A high-stability dyphylline injection and preparation method thereof

Abstract

The present invention provides a high-stability diphylline injection and a preparation method thereof, and relates to the field of medical inventions. The preparation method of the present invention solves the problem of raw material precipitation during the preparation of diphylline injection by using a step-by-step temperature increase program and a step-by-step temperature decrease program during the dissolution process. The preparation method provided by the present invention has a simple process and is easy to implement, reduces the risk of active component precipitation, improves the safety and stability of diphylline injection products, and sterilizes the product using a terminal sterilization process, reducing the risk of sterility in production.

Description

Technical Field

[0001] The invention belongs to the field of medical inventions, and particularly relates to a high-stability 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 astragallin and 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.

[0003] The dosage forms currently on the market are mainly tablets, injections, and suppositories, among which injections are the most common. Diphylline injection can withstand high temperatures and can be sterilized using a terminal sterilization process. However, after the preparation of diphylline injection, there is a risk of precipitation when stored for a long time at room temperature. Even the original injection will precipitate after opening. Once diphylline injection precipitates, it seriously affects the quality and efficacy of the product. In order to ensure product quality, the problem of precipitation of diphylline injection needs to be solved.

[0004] The Chinese invention patent with application number 201610105081.0 discloses a diphylline injection and its preparation method. The preparation amount is 50% hot water for injection and diphylline. After backfiltration until clear, add water for injection to the full amount and adjust the pH value; backfiltration with 0.45μm and 0.22μm polyethersulfone fins until clear; sampling for visible foreign matter inspection, and filtering with 0.22μm polyethersulfone fins for many times, sterilized at 100℃ for 30 minutes. The preparation method of this invention adopts secondary sterilization filtration, and the whole process is sterile, which reduces the visible foreign matter of the drug and ensures the product quality. However, this patent mainly invents the filtration method, and does not solve the precipitation problem of diphylline injection.

[0005] After searching a large number of documents, it is found that there is no special and in-depth research on the solution to the precipitation problem of diphylline injection. However, the inventors found in the process of studying diphylline injection that the preparation of high-stability diphylline injection can be achieved by using a specific temperature, solving the precipitation problem, improving the product quality of the injection, and greatly increasing the safety of clinical medication. Summary of the invention

[0006] The invention aims to solve the problems existing in the prior art and provides a high-stability diphylline injection and a preparation method thereof. The temperature is increased in a stepwise manner during the preparation of the diphylline injection, and the temperature is decreased in a stepwise manner after the weight is determined. The temperature and the insulation time are strictly controlled, the risk of precipitation of the diphylline injection is reduced, the stability is increased, and the quality of the product and the safety of clinical medication are greatly improved.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] In one aspect, the present invention provides a method for preparing a diphylline injection, comprising the steps of:

[0009] (1) Liquid preparation: Diphylline is mixed with 50-80% of the total amount of water for injection, and the temperature is raised to 50-65° C. using a step-wise temperature program, and the mixture is kept warm and stirred continuously to dissolve, thereby preparing a diphylline solution;

[0010] (2) Weighing: The dyphylline solution is mixed with the remaining amount of water for injection at the same temperature and weighed, and then cooled to 35-60°C using a step-by-step cooling program;

[0011] (3) Insulation filtration, filling and sterilization.

[0012] Preferably, the solid-liquid ratio of the diphylline to the total amount of water for injection is 100-200:1 mg / mL.

[0013] Further preferably, the solid-to-liquid ratio of the diphylline to the total amount of water for injection is 150:1 mg / mL.

[0014] Preferably, in step (1), the amount of water for injection accounts for 70% of the total amount of the preparation.

[0015] Preferably, in step (1), the mixing is carried out at room temperature of 20-30°C.

[0016] Preferably, in step (1), the stepwise heating program is specifically:

[0017] Heating steps Temperature(℃) Holding time (minutes) 1 20-30 10-20 2 40-50 20-30 3 50-65 50-60 .

[0018] Preferably, in step (2), the step-by-step cooling procedure is specifically:

[0019] Cooling steps Temperature(℃) Holding time (minutes) 1 50-65 15-30 2 35-60 / .

[0020] Preferably, in step (3), the temperature of the heat preservation filtration is maintained at 35-60°C, which is consistent with the temperature in the cooling step 2.

[0021] Preferably, in step (3), the filtration is performed using 0.45 μm and 0.22 μm filter membranes.

[0022] Further preferably, the filter membrane is a PES (polyethersulfone) filter membrane.

[0023] Preferably, in step (4), the sterilization temperature is 110-130° C., and the sterilization time is 10-20 min.

[0024] On the other hand, the present invention provides a highly stable dyphylline injection prepared by the above preparation method.

[0025] Preferably, the components of the dyphylline injection are dyphylline and water for injection.

