Diprophylline lyophilized powder and its preparation method

Abstract

The present invention provides a method for preparing the lyophilized powder of diprophylline, which comprises the following steps: mixing diprophylline, excipients and pH regulators, followed by concentrated preparation, adding carbon, carbon removal filtration, dilute preparation, sterile filtration, and lyophilization to obtain the product; the lyophilization includes pre-freezing, primary sublimation drying, and analytical drying. Through the above-mentioned lyophilization process of pre-freezing, primary sublimation drying, and analytical drying, the present invention effectively solves the problem of local melting points formed due to excessive heat. This freeze-drying process can effectively solve the problems of preparation shrinkage, high moisture content, and increased related substances, and also reduces the cross-linking between different material molecules formed by the melting of materials during the sublimation process, resulting in colloidal particles similar to those formed.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a diprophylline freeze-dried powder and a preparation method thereof. Background Art

[0002] The chemical name of diprophylline is: 1,3-dimethyl-7-(2,3-dihydroxypropyl)-3,7-dihydro-1H-purine-2,6-dione.

[0003] Diprophylline is a xanthine anti-asthmatic agent, also known as dyphylline, propylene glycol theophylline, and camellia alkaloid. Hydroxypropyl theophylline is a derivative of theophylline, which can promote the release of endogenous adrenaline-like substances. Its anti-asthmatic effect is similar to that of theophylline, with less adverse reactions. Its toxicity is 20%-25% of aminophylline, and it has less impact on the heart and nervous system. The cardiac excitatory effect is only 1 / 20 to 1 / 10 of aminophylline. It has less impact on the heart and nervous system. It is suitable for asthmatic patients with tachycardia. Especially suitable for patients who cannot tolerate aminophylline due to obvious gastrointestinal irritation symptoms or are not suitable for aminophylline due to tachycardia. This product has a direct relaxing effect on airway smooth muscle. Its mechanism of action is relatively complex. In the past, it was considered to be caused by inhibiting phosphodiesterase, resulting in an increase in intracellular cAMP content. Recently, experiments have shown that the bronchodilator effect of theophylline is partly due to the release of endogenous adrenaline and noradrenaline. In addition, theophylline is a purine receptor blocker and can counteract the constriction of the respiratory tract caused by adenine and the like. Theophylline can enhance the contractility of the diaphragm, especially when the contractility of the diaphragm is weak, so it helps to improve respiratory function.

[0004] The current diprophylline freeze-dried powder injection should comply with the regulations of the national drug standard WS1-(X-067)2010Z. However, when using diprophylline raw materials to produce diprophylline for injection freeze-dried powder injection, it is found that the drugs prepared by the formulation process and the freeze-drying process have poor drug properties after leaving the box. Some preparations are insoluble in rehydration, the clarity is unqualified (the turbidity of 5 tested drugs is inconsistent), and the related substances gradually increase to exceed the standard. Summary of the Invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide a diprophylline freeze-dried powder, and the freeze-dried powder provided by the present invention has good properties and good rehydration clarity.

[0006] Through repeated experimental studies, the present invention has found that the liquid medicines of each prescription of diprophylline have two freezing states, namely the crystalline state and the glassy state, in the pre-freezing stage of the freeze-drying process, resulting in differences in the quality of the products after sublimation is completed.

[0007] Through research and analysis of the existing diprophylline for injection and its freeze-drying curve, it is known that external gas doping has been used during the drying process of this drug. The temperature of the product will gradually rise above the eutectic point temperature, causing local melting of the product, thereby blocking the channels for water vapor sublimation, resulting in the atrophy of the drug's properties after leaving the drying chamber. Moreover, due to the formation of diprophylline copolymers in the melted part, the solubility of diprophylline is reduced, causing the phenomenon that some freeze-dried drugs are insoluble after rehydration. At the same time, the relatively high water content of the drug also accelerates the gradual increase of degradation impurities. The cross-linking between molecules at the melting point forms colloidal particles similar to those, resulting in unqualified clarity detection and affecting the clinical medication safety of patients.

[0008] The present invention creatively develops the "phase temperature-holding pre-freezing technology" of supercooling degree in the liquid medicine pre-freezing stage and repeated pre-freezing before the eutectic point, that is, when the product is about 2°C before the supercooling degree and the eutectic point, keep pre-freezing for a period of time to quickly cool the product to below the supercooling degree and the eutectic point at almost the same temperature. At this time, each component in the prescription changes from liquid to solid under almost the same initial conditions, and the molecular arrangement state after freezing is almost the same. It minimizes the product quality differences formed by drugs in different freezing states after sublimation.

[0009] In addition, considering the serious atrophy phenomenon of the drug, it is due to the excess heat provided by the shelf during the sublimation process, which causes the local temperature inside the drug mass to rise and form a melting point. After repeated experiments, the inventor of the present invention creatively applies the method of internal gas doping during the sublimation stage of the product to control the dynamic balance between the heat required for drug sublimation and the heat provided by the shelf. It effectively solves the local melting point formed by excess heat.

[0010] The freeze-drying process parameters of the present invention can effectively solve the problems of preparation atrophy, high moisture content, and increase in related substances. It also reduces the colloidal particles similar to those formed by cross-linking between different material molecules caused by material melting during sublimation (diprophylline molecular copolymer, with a radius of 1 - 100 nm). These colloidal particles will cause the solution to form the Tyndall effect and produce opalescence or the drug is insoluble after rehydration, that is, the clarity is unqualified. These colloidal particles may cause phlebitis, granuloma, tissue necrosis, etc. during the clinical application of the drug, and even cause tumor-like reactions in the body, seriously affecting the clinical medication safety of patients.

[0011] The present invention provides a diprophylline freeze-dried powder, comprising the following raw materials in parts by weight:

[0012] Diprophylline 250 parts;

[0013] Excipient 41 - 59 parts;

[0014] pH regulator 1 - 5 parts.

[0015] In some preferred embodiments of the present invention, a diprophylline lyophilized powder provided by the present invention comprises raw materials in the following parts by weight:

[0016] Diprophylline 250 parts;

[0017] Excipient 49 - 51 parts;

[0018] pH regulator 1 - 5 parts.

[0019] In some preferred embodiments of the present invention, a diprophylline lyophilized powder provided by the present invention comprises raw materials in the following parts by weight:

[0020] Diprophylline 250 parts;

[0021] Excipient 50 parts;

[0022] pH regulator 1 - 5 parts.

[0023] The raw materials of the diprophylline lyophilized powder provided by the present invention include 250 parts by weight of diprophylline.

[0024] The raw materials of the diprophylline lyophilized powder provided by the present invention include 50 parts by weight of excipient;

[0025] According to the present invention, the excipient includes mannitol and dextran 40;

[0026] Specifically, the mass ratio of the mannitol to the dextran 40 is (1 - 10) : (40 - 49).

[0027] The raw materials of the diprophylline lyophilized powder provided by the present invention include 1 - 5 parts by weight of pH regulator; specifically, it may include 1 part, 2 parts, 3 parts, 4 parts or 5 parts by weight.

[0028] The pH regulator of the present invention is one or more of hydrochloric acid, glacial acetic acid, propionic acid, citric acid, DL - malic acid or sodium dihydrogen phosphate; more preferably, the pH regulator is one or more of hydrochloric acid, glacial acetic acid, propionic acid or citric acid; most preferably, the pH regulator is citric acid.

