Diprophylline injection and its preparation method

Abstract

The application relates to the technical field of pharmaceutical preparations, and particularly discloses a dyphylline injection and a preparation method thereof. The dyphylline injection provided by the application comprises the following components: hydroxypropyl-beta-cyclodextrin, glycine, dyphylline and water for injection. By adding the hydroxypropyl-beta-cyclodextrin and the glycine into the dyphylline injection, the two components synergistically act, the stability of the dyphylline injection after long-term storage can be obviously improved, the increase of the content of impurities in the injection after long-term storage can be effectively prevented, and thus the quality and the pharmaceutical effect of the dyphylline injection product can be effectively improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a dihydroxypropyltheophylline injection and its preparation method. Background Technology

[0002] Diprophylline, chemically named 1,3-dimethyl-7-(2,3-dihydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione, also known as bronchodilator or glycerol theophylline, is a traditional xanthine bronchodilator. As a commonly used smooth muscle relaxant, diprophylline effectively inhibits phosphodiesterase, thereby increasing the intracellular CMP (cytosine monophosphate) content, promoting smooth muscle relaxation, and thus dilating the trachea. In addition, it promotes the release of endogenous adrenaline and noradrenaline, thereby dilating the coronary arteries and bronchi, effectively counteracting the constriction of the airways caused by bronchodilators, which is very helpful in controlling the progression of the disease. Diprophylline is suitable for relieving wheezing symptoms in bronchial asthma, wheezing bronchitis, obstructive emphysema, etc. It is especially suitable for asthmatic patients who cannot tolerate aminophylline due to significant gastrointestinal irritation or who have tachycardia and cannot use theophylline. Currently, the main dosage forms available on the market are tablets, injections, and suppositories, with injections being the most common. Currently, there is a risk of precipitation in dihydroxypropyltheophylline injection after long-term storage at room temperature after preparation. Once precipitation occurs, it will seriously affect the product's quality and efficacy. Therefore, to ensure product quality, it is necessary to solve the problem of dihydroxypropyltheophylline injection precipitation. Summary of the Invention

[0003] To address the issue of precipitation in existing dihydroxypropyltheophylline injections after prolonged storage, this invention provides a dihydroxypropyltheophylline injection. This invention adds hydroxypropyl-β-cyclodextrin and glycine to the dihydroxypropyltheophylline injection. The synergistic effect of these two components significantly improves the stability of the dihydroxypropyltheophylline injection after long-term storage, further reduces the content of impurities in the injection after prolonged storage, and effectively prevents the increase of impurities in the injection after long-term storage.

[0004] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:

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

[0006] Current research indicates that using stepwise heating and cooling during the preparation of dihydroxypropyltheophylline injection can reduce the risk of precipitation. However, the inventors have found through experimental research that dihydroxypropyltheophylline injection prepared using this method exhibits increased impurities after prolonged storage, which can negatively impact product quality and efficacy. Therefore, providing a new dihydroxypropyltheophylline injection solution is of significant importance in order to further improve its storage stability, prevent precipitation, and reduce impurity content.

[0007] Compared to existing technologies, the hydroxypropyl-β-cyclodextrin in the dihydroxypropyltheophylline injection provided by this invention has a hollow structure, allowing some of the dihydroxypropyltheophylline molecules to enter the hollow structure of the hydroxypropyl-β-cyclodextrin, thus improving the solubility of dihydroxypropyltheophylline in water to some extent. However, experiments have shown that while adding only hydroxypropyl-β-cyclodextrin can improve the solubility of dihydroxypropyltheophylline to some extent and reduce its precipitation in the short term, precipitation is still inevitable after long-term storage, and the impurity content also shows a significant increasing trend. Through numerous experiments, the inventors accidentally discovered that adding glycine to the dihydroxypropyltheophylline injection containing hydroxypropyl-β-cyclodextrin can... The study significantly improved the poor stability of dihydroxypropyltheophylline injection after long-term storage. Further research showed that glycine, as a solubilizer, synergistically enhances the solubility and stability of dihydroxypropyltheophylline, thus resolving the crystallization problem after long-term storage. Glycine also acts as an antioxidant and pH stabilizer in dihydroxypropyltheophylline injection. It interacts with dihydroxypropyltheophylline, inhibiting its decomposition reaction and improving its stability, thereby reducing the increase of impurities in the injection. Furthermore, glycine stabilizes the pH of the injection, further reducing impurities and resolving the crystallization problem after long-term storage.

