogen phosphate, dissolving it with water for injection and making up the volume to 50% of the total amount, adjusting the pH so that the pH after mixing equal volumes of solution A and solution B is 7.0-7.8, filtering with a 0.22 um filter membrane to obtain solution B; Step S3, mixing liquid A and liquid B, stirring evenly to obtain a suspension.

8. The method for preparing insulin aspart 50 injection according to claim 7, characterized in that: The ratio of insulin aspart to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride and disodium hydrogen phosphate is 100000 IU: 0.21-0.42 g: 16-20 g: 1.5-2 g: 1-2 g: 0.8-1 g: 1-1.5 g.

9. The method for preparing insulin aspart 50 injection according to claim 8, characterized in that: The ratio of insulin aspart to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride, and disodium hydrogen phosphate is 100000 IU: 0.21 g: 16 g: 1.5 g: 1 g: 0.8 g: 1 g; or the ratio of insulin aspart to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride, and disodium hydrogen phosphate is 100,000 IU: 0.31 g: 18 g: 1.75 g: 1.5 g: 0.9 g: 1.25 g; Or the ratio of aspart insulin to protamine sulfate, glycerol, meta-cresol, phenol, sodium chloride, and disodium hydrogen phosphate is 100,000 IU: 0.42 g: 20 g: 2 g: 2 g: 1 g: 1.5 g.

Images