[0029] In some preferred embodiments of the present invention, the diprophylline lyophilized powder comprises water and raw materials in the following parts by weight:

[0030]

[0031] The present invention provides a preparation method of the diprophylline lyophilized powder according to any one of the above technical solutions, comprising the following steps:

[0032] The dyphylline, excipients and pH regulator are mixed and concentrated, charcoal is added, charcoal is removed and filtered, diluted, sterilized and filtered, and freeze-dried to obtain the product;

[0033] The freeze drying includes pre-freezing, primary sublimation drying, and analytical drying;

[0034] The pre-freezing procedure is specifically as follows: the first stage: the temperature is cooled from 22.5°C to -46°C in 1h and maintained for 2 to 3h;

[0035] The second stage: after heating from -46℃ to -13℃ for 1h, keep it for 2~3h;

[0036] The third stage: 1 hour from -13℃ to -5℃ and then maintained for 2 to 3 hours;

[0037] The fourth stage: the temperature drops from -5℃ to -46℃ in 1 hour and is maintained for 1.5 to 2 hours.

[0038] The preparation method of the lyophilized diprophylline powder provided by the present invention firstly mixes the diprophylline, an excipient and a pH regulator. The present invention has clearly described the above specific components and proportions, which will not be repeated here.

[0039] The diprophylline, excipients and pH regulator are mixed and prepared into a concentrated form as follows:

[0040] Take about 50% to 60% of the preparation amount of water for injection at 70℃ to 85℃ or above, put mannitol and dextran 40 into the concentrated preparation tank, stir to completely dissolve. The stirring speed is 200 rpm; then put dihydroxypropylphylline into the concentrated preparation tank, stir well, and adjust the pH value of the liquid to 4.2 to 4.7 with citric acid.

[0041] After the concentration, add carbon: wet the activated carbon with injection water and add it into the concentration tank for adsorption for 15 to 20 minutes. The amount of activated carbon added is 0.3‰ of the total volume.

[0042] After adding carbon, the carbon removal filter is used; the carbon removal filter is specifically as follows: start the delivery pump and circulate the carbon removal for 10 minutes. Use 0.10-0.15MPa compressed air to filter the liquid medicine to the dilution tank, and rinse the filter system with injection water. During the filtration, observe the pressure difference between the upstream and downstream of the filter at any time, and the pressure difference range is 0.00-0.25Mpa.

[0043] After carbon removal and filtration, the mixture is diluted. The diluted mixture of the present invention is specifically:

[0044] Add water for injection to the prepared amount (drug solution density is 1.085 g / mL), set the stirring speed to 200 rpm, and stir for more than 10 minutes.

[0045] After dilution, sterilize and filter.

[0046] The sterilizing filtration in the present invention specifically is: filtering the liquid medicine with a 0.2μm sterilizing-grade filter element, turning on the compressed air, controlling the pressure at 0.10 - 0.20 Mpa, using the compressed air to pump the liquid medicine into the sterile liquid storage tank, and then filtering it to the liquid distributor for filling. Observe the pressure difference between the upstream and downstream of the filter at any time during filtration, and the pressure difference range is 0.00 - 0.10 Mpa.

[0047] Preferably, filling is also included after sterilizing filtration.

[0048] The filling is preferably: filling the liquid medicine under the background environment of Class A, and the standard filling volume is: 1.00 ml / branch for the 0.25g specification; 2.00 ml / branch for the 0.5g specification; 3.0 ml / branch for the 0.75g specification; controlling the filling speed at more than 330 branches / min, and checking the filling volume and visible foreign matters during both the starting stage and the filling process. The time from the end of drug filtration to the end of filling should not exceed 10 hours (the time from the dissolution of the liquid medicine to the end of filling should be completed within 16 hours).

[0049] After sterilizing filtration and filling, it is freeze-dried; the freeze-drying includes pre-freezing, primary sublimation drying, and analytical drying.

[0050] In the present invention, the freeze-drying includes pre-freezing, primary sublimation drying, and analytical drying;

[0051] The pre-freezing procedure specifically is:

[0052] The first stage: the temperature drops from 22.5°C to -46°C in 1 hour and remains for 2 - 3 hours;

[0053] The second stage: after rising from -46°C to -13°C in 1 hour, it remains for 2 - 3 hours;

[0054] The third stage: after rising from -13°C to -5°C in 1 hour, it remains for 2 - 3 hours;

[0055] The fourth stage: it drops from -5°C to -46°C in 1 hour and remains for 1.5 - 2 hours.

[0056] In some preferred embodiments of the present invention, the pre-freezing procedure specifically is:

[0057] The first stage: the temperature drops from 22.5°C to -46°C in 1 hour and remains for 2 - 3 hours;

[0058] The second stage: after rising from -46°C to -13°C in 1 hour, it remains for 2 - 3 hours;

[0059] The third stage: after rising from -13°C to -5°C in 1 hour, it remains for 2 - 3 hours;

[0060] The fourth stage: it drops from -5°C to -46°C in 1 hour and remains for 1.5 - 2 hours.

[0061] After rising from -46°C to -13°C to -11°C in 1 h, hold for 2 - 3 h;

[0062] Lower the temperature from -13°C to -11°C to the pre-freezing end point of -46°C in 1 h, and hold for 1.5 - 2 h.

[0063] In some preferred embodiments of the present invention, the pre-freezing procedure is specifically:

[0064] First stage: Lower the temperature from 22.5°C to -46°C in 1 h, and hold for 2 - 3 h;

[0065] Second stage: After rising from -46°C to -13°C in 1 h, hold for 2 - 3 h;

[0066] Third stage: After rising from -13°C to -5°C in 1 h, hold for 2 - 3 h;

[0067] Fourth stage: Lower the temperature from -5°C to -46°C in 1 h, and hold for 1.5 - 2 h.

[0068] After rising from -46°C to -5°C to -3°C in 1 h, hold for 2 - 3 h;

[0069] Lower the temperature from -5°C to -3°C to the pre-freezing end point of -46°C in 1 h, and hold for 1.5 - 2 h.

[0070] In some preferred embodiments of the present invention, the pre-freezing procedure is specifically:

[0071] First stage: Lower the temperature from 22.5°C to -46°C in 1 h, and hold for 2 - 3 h;

[0072] Second stage: After rising from -46°C to -13°C in 1 h, hold for 2 - 3 h;

[0073] Third stage: After rising from -13°C to -5°C in 1 h, hold for 2 - 3 h;

[0074] Fourth stage: Lower the temperature from -5°C to -46°C in 1 h, and hold for 1.5 - 2 h.

[0075] After rising from -46°C to -11°C in 1 h, hold for 2 h;

[0076] After rising from -11°C to -3°C in 1 h, hold for 2 h;

[0077] Lower the temperature from -3°C to the pre-freezing end point of -46°C in 1 h, and hold for 1.5 h.

[0078] Perform primary sublimation drying after pre-freezing; the procedure of the primary sublimation drying is preferably specifically:

[0079] Raise the temperature from -46°C to -15°C in 1 h and hold for 17.5 h;

[0080] When the temperature is raised from -15°C to -10°C in 0.5 h, it is maintained for 0.5 h;

[0081] When the temperature is raised from -10°C to -5°C in 0.5 h, it is maintained for 0.5 h;

[0082] When the temperature is raised from -5°C to 0°C in 0.5 h, it is maintained for 0.5 h;

[0083] When the temperature is raised from 0°C to +5°C in 0.5 h, it is maintained for 0.5 h;

[0084] During the primary sublimation process, sterile air is introduced into the front chamber in an internal aeration manner and the drying vacuum is controlled at 0.05 mbar.

