CN112999175B - Butylphthalide oral freeze-dried powder and preparation method and application thereof - Google Patents
Butylphthalide oral freeze-dried powder and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to butylphthalide oral freeze-dried powder, a preparation method and application thereof, wherein the butylphthalide oral freeze-dried powder is prepared by a freeze-drying method by using the following raw and auxiliary materials: butylphthalide, cyclodextrin or derivatives thereof; the freeze drying is divided into prefreezing and vacuum drying, and when the vacuum drying is carried out, the freeze drying is divided into a low-temperature section, a medium-temperature section and a high-temperature section; the temperature range of the low-temperature section is-20 ℃ to-30 ℃, and the residence time of the low-temperature section is 10-30 h; the temperature range of the middle temperature section is 0 +/-5 ℃, and the time from the low temperature section to the middle temperature section is 3-5 h; the temperature range of the high-temperature section is 35-45 ℃. According to the invention, a large number of detailed researches are carried out on the proportion of materials in the preparation process, process parameters, particularly a specific freeze-drying curve of freeze drying, the obtained butylphthalide oral freeze-drying powder has high inclusion rate and solubilization multiple, and high bioavailability, and pharmacokinetic experiments of animals prove that the oral freeze-drying powder has high absorption speed, quick drug effect, safety and reliability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to butylphthalide oral freeze-dried powder as well as a preparation method and application thereof.
Background
Butylphthalide, also known as apigenin (CAS number 6066-49-5), is a physiologically active substance extracted from celery seeds. The medicine is a new medicine (trade name: enbipu) in the first country with independent intellectual property rights for treating the cerebral vessels in China, has obvious cerebral ischemia resistant curative effect since the medicine is marketed in 2004, can improve the exhaustion of cerebral ischemia energy metabolism, reduce the cerebral infarction area caused by the local cerebral ischemia, improve the cerebral blood circulation, and relieve the symptoms of cerebral edema and the like caused by the local cerebral ischemia, and is an effective medicine for treating the acute ischemic stroke. The crude drug of butylphthalide is yellow oily liquid, and has low water solubility and poor bioavailability. The existing dosage forms on the market are soft capsules and injection, and the two dosage forms enter the national medical insurance catalogue
Cerebrovascular diseases are currently one of the main causes of death of the elderly worldwide, and the currently marketed oral preparations are in the form of capsules. On one hand, the capsule preparation has slow effect and is not beneficial to the rescue of patients with acute cerebral ischemia; on the other hand, most of people suffering from cerebral arterial thrombosis are the old, the capsule preparation has low bioavailability and needs to be taken three times a day, two capsules each time, and 600mg of butylphthalide is taken in total each day. Is not friendly to the stroke patients, solid particles are not easy to swallow, and dysphagia exists in the stroke patients in the acute stage.
CN1615938A discloses a freeze-dried powder injection for injection with butylphthalide as active component, which comprises butylphthalide, emulsifier, co-emulsifier, excipient and water in certain mass, and is prepared into freeze-dried powder injection by low-temperature sublimation. However, the injection preparation is lack of safety, the medicine is mainly used for treating cerebrovascular diseases and needs to be used for a long time, the injection needs to be intravenously instilled twice every day, patients cannot take the medicine by themselves, and the tolerance is poor. CN1839824A discloses an injection emulsion medicine containing butylphthalide, which is prepared by preparing a water phase mixture from an isotonic agent, a surfactant and water, adding butylphthalide, the surfactant and a stabilizer according to a ratio to prepare an oil phase, and stirring at a high speed at a temperature of between 60 and 90 ℃ for emulsification. Solves the problems of poor water solubility and low bioavailability of butylphthalide. However, the patent also prepares butylphthalide into an injection, which also lacks safety and is inconvenient to use.
Patents for oral administration include CN1031342151A (tablet), CN1943571A (drop pill), CN103830200A (coated preparation) and CN103169685A (sustained release preparation), and the oral preparation and soft capsule have the problem of difficult swallowing of the elderly patients.
