Puerarin derivatives powder injection and its production method

A technology of puerarin derivatives and powder injection, which is applied in the directions of powder delivery, drug combination, pharmaceutical formulation, etc., can solve the problems of drug effectiveness, safety impact, unacceptable for patients, and large dosage, avoiding instability, Guaranteed safety and ease of use

Inactive Publication Date: 2008-10-22
普尔药物科技开发(深圳)有限公司
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AI-Extracted Technical Summary

Problems solved by technology

Because the drug must be dissolved before it can be absorbed in the body, if tetraacetyl puerarin is prepared into quick-acting preparations such as dispersible tablets and dropping pills, the dosage will be large, which is difficult for patie...
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Method used

3.4 After the prediction test, we found that the excipient poloxamer 188, as the carrier material of tetraacetylpuerarin freeze-dried powder, not only improves the wettability of the drug...
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Abstract

The invention provides a puerarin derivant powder injection preparation, which is characterized in that each powder injection of the powder injection preparation contains 0.001g to 0.1g of active component of puerarin derivant; the pharmaceutic adjuvants of the injection are that: one or more of polysorbate 80, kollison K30, hydroxypropul beta cyclodextrin is selected as solubilizer; one of poloxamer 188 or mannite or the combination thereof is selected as addictive agent; and the weight ratio between the puerarin derivant and the solubilizer is 1: (6-16); the weight ratio between the puerarin derivant and the addictive agent is 1: (3-20). The invention also discloses a preparation method for the puerarin derivant powder injection preparation. The preparation technique makes use of solvent method to dissolve medicine and adjuvant into a same organic solvent, the solvent is removed through evaporation and the solid dispersion freeze-dried powder is finally obtained through freeze drying. The puerarin derivant powder injection preparation solves the problem of unstable quality of puerarin derivant liquid injection preparation and has advantages of good shaping, rapid dissolution, clearance, stability and convenient use, etc.

Application Domain

Powder deliveryOrganic active ingredients +2

Technology Topic

SolventAdjuvant +16

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  • Puerarin derivatives powder injection and its production method
  • Puerarin derivatives powder injection and its production method
  • Puerarin derivatives powder injection and its production method

Examples

  • Experimental program(5)
  • Effect test(1)

