A pharmaceutical composition injection solution of isosorbide dinitrate and a preparation method thereof

Abstract

This invention relates to an isosorbide dinitrate pharmaceutical composition injection and its preparation method. In addition to isosorbide dinitrate, the injection formulation also contains meglumine and glutathione. The preferred specifications are 5ml:5mg and 10ml:10mg. The isosorbide dinitrate injection prepared according to the formulation and process of this invention has the characteristics of high excipient safety, simple process, extremely high quality stability and good safety, which is significantly better than the prior art.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an isosorbide dinitrate pharmaceutical composition injection and its preparation method. Background Technology

[0002] Isosorbide dinitrate, chemically known as 1,4:3,6-dide-D-sorbitol dinitrate, pharmacologically relaxes smooth muscle directly, especially vascular smooth muscle; its vasodilatory effect on postcapillary veins is more persistent than on arteries. It has no significant direct effect on the myocardium. Due to the dilation of volumetric vessels, venous return decreases, reducing cardiac preload. Simultaneously, peripheral resistance vessels dilate, lowering blood pressure and reducing left ventricular ejection resistance, further decreasing cardiac afterload. This reduction in cardiac preload and afterload decreases myocardial oxygen consumption. It is primarily used to treat angina pectoris and congestive heart failure. It is widely used clinically, and currently marketed isosorbide dinitrate products include tablets, creams, and injections.

[0003] Given the widespread clinical use of isosorbide dinitrate, obtaining a more stable and safer isosorbide dinitrate injection is of great significance. Through extensive long-term research on isosorbide dinitrate, the inventors have obtained a formulation and preparation method for an isosorbide dinitrate pharmaceutical composition injection. The process is simple, requires minimal excipients, and the prepared isosorbide dinitrate formulation exhibits extremely high quality and stability, thus increasing the safety of medication use. Summary of the Invention

[0004] The purpose of this invention is to provide a stable isosorbide nitrate injection with low excipient usage, simple preparation process, and preparation method thereof.

[0005] The solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0006] A pharmaceutical composition comprising isosorbide dinitrate, meglumine, glutathione, and water for injection.

[0007] Preferably, the concentration of isosorbide dinitrate is 0.1%; the concentration of meglumine is 2%-2.4%, most preferably 2.2%; and the concentration of glutathione is 1.5%-2.0%, most preferably 1.8%.

[0008] Preferably, the isosorbide dinitrate composition injection is available in a specification of 5 ml: 5 mg or 10 ml: 10 mg.

[0009] The present invention also provides a method for preparing the above-mentioned isosorbide dinitrate composition injection, comprising the following steps:

[0010] (1) Add the prescribed amounts of isosorbide dinitrate, meglumine, and glutathione to 70% of the prescribed amount of water for injection, stir to dissolve, and obtain the first solution;

[0011] (2) Adjust the pH of the first solution to 6.0-6.2 with 0.1mol / L hydrochloric acid solution or 0.1mol / L sodium hydroxide solution, add water for injection to the total volume, cool to about 25℃ and measure the pH value and content of the solution, filter with a microporous filter, fill into ampoules according to specifications, sterilize, and obtain isosorbide dinitrate composition injection solution.

[0012] Preferably, the microporous filter element in step (2) is a 0.22 μm microporous filter element.

[0013] Preferably, the sterilization conditions in step (2) are moist heat sterilization at 121°C for 21 minutes.

[0014] This invention uses meglumine and glutathione as excipients for isosorbide dinitrate injection. Unexpectedly, it was found that the combined use of these two excipients had an unexpected effect on increasing the stability of isosorbide dinitrate. In particular, the specific ratio of meglumine (2.2%) to glutathione (1.8%) was the most effective. Detailed Implementation

[0015] To better understand the present invention, the following embodiments are further illustrations of the present invention, but the content of the present invention is not limited to the following embodiments.

[0016] Example 1: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0017] Prescription: Isosorbide dinitrate: 10g, glutathione: 18g, water for injection: 10000ml.

[0018] Example 2: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0019] Prescription: Isosorbide dinitrate: 10g, meglumine: 22g, water for injection: 10000ml.

[0020] Example 3: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0021] Prescription: Isosorbide dinitrate: 10g, glutathione: 18g, meglumine: 22g, water for injection: 10000ml.

[0022] Example 4: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0023] Prescription: Isosorbide dinitrate: 10g, glutathione: 15g, meglumine: 20g, water for injection: 10000ml.

[0024] Example 5: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0025] Prescription: Isosorbide dinitrate: 10g, glutathione: 20g, meglumine: 24g, water for injection: 10000ml.

[0026] Example 6: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0027] Prescription: Isosorbide dinitrate: 10g, glutathione: 15g, meglumine: 24g, water for injection: 10000ml.

[0028] Example 7: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0029] Prescription: Isosorbide dinitrate: 10g, glutathione: 20g, meglumine: 20g, water for injection: 10000ml.

[0030] Example 8: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0031] Prescription: Isosorbide dinitrate: 10g, glutathione: 14g, meglumine: 22g, water for injection: 10000ml.

[0032] Example 9: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0033] Prescription: Isosorbide dinitrate: 10g, glutathione: 18g, meglumine: 18g, water for injection: 10000ml.