In document 1 ("preparation and characterization of butylphthalide-hydroxypropyl-beta-cyclodextrin inclusion complex", ha Jing et al, proceedings of north river science and technology university, 2011, vol.32, No. 6, 617) 622), butylphthalide and hydroxypropyl beta cyclodextrin inclusion complex was prepared by freeze-drying, and solubilization of butylphthalide was obvious. However, according to the literature, hydroxypropyl beta-cyclodextrin (HP-beta-CD) has certain nephrotoxicity, and rats show obvious nephrotoxicity in the 30-day intraperitoneal administration of 200mg/kg and the 54mg/kg intravenous injection test, probably because the stable complex formed by the HP-beta-CD and cholesterol in blood leads to the accumulation of cholesterol/ester in bladder and renal pelvis, or is related to impurities in the preparation process of the HP-beta-CD. Therefore, the drug formulation with HP-beta-CD as the clathrate and butylphthalide is not suitable for patients with reduced renal function.
Document 2 ("preparation and characterization of butylphthalide-sulfobutyl-beta-cyclodextrin inclusion complex", Zhao xiao et al, China modern applied medicine, 2016, 6 th 33, 6 th, 762 one 767) discloses a method for preparing a lyophilized butylphthalide-sulfobutyl-beta-cyclodextrin inclusion complex, which has the advantages of low renal toxicity, good water solubility, low hemolytic effect and better inclusion ability compared with HP-beta-CD as an inclusion complex. However, the method does not study how to enhance bioavailability and stability of lyophilized powder for oral administration.
Therefore, the development of a butylphthalide preparation which has high safety and good bioavailability and is convenient for patients to swallow and take orally has high market value and research significance. At present, oral freeze-dried powder based on butylphthalide is not reported.
Disclosure of Invention
In order to overcome the defects that the safety, the bioavailability and the use convenience of a pharmaceutical preparation of butylphthalide in the prior art need to be improved, the invention adopts sulfobutyl betadex sodium as an auxiliary material to perform inclusion on oily butylphthalide, and obtains the oral lyophilized powder with high API solubility, high bioavailability, safety, reliability and stable quality through a specific lyophilization curve.
The technical scheme of the invention is realized by the following technical scheme:
the butylphthalide oral freeze-dried powder is characterized by being prepared from the following raw and auxiliary materials by a freeze-drying method: butylphthalide, and cyclodextrin or a derivative thereof;
the freeze drying is divided into prefreezing and vacuum drying, and when the vacuum drying is carried out, the freeze drying is divided into a low-temperature section, a medium-temperature section and a high-temperature section; the temperature range of the low-temperature section is-20 ℃ to-30 ℃, and the residence time of the low-temperature section is 10-30 h; the temperature range of the middle temperature section is 0 +/-5 ℃, and the time from the low temperature section to the middle temperature section is 3-5 h; the temperature range of the high-temperature section is 35-45 ℃.
Preferably, the cyclodextrin or derivative thereof is selected from sulfobutylbetacyclodextrin sodium. Cyclodextrins are a major class of pharmaceutical excipients often used to include insoluble drugs to improve the dissolution properties of pharmaceutical formulations. Through a large number of experimental researches, the inventor discovers that the butyl phthalide is included by adopting sulfobutyl-beta-CD-Na (SBE-beta-CD-Na), so that the safety is good, the inclusion rate is high, and the oral freeze-dried powder with excellent performance can be prepared by compounding. The sulfobutyl betacyclodextrin sodium is an anionic high-water-solubility cyclodextrin derivative, can be well included with butylphthalide to form a non-covalent compound, and has the advantages of improving the stability, water solubility and safety of the medicament, reducing the nephrotoxicity, relieving the hemolysis of the medicament and controlling the release rate of the medicament.
Further, the butylphthalide oral freeze-dried powder comprises the following raw and auxiliary materials in parts by mass: 15-45 parts of butylphthalide and 400-800 parts of sulfobutyl-beta-cyclodextrin sodium.
