ABSTRACT
Triptolide(TP), the main active and toxic component of Tripterygium wilfordii, has the limitations of low bioavailability, poor absorption, low concentration in plasma, and small lethal dose. Microneedle(MN), the hybrid of hypodermic needle and transdermal patch, is a physical penetration-enhancing system. Dissolving microneedles(DMNs) can be tailored to specific needs of degradation rate. In this study, the TP-loaded DMNs(DMNs-TP) were prepared with the two-step centrifugation method. The optimal ratio of PVA to PVP K30, water content in matrix solution, demoulding method, and plasticizer for preparing DMNs were investigated with the indexes of formability and mechanical strength. The drug loading capacity was determined by HPLC and morphological characteristics were observed under an optical microscope. The mechanical properties were investigated by H&E staining and Franz diffusion cell was used to detect the in vitro skin permeation characteristics. Through the experiment, we confirmed that the optimal backing material should be PVA and PVP K30(3∶1) and the optimal ratio of matrix material to water should be 3∶4. The prepared DMNs-TP were pyramidal with smooth surface and length of approximately 550 μm. Each patch(2.75 cm~2) had the drug loading capacity of(153.41±2.29) μg, and TP was located in the upper part of the needle. The results of in vitro skin permeation assay demonstrated that the cumulative penetration of TP in DMNs-TP reached 80% in 24 h, while little TP solution penetrated the skin, which proved that DMNs promoted the transdermal delivery of TP.
Subject(s)
Administration, Cutaneous , Diterpenes , Drug Delivery Systems , Epoxy Compounds , Needles , Phenanthrenes , SkinABSTRACT
OBJECTIVE： To study in vitro drug release and acute toxicity in vivo of Curcumin （Cur） solid lipid nanoparticles （SLN） dry powder inhaler （DPI） and its effects of inflammatory response in asthmatic model mice. METHODS： Cur-SLN-DPI was obtained with spray-drying method by micronizing the Cur-SLN suspension prepared by the microemulsion method and thoroughly mixing with lactose （200 mesh） etc. The drug release in vitro was investigated by dynamic membrane dialysis. Accumulative release rates （Q） of Cur raw material， Cur-SLN and Cur-SLN-DPI in 3 kinds of release mediums [phosphate buffer solution （PBS， pH 7.4） containing 1.0％ sodium dodecyl sulfate （SDS）， PBS （pH 7.4） containing 0.2％ tween 80， normal saline-20％ ethanol solution] were compared 5， 15， 30 min and 1， 1.5， 3， 6， 8， 12， 18， 24， 36， 48 h after releasing. Drug release model was fitted. The effects of intravenous injection of maximal dose 2 000 mg/kg Cur-SLN-DPI via tail vein on KM mice were investigated by acute toxicity test. KM mice were randomly divided into normal control group， model group， positive drug group （budesonide 3 mg）， Cur-SLN-DPI high-dose and low-dose groups （100， 50 mg/kg）， with 7 mice in each group. The ovalbumin （OVA） was used as sensitizer to induce asthma model； the model mice were given relevant medicine with aerosol administration 30 min before aerosol administration of OVA inducing asthma on Monday， Wednesday and Friday per week， for consecutive 3 weeks. Within 24 h after last induction， total number of leukocyte， the number of lymphocyte， neutrophil and eosinophil were counted in broncho alveolar lavage fluid （BALF）； the pathological changes of bronchus and lung tissue were observed. RESULTS： Compared with Cur raw material， Cur-SLN and Cur-SLN-DPI showed good sustained-release effect， and Cur-SLN-DPI had more stable sustained release in 3 kinds of release mediums. The characteristics of drug release conformed to the Weibull model. Intravenous injection of 2 000 mg/kg Cur-SLN-DPI via tail vein had no significant acute toxicity in mice. Compared with normal control group， total number of leukocyte， the number of lymphocyte， neutrophil and eosinophil were increased significantly （P＜0.01）； bronchial mucosal epithelium was covered with pseudostratified ciliated columnar cells， with severe infiltration of inflammatory cells， pulmonary congestion and moderate interstitial pneumonia. Compared with model group， the number of above cells in BALF of mice were decreased significantly in administration group （P＜0.01）； tracheal lesions of mice were improved in Cur-SLN-DPI low-dose and high-dose groups； pulmonary congestion of them were alleviated， and that of high-dose group was alleviated more significantly. CONCLUSIONS： Cur-SLN-DPI shows sustained-release effect in vitro and has no obvious acute toxicity to mice. Cur-SLN-DPI can improve the inflammatory response of the airway and the degree of pulmonary congestion in asthmatic model mice.