[0008] This invention, by adding hydroxypropyl-β-cyclodextrin and glycine to dihydroxypropyltheophylline injection, achieves a synergistic effect between the two components, significantly improving the stability of dihydroxypropyltheophylline injection after long-term storage and further preventing the increase of impurities in the injection after long-term storage, thereby effectively improving the quality and efficacy of dihydroxypropyltheophylline injection.

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

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

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

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

[0013] A second aspect of this invention provides a method for preparing the above-mentioned dihydroxypropyltheophylline injection, comprising the following steps:

[0014] Step a: At 50℃-55℃, add 70%-75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dihydroxypropyltheophylline and glycine to the preparation tank in sequence, mix well, add water for injection to the total volume, adjust the pH to 5-5.5, and obtain dihydroxypropyltheophylline solution.

[0015] Step b: Filter the dihydroxypropyltheophylline solution through a multi-stage polyethersulfone filter with progressively smaller pore sizes, fill, seal, and sterilize to obtain dihydroxypropyltheophylline injection.

[0016] During the research on the preparation method of dihydroxypropyltheophylline injection, the inventors discovered that the order of addition of hydroxypropyl-β-cyclodextrin, dihydroxypropyltheophylline, and glycine, as well as the distribution ratio of water for injection, have a significant impact on the solubility of dihydroxypropyltheophylline injection and its stability after long-term storage. Only by using the specific preparation method provided by this invention, by determining the distribution ratio of water for injection and the dissolution order of hydroxypropyl-β-cyclodextrin, dihydroxypropyltheophylline, and glycine, and by preparing the solution at a specific temperature, can the stability of dihydroxypropyltheophylline injection be greatly improved, preventing precipitation even after long-term storage.

[0017] Preferably, in step a, the conditions for achieving 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] More preferably, in step b, the pore size of the first-stage polyethersulfone filter element in the secondary polyethersulfone filter element is 0.45 μm, and the pore size of the second-stage polyethersulfone filter element is 0.22 μm.

[0020] This invention employs a two-stage polyethersulfone filter cartridge with a specific pore size for sequential filtration. This not only ensures that the product meets the standards for bacterial and endotoxin content, but also ensures that the product meets the standards for particulate matter and visible foreign matter. Furthermore, it eliminates the use of activated carbon during the production process, reducing pollution to the clean production area, alleviating environmental pressure, and reducing the impurities and insoluble particles that activated carbon may introduce. This is beneficial for 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 15-20 minutes.

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

[0023] The preparation method of dihydroxypropyltheophylline injection provided by this invention improves the storage stability of dihydroxypropyltheophylline injection. The increase in impurity content is not significant in stability and accelerated testing, and the injection does not crystallize even after long-term storage. This improves production efficiency, reduces production costs, facilitates industrial production, and has broad application prospects. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0025] To better illustrate the present invention, further examples are provided below.

[0026] Example 1

[0027] This embodiment also provides a dihydroxypropyltheophylline injection, with the following prescription dosage:

[0028]

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

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

[0031] Step b: The dihydroxypropyltheophylline solution is filtered through a two-stage polyethersulfone filter, wherein the pore size of the first-stage polyethersulfone filter is 0.45 μm and the pore size of the second-stage polyethersulfone filter is 0.22 μm. The solution is then filled, sealed, and sterilized to obtain dihydroxypropyltheophylline injection solution. The sterilization temperature is 121℃ and the sterilization time is 15 min.

