| Background and Purpose:HBW-004 is a safe,efficient and non-addictive Nav1.8 inhibitor analgesic drug independently developed by the cooperative tutor group.Complex aromatic rings are introduced into its molecular structure.This drug belongs to BCS classification type Ⅱ,with large particle size of the API,poor solubility and low oral bioavailability.In this thesis,the micro-pulverization technology is used to reduce the particle size of the API and speed up the dissolution rate,so as to lay the foundation for improving the bioavailability of the preparation.In combination with the relevant guiding principles and regulations of the preparation,the formulation process is standardized and comprehensively designed,and a preparation suitable for industrial production with good stability is developed,and the preliminary quality evaluation is carried out.Method:1.Study on micronization of API.The API was pulverized by air flow and the process was scaled up.The physicochemical properties of the API before and after crushing were compared by the appearance characters,Angle of repose and compression,humidification,melting point,crystal shape,related substances and saturated solubility in water.The dissolution rate of different particle size API capsules was investigated by dissolution test.The in vivo absorption of drugs with different particle sizes was investigated by pharmacokinetic study in rats.2.Pre-prescription study.The relevant characteristic data were obtained by measuring the solubility of the API(powder)in different solvents,the solubility of different p H buffers and the oil-water partition coefficient.The in vivo dissolution of drugs was evaluated by simulated gastrointestinal transport tests in vitro.The stability of the API(powder)was investigated by influencing factor test.Through the compatibility test of API,the auxiliary materials to be selected are initially screened.3.Preparation formulation process development.Dosage form and specification were determined according to the characteristics of biopharmaceutical and clinical application requirements.Dissolution degree was used as the main evaluation index to screen and determine the formulation.With powder state and dissolution degree as the main evaluation index,the wet granulation process was optimized,the preparation process was determined,and the preparation of small and pilot quantities of capsules was carried out.4.Preliminary quality evaluation of the preparation.The quality characteristics of capsules were investigated according to the provisions of Chinese Pharmacopoeia.The stability of the capsule was investigated by influence factor test and acceleration test.The bioavailability of the preparation in vivo was investigated by pharmacokinetic test in rats.Results:1.The API was crushed by crushing pressure of 0.7 Mpa,feeding pressure of 0.5Mpa,crushing once.The average particle size was about 4.1 μm after scale-up batch crushing;After grinding,the appearance of the substance changed from yellow crystalline solid to white powder,the Angle of repose increased from 23° to 51°,the compression degree increased from 10.7% to 36.2%,and the moisture rate increased from 0.16% to 0.31%,and the melting point,crystal type,related substances and saturated solubility in water almost did not change.The dissolution rate of API capsule increased from 17.69% to 99.38% within 60 min.The relative bioavailability of the drug in rats was increased by 3.76 times.2.The solubility of the API(powder)in water < 0.1 mg/m L,and the maximum saturation solubility was 0.1545 mg/m L at p H1.0,and the Log P value of the drug was4.55;After the drug dissolved in the simulated gastric fluid,it would not precipitate when transferred to the simulated intestinal fluid.The test results of stress testing of API(powder)showed that under the condition of light,the relative substance A increased from 0.08% on day 0 to 0.22% on day 15,and there was almost no change in other test items under other conditions.The results of the compatibility test of raw and auxiliary materials showed that the composition increase trend of related substance A under light condition was consistent with that of the API(powder),while the other conditions showed almost no change in each test item.3.Capsule size is 50 mg;The optimal prescription was 90.0 mg unit dose,including 50.0 mg main drug,33.6 mg mannitol,3.6 mg povidone,1.8 mg crosslinked povidone,1.0 mg magnesium stearate;The batch formulation volume was 80 g,The optimal wet granulation process was as follows: stirring revolution 200 rpm,shearing revolution 1600 rpm,purified water 15 m L,granulation time 5 min;and the process and parameters were appropriately adjusted according to the enlarged batch(prescription volume 240 g,3600 g).About 2660 capsules were prepared for small scale and 40,000 capsules for pilot scale.4.The test items of small test release and pilot test release of large number of capsules meet acceptable standards;The results of influence factor test and acceleration test showed that each test item of capsule was basically consistent with that of day 0.The absolute bioavailability of the preparation in rats was 32%.Conclusion:1.The gas flow crushing process of the API is stable and feasible,suitable for scale-up production;After crushing,the fluidity of the API becomes worse and it has a slight humidification,so attention should be paid to waterproof storage.The comminution process can accelerate the dissolution rate of the API and improve the bioavailability of the drug in rats.2.The API(powder)is almost insoluble or insoluble in water,and the solubility in each p H buffer is p H-dependent.with the increase of p H,the solubility decreases gradually.The drug has high oil-water distribution coefficient,good fat solubility and easy diffusion through biofilm.It is estimated that the drug will not precipitate after being dissolved in the organism’s stomach and transferred to the intestine.The API(powder)is sensitive to light and should be stored away from light.The API(powder)has good compatibility with various excipients and can be used as an alternative for formulation.3.The formulation process is stable and feasible,and can be scaled up step by step;The capsule has good stability during storage.In conclusion,micronization technology is feasible to accelerate the dissolution rate of insoluble drug HBW-004,which can lay a foundation for improving the bioavailability of the preparation.The formulation process is suitable for industrial production,the quality of capsules meets the relevant requirements and standards,and achieves the goal of innovative pharmaceutical preparation. |
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