Example Embodiment

1. Study on the preparation process of tetraacetylpuerarin freeze-dried powder injection
1.1 Preparation process screening
1.1.1 Research route, see Figure 3.
1.1.2 Screening of the types of solubilizing excipients
1.1.2.1 Single factor screening of solubilizing excipients
Take 0.05g of tetraacetylpuerarin, accurately weigh, and mix with 0.2g of polysorbate 80, PVP, HP-β-CD, glycerin, PEG400 (polyethylene glycol 400) and F68 (poloxamer 188) respectively , Add 5ml deionized water to grind to make it into a supersaturated solution. Pour into a stoppered centrifuge tube, shake well, centrifuge at 3000r/min for 10min, aspirate the supernatant, and immediately inject 1μL after passing through a 0.22μm filter membrane for HPLC determination. Calculate its solubility in different solubilizing excipients and repeat it twice. The results are shown in Table 2-8.
Table 2-8 Single factor investigation results of tetraacetylpuerarin solubilizing excipients (n=2)
The results show that the solubilization effect of polysorbate 80 is far superior to other excipients.
1.1.2.2 Screening of interaction between various solubilizing excipients and polysorbate 80
Take 0.05g tetraacetylpuerarin and 0.1g polysorbate 80, accurately weigh them, mix them with 0.1g polysorbate 80, PVP (k30), HP-β-CD, glycerin, PEG400 and F68, and add 5ml deionized Triturate with water to make a supersaturated solution. Pour into a stoppered centrifuge tube, shake well, centrifuge at 3000r/min for 10min, aspirate the supernatant, and immediately inject 1μL after passing through a 0.22μm filter membrane for HPLC determination. Calculate its solubility in different solubilizing excipients and repeat it twice. The results are shown in Table 2-9.
Table 2-9 Investigation results of interaction between various solubilizing excipients and polysorbate 80 (n=2)
The results show that the compatibilization effect of polysorbate 80 alone is far better than the solubilization effect of the interaction between polysorbate 80 and other excipients under the same usage amount, indicating that the solubilization of tetraacetylpuerarin plays a major role Is the excipient polysorbate 80.
1.1.3 Screening of preparation methods
1.1.3.1 Screening the preparation method with the solubility of tetraacetylpuerarin as the evaluation index
I Take 0.3g of polysorbate 80, accurately weigh it, add 5ml of deionized water, ultrasound for 10 minutes to dissolve it, and slowly add it to 0.05g of tetraacetylpuerarin, grind for 20min, and centrifuge at 3000r/min in a centrifuge 10min, take the supernatant through a 0.22μm filter membrane, add mobile phase to dilute, and enter the high performance liquid chromatograph to determine the solubility of tetraacetylpuerarin.
II Take 0.3 g of polysorbate 80, accurately weigh it, add 5 ml of deionized water, and ultrasound for 10 minutes to dissolve it. Take 0.05g of tetraacetylpuerarin, accurately weigh it, add 5ml of absolute ethanol and grind for 5min to dissolve it. Then mix the two solutions, evaporate to dryness under reduced pressure at 60°C, evaporate the ethanol and dilute to 5ml with deionized water, pass through a 0.22μm filter membrane, dilute with mobile phase, and measure the solubility of tetraacetylpuerarin by high performance liquid chromatography. .
III Take 0.3 g of polysorbate 80, accurately weigh it, add 5 ml of deionized water, and ultrasound for 10 minutes to dissolve it. Take 0.05g of tetraacetylpuerarin, accurately weigh it, add 5ml of absolute ethanol and ultrasonic for 10min to dissolve it. Then mix the two solutions with ultrasonic for 15min, evaporate to dryness under reduced pressure at 60℃, evaporate the ethanol and dilute to 5ml with deionized water, pass through a 0.22μm filter membrane, add mobile phase to dilute, and enter the high performance liquid chromatograph to determine tetraacetylpuerarin Solubility.
Taking the solubility of the tetraacetylpuerarin solution as the evaluation index, the three preparation methods were compared, and the results are shown in Table 2-10.
Table 2-10 Investigation results of the solubility of tetraacetylpuerarin
The results show that: Preparation methods II and III are better than preparation method I.
1.1.3.2 Use the clarification time of the tetraacetylpuerarin solution as the evaluation index to screen the preparation method
Place the tetraacetylpuerarin aqueous solution prepared in Preparation Methods II and III in 2.1.3.1 at room temperature, and observe its clarity with naked eyes until fine particle precipitates appear in the solution. Record the time. The results are shown in Table 2-11. .
Table 2-11 Results of the investigation of clarification time
The results show that: Preparation Method II is better than Preparation Method III.
1.1.4 Screening of stent agent types
In order to prevent the drug from dispersing with water vapor when vacuuming during freeze-drying, or becoming a fluffy loose structure after drying, some scaffolding agent needs to be added to improve its appearance and maintain the original volume, so that it does not collapse or shrink , The surface is smooth and the color is uniform.
1.1.4.2 Use tetraacetylpuerarin freeze-dried powder injection molding as an evaluation index to screen scaffolds
Take 0.05 g of tetraacetylpuerarin, accurately weigh, and mix them with 0.2 g of Poloxamer 188, HP-β-CD, mannitol, and glucose respectively, add 5 ml of absolute ethanol and grind for 5 minutes to fully dissolve it. And mix with 5ml of deionized water containing 0.3g of polysorbate 80, evaporate to dryness under reduced pressure at 60°C, evaporate the ethanol, add deionized water to make the volume to 5ml.
The clarity of the solution was used as an evaluation index to screen the scaffold. The results are shown in Table 2-12.
Table 2-12 Investigation results of the clarity of the solution before lyophilization
The results show that: Poloxamer 188 and mannitol are better than HP-β-CD and mannitol.
1.1.4.2 Use tetraacetylpuerarin freeze-dried powder injection molding as an evaluation index to screen scaffolds
The clear solution of poloxamer 188 and mannitol in 2.1.4.1 was freeze-dried at the same time, and the scaffold was screened with tetraacetylpuerarin freeze-dried powder injection molding as the evaluation index. The results are shown in Table 2-13.
Table 2-13 Investigation results of tetraacetylpuerarin freeze-dried powder injection molding
The results showed that poloxamer 188 and mannitol had good molding effects.
1.1.4.3 Screening of scaffolds based on the reconstitution time of tetraacetylpuerarin freeze-dried as an evaluation index
Dissolve the tetraacetylpuerarin powder sample that was freeze-dried in 2.1.4.2 in 62.5ml of water and place it at room temperature. Observe the clarity of the solution with naked eyes until fine particles begin to appear in the solution. Record the time and measure the The reconstitution time is the evaluation index to screen the scaffold, and the results are shown in Table 2-14.
Table 2-14 Investigation results of reconstitution time after lyophilization of tetraacetylpuerarin
The results showed that poloxamer 188 and mannitol had good molding effects.
1.1.5 Research on freeze-drying technology