Further, the butylphthalide oral freeze-dried powder also comprises the following auxiliary materials in parts by mass: 4000-4500 parts of water for injection and 0.1-20 parts of flavoring agent.
The flavoring agent is at least one of sucralose, aspartame, xylitol, sorbitol, citric acid, ethyl maltol and grape essence.
The invention provides a preparation method of butylphthalide oral freeze-dried powder, which comprises the following steps:
adding sulfobutyl-beta-cyclodextrin sodium into sterilized water for injection, optionally adding correctant, stirring, adding the rest sterilized water for injection to full volume, stirring, filtering with filter core, and lyophilizing.
Preferably, the sterile water for injection added to the raw and auxiliary materials accounts for 50-90%, more preferably 60-70% of the total sterile water for injection.
Preferably, the heating is carried out under stirring, and the heating temperature is 30-80 ℃, preferably 40-70 ℃; the stirring speed is 200-400r/min, preferably 300-350 r/min; the stirring time is 1-5 h.
Preferably, the freeze-drying process comprises prefreezing and vacuum drying:
pre-freezing: 1) T0-T1, T1; 2) T1-T1, T2;
and (3) vacuum drying: vacuumizing to ensure that the system pressure is less than or equal to 20Pa, 3) T1-T2, T3; 4) T2-T2, T4; 5) T2-T3, T5; 6) T3-T4, T6; 7) T4-T4, T7.
T in each of the above-mentioned stages represents a temperature, and T represents a time, which represents a time taken for the temperature rise/fall in the section or a maintenance time at the temperature. When the temperatures of the intervals are different, that is, the time taken for raising/lowering the temperature, and when the temperatures are the same, that is, the holding time at the temperatures, for example, "T1-T2, T3" means that the temperature is changed from T1 to T2, the time taken is T3, and "T2-T2, T4" means that the holding time at the temperature of T2 is T4.
Wherein T0 is 0-30 deg.C, T1 is-45 deg.C to-35 deg.C, and T1 is 0.5-1 h; t2 is 1-5 h; t2 is-30 ℃ to-20 ℃, and T3 is 1-2 h; t4 is 10-30 h; t3 is 0 +/-5 ℃, and T5 is 3-5 h; t4 is 35-45 ℃, T6 is 0.5-1 h; t7 is 3-5 h.
Preferably, T0 is 20 + -5 deg.C, T1 is-45 deg.C to-35 deg.C, T1 is 0.5-1 h; t2 is 2-3 h; t2 is between-25 ℃ and-20 ℃, and T3 is 1-2 h; t4 is 20-25 h; t3 is 0 +/-2 ℃, and T5 is 3-5 h; t4 is 35-45 ℃, T6 is 0.5-1 h; t7 is 3-5 h.
Further, T1 is any temperature in the range of-45 ℃ to-35 ℃, such as-35 ℃, -37 ℃, -39 ℃, -40 ℃, -42 ℃, -45 ℃; t1 is any time period between 0.5 and 1h, such as 30min, 40min, 50min, 60 min;
t2 is any time period between 1-5h, such as 1h, 2h, 3h, 3.5h,4h, 5 h;
t2 is any temperature in the range of-30 ℃ to-20 ℃, such as-20 ℃, -22 ℃, -24 ℃, -25 ℃, -26 ℃, -30 ℃; t3 is any time period between 1-2h, such as 1h, 1.5h, 2 h;
t4 is any time period between 10 and 30h, such as 10h, 15h, 18h, 20h, 22h, 25h and 30 h;
t5 is any time period between 3 and 5h, such as 3h, 3.5h,4h, 4.5h, 5 h;
t4 is any temperature in the range of 35 ℃ to 45 ℃, such as 35 ℃, 37 ℃, 40 ℃, 45 ℃; t6 is any time period between 0.5 and 1h, such as 30min, 40min, 50min, 60 min;
t7 is any time period between 3 and 5h, such as 3h, 3.5h,4h, 4.5h, 5 h.
