| Most candidate new drugs under development are insoluble in water,which has become a major problem in the pharmaceutical field.Improving the bioavailability of these drugs by improving the solubility/dissolution rate has become the main goal of pharmaceutical enterprises to develop effective drugs and provide patients with reasonable dosage schemes.Compared with crystalline drugs,amorphous drugs have higher solubility and dissolution without overcoming lattice energy.However,amorphous drugs are prone to recrystallization during preparation and storage.In the past ten years,many studies on co-amorphous drug delivery systems have been reported,and good progress has been made in improving the in vitro and in vivo performance and stability of low water-soluble drugs.The system is characterized by a single-phase amorphous solid-state system composed of binary or multicomponent small molecular components.According to the different excipients,it can be divided into drug-small molecular excipients and drug-drug co-amorphous system.In the drug-small molecular excipients co-amorphous system,small molecular excipients can be sugars,nicotinamide,amino acids,urea and carboxylic acids.In order to increase solubility and stability,amino acids have been widely used as co-forms of co-amorphous systems.Drug-drug components can usually effectively stabilize the amorphous state with each other,so that the drug has high solubility under supersaturation and remains stable at the same time.More importantly,the use of two drugs with synergistic pharmacological effects is of great guiding significance for the synergistic effect of combined medication.Traditional Chinese medicine is mostly used in clinic in the form of compound preparation,and most of the drugs in the prescription have the same pharmacology or have synergistic effect,but few of them are used in the form of dosage forms.Therefore,in this paper,the single effective components in medicinal materials are selected to be used in the form of co-amorphous compatibility to understand the difficulty of their preparation,and then their stability and stability mechanism are investigated respectively,and the in vitro and in vivo performance of the system is studied.The specific research content of this paper is divided into the following four parts:1.Effects of preparation process and component ratio on the formation and storage stability of Baicalin-Puerarin co-amorphous system.Baicalin(Bai)and Puerarin(Pue)have many similar pharmacological effects in clinic,and both belong to flavonoids.However,their low solubility and poor permeability limit their clinical application.In order to understand the co-amorphous ability of the two drugs and their influence on system stability.In this chapter,Bai-Pue mixture samples with molar ratios of 0∶1,1∶2,1∶1,2∶1 and 1∶0 were prepared by Cryogenic Grinding(CG),Rotary Evaporation(RE)and Spray Drying(SD).Polarization microscope(PLM),X-ray single crystal diffraction(XRD)and Differential scanning calorimetry(DSC)were used to characterize the solid state,and the physical stability of the amorphous and co-amorphous systems was investigated.The results show that among the three preparation methods,the mixture with three molar ratios of two compounds and Pue monomer prepared by rotary evaporation method and spray drying method,and the Bai monomer prepared by spray drying method have no crystal-specific birefringence under PLM,showing a shadow state;There is no crystal characteristic peak in XRD pattern,which is amorphous halo;DSC results show that all amorphous samples have only one glass transition temperature(T_g),which indicates that co-amorphous or amorphous samples have been successfully prepared.The stability results under different conditions show that the non-equimolar ratio stability is higher than the equimolar ratio and the Bai monomer is amorphous.The stability of samples prepared by spray drying method is higher than that prepared by rotary evaporation method.It is suggested that the amorphous ability of Pue is higher than that of Bai,and the solvent evaporation method is easier to form amorphous ability than grinding method,and the faster the evaporation speed,the more useful it is to form amorphous.2.Effects of preparation process and component ratio on the formation and storage stability of Imperatorin-Puerarin co-amorphous system.In order to study the ability of drugs with fewer hydrogen bond donors to form a co-amorphous system with Puerarin and its influence on the stability of the system.In this chapter,Imperatorin(Imp)was used as a model drug to prepare a co-amorphous system with Pue.Samples of Imp-Pue mixture with molar ratios of 3∶1,2∶1,1∶1,1∶0,1∶2 and 1∶3 were prepared by the same preparation method as in the first chapter,and were characterized by the same method as in 1.The physical stability of the system forming co-amorphous samples was investigated.The results show that among the six proportions of samples prepared by the three methods,Imp-Pue samples with molar