[0085] Primary sublimation drying and analytical drying; the specific procedure of the analytical drying is as follows:

[0086] When the temperature is raised from +5°C to +33°C in 0.5 h, it is maintained for 1 h

[0087] During the analytical drying process, the vacuum is controlled at 0.15 mbar by an external aeration method. Then, after closing the aeration valve of the drying chamber and maintaining for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum is used to press the plug out of the chamber.

[0088] The present invention provides a method for preparing diprophylline lyophilized powder, comprising the following steps: mixing diprophylline, excipients and pH regulators, followed by concentrated preparation, adding carbon, carbon removal filtration, diluted preparation, sterilization filtration, and freeze-drying to obtain; the freeze-drying includes pre-freezing, primary sublimation drying and analytical drying; the specific procedure of the pre-freezing is as follows: First stage: the temperature is lowered from 22.5°C to -46°C in 1 h and maintained for 2 - 3 h; Second stage: it is raised from -46°C to -13°C in 1 h and then maintained for 2 - 3 h; Third stage: it is raised from -13°C to -5°C in 1 h and then maintained for 2 - 3 h; Fourth stage: it is lowered from -5°C to -46°C in 1 h and maintained for 1.5 - 2 h. The present invention effectively solves the problem of local melting points formed due to excessive heat through the above freeze-drying processes of pre-freezing, primary sublimation drying and analytical drying. This freeze-drying process can effectively solve the problems of preparation shrinkage, high moisture content and increased related substances, and also reduces the cross-linking between different material molecules formed by the melting of the material during the sublimation process, resulting in colloidal particles similar to those formed. Description of the Drawings

[0089] Figure 1 For the diprophylline lyophilized powder injection products of Examples 1 - 10, after accelerating at 40°C for 6 months, the appearance is a loose block;

[0090] Figure 2 For the diprophylline lyophilized powder injection products of Examples 1 - 10, after accelerating at 40°C for 6 months and re-dissolving, it is clear and colorless (lighter than the 0.5 turbidity standard solution);

[0091] Figure 3 For Comparative Examples 1-5, the diprophylline lyophilized powder product at 0 month was in the form of non-porous lumps and severely shrunk;

[0092] Figure 4 For Comparative Examples 1-5, after reconstitution of the diprophylline lyophilized powder product at 0 month, there was opalescence and it was darker than the 0.5 turbidity standard solution;

[0093] Figure 5 It is the flowchart for capping.

[0094] Figure 6 It is the flowchart for visual inspection. Detailed implementation manners

[0095] The present invention provides a diprophylline lyophilized powder and a preparation method thereof. Those skilled in the art can draw on the content herein and appropriately modify process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they all fall within the protection scope of the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate alterations and combinations to the methods and applications herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0096] Supercooling degree: Each substance has its own equilibrium crystallization temperature or theoretical crystallization temperature. However, in the actual crystallization process, the actual crystallization temperature is always lower than the theoretical crystallization temperature. This phenomenon is called supercooling, and the temperature difference between the two is called the supercooling degree.

[0097] Eutectic point temperature: The eutectic point temperature is the highest temperature at which the solution is completely frozen and solidified. For a solution, the freezing and solidification point is the starting point of melting, so it is also called the eutectic point temperature.

[0098] External gas injection: In the primary sublimation stage of vacuum freeze-drying of drugs, generally, sterile normal-temperature (25°C) air or nitrogen and other gases are introduced into the drying chamber to increase the convective heat conduction, improve the heat supply for ice sublimation, increase the sublimation speed, reduce the time required for primary sublimation, and reduce production costs. This method is called external gas injection.

[0099] Internal gas injection: In the primary sublimation stage of vacuum freeze-drying of drugs, the vacuum degree of the drying chamber can be controlled between 0.03 mbar and 0.3 mbar by repeatedly opening and closing the connection valve between the vacuum pump and the drying chamber (commonly known as the small butterfly valve). At this time, the gas for convective heat conduction in the chamber is the water vapor generated by the sublimation of the drug, and its temperature is generally below -10°C (lower than the eutectic point of the drug). This method can appropriately increase the sublimation speed, reduce the time required for primary sublimation, and reduce production costs. This method is called internal gas injection.

[0100] To further illustrate the present invention, a detailed description of a diprophylline lyophilized powder and its preparation method provided by the present invention will be given below in conjunction with embodiments.

[0101] Main equipment for project implementation

[0102]

[0103] Example 1

[0104] 1.1 Composition components:

[0105] Composition Dosage Function Diprophylline 250mg Active ingredient Mannitol 1mg Lyoprotectant, excipient Dextran 40 49mg Lyoprotectant, excipient Citric acid 2.5mg pH regulator Water for injection 782.5mg Solvent

[0106] In the embodiment of the present invention, the total amount of mannitol and dextran 40 only needs to meet 50 mg.

[0107] 2. Process

[0108] 2.1 Preparation:

[0109] 2.1.1 Concentrated preparation: Take about 50%-60% of the injection water at 70°C - above 85°C of the preparation amount, put the weighed mannitol and dextran 40 into the concentrated preparation tank, set the stirring speed at 200 revolutions per minute, and stir until completely dissolved. Then put the weighed diprophylline into the concentrated preparation tank, fully stir until completely dissolved, and adjust the pH value of the liquid medicine to between 4.2 and 4.7 with citric acid.

[0110] 2.1.2 Adding carbon: Add activated carbon (activated carbon with 0.3‰ of the total preparation volume), moisten it with injection water and then add it into the concentrated preparation tank, and adsorb for 20 minutes.

[0111] 2.1.3 Carbon removal filtration: Start the transfer pump, circulate for carbon removal for 10 minutes. Press-filter with compressed air at 0.10 - 0.15 MPa, filter and transport the liquid medicine to the dilute preparation tank, and rinse the preparation and filtration system with about 5 kg of injection water. Observe the pressure difference between the upstream and downstream of the filter at any time during filtration, and the pressure difference range is 0.00 - 0.25 Mpa.

[0112] 2.1.4 Dilute preparation: Supplement injection water to the preparation amount (the density of the liquid medicine is 1.085 g / ml), set the stirring speed at 200 revolutions per minute, and stir for more than 10 minutes. The preparation amount is jointly confirmed by the person in charge of the post and the on-site monitor of QA.

[0113] 2.1.5 Sampling for inspection: The personnel at the post fill in the inspection request form for the intermediate product, and the quality control personnel take samples and conduct inspections.

[0114] 2.1.6 Bactericidal Filtration: Filter the liquid medicine with a 0.2μm bactericidal filter element. Turn on the compressed air, and control the pressure at 0.10 - 0.20 Mpa. Use the compressed air to pump the liquid medicine into the sterile liquid storage tank, and then filter it to the liquid distributor for filling. Observe the pressure difference between the upstream and downstream of the filter at any time during filtration, and the pressure difference range is 0.00 - 0.10 Mpa.

