Diprophylline injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a diprophylline injection and a preparation method thereof. The diprophylline injection provided by the invention is prepared from the following components: hydroxypropyl-beta-cyclodextrin, glycine, diprophylline and water for injection. The hydroxypropyl-beta-cyclodextrin and the glycine are added into the diprophylline injection, and the two components have a synergistic effect, so that the stability of the diprophylline injection after being placed for a long time can be obviously improved, and the increase of the content of impurities in the injection after being placed for a long time can be effectively prevented; therefore, the quality and the drug effect of the diprophylline injection product are effectively improved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a dyphylline injection and a preparation method thereof. Background Art

[0002] Diprophylline, chemically named 1,3-dimethyl-7-(2,3-dihydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione, is also called theophylline or glyceryl theophylline. It is a traditional xanthine bronchodilator. As a commonly used smooth muscle relaxant, diprophylline effectively inhibits phosphodiesterase, thereby increasing the CMP (cytosine nucleotide) content in cells, promoting smooth muscle relaxation, and thus dilating the trachea. In addition, it can also promote the release of endogenous adrenaline and norepinephrine, thereby dilating the coronary arteries and bronchi, which can effectively counteract the contraction of the respiratory tract by regulations, which is also very helpful in controlling the development of the disease. Diprophylline is suitable for relieving wheezing symptoms in bronchial asthma, asthmatic bronchitis, obstructive pulmonary emphysema, etc. It is especially suitable for patients with asthma who cannot tolerate aminophylline or have tachycardia due to gastrointestinal irritation symptoms and are not suitable for theophylline. The dosage forms currently on the market are mainly tablets, injections and suppositories, among which injections are the most common. At present, after the preparation of the diphylline injection, there is a risk of precipitation when it is stored for a long time at room temperature. Once the diphylline injection precipitates, it will seriously affect the quality and efficacy of the product. Therefore, in order to ensure product quality, it is necessary to solve the problem of precipitation of the diphylline injection. Summary of the invention

[0003] Aiming at the problem that the existing diphylline injection is easy to precipitate after long-term storage, the present invention provides a diphylline injection. The present invention adds hydroxypropyl-β-cyclodextrin and glycine to the diphylline injection. The two components act synergistically, thereby significantly improving the stability of the diphylline injection after long-term storage, further reducing the content of impurities in the injection after long-term storage, and effectively preventing the increase of the content of impurities in the injection after long-term storage.

[0004] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0005] A diprophylline injection comprises the following components: hydroxypropyl-β-cyclodextrin, glycine, diprophylline and water for injection.

[0006] At present, existing studies have shown that in the process of preparing diphylline injection, the risk of precipitation of diphylline injection can be reduced by adopting step-by-step heating and step-by-step cooling. However, the inventors have found through experimental studies that the diphylline injection prepared by the method will have an increase in impurities after long-term storage, thereby affecting the quality and efficacy of the product to a certain extent. Therefore, in order to further improve the storage stability of diphylline injection, avoid the precipitation of diphylline injection, and reduce its impurity content, it is of great significance to provide a diphylline injection.

[0007] Compared with the prior art, the hydroxypropyl-β-cyclodextrin in the dihydroxypropyl theophylline injection provided by the present invention has a cavity structure inside, and part of the molecular structure of the dihydroxypropyl theophylline can enter the cavity structure of the hydroxypropyl-β-cyclodextrin, thereby improving the solubility of the dihydroxypropyl theophylline in water to a certain extent; however, it has been found through experiments that although only adding hydroxypropyl-β-cyclodextrin can improve the solubility of the dihydroxypropyl theophylline to a certain extent and reduce the precipitation of the dihydroxypropyl theophylline in a short period of time, the precipitation of the dihydroxypropyl theophylline is inevitable after long-term storage, and, after testing, the impurity content thereof also shows a significant increasing trend; the inventors accidentally discovered through a large number of experiments that by adding glycine to the dihydroxypropyl theophylline injection added with hydroxypropyl-β-cyclodextrin, the dihydroxypropyl theophylline injection can be improved. The problem of poor stability of diphylline injection after long-term storage is significantly improved. Further research shows that glycine, as a cosolvent, can also play a synergistic role with hydroxypropyl-β-cyclodextrin, greatly improving the solubility and stability of diphylline, thereby solving the problem of crystallization of diphylline injection after long-term storage; glycine also acts as an antioxidant and pH stabilizer in diphylline injection, and glycine can interact with diphylline to inhibit its decomposition reaction, thereby improving the stability of diphylline and reducing the increase of impurities in diphylline injection; glycine can also stabilize the pH of diphylline injection, further reducing the increase of impurities in diphylline injection, and solving the problem of easy crystallization of diphylline injection after long-term storage.