Freeze-drying is the drying done by directly sublimating the frozen solution from the frozen state without sublimation to remove the water under the condition of low temperature and low pressure. It can be used to solve the problem of unstable quality during the storage of aqueous injections (such as the active ingredients are easy to degrade and precipitate Precipitation, etc.). After exploring the freeze-drying process conditions (including the thickness inspection of the liquid medicine in the vials of different specifications, the pre-freezing time, the sublimation drying vacuum degree, the sublimation heating plate temperature and time, and the re-drying temperature and time, etc.), the final drawing The freeze-drying curve diagram of tetraacetylpuerarin freeze-dried powder injection, namely
Vial bottle specification: 15ml
Pre-freezing: The temperature of the lyophilizer is -45°C, and the samples are pre-frozen for 5 hours. The temperature of the cold trap is -50°C.
One-time drying to remove free moisture: under 10Pa pressure, the temperature of the plate layer is: -20°C for 24 hours; -10°C for 18 hours. The temperature of the cold trap is -50°C.
Second drying to remove bound water: Under 5Pa pressure, the temperature of the plate layer is: 10℃, sublimation for 24 hours; 20℃, sublimation for 10 hours. The temperature of the cold trap is -50°C.
1.1.6 Determination of preparation process
After experimentation, under the proposed freeze-drying process conditions, the solubilizing excipient is polysorbate 80, the scaffolding agent is poloxamer 188, and the preparation method is II, the solubility of the tetraacetylpuerarin freeze-dried powder is the best, and it is molded. The best and the longest reconstitution time.
1.2 Optimization of preparation process
Under the conditions determined by the preparation process of tetraacetylpuerarin freeze-dried powder injection, the process conditions were optimized to obtain the best preparation process.
1.2.1 Screening of the ratio of tetraacetylpuerarin to polysorbate 80
Take 0.05g of tetraacetylpuerarin, accurately weigh it, add 5ml of absolute ethanol and grind for 5min to dissolve it. Take different amounts of polysorbate 80, accurately weigh it, add 5ml of deionized water, and ultrasound for 10min to dissolve it. Then mix the two solutions uniformly, evaporate and evaporate the ethanol under reduced pressure at 60°C, add deionized water to make the volume to 5ml, pass through a 0.22μm filter membrane, dilute with mobile phase, and measure the solubility of tetraacetylpuerarin by high performance liquid chromatography. .
The clarity of the solution and the solubility of tetraacetylpuerarin were used as evaluation indicators to screen the ratio of tetraacetylpuerarin to polysorbate 80. The results are shown in Table 2-15.
Table 2-15 Investigation results of clarity and solubility of the solution
The results showed that when the ratio of tetraacetylpuerarin to polysorbate 80 was greater than or equal to 1:6, the solution was clear and completely dissolved in water.
1.2.2 Screening of the ratio of tetraacetylpuerarin to poloxamer 188
Take 0.05 g of tetraacetylpuerarin, accurately weigh, and mix them with 0.2 g of Poloxamer 188, HP-β-CD, mannitol, and glucose respectively, add 5 ml of absolute ethanol and grind for 5 minutes to fully dissolve it. And mix with 5ml of deionized water containing 0.3g of polysorbate 80, evaporate to dryness under reduced pressure at 60°C, evaporate the ethanol, add deionized water to make the volume to 5ml.
The tetraacetylpuerarin freeze-dried powder injection molding was used as the evaluation index to screen the ratio of tetraacetylpuerarin to poloxamer 188. The results are shown in Table 2-16.
Table 2-16 Investigation results of freeze-dried powder injection molding
The results show that when the ratio of tetraacetylpuerarin to poloxamer 188 is greater than or equal to 1:3, the tetraacetylpuerarin freeze-dried powder injection is well formed.
1.2.3 Orthogonal design experiment
Predictive experiments show that the main factors affecting the preparation process of tetraacetylpuerarin freeze-dried powder injection are the dosage of polysorbate 80, the dosage of poloxamer 188, and the drying temperature under reduced pressure, so the three-factor three-level orthogonal experiment is used for its preparation process optimize.
1.2.3.1 Factor level table
Based on the screening results of the ratio of tetraacetylpuerarin to polysorbate 80 and poloxamer 188, select the appropriate three levels, and the factor levels are shown in Table 2-17.
Table 2-17 Preparation process factor level table of tetraacetylpuerarin freeze-dried powder injection
1.2.3.2.3 Experimental methods and results
1.2.3.2.1 Evaluation Index
The forming, reconstitution time and content of the tetraacetylpuerarin freeze-dried powder injection are used as evaluation indicators for comprehensive evaluation, and the weight coefficients are 20, 40, and 40, respectively.
1.2.3.2.2 Evaluation method
The molding and reconstitution time were observed with naked eyes; the content was determined by high performance liquid chromatography.
Chromatographic conditions: Agilent Eclipse polysorbate 80DB-C18 column (4.6×250mm, 5μm); mobile phase: acetonitrile-water (40:60); flow rate: 1ml/min; detection wavelength: 320nm; injection volume: 20μl ; Column temperature: 27℃; The number of theoretical plates should not be less than 5000 based on the peak of tetraacetylpuerarin.
Content percentage investigation: the known amount of tetraacetylpuerarin (Wi) added to a bottle of freeze-dried powder injection, the amount of tetraacetylpuerarin (Wz) in a bottle determined by high performance liquid chromatography, calculate the tetraacetyl by the following formula The content percentage of puerarin freeze-dried powder injection, namely
Content%=(Wz/Wi)*100%
1.2.3.2.3 Experimental methods and results
Take 0.05 g of tetraacetylpuerarin, accurately weigh it, and prepare the tetraacetylpuerarin freeze-dried powder injection according to the arrangement in the orthogonal table. The results are shown in Table 2-18.
Table 2-18 Orthogonal experiment results of preparation process of tetraacetylpuerarin freeze-dried powder injection
Note: In the molding evaluation, 1 means good molding, 0.5 means normal molding, 0.25 means poor molding, and 0 means no molding.
The results of the above orthogonal experiment were analyzed by variance analysis, and the results are shown in Table 2-19.
Table 2-19 Analysis of variance table
*Indicating P<0.05, P0.05(2,2)=19
The intuitive analysis results show that the order of the factors affecting the preparation of tetraacetylpuerarin freeze-dried powder injection is: A>B>C; the analysis of variance results show that the influence of factor A is significant (P<0.05), B, C The influence of the factors has no significant meaning, so the best preparation process conditions are A3B3C1. Considering that too much polysorbate 80 can cause hemolysis in the body, and the influence of factor B has no significant significance. Based on the principles of energy saving, cost reduction and drug safety, the preparation process conditions should be selected as A2B2C1, that is, polysorbate The amount of Ester 80 and Poloxamer 188 were both 0.5 g, and the drying temperature under reduced pressure was 40°C.
1.2.4 Verification experiment
According to the above-mentioned optimal preparation process conditions A2B2C1, three repeated experiments were carried out to verify the reliability of the results. The results are shown in Table 2-20.
Table 2-20 Verification experiment data table
The results show that the preparation process conditions are relatively stable and feasible.