[0115] 2.2 Filling:

[0116] The liquid medicine is filled under the background environment of Class A. The standard filling volume is: 1.00 ml / branch for the 0.25g specification; 2.00 ml / branch for the 0.5g specification; 3.0 ml / branch for the 0.75g specification. The filling speed is controlled above 330 branches / min. The filling volume and visible foreign matters should be inspected at the beginning stage and during the filling process. The time from the end of drug filtration to the end of filling should not exceed 10 hours (the time from the dissolution of the liquid medicine to the end of filling should be completed within 16 hours).

[0117] 2.3 Freeze-drying: (Note: For the detailed comparison design of the freeze-drying parameters of all examples and comparative examples, please refer to Table 1 and Table 2).

[0118] 2.3.1 Product Pre-freezing:

[0119] Set the cooling rate of the heat transfer oil to drop from +22.5°C to -46°C in 1 hour, and then maintain it for 2 hours.

[0120] Set the heating rate of the heat transfer oil to rise from -46°C to -13°C in 1 hour, and then maintain it for 2 hours.

[0121] Then set the heat transfer oil to rise from -13°C to -5°C in 1 hour and maintain it for 2 hours.

[0122] Then set the heat transfer oil to drop from -5°C to the pre-freezing end point of -46°C in 1 hour and maintain it for 1.5 hours.

[0123] 2.3.2 Primary Sublimation Drying:

[0124] During the sublimation process, set the heating rate of the heat transfer oil to rise from -46°C to -15°C in 1 hour and maintain it for 17.5 hours. Then set the heating rate of the heat transfer oil to rise from -15°C to -10°C in 0.5 hour and maintain it for 0.5 hour. Then set the heating rate of the heat transfer oil to rise from -10°C to -5°C in 0.5 hour and maintain it for 0.5 hour. Then set the heating rate of the heat transfer oil to rise from -5°C to 0°C in 0.5 hour and maintain it for 0.5 hour. Then set the heating rate of the heat transfer oil to rise from 0°C to +5°C in 0.5 hour and maintain it for 0.5 hour. During the whole primary sublimation process, sterile air is incorporated into the front chamber by the method of internal gas mixing, and the vacuum degree of the drying chamber is controlled at 0.05 mbar.

[0125] 2.3.3 Analytical Drying (Secondary Sublimation):

[0126] When the heating rate of the heat transfer oil is set to increase from +5°C to +33°C in 0.5 h and then maintained for 1 h, during this stage, the vacuum degree of the drying oven is controlled by the method of external air injection at 0.15 mbar. Then, after closing the air injection valve of the drying oven and maintaining it for 0.5 h, the freeze-drying process of the medicine ends, and the vacuum plug is taken out of the oven.

[0127] 2.4 Capping:

[0128] 2.4.1 The capping operation is carried out in an A / B grade clean area environment.

[0129] 2.4.2 Figure 5 is the capping flow chart; 2.5 Visual inspection:

[0130] 2.5.1 The visual inspection operation is carried out in the general production area.

[0131] 2.5.2 Figure 6 is the visual inspection flow chart;

[0132] Example 2

[0133] 1. The composition and other process steps are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0134] 2.3.1 Product pre-freezing: (Note: For the detailed comparison and design of the freeze-drying parameters of all examples and comparative examples, see Table 1 and Table 2).

[0135] The cooling rate of the heat transfer oil is set to decrease from +22.5°C to -46°C in 1 h and then maintained for 3 h.

[0136] The heating rate of the heat transfer oil is set to increase from -46°C to -13°C in 1 h and then maintained for 3 h.

[0137] Then the heat transfer oil is set to increase from -13°C to -5°C in 1 h and then maintained for 3 h.

[0138] Then the heat transfer oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and maintained for 2 h.

[0139] 2.3.2 Primary sublimation drying:

[0140] During the sublimation process, the heating rate of the heat transfer oil is set to increase from -46°C to -15°C in 1 h and maintained for 20 h. Then the heating rate of the heat transfer oil is set to increase from -15°C to -10°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from -10°C to -5°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from -5°C to 0°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from 0°C to +5°C in 0.5 h and maintained for 1 h. During the whole primary sublimation process, sterile air is introduced into the front chamber by the method of internal air injection and the vacuum degree of the drying oven is controlled at 0.05 mbar;

[0141] 2.3.3 Analytical drying (secondary sublimation):

[0142] Set the heating rate of the heat transfer oil to increase from +5°C to +33°C at 0.5 h and maintain for 2 h. During this stage, control the vacuum degree of the drying oven to 0.15 mbar by means of external air injection. Then, after closing the air injection valve of the drying oven and maintaining for 0.5 h, end the freeze-drying process of the drug, and take out the box with vacuum pressure plugging.

[0143] Example 3

[0144] 1. The composition and other process procedures are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0145] 2.3 Freeze-drying:

[0146] 2.3.1 Product pre-freezing:

[0147] Set the cooling rate of the heat transfer oil to decrease from +22.5°C to -46°C at 1 h and maintain for 2 h.

[0148] Set the heating rate of the heat transfer oil to increase from -46°C to -13°C at 1 h and maintain for 2 h.

[0149] Then set the heat transfer oil to increase from -13°C to -5°C at 1 h and maintain for 2 h.

[0150] Then set the heat transfer oil to decrease from -5°C to the pre-freezing end point of -46°C at 1 h and maintain for 1.5 h.

[0151] Then set the heating rate of the heat transfer oil to increase from -46°C to -13°C at 1 h and maintain for 2 h.

[0152] Then set the heat transfer oil to decrease from -13°C to the pre-freezing end point of -46°C at 1 h and maintain for 1.5 h.

[0153] 2.3.2 Primary sublimation drying:

[0154] During the sublimation process, set the heating rate of the heat transfer oil to increase from -46°C to -15°C at 1 h and maintain for 17.5 h. Then set the heating rate of the heat transfer oil to increase from -15°C to -10°C at 0.5 h and maintain for 0.5 h. Then set the heating rate of the heat transfer oil to increase from -10°C to -5°C at 0.5 h and maintain for 0.5 h. Then set the heating rate of the heat transfer oil to increase from -5°C to 0°C at 0.5 h and maintain for 0.5 h. Then set the heating rate of the heat transfer oil to increase from 0°C to +5°C at 0.5 h and maintain for 0.5 h. During the whole primary sublimation process, keep sterile air injected into the front box by means of internal air injection and control the vacuum degree of the drying oven to 0.05 mbar;

[0155] 2.3.3 Analytical drying (secondary sublimation):

[0156] When the heating rate of the heat transfer oil is set to increase from +5°C to +33°C in 0.5 h and then maintained for 1 h, during this stage, the vacuum degree of the drying oven is controlled by the method of external air injection at 0.15 mbar. Then, after closing the air injection valve of the drying oven and maintaining for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum plug is taken out of the oven.

[0157] Example 4

[0158] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0159] 2.3.1 Product pre-freezing:

[0160] When the cooling rate of the heat transfer oil is set to decrease from +22.5°C to -46°C in 1 h and then maintained for 3 h,

[0161] When the heating rate of the heat transfer oil is set to increase from -46°C to -13°C in 1 h and then maintained for 3 h,

[0162] Then the heat transfer oil is set to increase from -13°C to -5°C in 1 h and then maintained for 3 h,

[0163] Then the heat transfer oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and maintained for 2 h.