[0026] Preferably, in the diphylline injection, the solid-liquid ratio of diphylline to water for injection is 100-200 mg / mL.

[0027] Further preferably, in the dyphylline injection, the solid-to-liquid ratio of dyphylline to water for injection is 150:1 mg / mL.

[0028] Preferably, the diprophylline injection is still stable at room temperature for 10 days without precipitation; and is still stable, colorless and clear without precipitation after being opened and placed for 24 hours.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The preparation method of the diphylline injection of the present invention realizes the large-scale production of the diphylline injection, reduces the risk of product precipitation, improves the quality of the product, has a lower risk of precipitation after opening than the original preparation, greatly increases the safety of clinical medication, and has very important significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a diagram of the precipitation of diphylline injection after being left at room temperature for 10 days. DETAILED DESCRIPTION

[0032] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of protection claimed in this application, and those skilled in the art can make various changes and modifications to the invention of this application based on the disclosed content, which should also fall within the scope of protection claimed in this application.

[0033] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. The raw material manufacturer used in the present invention is Shanghai Wanxiang.

[0034] Example 1

[0035] Composition of diprophylline injection: 300 mg of diprophylline, prepared with water for injection and weighed to 2 mL.

[0036] The preparation method of dyphylline injection comprises the steps of:

[0037] (1) Liquid preparation: The dyphylline is mixed with 70% of the total amount of water for injection (water temperature 25° C.), and the temperature is increased using the following step-wise temperature increase program. The mixture is kept warm and stirred continuously until it is completely dissolved, thereby preparing a dyphylline solution.

[0038] Heating program steps Temperature(℃) Holding time (minutes) 1 20-30 10 2 40-50 20 3 50-65 50

[0039] (2) Determination of weight: The dyphylline solution is mixed with the remaining 30% of the prepared water for injection at the same temperature (50-65° C.) to determine the weight. After determination of weight, the temperature is cooled using the following step-by-step cooling program;

[0040] Cooling procedure steps Temperature(℃) Holding time (minutes) 1 50-65 15 2 35 /

[0041] (3) Filtration: Filter the weighed drug solution using 0.45 μm and 0.22 μm PES filter membranes and filter at 35°C until the filtration is completed;

[0042] (4) Filling and sterilization: Fill 2 ml of the drug solution into a 2 ml colorless transparent ampoule and sterilize at 121°C for 15 min to obtain a sterile drug solution.

[0043] Example 2

[0044] The difference from Example 1 is that the heating program and the cooling program are different, as shown below:

[0045] (1) Liquid preparation: The dyphylline is mixed with 70% of the total amount of water for injection (water temperature 20° C.), and the temperature is increased using the following step-by-step temperature increase program. The mixture is kept warm and stirred continuously until it is completely dissolved, thereby preparing a dyphylline solution.

[0046] Heating program steps Temperature(℃) Holding time (minutes) 1 20-30 20 2 40-50 30 3 50-65 60

[0047] (2) Determination of weight: The dyphylline solution is mixed with the remaining 30% of the prepared water for injection at the same temperature (50-65° C.) to determine the weight. After determination of weight, the temperature is cooled using the following step-by-step cooling program;

[0048] Cooling procedure steps Temperature(℃) Holding time (minutes) 1 50-65 30 2 50 /

[0049] (3) Filtration: Filter the weighed liquid through 0.45 μm and 0.22 μm PES filter membranes, and filter at 50°C until the filtration is completed;

[0050] (4) Filling and sterilization: Fill 2 ml of the drug solution into a 2 ml colorless transparent ampoule and sterilize at 121°C for 15 min to obtain a sterile drug solution.

[0051] Example 3

[0052] The difference from Example 1 is that the heating program and the cooling program are different, as shown below:

[0053] (1) Liquid preparation: The dyphylline is mixed with 70% of the total amount of water for injection (water temperature 30° C.), and the temperature is increased using the following step-wise temperature increase program. The mixture is kept warm and stirred continuously until it is completely dissolved, thereby preparing a dyphylline solution.

[0054] Heating program steps Temperature(℃) Holding time (minutes) 1 20-30 10 2 40-50 20 3 50-65 50

[0055] (2) Determination of weight: The dyphylline solution is mixed with the remaining 30% of the prepared water for injection at the same temperature (50-65° C.) to determine the weight. After determination of weight, the temperature is cooled using the following step-by-step cooling program;

[0056] Cooling procedure steps Temperature(℃) Holding time (minutes) 1 50-65 15 2 60 /

[0057] (3) Filtration: Filter the weighed drug solution using 0.45 μm and 0.22 μm PES filter membranes, and filter at 60°C until the filtration is completed;

[0058] (4) Filling and sterilization: Fill 2 ml of the drug solution into a 2 ml colorless transparent ampoule and sterilize at 121°C for 15 min to obtain a sterile drug solution.