The inventor conducts careful research on a freeze-drying curve of freeze-drying, optimizes the technological parameters of freeze-drying, ensures that a product with stable and uniform quality is obtained, is looser, improves the re-dissolubility of the product, can improve the compliance of patients, and simultaneously improves the bioavailability. The inventors have also unexpectedly found that when vacuum drying is carried out at the end of prefreezing, the heating vacuum drying is carried out at a temperature which is increased from-35 ℃ to-45 ℃ to 35 ℃ to 45 ℃ and is divided into three different stages, namely a low temperature stage, a medium temperature stage and a high temperature stage. The low temperature section is a temperature range from minus 20 ℃ to minus 30 ℃, the retention time in the temperature range is longer and reaches 10-30h, and the medicament can be fully sublimated stably for enough time in the temperature range through slow sublimation; then, slowly raising the temperature from a temperature range of-20 ℃ to-30 ℃ to a temperature section at the middle temperature section near 0 ℃, so that the finally obtained freeze-dried powder is more loose, the product is uniform and stable, and the dissolving speed is high; and finally, a high temperature section is 35-45 ℃, the temperature section is mainly used for removing residual moisture in the medicament at relatively high temperature, and the heating rate can be properly increased.
The invention also provides application of the butylphthalide oral freeze-dried powder in preparation of a medicament for treating cerebrovascular diseases.
Because the existing butylphthalide preparation is mainly soft capsule or injection, the soft capsule is difficult to take, especially for the elderly patients; the freeze-dried oral preparation developed by the invention conforms to the medication principle of 'taking oral medicine without injection', is convenient for patients to take medicine at home, saves the time for going to the hospital and the pain of instillation, and can increase the tolerance of the patients.
The butylphthalide oral freeze-dried powder provided by the invention overcomes the defects of capsule preparations and injection, and the freeze-dried powder is liquid after being redissolved, so that the butylphthalide oral freeze-dried powder is easier to take by patients. In addition, the peak reaching time of the butylphthalide capsule plasma is 60-80min, after the butylphthalide oral freeze-dried powder is dissolved again, the peak reaching time of the oral liquid is less than 30min, and the oral liquid can quickly take effect after being taken, thereby having important significance for rescuing patients with cerebral apoplexy. Compared with the existing butylphthalide capsules and injections, the butylphthalide oral freeze-dried powder has obvious advantages.
Drawings
FIG. 1 is a plot of mean drug concentration-time of butylphthalide in plasma after Wistar rats were administered sample 1 (butylphthalide soft capsules) and sample 2 (butylphthalide oral lyophilized powder).
Detailed Description
Butylphthalide was purchased from Suzhou second pharmaceutical Co., Ltd, and sulfobutylbetacyclodextrin sodium was purchased from Xiande De Li Biochemical Co., Ltd.
The vacuum freeze drying instrument is Beijing Songyuan Huaxing science and technology Limited company, model: LGJ-20F.
The inclusion rate was measured by measuring the absorbance at 229nm at various concentrations to form a standard curve. Precisely weighing 5mg of the freeze-dried powder prepared in each example, dissolving the freeze-dried powder in an ethanol water solution (v/v = 1: 1), measuring the absorbance at 229nm after constant volume, calculating the concentration according to a standard curve linear equation, and calculating the inclusion rate according to the content of butylphthalide in the clathrate divided by the amount of butylphthalide added in the raw material.