Example Embodiment

Example 1:
Prescription (calculated by 1000)
Tetraacetylpuerarin 50g
Poloxamer 500g
Polysorbate 80500g
Add water for injection to 5000ml
Made into 1000
Among them, poloxamer is the carrier and scaffold of the dispersion, and polysorbate 80 is the solubilizer.
2. Preparation process
(1) Liquid preparation: weigh 50 g of tetraacetylpuerarin and 500 g of poloxamer in a sterile operating room, mix them, add 5000 ml of absolute ethanol and grind for 5 minutes to fully dissolve them. Then weigh 500 g of polysorbate 80 and add 5000 ml of sterile water for injection to dissolve it with slight heat. Mix the two evenly, recover the ethanol at low temperature, and add sterile water for injection to 5000ml.
(2) Filtration, intermediate inspection and packaging: use 1‰ activated carbon to remove pyrogens, and then use sterilized φ0.22μm (Sartobran-p produced by SARTORIUS, Germany) filter for suction; take a sample to measure the pH value And content. Divide, 5ml per bottle.
(3) Pre-freeze the aliquoted sample in a freeze dryer for 12 hours, control the pre-freezing temperature at -50°C, turn on the vacuum pump and heat the partition, the entire freeze-drying process is about 70 hours, the sample is dried, sealed, packaged, Check, put in storage, and get it.

Example Embodiment

Example 2:
Prescription (calculated by 1000)
Tetraacetylpuerarin 1g
Poloxamer 5g
Polysorbate 806g
Add water for injection to 5000ml
Made into 1000
Preparation process: the same as in Example 1.

PUM

no PUM

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