[0059] Comparative Example 1

[0060] The only difference from Example 1 is that the temperature rising procedure does not have the heat preservation of step 1, and the temperature is directly raised to step 2.

[0061] Comparative Example 2

[0062] The only difference from Example 1 is that there is no heating step 2 in the heating program, and the temperature is directly raised to step 3.

[0063] Comparative Example 3

[0064] The only difference from Example 1 is that there is no heating step 3 in the heating program.

[0065] Comparative Example 4

[0066] The only difference from Example 1 is that the holding time in step 1 of the heating program is 9 minutes.

[0067] Comparative Example 5

[0068] The only difference from Example 1 is that the holding time in step 1 of the heating program is 22 minutes.

[0069] Comparative Example 6

[0070] The only difference from Example 1 is that in step 2 of the heating procedure, the holding time is 16 minutes.

[0071] Comparative Example 7

[0072] The only difference from Example 1 is that in step 2 of the heating procedure, the holding time is 32 minutes.

[0073] Comparative Example 8

[0074] The only difference from Example 1 is that in step 3 of the heating procedure, the holding time is 46 minutes.

[0075] Comparative Example 9

[0076] The only difference from Example 1 is that in step 3 of the heating procedure, the holding time is 65 minutes.

[0077] Comparative Example 10

[0078] The only difference from Example 1 is that there is no step 1 in the cooling procedure after weighing.

[0079] Comparative Example 11

[0080] The only difference from Example 1 is that there is no step 2 in the cooling procedure after weighing.

[0081] Comparative Example 12

[0082] The only difference from Example 1 is that in the cooling procedure after weighing, step 1 is to naturally cool the temperature to 35-48° C., and there is no cooling step 2.

[0083] Comparative Example 13

[0084] The only difference from Example 1 is that the holding time in step 1 of the cooling procedure after weighing is 12 minutes.

[0085] Comparative Example 14

[0086] The only difference from Example 1 is that in step 2 of the cooling procedure after weighing, the temperature is 30-34°C.

[0087] Precipitation detection:

[0088] The original preparation (batch number: 09WE2F, specification 2ml: 300mg, licensed manufacturer Eisai Co., Ltd.) and the preparations obtained in Example 1 and Comparative Examples 1-14 were placed at room temperature for 10 days, and then placed at room temperature for 24 hours after opening, and the precipitation of each sample was noted. Figure 1 The precipitation of the original preparation, Example 1, and Comparative Examples 1-14 placed at room temperature for 10 days and placed at room temperature for 24 hours after opening is shown in Table 1.

[0089] The results show that: (1) Examples 1 to 3 and the original preparation did not precipitate after being placed at room temperature for 10 days, while Comparative Examples 1 to 14 precipitated to varying degrees after being placed at room temperature for 10 days; (2) Examples 1 to 3 did not precipitate 24 hours after the ampoules were opened, while the original preparation precipitated after 12 hours, and Comparative Examples 1 to 14 precipitated to varying degrees; (3) It is shown that the embodiments outside the claims of the present application cannot achieve the expected effect, and the present invention is superior to the original preparation, and the risk of precipitation of diprophylline injection is lower.

[0090] Table 1

[0091]

[0092]

[0093] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing dyphylline injection, characterized in that: Includes steps: (1) Liquid preparation: Diphylline is mixed with 50-80% of the total amount of water for injection, and the temperature is raised to 50-65°C using a step-by-step temperature increase program, and the mixture is kept warm and stirred continuously to obtain a diphylline solution. In step (1), the mixing is carried out at room temperature of 20-30°C. The step-by-step temperature increase program is specifically as follows: ； (2) Determining weight: The dihydroxypropylphylline solution is mixed with the remaining amount of water for injection at the same temperature and weighed, and after weighing, the temperature is cooled to 35-60° C. using a step-by-step cooling program; in step (2), the step-by-step cooling program is specifically as follows: ； (3) Insulated filtration, potting, and sterilization; the temperature of the insulated filtration is maintained at 35-60°C, which is consistent with the temperature in the cooling step 2; 0.45 μm and 0.22 μm filter membranes are used for filtration.

2. The preparation method according to claim 1, characterized in that: The solid-liquid ratio of the diphylline to the total amount of water for injection is 100-200:1 mg / mL.

3. The preparation method according to claim 2, characterized in that: The solid-liquid ratio of the diphylline to the total amount of water for injection is 150:1 mg / mL.

4. The preparation method according to claim 1, characterized in that: In step (3), the sterilization temperature is 110-130°C and the sterilization time is 10-20 minutes.

5. A highly stable diphylline injection prepared by the preparation method according to any one of claims 1 to 4.

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