脂质体肺部给药的研究

由于脂质体肺部给药具有刺激性小、吸收迅速、生物利用度高、安全性好、可实现持续缓慢释药等独特优势而成为近年来制剂领域的研究热点之一。本文论述脂质体肺部给药的特点、稳定性以及在药代动力学、药效学和安全性等方面的最新研究进展。     

我国药物释放系统发展对策与建议

在综合分析药物释放系统发展趋势、我国药物释放系统发展的实际水平及存在问题的基础上,提出我国药物释放系统发展的对策与建议。     

国内外药物释放系统研究的文献计量学分析

利用互联网Medline数据库、清华全文数据库、欧洲专利数据库和中国知识产权局专利数据库,应用统计和情报分析的方法,对国内外近年来发表的有关药物释放系统(DDS)主题文献的论文进行文献数量、年代及研究内容的统计分析,同时对国内外药物制剂专利公布情况进行资料统计,对比分析国内外DDS的研究领域、研究重点变化及发展趋势,探讨我国未来DDS的研究重点与发展前景。     

A natural lipopeptide of surfactin for oral delivery of insulin

Abstract

Surfactin, a natural lipopeptide produced by Bacillus, is gaining attention for potentially biomedical and pharmaceutical applications. Here, surfactin was assayed for oral delivery of insulin (INS) by its ability to bind to and promote protein to penetrate through the cell membrane. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, surfactin was found to form co-precipitates with INS to protect it from acidic and enzymatic attack in the gastrointestinal tract. Further analysis by non-reductive electrophoresis showed surfactin could bind to INS forming heteropolymers. Analysis with circular dichroism, we found this binding significantly influenced the INS structure with decreased rigid α-helix and β-turn, but with increased flexible β-sheet and random coil. The change with more flexible structure was favorable for INS to penetrate through the cell membrane. Fluorescence spectra analysis also showed surfactin could lead Phe and Tyr in the inner of INS exposed outside, further promoting INS permeabilization by improving the hydrophobic-lipophilic interactions between INS and cell membrane. As a result, the effective permeability (Peff) of INS plus surfactin was 4.3 times of that of INS alone. In vivo assay showed oral INS with surfactin displayed excellent hypoglycemic effects with a relative bioavailability of 12.48% and 5.97% in diabetic mice and non-diabetic dogs, respectively. Summary, surfactin is potential for oral delivery of INS by its role as an effective protease inhibitor and permeability enhancer.     

PLGA-modified Syloid®-based microparticles for the ocular delivery of terconazole: in-vitro and in-vivo investigations

The eye is an invulnerable organ with intrinsic anatomical and physiological barriers, hindering the development of a pioneer ocular formulation. The aim of this work was to develop an efficient ocular delivery system that can augment the ocular bioavailability of the antifungal drug, terconazole. Mesoporous silica microparticles, Syloid^® 244 FP were utilized as the carrier system for terconazole. Preliminary studies were carried out using different drug:Syloid^® weight ratios. The optimum weight ratio was mixed with various concentrations (30 and 60%w/w) of poly (lactic-co-glycolic acid) (PLGA), ester or acid-capped and with different monomers-ratio (50:50 and 75:25) using the nano-spray dryer. Results revealed the superiority of drug:Syloid^® weight ratio of 1:2 in terms of yield percentage (Y%), SPAN and drug content percentage (DC%). Furthermore, incorporation of PLGA with lower glycolic acid monomer-ratio significantly increased Y%. In contrast, increasing the glycolic acid monomer-ratio resulted in higher DC% and release efficiency percentage (RE%). Additionally, doubling PLGA concentration significantly reduced Y%, DC%, drug loading percentage (DL%) and RE%. Applying desirability function in terms of increasing DC%, DL% besides RE% and decreasing SPAN, the selected formulation was chosen for DSC, XRD and SEM investigations. Results confirmed the successful loading of amorphized terconazole on PLGA-modified Syloid^® microparticles. Moreover, pharmacokinetic studies for the chosen formulation on male Albino rabbits’ eyes revealed a 2, 6.7 and 25.3-fold increase in mean residence time, C_max and AUC_0–24-values, respectively, compared to the drug suspension. PLGA-modified Syloid^® microparticles represent a potential option to augment the bioavailability of ocular drugs.     

Multi-Timescale Rhythmicity of Blood Glucose and Insulin Delivery Reveals Key Advantages of Hybrid Closed Loop Therapy

Background:Blood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users.Methods:Wavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16).Results:Glycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals.Conclusions:SAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.     