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Objective:To prepare thermosensitive liquid suppositories of mesalazine( MSZ) HP-β-CD complex and study the in vitro properties. Methods:Poloxamer 407 (P407) and poloxamer 188 (P188) were used as the thermosensitive polymers to load MSZ HP-β-CD complex to prepare the thermosensitive liquid suppositories. The viscosity, gel strength, bioadhesion,in vitro gel erosion and drug release of MSZ HP-β-CD complex were compared with those of MSZ liquid suppositories. Results: Compared with that of MSZ liquid suppositories, the gel temperature of MSZ HP-β-CD complex liquid suppositories was stable, while the viscosity, gel strength and bioadhesion of MSZ HP-β-CD complex liquid suppositories were increased significantly. The in vitro gel erosion was not affected by MSZ HP-β-CD complex, while the drug release was notably enhanced. The drug release and gel erosion showed a good linear relation-ship. Conclusion:MSZ HP-β-CD complex liquid suppositories show good gel temperature, viscosity, gel erosion and bioadhesion, and the in vitro release rate is faster than that of MSZ liquid suppositories.
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Objective: To prepare mesalazine thermosensitive liquid suppositories and study the in vitro properties. Methods:Poloxamer 407 (P407) and poloxamer 188 (P188) were used as the temperature-sensitive materials, and mesalazine thermosensitive liquid suppositories were prepared by a cold method. The optimal ratio of P407 and P188 was screened using gel temperature as the in-dex. The gel strength and bioadhesive force of mesalazine thermosensitive liquid suppositories were studied, and the in vitro gel erosion and drug release were investigated as well. Results:The optimal ratio of P407 and P188 was 20%: 2. 5%, and the gel temperature was (36.9 ±0.2)℃, the gel strength was (115.1 ±3.2)s and the bioadhesive force was (130.7 ±5.8) ×102 dyne·cm-2. The drug release and gel erosion in vitro were both fitted first-order kinetics, and the two had promising linear relationship, suggesting good sustained-release property based on gel erosion mechanism of mesalazine liquid suppositories. Conclusion:The preparation of mesala-zine liquid suppositories is simple, and the gelation, bioadhesion and sustained-release of the suppositories are promising. Mesalazine liquid suppositories are valuable to be studied further.
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Objective:To prepare sirolimus ( SRL) dropping pills to improve SRL solubility and dissolution. Methods:The base of SRL dropping pills was screened. The optimal formula and preparation process were also optimized by orthogonal design. The equi-librium solubility, hygroscopicity and drug release in vitro of SRL dropping pills were studied. Results: PEG6000 was chosen as the base. The optimal preparation conditions of SRL dropping pills were as follows: the ratio of SRL and base was 1∶10, the dropping speed was 65 drops/min, the dropping temperature was 95℃ and the temperature of cooling solvent was 5℃. The equilibrium solubili-ty of SRL dropping pills in different solvents was increased significantly compared with that of SRL. The hygroscopicity of the dropping pills was notable. The drug release in vitro of SRL dropping pills was similar to that of the marketed tablets with quick and complete re-lease. Conclusion:SRL dropping pills exhibit increased solubility and improved dissolution, which are valuable to be studied further.