[0164] Then the heating rate of the heat transfer oil is set to increase from -46°C to -13°C in 1 h and then maintained for 3 h,

[0165] Then the heat transfer oil is set to decrease from -13°C to the pre-freezing end point of -46°C in 1 h and maintained for 2 h.

[0166] 2.3.2 Primary sublimation drying:

[0167] During the sublimation process, the heating rate of the heat transfer oil is set to increase from -46°C to -15°C in 1 h and maintained for 20 h. Then the heating rate of the heat transfer oil is set to increase from -15°C to -10°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from -10°C to -5°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from -5°C to 0°C in 0.5 h and maintained for 1 h. Then the heating rate of the heat transfer oil is set to increase from 0°C to +5°C in 0.5 h and maintained for 1 h. During the whole primary sublimation process, sterile air is introduced into the front chamber by the method of internal air injection and the vacuum degree of the drying oven is controlled at 0.05 mbar;

[0168] 2.3.3 Analytical drying (secondary sublimation):

[0169] Set the heating rate of the heat transfer oil to increase from +5°C to +33°C in 0.5 h and hold for 1 h. During this stage, the vacuum degree of the drying oven is controlled at 0.15 mbar by the method of external air injection. Then, after closing the air injection valve of the drying oven and holding for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum plug is taken out of the oven.

[0170] Example 5

[0171] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0172] 2.3 Freeze-drying:

[0173] 2.3.1 Product pre-freezing:

[0174] Set the cooling rate of the heat transfer oil to decrease from +22.5°C to -46°C in 1 h and hold for 2 h.

[0175] Set the heating rate of the heat transfer oil to increase from -46°C to -13°C in 1 h and hold for 2 h.

[0176] Then set the heat transfer oil to increase from -13°C to -5°C in 1 h and hold for 2 h.

[0177] Then set the heat transfer oil to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and hold for 1.5 h.

[0178] Then set the heating rate of the heat transfer oil to increase from -46°C to -5°C in 1 h and hold for 2 h.

[0179] Then set the heat transfer oil to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and hold for 1.5 h.

[0180] 2.3.2 Primary sublimation drying:

[0181] During the sublimation process, set the heating rate of the heat transfer oil to increase from -46°C to -15°C in 1 h and hold for 17.5 h. Then set the heating rate of the heat transfer oil to increase from -15°C to -10°C in 0.5 h and hold for 0.5 h. Then set the heating rate of the heat transfer oil to increase from -10°C to -5°C in 0.5 h and hold for 0.5 h. Then set the heating rate of the heat transfer oil to increase from -5°C to 0°C in 0.5 h and hold for 0.5 h. Then set the heating rate of the heat transfer oil to increase from 0°C to +5°C in 0.5 h and hold for 0.5 h. During the whole primary sublimation process, keep the front chamber filled with sterile air by internal air injection and control the vacuum degree of the drying oven at 0.05 mbar;

[0182] 2.3.3 Analytical drying (secondary sublimation):

[0183] When the heating rate of the heat-conducting oil is set to increase from +5°C to +33°C in 0.5 h and then maintained for 1 h, the heat is conducted. During this stage, the vacuum degree of the drying oven is controlled by the method of external air injection at 0.15 mbar. Then, after closing the air injection valve of the drying oven and maintaining for 0.5 h, the freeze-drying process of the medicine ends, and the vacuum plug is taken out of the oven.

[0184] Example 6

[0185] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0186] 2.3.1 Product pre-freezing:

[0187] When the cooling rate of the heat-conducting oil is set to decrease from +22.5°C to -46°C in 1 h and then maintained for 3 h,

[0188] When the heating rate of the heat-conducting oil is set to increase from -46°C to -13°C in 1 h and then maintained for 3 h,

[0189] Then, the heat-conducting oil is set to increase from -13°C to -5°C in 1 h and then maintained for 3 h,

[0190] Then, the heat-conducting oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and maintained for 2 h.

[0191] Then, the heating rate of the heat-conducting oil is set to increase from -46°C to -5°C in 1 h and then maintained for 3 h,

[0192] Then, the heat-conducting oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and maintained for 2 h.

[0193] 2.3.2 Primary sublimation drying:

[0194] During the sublimation process, the heating rate of the heat-conducting oil is set to increase from -46°C to -15°C in 1 h and then maintained for 20 h. Then, the heating rate of the heat-conducting oil is set to increase from -15°C to -10°C in 0.5 h and maintained for 1 h. Then, the heating rate of the heat-conducting oil is set to increase from -10°C to -5°C in 0.5 h and maintained for 1 h. Then, the heating rate of the heat-conducting oil is set to increase from -5°C to 0°C in 0.5 h and maintained for 1 h. Then, the heating rate of the heat-conducting oil is set to increase from 0°C to +5°C in 0.5 h and maintained for 1 h. During the whole primary sublimation process, sterile air is introduced into the front chamber by the method of internal air injection and the vacuum degree of the drying oven is controlled at 0.05 mbar;

[0195] 2.3.3 Desorption drying (secondary sublimation):

[0196] Set the heating rate of the heat transfer oil to increase from +5°C to +33°C in 0.5 h and maintain for 1 h. During this stage, control the vacuum degree of the drying oven to 0.15 mbar by the method of external air injection. Then, close the air injection valve of the drying oven and maintain for 0.5 h, and then end the freeze-drying process of the drug, and take out the box with vacuum plugging.

[0197] 2.3.3 Analytical drying and plugging:

[0198] After reaching the primary sublimation end point, set the heating rate of the heat transfer oil to 20°C / h. When the temperature of the heat transfer oil reaches 30°C, maintain for 1.5 h. Keep the temperature of the heat transfer oil unchanged, close the air injection valve and maintain for 0.5 h, and then plug and take out the box.

[0199] Example 7

[0200] 1. The composition and other process procedures are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0201] 2.3 Freeze-drying:

[0202] 2.3.1 Product pre-freezing:

[0203] Set the cooling rate of the heat transfer oil to decrease from +22.5°C to -46°C in 1 h, and then maintain for 2 h.

[0204] Set the heating rate of the heat transfer oil to increase from -46°C to -13°C in 1 h, and then maintain for 2 h.

[0205] Then set the heat transfer oil to increase from -13°C to -5°C in 1 h and maintain for 2 h.

[0206] Then set the heat transfer oil to decrease from -5°C to the pre-freezing end point of -46°C in 1 h and maintain for 1.5 h.

[0207] Then set the heating rate of the heat transfer oil to increase from -46°C to -11°C in 1 h, and then maintain for 2 h.

[0208] Then set the heat transfer oil to decrease from -11°C to the pre-freezing end point of -46°C in 1 h and maintain for 1.5 h.

[0209] 2.3.2 Primary sublimation drying:

[0210] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it is heated from -46°C to -15°C at a rate of 1 hour and maintained for 17.5 hours, then the heating rate of the heat transfer oil is set to be heated from -15°C to -10°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -10°C to -5°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -5°C to 0°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from 0°C to +5°C in 0.5 hours and maintained for 0.5 hours. During the entire primary sublimation process, sterile air is incorporated into the front chamber in an internal gas injection manner and the vacuum degree of the drying chamber is controlled at 0.05 mbar;

[0211] 2.3.3 Analytical drying (secondary sublimation):

[0212] The heating rate of the heat transfer oil is set to be heated from +5°C to +33°C in 0.5 hours and maintained for 1 hour. During this stage, the vacuum degree of the drying chamber is controlled at 0.15 mbar by an external gas injection method. Then, after closing the gas injection valve of the drying chamber and maintaining for 0.5 hours, the freeze-drying process of the drug is completed, and the vacuum plug is taken out of the chamber.