Example 1
Accurately weighing 25 parts of butylphthalide, 400 parts of sulfobutyl sodium betacyclodextrin and 4 parts of sucralose, adding 3500 parts of sterile water for injection into a liquid preparation tank, controlling the stirring speed at 300r/min, controlling the temperature at 50 ℃ and stirring for 2 hours, stopping heating after stirring, then adding 1500 parts of sterile water for injection, continuing stirring for 1 hour, filtering by a Jinteng 0.22 mu m PES filter, and carrying out a freeze-drying procedure of the following freeze-drying curve: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5) -25 ℃ to 0 ℃,4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
The specific freeze-drying procedure is as follows: 1) rapidly cooling the medicinal liquid to-40 deg.C within 40min at 25 deg.C; 2) maintaining at-40 deg.C for 3h to complete pre-freezing; vacuumizing to 5 Pa; 3) heating from-40 deg.C to-25 deg.C for 1 h; 4) maintaining at-25 deg.C for 25 hr; 5) heating to 0 ℃ from-25 ℃ for 4 h; 6) heating from 0 ℃ to 40 ℃ in 1 h; 7) maintaining the temperature at 40 ℃ for 4h, and completing the freeze-drying process to obtain a white loose block, namely the butylphthalide oral freeze-dried powder. Through detection, the inclusion rate reaches 99.2%.
The standard test is carried out on the oral freeze-dried powder, and the results are shown in the following table 1:
TABLE 1
Application example 1Animal experimental data:
1. rat pharmacokinetic experiment
1.1 orally administering a sample of 1-butylphthalide soft capsule to Wistar rats (mice are 6-8 weeks old, and the weight of the rats is 180 +/-20 g, and female), specifically breaking the capsule, diluting the capsule to 10mg/mL by using vegetable oil, performing intragastric administration according to the weight conversion of animals, wherein the administration dose is 120mg/kg, and N =8, and then testing blood collection time and the concentration of the butylphthalide drug in blood plasma. The results are shown in the following Table 2-1:
TABLE 2-1
Note: linear range: 5-10000ng/mL, LLOQ: 5ng/mL, NA: not Available.
1.2 Wistar rats were administered sample 2, namely the butylphthalide oral lyophilized powder of example 1, specifically by diluting the oral lyophilized powder to 10mg/mL with water, and gavage administration was performed according to the weight of animals, with the administration dose of 120mg/kg, specifically N =8, and then the blood collection time and the concentration of butylphthalide drug in plasma were tested. The results are shown in the following Table 2-2:
tables 2 to 2
Note: linear range: 5-10000ng/mL, LLOQ: 5ng/mL, NA: not Available (Not applicable).
Figure 1 is a plot of mean drug concentration versus time of butylphthalide in plasma after oral administration to Wistar rats of sample 1 and sample 2.
Further studying the pharmacokinetic performance of the capsules and the oral lyophilized powder of the present invention, the pharmacokinetic data of Wistar rats given the same dose (120mg/kg) of the above samples 1 and 2 are shown in the following tables 2-3:
tables 2 to 3
As can be seen from the data in tables 2-3, in the Pharmacokinetic (PK) test data, sample 2, i.e., C of the oral lyophilized powder of the present invention, was administered at the same dose (120mg/kg)max，AUC0-t，AUC0-∞Are all higher than sample 1, i.e. soft capsule, oral lyophilized powder CmaxCompared with soft capsules, the medicine is approximately 3 times higher, and the AUC is approximately 1.5 times higher than the soft capsules, which shows that the oral freeze-dried powder of the invention is biologicalThe utilization degree is higher; t of sample 2maxThe content of the freeze-dried powder is lower than that of the sample 1, which indicates that the absorption speed of the oral freeze-dried powder is higher and the drug effect is fast; at the same time, t of sample 21/2The two medicines are similar in action time, and the oral freeze-dried powder is easier to discharge out of the body and cannot accumulate in the body. In addition, the Standard Deviation (SD) of the data for the sample 1, i.e., the butylphthalide soft capsule, was large, and was somewhat even higher than the Mean (Mean), indicating that the data was relatively discrete; the quality of the butylphthalide oral freeze-dried powder obtained by the invention is more stable and uniform.