[0032] Example 2

[0033] This embodiment also provides a dihydroxypropyltheophylline injection, with the following prescription dosage:

[0034]

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

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

[0037] Step b: The dihydroxypropyltheophylline solution is filtered through a two-stage polyethersulfone filter, wherein the pore size of the first-stage polyethersulfone filter is 0.45 μm and the pore size of the second-stage polyethersulfone filter is 0.22 μm. The solution is then filled, sealed, and sterilized to obtain dihydroxypropyltheophylline injection solution. The sterilization temperature is 121℃ and the sterilization time is 20 min.

[0038] Example 3

[0039] This embodiment also provides a dihydroxypropyltheophylline injection, with the following prescription dosage:

[0040]

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

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

[0043] Step b: The dihydroxypropyltheophylline solution is filtered through a two-stage polyethersulfone filter, wherein the pore size of the first-stage polyethersulfone filter is 0.45 μm and the pore size of the second-stage polyethersulfone filter is 0.22 μm. The solution is then filled, sealed, and sterilized to obtain dihydroxypropyltheophylline injection solution. The sterilization temperature is 121℃ and the sterilization time is 18 min.

[0044] Comparative Example 1

[0045] This comparative example provides a dihydroxypropyltheophylline injection, which is prepared in the same way as in Example 1, except that glycine in the formula is replaced with an equal amount of serine, and other operations are the same as in Example 1.

[0046] Comparative Example 2

[0047] This comparative example provides a dihydroxypropyltheophylline injection, which is prepared in the same way as in Example 1, except that the hydroxypropyl-β-cyclodextrin in the formula is replaced with an equal amount of polyethylene glycol. All other operations are the same as in Example 1.

[0048] Comparative Example 3

[0049] This comparative example provides a dihydroxypropyltheophylline injection, which is prepared in exactly the same way as in Example 1, except that glycine in the formula is replaced with an equal amount of hydroxypropyl-β-cyclodextrin. All other operations are the same as in Example 1.

[0050] Comparative Example 4

[0051] This comparative example provides a dihydroxypropyltheophylline injection, which is prepared in the same way as in Example 1, except that the hydroxypropyl-β-cyclodextrin in the formula is replaced with an equal amount of glycine. All other operations are the same as in Example 1.

[0052] Comparative Example 5

[0053] This comparative example provides a dihydroxypropyltheophylline injection, whose formulation 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, dihydroxypropyltheophylline and glycine to the preparation vessel in sequence, stir at a rate of 30 r / min for 28 min, add water for injection to the total volume, adjust the pH to 5.5, and obtain dihydroxypropyltheophylline solution.

[0055] Other operations are the same as in Example 1.

[0056] Comparative Example 6

[0057] This comparative example provides a dihydroxypropyltheophylline injection, whose formulation 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, dihydroxypropyltheophylline, and hydroxypropyl-β-cyclodextrin sequentially to the preparation vessel. Stir at 30 rpm for 28 minutes, then add water for injection to the total volume required for preparation. Adjust the pH to 5.5 to obtain the dihydroxypropyltheophylline solution.

[0059] Other operations are the same as in Example 1.

[0060] Comparative Example 7

[0061] This comparative example provides a dihydroxypropyltheophylline injection, whose formulation 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, dihydroxypropyltheophylline and glycine to the preparation vessel in sequence, stir at a rate of 30 r / min for 28 min, add water for injection to the total volume, adjust the pH to 5.5, and obtain dihydroxypropyltheophylline solution.

[0063] Other operations are the same as in Example 1.

[0064] Accelerated tests were conducted on the dihydroxypropyltheophylline injection products prepared in Examples 1-3 and Comparative Examples 1-7. The temperature treatment conditions were 40±2℃ and the humidity treatment conditions were 75%±5%. The results are shown in Tables 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 Results of Comparative Examples 1-3

[0069]

[0070]

[0071] Table 3. Results of comparative examples 4-5

[0072]

[0073]

[0074] Table 4. Results of comparative examples 6-7

[0075]

[0076]

[0077] Stability tests were conducted on the dihydroxypropyltheophylline injection products prepared in Examples 1-3 and Comparative Examples 1-7. The temperature treatment conditions were 30±2℃ and the humidity treatment conditions were 65%±5%. The results are shown in Tables 5-9.