[0008] The invention adds hydroxypropyl-β-cyclodextrin and glycine to the diphylline injection, and the two components act synergistically, which can significantly improve the stability of the diphylline injection after long-term storage, and further prevent the increase of the content of impurities in the injection after long-term storage, thereby effectively improving the quality and efficacy of the diphylline injection.

[0009] Preferably, the mass ratio of hydroxypropyl-β-cyclodextrin to dyphylline is (3-4):1.

[0010] Preferably, the mass ratio of glycine to dyphylline is (0.4-0.5):1.

[0011] The present invention further defines the dosage relationship between hydroxypropyl-β-cyclodextrin, glycine and diprophylline, which can further improve the solubility of diprophylline and solve the problem of precipitation of diprophylline injection after long-term storage; the preferred ratio prevents the increase of impurity content in the diprophylline injection, thereby greatly improving the stability of the diprophylline injection.

[0012] Preferably, the mass volume ratio of the diphylline to water for injection is 300 mg:2 mL.

[0013] The second aspect of the present invention provides a method for preparing the above-mentioned dyphylline injection, comprising the following steps:

[0014] Step a, at 50° C.-55° C., add 70%-75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dyphylline and glycine to a preparation tank in sequence, mix well, add water for injection to the total amount of preparation, adjust the pH to 5-5.5, and obtain dyphylline solution;

[0015] Step b, filtering the diphylline solution through a multi-stage polyethersulfone filter element with successively decreasing pore sizes, filling, sealing, and sterilizing to obtain a diphylline injection.

[0016] The inventors found in the process of studying the preparation method of diprophylline injection that the order of adding hydroxypropyl-β-cyclodextrin, diprophylline and glycine and the distribution ratio of water for injection have a great influence on the solubility of diprophylline injection and the stability of diprophylline after long-term storage. Only in the specific preparation method provided by the present invention, by determining the distribution ratio of water for injection and the dissolution order of hydroxypropyl-β-cyclodextrin, diprophylline and glycine, and preparing at a specific temperature, the stability of diprophylline injection is greatly improved, so that no precipitation phenomenon will occur after long-term storage.

[0017] Preferably, in step a, the conditions for uniform mixing are: stirring at a rate of 28 r / min-30 r / min for 28 min-30 min.

[0018] Preferably, in step b, the multi-stage polyethersulfone filter element is a two-stage polyethersulfone filter element.

[0019] Further preferably, in step b, the pore size of the first-stage polyethersulfone filter element in the two-stage polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm.

[0020] The present invention adopts a two-stage polyethersulfone filter element with a specific pore size for sequential filtration, which can not only ensure that the bacteria and endotoxin content of the product are qualified, but also ensure that the particles and visible foreign matter of the product are qualified. In addition, no activated carbon is used in the production process, which reduces the pollution to the production clean area, alleviates the environmental protection pressure, and also reduces the impurities and insoluble particles that may be introduced by the activated carbon, which is conducive to further improving the effectiveness, safety and stability of product quality.

[0021] Preferably, in step b, the sterilization temperature is 121° C. and the sterilization time is 15 min-20 min.

[0022] The sterilization conditions provided by the present invention improve the impurity level of the product and also enhance the sterility assurance level of the product.

[0023] The preparation method of the diphylline injection provided by the present invention improves the storage stability of the diphylline injection, does not significantly increase the impurity content in stability and acceleration investigation tests, and does not cause crystallization when the injection is placed for a long time, thereby improving production efficiency, reducing production costs, facilitating industrial production, and having broad application prospects. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0025] In order to better illustrate the present invention, further examples are given below.