[0213] Example 8

[0214] 1. The composition and other process procedures are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0215] 2.3 Freeze-drying:

[0216] 2.3.1 Product pre-freezing:

[0217] The cooling rate of the heat transfer oil is set to be cooled from +22.5°C to -46°C in 1 hour and maintained for 2 hours,

[0218] The heating rate of the heat transfer oil is set to be heated from -46°C to -13°C in 1 hour and maintained for 2 hours,

[0219] Then the heat transfer oil is set to be heated from -13°C to -5°C in 1 hour and maintained for 2 hours,

[0220] Then the heat transfer oil is set to be cooled from -5°C to the pre-freezing end point of -46°C in 1 hour and maintained for 1.5 hours,

[0221] Then the heating rate of the heat transfer oil is set to be heated from -46°C to -3°C in 1 hour and maintained for 2 hours,

[0222] Then the heat transfer oil is set to be cooled from -3°C to the pre-freezing end point of -46°C in 1 hour and maintained for 2 hours.

[0223] 2.3.2 Primary sublimation drying:

[0224] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it rises from -46°C to -15°C in 1 hour and remains at -15°C for 17.5 hours. Then, the heating rate of the heat transfer oil is set to rise from -15°C to -10°C in 0.5 hour and remains at -10°C for 0.5 hour. Next, the heating rate of the heat transfer oil is set to rise from -10°C to -5°C in 0.5 hour and remains at -5°C for 0.5 hour. Then, the heating rate of the heat transfer oil is set to rise from -5°C to 0°C in 0.5 hour and remains at 0°C for 0.5 hour. Subsequently, the heating rate of the heat transfer oil is set to rise from 0°C to +5°C in 0.5 hour and remains at +5°C for 0.5 hour. During the entire primary sublimation process, sterile air is introduced into the front chamber in an internal air-intrusion manner, and the vacuum degree of the drying chamber is controlled at 0.05 mbar.

[0225] 2.3.3 Analytical drying (secondary sublimation):

[0226] The heating rate of the heat transfer oil is set to rise from +5°C to +33°C in 0.5 hour and remains at +33°C for 1 hour. During this stage, the vacuum degree of the drying chamber is controlled at 0.15 mbar by an external air-intrusion method. Then, after closing the air-intrusion valve of the drying chamber and maintaining for 0.5 hour, the freeze-drying process of the drug ends, and the product is removed from the chamber under vacuum pressure.

[0227] Example 9

[0228] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0229] 2.3.1 Product pre-freezing:

[0230] The cooling rate of the heat transfer oil is set to decrease from +22.5°C to -46°C in 1 hour and remains at -46°C for 2 hours.

[0231] The heating rate of the heat transfer oil is set to increase from -46°C to -13°C in 1 hour and remains at -13°C for 2 hours.

[0232] Then, the heat transfer oil is set to increase from -13°C to -5°C in 1 hour and remains at -5°C for 2 hours.

[0233] Then, the heat transfer oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 hour and remains at -46°C for 1.5 hours.

[0234] Then, the heating rate of the heat transfer oil is set to increase from -46°C to -11°C in 1 hour and remains at -11°C for 2 hours.

[0235] Then, the heat transfer oil is set to increase from -11°C to -3°C in 1 hour and remains at -3°C for 2 hours.

[0236] Then, the heat transfer oil is set to decrease from -3°C to the pre-freezing end point of -46°C in 1 hour and remains at -46°C for 1.5 hours.

[0237] 2.3.2 Primary sublimation drying:

[0238] During the sublimation process, the heating rate of the heat transfer oil is set such that it rises from -46°C to -15°C in 1 hour and remains at -15°C for 17.5 hours. Then, the heating rate of the heat transfer oil is set to rise from -15°C to -10°C in 0.5 hour and remains at -10°C for 0.5 hour. Next, the heating rate of the heat transfer oil is set to rise from -10°C to -5°C in 0.5 hour and remains at -5°C for 0.5 hour. Then, the heating rate of the heat transfer oil is set to rise from -5°C to 0°C in 0.5 hour and remains at 0°C for 0.5 hour. Subsequently, the heating rate of the heat transfer oil is set to rise from 0°C to +5°C in 0.5 hour and remains at +5°C for 0.5 hour. During the entire primary sublimation process, sterile air is introduced into the front chamber in an internal air injection manner, and the vacuum degree of the drying chamber is controlled at 0.05 mbar.

[0239] 2.3.3 Analytical drying (secondary sublimation):

[0240] The heating rate of the heat transfer oil is set to rise from +5°C to +33°C in 0.5 hour and remains at +33°C for 1 hour. During this stage, the vacuum degree of the drying chamber is controlled at 0.15 mbar by means of external air injection. Then, after closing the air injection valve of the drying chamber and maintaining for 0.5 hour, the freeze-drying process of the drug is completed, and the product is removed from the chamber under vacuum pressure.

[0241] Example 10

[0242] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0243] 2.3.1 Product pre-freezing:

[0244] The cooling rate of the heat transfer oil is set to decrease from +22.5°C to -46°C in 1 hour and remains at -46°C for 2 hours.

[0245] The heating rate of the heat transfer oil is set to increase from -46°C to -13°C in 1 hour and remains at -13°C for 2 hours.

[0246] Then, the heat transfer oil is set to increase from -13°C to -5°C in 1 hour and remains at -5°C for 2 hours.

[0247] Then, the heat transfer oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 hour and remains at -46°C for 1.5 hours.

[0248] Then, the heating rate of the heat transfer oil is set to increase from -46°C to -11°C in 1 hour and remains at -11°C for 2 hours.

[0249] Then, the heat transfer oil is set to increase from -11°C to -3°C in 1 hour and remains at -3°C for 2 hours.

[0250] Then, the heat transfer oil is set to decrease from -3°C to the pre-freezing end point of -46°C in 1 hour and remains at -46°C for 1.5 hours.

[0251] 2.3.2 Primary sublimation drying:

[0252] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it is heated from -46°C to -15°C at a rate of 1 hour and maintained for 17.5 hours, then the heating rate of the heat transfer oil is set to be heated from -15°C to -10°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -10°C to -5°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -5°C to 0°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from 0°C to +5°C in 0.5 hours and maintained for 0.5 hours. During the entire primary sublimation process, sterile air is introduced into the front chamber by means of internal aeration, and the vacuum degree of the drying chamber is controlled at 0.05 mbar;

[0253] 2.3.3 Analytical drying (secondary sublimation):

[0254] The heating rate of the heat transfer oil is set to be heated from +5°C to +33°C in 0.5 hours and maintained for 1 hour. During this stage, the vacuum degree of the drying chamber is controlled at 0.15 mbar by means of external aeration. Then, after closing the aeration valve of the drying chamber and maintaining it for 0.5 hours, the freeze-drying process of the drug is completed. The drying chamber is filled with sterile nitrogen to 750 mbar - 850 mbar and then the plug is pressed out of the chamber.

[0255] Comparative Example 1

[0256] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0257] 2.3 Freeze-drying:

[0258] 2.3.1 Product pre-freezing:

[0259] The cooling rate of the heat transfer oil is set to be cooled from +22.5°C to -46°C in 1 hour and then maintained for 2 hours.