[0078] Table 5. Experimental Results of Examples 1-2

[0079]

[0080]

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

[0082]

[0083]

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

[0085]

[0086]

[0087] Table 8. Results of Comparative Examples 4-5

[0088]

[0089]

[0090] Table 9. Results of comparative examples 6-7

[0091]

[0092] The above experimental data show that, compared with Comparative Examples 1-7, the dihydroxypropyltheophylline injection prepared in Examples 1-3 of this invention has lower impurity content and higher stability. The increase in impurity content during the accelerated 3-month and accelerated 6-month tests was significantly lower than that of Comparative Examples 1-7, and no precipitation occurred after 6 months of accelerated storage. In the long-term stability test, the dihydroxypropyltheophylline injection provided in this invention showed no precipitation after 24 months of long-term storage, and the impurity content was significantly lower than that of the dihydroxypropyltheophylline injection provided in Comparative Examples 1-7. This demonstrates that the dihydroxypropyltheophylline injection prepared in this invention has better stability and safety, thus improving the safety of clinical applications.

[0093] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A dihydroxypropyltheophylline injection, characterized in that, It includes the following components: hydroxypropyl-β-cyclodextrin, glycine, dihydroxypropyltheophylline, and water for injection; The mass ratio of hydroxypropyl-β-cyclodextrin to dihydroxypropyltheophylline is (3-4):1; The mass ratio of glycine to dihydroxypropyltheophylline is (0.4-0.5):1; The mass-to-volume ratio of dihydroxypropyltheophylline to water for injection is 300 mg: 2 mL. The preparation method of the dihydroxypropyltheophylline injection includes the following steps: Step a: At 50℃-55℃, add 70%-75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dihydroxypropyltheophylline and glycine to the preparation vessel in sequence, mix well, add water for injection to the total volume, adjust the pH to 5-5.5, and obtain dihydroxypropyltheophylline solution. Step b: Filter the dihydroxypropyltheophylline solution through a multi-stage polyethersulfone filter with progressively smaller pore sizes, fill, seal, and sterilize to obtain dihydroxypropyltheophylline injection.

2. A method for preparing the dihydroxypropyltheophylline injection according to claim 1, characterized in that, Includes the following steps: Step a: At 50℃-55℃, add 70%-75% of the total volume of water for injection, hydroxypropyl-β-cyclodextrin, dihydroxypropyltheophylline and glycine to the preparation vessel in sequence, mix well, add water for injection to the total volume, adjust the pH to 5-5.5, and obtain dihydroxypropyltheophylline solution. Step b: Filter the dihydroxypropyltheophylline solution through a multi-stage polyethersulfone filter with progressively smaller pore sizes, fill, seal, and sterilize to obtain dihydroxypropyltheophylline injection.

3. The method for preparing dihydroxypropyltheophylline injection as described in claim 2, characterized in that, In step a, the conditions for achieving uniform mixing are: stirring at a rate of 28 r / min-30 r / min for 28 min-30 min.

4. The method for preparing dihydroxypropyltheophylline injection as described in claim 2, characterized in that, In step b, the multi-stage polyethersulfone filter element is a two-stage polyethersulfone filter element.

5. The method for preparing dihydroxypropyltheophylline injection as described in claim 4, characterized in that, In step b, the pore size of the first-stage polyethersulfone filter element in the secondary polyethersulfone filter element is 0.45µm, and the pore size of the second-stage polyethersulfone filter element is 0.22µm.

6. The method for preparing dihydroxypropyltheophylline injection as described in claim 2, characterized in that, In step b, the sterilization temperature is 121°C and the sterilization time is 15-20 minutes.

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