ratios of 1∶2 and 1∶3 can only be prepared by spray drying method.When observed under PLM,the XRD pattern is amorphous halo,the DSC curve is only one T_g,and there is no crystal endothermic melting peak,which indicates that the samples of the two proportions are co-amorphous.The stability results show that the more puerarin content in Imp-Pue co-amorphous system,the more stable the system is,and its stability is much worse than that of Bai-Pue co-amorphous system.The results showed that the amorphous ability of Imperatorin was poor.Drugs with different molecular structures have great influence on the formation and stability of Puerarin co-amorphous system;At the same time,it shows once again that the solvent evaporation method is easier to form amorphous ability than the grinding method,and the faster the evaporation speed,the more useful it is to form amorphous.3.Study on preparation and storage stability mechanism of Baicalin-Puerarin and Imperatorin-Puerarin co-amorphous systems.In order to study the mechanism of maintaining stability among different components of Puerarin.Taking Pue as a co-forming agent and Bai and Imp as model drugs,the nucleation time of the two drugs was determined by analyzing the number and molecular weight of hydroxyl donors and receptors in the drug structure,and the T_gof the co-amorphous system was determined by DSC and compared with the theoretical value,and the reduced glass transition temperature was calculated.The force between components was analyzed by FT-IR.The results show that Pue and Bai have larger molecular weight and more hydroxyl groups,while Imp has smaller molecular weight and no hydroxyl groups in its structure.Under the condition of supersaturation of 10,the nucleation time of Bai is 11.6 min,while that of Imp is only4.8 min,which may be because Imp is easy to crystallize quickly,and its amorphous state cannot be obtained by three methods.The actual measured T_gof the two co-amorphous systems is higher than the theoretical value,which indicates that there is interaction between the co-amorphous components.The?T_gvalue of Imp-Pue co-amorphous system is very large,but Imp itself has no hydroxyl donor and is easy to crystallize,which may be the strong interaction to maintain its long-term stability.The difference of?T_gvalue of Bai-Pue co-amorphous system is not as big as that of Imp-Pue system,but due to the structure and polyhydroxy of Pue and Bai molecule,it is easy to form amorphous,so it can remain amorphous for a long time in weak interaction.FT-IR analysis shows that hydrogen bonds may be formed in Bai-Pue system,and hydrogen bonds orπ-πstacking interactions may occur in Imp-Pue system.To sum up,molecular structure has a great influence on co-amorphism.Two compounds with hydrogen bond donors and acceptors are easy to prepare into co-amorphism,and the interaction between molecules is easy to occur,which can maintain stability for a longer time.4.Evaluation of dissolution and absorption properties of Baicalin-Puerarin and Imperatorin-Puerarin co-amorphous systems.In order to study the effects of Bai-Pue and Imp-Pue co-amorphous systems on the solubility,dissolution and in vitro absorption of each component.The equilibrium solubility and supersaturated powder dissolution of Bai-Pue and Imp-Pue co-amorphous samples prepared by spray drying method were determined,and the proportion that can maintain the maximum supersaturation was selected to carry out in vitro intestinal absorption experiment to study the effect of co-amorphous on drug solubility,dissolution and absorption.The results show that in the co-amorphous system of Bai-Pue with different molar ratios,Bai can maintain a high degree of supersaturation,and the solubility of Bai is higher than that of physical mixture with different ratios,higher than that of monomer amorphous and higher than that of crystal,while the solubility of Pue is not much different from that of physical mixture with different ratios.In the co-amorphous system with different molar ratios of Imp-Pue,the solubility of Imp and Pue is not significantly different from that of physical mixture and crystal,which may be due to the gelation phenomenon in the system,resulting in poor dissolution effect of components.The results of equilibrium solubility determination are consistent with those of supersaturated powder dissolution.The experimental results of intestinal absorption in vitro show that the absorption of co-amorphous system components is the largest in all intestinal segments.In physical mixture Bai-Pue,the absorption of Bai in duodenum and jejunum is higher than that of crystal,while in Imp-Pue,the absorption of Imp in duodenum and ileum is higher than that of crystal,and Pue is higher than that of crystal in all intestinal segments.To sum up,the compatibility of the two components to prepare co-amorphous can promote absorption,and play a synergistic role in solubilization and absorption promotion of compatible components. |
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