[0260] 2.3.2 Primary sublimation drying:

[0261] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it is heated from -46°C to -15°C at a rate of 1 hour and maintained for 17.5 hours, then the heating rate of the heat transfer oil is set to be heated from -15°C to -10°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -10°C to -5°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from -5°C to 0°C in 0.5 hours and maintained for 0.5 hours, then the heating rate of the heat transfer oil is set to be heated from 0°C to +5°C in 0.5 hours and maintained for 0.5 hours. During the entire primary sublimation process, sterile air is introduced into the front chamber by means of internal aeration, and the vacuum degree of the drying chamber is controlled at 0.05 mbar;

[0262] 2.3.3 Analytical drying (secondary sublimation):

[0263] When the heating rate of the heat-conducting oil is set to increase from +5°C to +33°C in 0.5 h and then maintained for 1 h, the heat is conducted. During this stage, the vacuum degree of the drying oven is controlled by the method of external air injection at 0.15 mbar. Then, after closing the air injection valve of the drying oven and maintaining for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum plug is taken out of the oven.

[0264] Comparative Example 2

[0265] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0266] 2.3.1 Product pre-freezing:

[0267] When the cooling rate of the heat-conducting oil is set to decrease from +22.5°C to -46°C in 1 h and then maintained for 2 h,

[0268] When the heating rate of the heat-conducting oil is set to increase from -46°C to -13°C in 1 h and then maintained for 2 h,

[0269] Then the heat-conducting oil is set to decrease from -13°C to the pre-freezing end point of -46°C in 1 h and maintained for 1.5 h.

[0270] 2.3.2 Primary sublimation drying:

[0271] During the sublimation process, the heating rate of the heat-conducting oil is set to increase from -46°C to -15°C in 1 h and maintained for 17.5 h. Then the heating rate of the heat-conducting oil is set to increase from -15°C to -10°C in 0.5 h and maintained for 0.5 h. Then the heating rate of the heat-conducting oil is set to increase from -10°C to -5°C in 0.5 h and maintained for 0.5 h. Then the heating rate of the heat-conducting oil is set to increase from -5°C to 0°C in 0.5 h and maintained for 0.5 h. Then the heating rate of the heat-conducting oil is set to increase from 0°C to +5°C in 0.5 h and maintained for 0.5 h. During the whole primary sublimation process, sterile air is incorporated into the front chamber by the method of internal air injection and the vacuum degree of the drying oven is controlled at 0.05 mbar;

[0272] 2.3.3 Analytical drying (secondary sublimation):

[0273] When the heating rate of the heat-conducting oil is set to increase from +5°C to +33°C in 0.5 h and then maintained for 1 h, the heat is conducted. During this stage, the vacuum degree of the drying oven is controlled by the method of external air injection at 0.15 mbar. Then, after closing the air injection valve of the drying oven and maintaining for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum plug is taken out of the oven.

[0274] Comparative Example 3

[0275] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0276] 2.3.1 Product pre-freezing:

[0277] After the temperature reduction rate of the heat transfer oil is set to drop from +22.5°C to -46°C in 1 hour and then maintained for 3 hours,

[0278] Set the temperature increase rate of the heat transfer oil to rise from -46°C to -13°C in 1 hour and then maintain for 3 hours,

[0279] Then set the heat transfer oil to drop from -13°C to the pre-freezing end point of -46°C in 1 hour and maintain for 2 hours.

[0280] 2.3.2 Primary sublimation drying:

[0281] During the sublimation process, when the temperature increase rate of the heat transfer oil is set to rise from -46°C to -15°C in 1 hour, maintain for 20 hours. Then set the temperature increase rate of the heat transfer oil to rise from -15°C to -10°C in 0.5 hour and maintain for 1 hour. Then set the temperature increase rate of the heat transfer oil to rise from -10°C to -5°C in 0.5 hour and maintain for 1 hour. Then set the temperature increase rate of the heat transfer oil to rise from -5°C to 0°C in 0.5 hour and maintain for 1 hour. Then set the temperature increase rate of the heat transfer oil to rise from 0°C to +5°C in 0.5 hour and maintain for 1 hour. During the whole primary sublimation process, keep the front chamber doped with sterile air in the way of internal air doping and control the vacuum degree of the drying chamber at 0.05 mbar;

[0282] 2.3.3 Desorption drying (secondary sublimation):

[0283] Set the temperature increase rate of the heat transfer oil to rise from +5°C to +33°C in 0.5 hour and maintain for 1 hour. In this stage, control the vacuum degree of the drying chamber at 0.15 mbar by the way of external air doping. Then close the air doping valve of the drying chamber and maintain for 0.5 hour, and then end the freeze-drying process of the medicine, and take out the box under vacuum pressure plug.

[0284] Comparative Example 4

[0285] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0286] 2.3.1 Product pre-freezing:

[0287] After the temperature reduction rate of the heat transfer oil is set to drop from +22.5°C to -46°C in 1 hour and then maintained for 2 hours,

[0288] Set the temperature increase rate of the heat transfer oil to rise from -46°C to -5°C in 1 hour and then maintain for 2 hours,

[0289] Then set the heat transfer oil to drop from -5°C to the pre-freezing end point of -46°C in 1 hour and maintain for 1.5 hours.

[0290] 2.3.2 Primary sublimation drying:

[0291] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it rises from -46°C to -15°C in 1 hour and remains at -15°C for 17.5 hours. Then, the heating rate of the heat transfer oil is set to rise from -15°C to -10°C in 0.5 hour and remain at -10°C for 0.5 hour. Next, the heating rate of the heat transfer oil is set to rise from -10°C to -5°C in 0.5 hour and remain at -5°C for 0.5 hour. Then, the heating rate of the heat transfer oil is set to rise from -5°C to 0°C in 0.5 hour and remain at 0°C for 0.5 hour. Subsequently, the heating rate of the heat transfer oil is set to rise from 0°C to +5°C in 0.5 hour and remain at +5°C for 0.5 hour. During the entire primary sublimation process, sterile air is introduced into the front chamber by means of internal air injection, and the vacuum degree of the drying chamber is controlled at 0.05 mbar.

[0292] 2.3.3 Analytical drying (secondary sublimation):

[0293] The heating rate of the heat transfer oil is set to rise from +5°C to +33°C in 0.5 hour and remain at +33°C for 1 hour. During this stage, the vacuum degree of the drying chamber is controlled at 0.15 mbar by means of external air injection. Then, after closing the air injection valve of the drying chamber and maintaining for 0.5 hour, the freeze-drying process of the drug is completed, and the product is removed from the chamber under vacuum pressure.

[0294] Comparative Example 5

[0295] 1. The composition and other technological processes are the same as those in Embodiment 1; only the freeze-drying process is different as follows:

[0296] 2.3.1 Product pre-freezing:

[0297] The cooling rate of the heat transfer oil is set to decrease from +22.5°C to -46°C in 1 hour and then remain at -46°C for 3 hours.

[0298] The heating rate of the heat transfer oil is set to increase from -46°C to -5°C in 1 hour and then remain at -5°C for 3 hours.

[0299] Then, the heat transfer oil is set to decrease from -5°C to the pre-freezing end point of -46°C in 1 hour and remain at -46°C for 2 hours.