[0034] Example 10: Isosorbide dinitrate injection (specification: 10 ml: 10 mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0035] Prescription: Isosorbide dinitrate: 10g, glutathione: 21g, meglumine: 25g, water for injection: 10000ml.

[0036] Example 11: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0037] Prescription: Isosorbide dinitrate: 10g, glutathione: 14g, meglumine: 19g, water for injection: 10000ml.

[0038] Example 12: Isosorbide dinitrate injection (specification: 5ml: 5mg) was prepared according to a prescription of 2000 pharmaceutical units.

[0039] Prescription: Isosorbide dinitrate: 10g, glutathione: 18g, meglumine: 22g, water for injection: 10000ml.

[0040] Example 13: Isosorbide dinitrate injection (specification: 10ml: 10mg) was prepared according to a prescription of 1000 pharmaceutical units.

[0041] Prescription: Isosorbide dinitrate: 10g, Water for injection: 10000ml.

[0042] The above Examples 1-12 were all prepared into injection solutions according to the following steps:

[0043] (1) Add the prescribed amounts of isosorbide dinitrate, meglumine, and glutathione to 70% of the prescribed amount of water for injection, stir to dissolve, and obtain the first solution;

[0044] (2) Adjust the pH of the first solution to 6.0-6.2 with 0.1mol / L hydrochloric acid solution or 0.1mol / L sodium hydroxide solution, add water for injection to the total volume, cool to about 25℃ and measure the pH value and content of the solution, filter with a 0.22μm microporous filter, fill into ampoules according to specifications, and sterilize by moist heat at 121℃ for 21 minutes to obtain isosorbide dinitrate composition injection solution.

[0045] In Examples 10 and 11, the prepared injection solutions crystallized after filling, failing to meet the required properties of the injection solution.

[0046] The isosorbide dinitrate injections prepared according to the formulations of Examples 1-9 and Examples 12-13 above were subjected to influencing factor tests. They were placed at 60℃ under strong light (4500lx±500lx) for 10 days. The light test involved directly placing the ampoules under the light source without additional packaging. Samples were taken and tested on day 30, and the results were compared with those from day 0 to examine the stability of the samples. The results are shown in Tables 1-2.

[0047] Table 1. Results of content and impurity stability tests at 60℃

[0048]

[0049] Table 2. Test results of strong light (4500lx±500lx) content and impurity stability.

[0050]

[0051] As can be seen from the results in Table 1-2, the combined use of meglumine and glutathione in this invention has an unexpected effect on improving the stability of isosorbide dinitrate. Even slight changes in the amount of meglumine and glutathione will produce significant differences. The combined amount of meglumine and glutathione in this invention is crucial to the technical effect of this invention.

[0052] This invention provides the following experimental and comparative results:

[0053] 1. Sample 1 (Isosorbide dinitrate injection prepared in Example 3 of this invention).

[0054] 2. Sample 2 (Isosorbide dinitrate injection prepared in Example 12 of this invention);

[0055] 3. Sample 3 (commercially available isosorbide dinitrate injection);

[0056] Samples 1 to 3 were subjected to accelerated stability testing (40℃±2℃, RH 75%±5%) for 6 months. The results are shown in Table 3.

[0057] Table 3. Accelerated test stability results

[0058]

[0059] As can be seen from the results in Table 3, the isosorbide dinitrate injection prepared by the formulation and process of this invention maintains extremely high stability and has significant advantages in content, related substances, and marketed products.

[0060] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. An isosorbide dinitrate pharmaceutical composition injection, characterized in that: It is composed of isosorbide dinitrate, meglumine, glutathione and water for injection.

2. The isosorbide dinitrate pharmaceutical composition injection as described in claim 1, characterized in that: The concentration of isosorbide dinitrate is 0.1%; the concentration of meglumine is 2%-2.4%; and the concentration of glutathione is 1.5%-2.0%.

3. The isosorbide dinitrate pharmaceutical composition injection as described in claim 2, characterized in that: The concentration of meglumine is 2.2%, and the concentration of glutathione is 1.8%.

4. The isosorbide dinitrate pharmaceutical composition injection according to any one of claims 1-3, characterized in that: The specifications of the injection solution are: 5ml:5mg and 10ml:10mg.

5. A method for preparing the isosorbide nitrate composition injection according to any one of claims 1-4, characterized in that, It can be prepared by the following methods: (1) Add the prescribed amounts of isosorbide dinitrate, meglumine, and glutathione to 70% of the prescribed amount of water for injection, stir to dissolve, and obtain the first solution; (2) Dissolve the first solution in 0.1 mol / L hydrochloric acid solution or 0.1 mol / L sodium hydroxide solution, adjust the pH of the first solution to 6.0-6.2, add water for injection to the total volume, cool to about 25℃ and measure the pH value and content of the solution, filter with a microporous filter, fill into ampoules according to specifications, sterilize, and obtain isosorbide dinitrate composition injection solution.

6. The preparation method according to claim 5, characterized in that: The microporous filter element in step (2) is a 0.22μm microporous filter element.

7. The preparation method according to claim 5, characterized in that: The sterilization conditions described in step (2) are moist heat sterilization at 121°C for 21 minutes.

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