2. Canine drug test
2.1 Butylphthalide capsule (sample 1) and Butylphthalide oral lyophilized powder of example 1 (sample 2) were orally administered to beagle dogs (dog aged 1, body weight 10 ± 0.5kg, male), the oral lyophilized powder was diluted with water to 10mg/mL for intragastric administration) at an administration dose of 240mg/kg, N =2, after which the blood collection time and the concentration of the butylphthalide drug in plasma were measured. The results are shown in tables 2-4 below:
tables 2 to 4
Note: linear range 5-10000ng/mL, LLOQ: 5ng/mL, BQL: below the lower limit of quantitation.
As analyzed by the data in tables 2-4, the oral lyophilized powder of the present invention has higher bioavailability, faster absorption rate and easier excretion from the body compared to the capsule under the same dosage condition (240 mg/kg).
Example 2
The other conditions and operations were the same as in example 1 except that sulfobutylbetacyclodextrin sodium was used in an amount of 200 parts. Oil drops float on the surface of the intermediate liquid medicine, which is not in accordance with the requirement and can not be frozen and dried.
Example 3
The other conditions and operations were the same as in example 1 except that 600 parts of sodium sulfobutylbetacyclodextrin was used. A white loose mass was obtained, but with about 10% atrophy. Through tests, the inclusion rate and the solubilization multiple are basically consistent with those of the example 1.
Example 4
The other conditions and operations were the same as in example 1 except that the procedure of freeze-drying was: pre-freezing: 1),20 ℃ to- 40℃40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) from-25 ℃ to-25 ℃,10h(ii) a 5) -25 ℃ to 0 ℃,4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 5
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) from-25 ℃ to-25 ℃,30h(ii) a 5) -25 ℃ to 0 ℃,4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 6
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1),18 ℃ to-35 DEG C，40min；2)，-35 ℃ to-35 DEG C3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-35 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5) -25 ℃ to 0 ℃,4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 7
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, 3-40 deg.C-20℃，1h；4）-20℃To-20℃，25h；5）-20℃The temperature is reduced to 0 ℃ for 4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 8
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, 3-40 deg.C-30℃，1h；4）-30℃To-30℃，25h；5）-30℃The temperature is reduced to 0 ℃ for 4 h; 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 9
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) from-25 ℃ to-25 ℃,20h(ii) a 5) -25 ℃ to 0 ℃,2h(ii) a 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 10
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5) -25 ℃ to 0 ℃,1h(ii) a 6) 0-40 ℃ for 1 h; 7)40 ℃ to 40 ℃ for 4 h.
Example 11
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5) -25 ℃ to 0 ℃,4 h; 6)0 ℃ to45℃，1h；7)45℃To45 ℃，4h。
Example 12
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5) -25 ℃ to 0 ℃,4 h; 6)0 ℃ to35℃，1h；7)35℃To35 ℃，4h。
Example 13
The other conditions and procedures were the same as in example 1 except that the lyophilization profile was differentThe procedure for freeze-drying was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, and heating to-40 deg.C to-25 deg.C for 1 h; 4) 25 hours at-25 ℃ to-25 ℃; 5)-25 ℃ to 40 DEG C4 h; 6)40 ℃ to 40 ℃ for 4 h.
Example 14
The other conditions and procedures were the same as in example 1, except that the lyophilization profile was different in that the procedure for lyophilization was: pre-freezing: 1) at 25 ℃ to-40 ℃ for 40 min; 2) -40 ℃ to-40 ℃ for 3 h; and (3) vacuum drying: vacuumizing to about 5Pa, 3-40 deg.C-15℃，4h；4）-15 ℃ to-15 DEG C，25h；5)-15℃Heating to 40 ℃ for 3 h; 6)40 ℃ to 40 ℃ for 4 h.