Total failure of spinal anesthesia for cesarean delivery,associated factors,and outcomes: A retrospective case–control study

Spinal anesthesia is the anesthetic technique of choice for patients undergoing cesarean delivery. In the present study, total spinal anesthesia failure was defined as a case when an absent blockade or inadequate surgery required general anesthesia administration with an endotracheal tube. This study aimed to investigate factors related to this condition and report its maternal and neonatal outcomes.This retrospective matched case–control study was conducted by recruiting 110 patients with failed spinal anesthesia and 330 control patients from September 1, 2016, to April 30, 2020, in the largest university hospital, Thailand.Of 12,914 cesarean deliveries, 12,001 patients received single-shot spinal anesthesia (92.9%) during the study period. Total spinal anesthesia failure was experienced by 110/12,001 patients, giving an incidence of 0.9%. Factors related to the failures were a patient body mass index (BMI) ≤29.5 kg/m² (adjusted odds ratio 1.9; 95% confidence interval 1.2–3.1; P = .010) and a third-year resident (the most senior trainee) performing the spinal block (adjusted odds ratio 2.4; 95% confidence interval 1.5–3.7; P < .001). In the group with failed spinal anesthesia, neonatal Apgar scores at 1 and 5 minutes were lower than those of the control group (both P < .001). Two patients in the failed spinal anesthesia group (2/110; 1.8%) had difficult airways and desaturation.Independent factors associated with total spinal anesthesia failure were a BMI of ≤29.5 kg/m² and a third-year resident performing the spinal block. Although the incidence of total failure was infrequent, there were negative consequences for the mothers and neonates. Adjusting the dose of bupivacaine according to the weight and height of a patient is recommended, with a higher dose appropriate for patients with a lower BMI.     

Low-density lipoprotein encapsulated thiosemicarbazone metal complexes is active targeting vehicle for breast,lung, and prostate cancers

Cancer is a leading cause of death worldwide and affects society in terms of the number of lives lost. Current cancer treatments are based on conventional chemotherapy which is nonspecific in targeting cancer. Therefore, intensive efforts are underway to better target cancer-specific cells while minimizing the side effects on healthy tissues by using LDL particles as active drug delivery vehicles. The goal is to encapsulate anticancer agents thiosemicarbazone metal-ligand complexes into LDL particles to increase the cytotoxic effect of the agent by internalization through LDL receptors into MCF7, A549, and C42 cancer cell lines as segregate models for biological evaluations targeting tubulin. Zeta potential data of LDL-particles encapsulated anticancer agents showed an acceptable diameter range between 66–91 nm and uniform particle morphology. The results showed cell proliferation reduction in all tested cell lines. The IC₅₀ values of LDL encapsulated thiosemicarbazone metal-ligand complexes treated with MCF7, A549, and C42 ranged between 1.18–6.61 µM, 1.17–9.66 µM, and 1.01–6.62 µM, respectively. Western blot analysis showed a potent decrease in tubulin expression when the cell lines were treated with LDL particles encapsulated with thiosemicarbazone metal-ligand complexes as anticancer agents. In conclusion, the data provide strong evidence that LDL particles are used as an active drug delivery strategy for cancer therapy.     

Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first‐line treatment in several countries. However, irinotecan has not been successfully introduced as a second‐line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal‐IRI) combined with 5‐fluorouracil and leucovorin (5‐FU/LV) was reported in the phase III NAPOLI‐1 trial in metastatic PDAC following failure of gemcitabine‐based therapy. Several features of nal‐IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN‐38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN‐38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half‐life and higher area under the concentration‐time curve (0–∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal‐IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small‐cell lung cancer.     

聚乙二醇1000维生素E琥珀酸酯在纳米制剂中的应用进展

目的综述聚乙二醇1000维生素E琥珀酸酯(D-α-tocopherol polyethylene glycol 1000 succi-nate,TPGS)在各种纳米制剂中的最新进展。方法查阅国内外相关文献共48篇,对这些文献进行分析、概括和总结。结果 TPGS能够提高药物包封率和细胞吸收,改善药物释放,提高药物生物利用度,并能协同起抗癌疗效。广泛应用于聚合物纳米粒、聚合物胶束、纳米脂质体、纳米药物等纳米给药系统中。结论 TPGS在纳米制剂中有着良好应用前景。