[0026] Example 1

[0027] This embodiment also provides a diprophylline injection, the prescription dosage is as follows:

[0028]

[0029] This embodiment also provides a method for preparing diprophylline injection, and the specific steps are as follows:

[0030] Step a, at 55° C., add 75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, diprophylline and glycine to a preparation tank in sequence, stir at a rate of 30 r / min for 28 min, add water for injection to the total amount of preparation, adjust the pH to 5.5, and obtain diprophylline solution;

[0031] Step b, filtering the diprophylline solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm, filling, sealing, and sterilizing to obtain diprophylline injection, wherein the sterilization temperature is 121° C. and the sterilization time is 15 min.

[0032] Example 2

[0033] This embodiment also provides a diprophylline injection, the prescription dosage is as follows:

[0034]

[0035] This embodiment also provides a method for preparing diphylline injection, and the specific steps are as follows:

[0036] Step a, at 50° C., add 70% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dyphylline and glycine to a preparation tank in sequence, stir at a rate of 28 r / min for 30 min, add water for injection to the total amount of preparation, adjust the pH to 5, and obtain dyphylline solution;

[0037] Step b, filtering the diprophylline solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm, filling, sealing, and sterilizing to obtain diprophylline injection, wherein the sterilization temperature is 121° C. and the sterilization time is 20 min.

[0038] Example 3

[0039] This embodiment also provides a diprophylline injection, the prescription dosage is as follows:

[0040]

[0041] This embodiment also provides a method for preparing diphylline injection, and the specific steps are as follows:

[0042] Step a, at 53° C., add 73% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dyphylline and glycine to a preparation tank in sequence, stir at a rate of 30 r / min for 29 min, add water for injection to the total amount of preparation, adjust the pH to 5.3, and obtain dyphylline solution;

[0043] Step b, filtering the diprophylline solution through a two-stage polyethersulfone filter element, wherein the pore size of the first-stage polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm, filling, sealing, and sterilizing to obtain diprophylline injection, wherein the sterilization temperature is 121° C. and the sterilization time is 18 min.

[0044] Comparative Example 1

[0045] This comparative example provides a diprophylline injection, and its preparation method is exactly the same as that of Example 1, except that glycine in the formula is replaced by an equal amount of serine, and other operations are the same as those of Example 1.

[0046] Comparative Example 2

[0047] This comparative example provides a diprophylline injection, and its preparation method is exactly the same as that of Example 1, except that the hydroxypropyl-β-cyclodextrin in the formula is replaced by an equal amount of polyethylene glycol, and the other operations are the same as those of Example 1.

[0048] Comparative Example 3

[0049] This comparative example provides a diprophylline injection, and its preparation method is exactly the same as that of Example 1, except that glycine in the formula is replaced by an equal amount of hydroxypropyl-β-cyclodextrin, and other operations are the same as those of Example 1.

[0050] Comparative Example 4

[0051] This comparative example provides a diprophylline injection, and its preparation method is exactly the same as that of Example 1, except that the hydroxypropyl-β-cyclodextrin in the formula is replaced by an equal amount of glycine, and the other operations are the same as those of Example 1.

[0052] Comparative Example 5

[0053] This comparative example provides a diprophylline injection, the formula of which is exactly the same as that of Example 1, except that:

[0054] Step a, at 65° C., add 75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, diprophylline and glycine to a preparation tank in sequence, stir at a rate of 30 r / min for 28 min, add water for injection to the total amount of preparation, adjust the pH to 5.5, and obtain diprophylline solution;

[0055] The other operations are the same as those in Example 1.

[0056] Comparative Example 6

[0057] This comparative example provides a diprophylline injection, the formula of which is exactly the same as that of Example 1, except that:

[0058] Step a, at 55°C, add 75% of the total volume of water for injection, glycine, diprophylline and hydroxypropyl-β-cyclodextrin to the preparation tank in sequence, stir at a rate of 30r / min for 28min, add water for injection to the total volume, adjust the pH to 5.5, and obtain diprophylline solution

[0059] The other operations are the same as those in Example 1.

[0060] Comparative Example 7

[0061] This comparative example provides a diprophylline injection, the formula of which is exactly the same as that of Example 1, except that:

[0062] Step a, at 55° C., add 85% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, diprophylline and glycine to a preparation tank in sequence, stir at a rate of 30 r / min for 28 min, add water for injection to the total amount of preparation, adjust the pH to 5.5, and obtain diprophylline solution;

[0063] The other operations are the same as those in Example 1.