[0300] 2.3.2 Primary sublimation drying:

[0301] During the sublimation process, the heating rate of the heat transfer oil is set as follows: it rises from -46°C to -15°C in 1 hour and remains at -15°C for 20 hours. Then, the heating rate of the heat transfer oil is set to rise from -15°C to -10°C in 0.5 hour and remain at -10°C for 1 hour. Next, the heating rate of the heat transfer oil is set to rise from -10°C to -5°C in 1 hour and remain at -5°C for 1 hour. Then, the heating rate of the heat transfer oil is set to rise from -5°C to 0°C in 0.5 hour and remain at 0°C for 1 hour. Subsequently, the heating rate of the heat transfer oil is set to rise from 0°C to +5°C in 0.5 hour and remain at +5°C for 1 hour. During the entire primary sublimation process, sterile air is introduced into the front chamber by means of internal air injection, and the vacuum degree of the drying chamber is controlled at 0.05 mbar.

[0302] 2.3.3 Analytical drying (secondary sublimation):

[0303] When the heating rate of the heat-conducting oil is set to increase from +5°C to +33°C at a rate of 0.5 h and maintained for 1 h, the vacuum degree of the drying oven is controlled at 0.15 mbar by the method of external air injection during this stage. Then, after closing the air injection valve of the drying oven and maintaining it for 0.5 h, the freeze-drying process of the drug is ended, and the vacuum plug is taken out of the oven.

[0304] Table 1: Summary Table of Freeze-Drying Processes for Examples 1-10

[0305]

[0306]

[0307]

[0308]

[0309]

[0310] Table 2: Summary Table of Freeze-Drying Processes for Comparative Examples 1-5

[0311]

[0312]

[0313]

[0314] Table 3: Test Results of Examples 1-10

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] Note: For the properties and solution clarity of the examples and comparative examples, please refer to Figures 1 - 4 。

[0322] Table 4: Test Results of Comparative Examples 1-5

[0323]

[0324]

[0325] Result Analysis

[0326] Analysis of the inspection results of the 6-month accelerated stability samples at 40°C for the implementation plans shows that all the inspection items of Plans 1 to 10 meet the requirements, and among them, the inspection data of Plan 9 is the most stable. Since the properties, clarity of the comparative example at 0 month are unqualified, and the moisture and related substances are both close to the upper limit, there is no need to conduct an accelerated stability experiment. The pictures of the inspection results of the properties and solution clarity are as follows: Figure 1 : For the diprophylline lyophilized powder injection products of Examples 1-10, after 6 months of acceleration at 40°C, the property is a loose block. Figure 2 : For the diprophylline lyophilized powder injection products of Examples 1-10, after 6 months of acceleration at 40°C and reconstitution, it is clear and colorless (lighter than the 0.5 turbidity standard solution). Figure 3 : For the diprophylline lyophilized powder products of Comparative Examples 1-5 at 0 month, the property is not a loose block and is severely shrunken. Figure 4 : For the diprophylline lyophilized powder products of Comparative Examples 1-5 at 0 month, there is opalescence after reconstitution and it is darker than the 0.5 turbidity standard solution.

[0327] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A diprophylline lyophilized powder, characterized in that, It comprises raw materials in the following parts by weight: 250 parts of diprophylline; 41 - 59 parts of excipient; 1 - 5 parts of pH regulator; The excipient includes mannitol and dextran 40; The pH regulator is one or more of hydrochloric acid, glacial acetic acid, propionic acid, citric acid, DL - malic acid or sodium dihydrogen phosphate; The preparation method of the diprophylline freeze - dried powder comprises the following steps: Mix diprophylline, excipient and pH regulator, then conduct concentrated preparation, add carbon, filter to remove carbon, conduct dilute preparation, filter for sterilization, and then freeze - dry to obtain it; The freeze - drying includes pre - freezing, primary sublimation drying and analytical drying; The specific pre - freezing procedure is: First stage: The temperature drops from 22.5°C to - 46°C in 1 h and is maintained for 2 - 3 h; Second stage: It rises from - 46°C to - 13°C in 1 h and is then maintained for 2 - 3 h; Third stage: It rises from - 13°C to - 5°C in 1 h and is maintained for 2 - 3 h; Fourth stage: It drops from - 5°C to - 46°C in 1 h and is maintained for 1.5 - 2 h.

2. The lyophilized powder according to claim 1, wherein The mass ratio of mannitol to dextran 40 is (1 - 10):(40 - 49).

3. The lyophilized powder according to claim 1, wherein The diprophylline freeze - dried powder includes water and raw materials in the following parts by weight:

4. A method for preparing the diprophylline lyophilized powder according to any one of claims 1 to 3, characterized in that, Comprising the following steps: Mix diprophylline, excipient and pH regulator, then conduct concentrated preparation, add carbon, filter to remove carbon, conduct dilute preparation, filter for sterilization, and then freeze - dry to obtain it; The freeze - drying includes pre - freezing, primary sublimation drying and analytical drying; The specific pre - freezing procedure is: First stage: The temperature drops from 22.5°C to - 46°C in 1 h and is maintained for 2 - 3 h; Second stage: It rises from - 46°C to - 13°C in 1 h and is then maintained for 2 - 3 h; Third stage: It rises from - 13°C to - 5°C in 1 h and is maintained for 2 - 3 h; Fourth stage: It drops from - 5°C to - 46°C in 1 h and is maintained for 1.5 - 2 h.

5. The preparation method according to claim 4, characterized in that, After the fourth stage, the pre - freezing procedure further includes: It rises from - 46°C to - 13°C to - 11°C in 1 h and is maintained for 2 - 3 h; It drops from - 13°C to - 11°C to the pre - freezing end point of - 46°C in 1 h and is maintained for 1.5 - 2 h.

6. The preparation method according to claim 4, characterized in that, After the fourth stage, the pre - freezing procedure further includes: It rises from - 46°C to - 5°C to - 3°C in 1 h and is maintained for 2 - 3 h; It drops from - 5°C to - 3°C to the pre - freezing end point of - 46°C in 1 h and is maintained for 1.5 - 2 h.

7. The preparation method according to claim 4, characterized in that, After the fourth stage, the pre - freezing procedure further includes: It rises from - 46°C to - 11°C in 1 h and is maintained for 2 h; It rises from - 11°C to - 3°C in 1 h and is maintained for 2 h; It drops from - 3°C to the pre - freezing end point of - 46°C in 1 h and is maintained for 1.5 h.

8. The preparation method according to claim 5, characterized in that, The specific primary sublimation drying procedure is: It rises from - 46°C to - 15°C in 1 h and is maintained for 17.5 h; It rises from - 15°C to - 10°C in 0.5 h and is maintained for 0.5 h; It rises from - 10°C to - 5°C in 0.5 h and is maintained for 0.5 h; It rises from - 5°C to 0°C in 0.5 h and is maintained for 0.5 h; It rises from 0°C to + 5°C in 0.5 h and is maintained for 0.5 h; During the primary sublimation process, sterile air is incorporated in an internal aeration manner and the drying vacuum degree is controlled at 0.05 mbar.

9. The preparation method according to claim 5, characterized in that, The specific analytical drying procedure is: It rises from + 5°C to + 33°C in 0.5 h and is maintained for 1 h The vacuum degree is controlled at 0.15 mbar by the way of externally introducing air during the analytical drying process.

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