The lyophilized products obtained in the above examples were administered to Wistar rats at the same dose (120mg/kg) under the same conditions as in example 1, and the pharmacokinetic data thereof are shown in the following Table 3:
TABLE 3
As can be seen from the data in Table 3, the butylphthalide oral freeze-dried powder prepared in the embodiment of the invention shows higher C in pharmacokinetic test compared with capsules with the same dosagemaxAnd the AUC value shows that the butylphthalide oral freeze-dried powder provided by the invention has obviously improved bioavailability compared with capsules, is more favorable for patients to absorb and take, and has better oral safety. It is worth noting that the specific freeze-drying process conditions, particularly the temperature rise program during vacuum drying, are divided into three different stages, namely, the freeze-drying curve conditions of a low temperature section, a medium temperature section and a high temperature section are optimized and screened, and finally the obtained freeze-dried powder is looser, the product is uniform and stable, and the bioavailability is higher.
Claims (4)
1. The butylphthalide oral freeze-dried powder is characterized by being prepared from the following raw and auxiliary materials in parts by mass by a freeze-drying method: 25 parts of butylphthalide, 400-600 parts of sulfobutyl-beta-cyclodextrin sodium, 4000-4500 parts of water for injection and 0.1-20 parts of flavoring agent;
the preparation method of the butylphthalide oral freeze-dried powder comprises the following steps: weighing butylphthalide and sulfobutyl-beta-cyclodextrin sodium according to the feeding amount, adding into sterilized water for injection, adding correctant, stirring, adding the rest sterilized water for injection to full volume, continuing stirring, filtering with filter element, and freeze drying to obtain the final product;
the freeze drying comprises prefreezing and vacuum drying, wherein the prefreezing comprises the following steps: 1) T0-T1, T1; 2) T1-T1, T2;
and (3) vacuum drying: vacuumizing to ensure that the system pressure is less than or equal to 20Pa, 3) T1-T2, T3; 4) T2-T2, T4; 5) T2-T3, T5; 6) T3-T4, T6; 7) T4-T4, T7;
t0 is 20 +/-5 ℃, T1 is-45 ℃ to-35 ℃, and T1 is 0.5-1 h; t2 is 2-3 h; t2 is between-25 ℃ and-20 ℃, and T3 is 1-2 h; t4 is 20-25 h; t3 is 0 +/-2 ℃, and T5 is 3-5 h; t4 is 35-45 ℃, T6 is 0.5-1 h; t7 is 3-5 h.
2. The butylphthalide oral lyophilized powder according to claim 1, wherein T1 is-35 ℃, -37 ℃, -39 ℃, -40 ℃, -42 ℃ or-45 ℃; t1 is 40min, 50min or 60 min;
t2 is 2h or 3 h;
t2 is-20 deg.C, -22 deg.C, -24 deg.C or-25 deg.C; t3 is 1h, 1.5h or 2 h;
t4 is 20h, 22h or 25 h;
t5 is 3h, 3.5h,4h, 4.5h or 5 h;
t4 is 35 ℃, 37 ℃, 40 ℃ or 45 ℃; t6 is 30min, 40min, 50min or 60 min;
t7 is 3h, 3.5h,4h, 4.5h or 5 h.
3. The butylphthalide oral lyophilized powder according to claim 1, wherein sterile water for injection added to raw and auxiliary materials accounts for 60-70% of the total sterile water for injection; the stirring is heating and stirring, and the heating temperature is 40-70 ℃; the stirring speed is 300-350 r/min; the stirring time is 1-5 h.
4. Use of the butylphthalide oral lyophilized powder of any one of claims 1-3 in the preparation of a medicament for treating cerebrovascular diseases.
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| CN112386571A (en) * | 2020-12-04 | 2021-02-23 | 成都施贝康生物医药科技有限公司 | Stable butylphthalide sodium chloride injection, preparation method and application thereof |
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| CN1394880A (en) * | 2001-06-18 | 2003-02-05 | 石家庄制药集团制药技术开发有限公司 | Butylbenzene phthalein cyclodextrin or cyclodextrin derivative clathrate, its preparation method and application |
| EP1535916A1 (en) * | 2002-08-21 | 2005-06-01 | Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology (Shijianzhuang) Co., Ltd. | Clathrates of butylphtualide with cyclodextrin or its derivatives,a process for their preparations and the use there of |
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