Injectable composition containing prodrug of caspase inhibitors, and preparation method therefor
A composition and drug technology, applied in the field of injection pharmaceutical composition and its preparation, can solve the problems of low encapsulation efficiency, limitation of in vitro drug release period, loss of drug, etc.
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[0054] Preparation Example: Synthesis of (2S,3S)-2-(fluoromethyl)-3-((R)-5-isopropyl-3-(isoquinolin-1-yl)-4, 5-Dihydroiso Azole-5-carboxamido)-5-oxotetrahydrofuran-2-yl ester
[0055]
[0056] Niflecagen ((R)-N-((2S,3S)-2-(fluoromethyl)-2-hydroxy-5-oxotetrahydrofuran-3-yl]-5-isopropyl-3- (isoquinolin-1-yl)-4,5-dihydroiso Azole-5-carboxamide; 5.0g, 12.0mmol) was dissolved in dichloromethane (50mL), and then acetyl chloride (0.94mL, 13.2mmol, 1.1 equivalents), triethylamine (2.52mL, 18.0mmol, 1.5 eq) and 4-dimethylaminopyridine (0.15 g, 1.2 mmol, 0.1 eq) while maintaining the temperature at 5°C or lower. The reaction mixture was stirred at 25 °C for about 2 hours and quenched by the addition of 10% aqueous sodium bicarbonate (25 mL). After adding water (25 mL) and stirring, the organic layer was separated and distilled under reduced pressure. The resulting mixture was recrystallized in a 1:5 mixture of ethyl acetate and hexane (EtOAc:hexane=1:5) to obtain 3.0 g (y...
Embodiment 1 to 7
[0058] Examples 1 to 7: Preparation of Microspheres Encapsulating Caspase Inhibitor Prodrugs
[0059] According to the compositions shown in Table 1 below, microspheres encapsulated with prodrugs of caspase inhibitors were prepared.
[0060] The compound of formula 1 and PLGA, which are prodrugs of caspase inhibitors, were weighed according to the weight ratio shown in Table 1, and the organic solvent dichloromethane was added thereto and stirred to prepare a dispersed phase. The PLGAs used are the following 3 types: 5050PLGA (L / G ratio 50:50, M.W.38,000-54,000), 7525PLGA (L / G ratio 75:25, M.W.76,000-115,000) and 5050PLGA and 7525PLGA in 6: 4 weight ratio mixed with PLGA.
[0061] For the continuous phase, use 150 mL of 2% polyvinyl alcohol (M.W. 31,000-50,000, degree of hydrolysis 87-89%) or 5,100 mL of 1% polyvinyl alcohol (M.W. 31,000-50,000, degree of hydrolysis 87-89%), and pass Membrane emulsification to prepare emulsions.
[0062] The prepared emulsion was stirred ...
experiment example 1
[0065] Experimental Example 1: Analysis of Microsphere Properties and Drug Encapsulation Efficiency
[0066] The properties of the microspheres prepared in Examples 1 to 7 were characterized by the morphology and encapsulation efficiency of the lyophilized microspheres.
[0067] The morphology of the freeze-dried microspheres was observed by scanning electron microscopy. For the amount of drug encapsulated in the microspheres, 30 mg of microspheres were dissolved in 50 mL of acetonitrile, and the supernatant obtained by ultracentrifugation was analyzed using HPLC (High Performance Liquid Chromatography). Encapsulation efficiency was calculated by measuring encapsulation efficiency.
[0068] -Encapsulation efficiency=(the weight of the tested drug) / (the weight of the tested microsphere (MS))*100(%)
[0069] -Encapsulation efficiency=(the weight of the tested drug) / (the weight of the initially added drug)*100(%)
[0070] The results observed by scanning electron microscopy ...
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