[0064] The diprophylline injection products prepared in Examples 1-3 and Comparative Examples 1-7 were subjected to an accelerated test, wherein the temperature treatment condition was 40±2°C and the humidity treatment condition was 75%±5%. The results are shown in Table 1-4.

[0065] Among them, impurity A is theophylline, impurity B is theophylline, impurity C is hydroxyethyltheophylline, and impurity D is hydroxypropyltheophylline.

[0066] Table 1 Experimental results of Examples 1-3

[0067]

[0068] Table 2 Comparative Examples 1-3 Test Results

[0069]

[0070]

[0071] Table 3 Comparative Examples 4-5 Test Results

[0072]

[0073]

[0074] Table 4 Comparative Examples 6-7 Test Results

[0075]

[0076]

[0077] The stability test was conducted on the diphylline injection products prepared in Examples 1-3 and Comparative Examples 1-7, wherein the temperature treatment condition was: 30±2°C, and the humidity treatment condition was: 65%±5%. The results are shown in Tables 5-9;

[0078] Table 5 Experimental results of Example 1-2

[0079]

[0080]

[0081] Table 6 Experimental results of Example 3 and Comparative Example 1

[0082]

[0083]

[0084] Table 7 Comparative Examples 2-3 Test Results

[0085]

[0086]

[0087] Table 8 Comparative Examples 4-5 Test Results

[0088]

[0089]

[0090] Table 9 Comparative Examples 6-7 Test Results

[0091]

[0092] It can be seen from the above test data that compared with Comparative Examples 1-7, the impurity content in the dihydroxypropylphylline injection prepared in Examples 1-3 of the present invention is lower and the stability is higher. The increase in impurity content during the accelerated 3-month and 6-month tests is significantly lower than that in Comparative Examples 1-7, and there is no precipitation in the injection after accelerated placement for 6 months; when doing a long-term stability test, the dihydroxypropylphylline injection provided by the embodiment of the present invention still has no precipitation after long-term placement for 24 months, and the impurity content is significantly lower than that of the dihydroxypropylphylline injection provided in Comparative Examples 1-7; This proves that the dihydroxypropylphylline injection prepared in the embodiment of the present invention has better stability and safety, which is more conducive to improving the safety of clinical application.

[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A diphylline injection, characterized in that: The invention comprises the following components: hydroxypropyl-β-cyclodextrin, glycine, dihydroxypropylphylline and water for injection.

2. The dyphylline injection according to claim 1, characterized in that The mass ratio of hydroxypropyl-β-cyclodextrin to dyphylline is (3-4):

1.

3. The dyphylline injection according to claim 1, characterized in that: The mass ratio of glycine to dyphylline is (0.4-0.5):

1.

4. The dyphylline injection according to claim 1, characterized in that The mass volume ratio of the diprophylline to water for injection is 300 mg:2 mL.

5. A method for preparing the dyphylline injection according to any one of claims 1 to 4, characterized in that: The steps include: Step a, at 50° C.-55° C., add 70%-75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dyphylline and glycine to a preparation tank in sequence, mix well, add water for injection to the total amount of preparation, adjust the pH to 5-5.5, and obtain dyphylline solution; Step b, filtering the diphylline solution through a multi-stage polyethersulfone filter element with successively decreasing pore sizes, filling, sealing, and sterilizing to obtain a diphylline injection.

6. The method for preparing dyphylline injection according to claim 5, characterized in that: In step a, the uniform mixing condition is: stirring at a rate of 28 r / min-30 r / min for 28 min-30 min.

7. The method for preparing dyphylline injection according to claim 5, characterized in that: In step b, the multi-stage polyethersulfone filter element is a two-stage polyethersulfone filter element.

8. The method for preparing dyphylline injection according to claim 7, characterized in that: In step b, the pore size of the first-stage polyethersulfone filter element in the two-stage polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm.

9. The method for preparing dyphylline injection according to claim 1, characterized in that: In step b, the sterilization temperature is 121° C. and the sterilization time is 15 min-20 min.

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