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  • 1.

    【2hr】Aerodynamic and Electrostatic Properties of Model Dry Powder Aerosols: a Comprehensive Study of Formulation Factors

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    机译 模型干粉气溶胶的空气动力学和静电性能：配方因素的综合研究
    摘要：The impact of formulation variables on aerodynamic and electrostatic properties of dry powder aerosol particles is of great importance to the development of efficient and reproducible inhaler products. Systematic evaluation requires a well-designed series of experiments using appropriate methods. A factorial experimental design was employed. In broad terms, the conditions considered were two drugs, albuterol and budesonide, in combination with different excipients, drug concentrations, delivered doses, and metering system (capsule composition) and sampled under different flow conditions using standard entrainment tubes. Samples were collected in an electrical low-pressure impactor, to evaluate distribution of electrostatic properties, and an Andersen eight-stage nonviable cascade impactor, to estimate aerodynamic particle size distribution, concurrently. The deposition studies allowed calculation of approximate per particle charge levels for drug. The results showed very high particle charge levels, often in the 1,000–10,000 of elementary charges per particle range, orders of magnitude higher than charge levels predicted by the Boltzmann charge distribution. The charge levels are considerably higher than had previously been estimated (200e per particle).
  • 2.

    【2hr】Glass Delamination: a Comparison of the Inner Surface Performance of Vials and Pre-filled Syringes

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    机译 玻璃分层：小瓶和预填充注射器的内表面性能比较
    摘要：The occurrence of glass delamination is a serious concern for parenteral drug products. Over the past several years, there has been a series of product recalls involving glass delamination in parenteral drugs stored in vials which has led to heightened industry and regulatory scrutiny. In this study, a two-pronged approach was employed to assess the inner surface durability of vials and pre-filled syringes. Non-siliconized syringes were used in order to directly compare glass to glass performance between vials and syringes. The vial and syringe performance was screened with pharmaceutically relevant formulation conditions. The influence of pH, buffer type, ionic strength, and glass type and source was evaluated. In addition, an aggressive but discriminating formulation condition (glutaric acid, pH 11) was used to ascertain the impact of syringe processing. Advanced analytical tools including inductively coupled plasma/mass spectrometry, scanning electron microscopy, atomic force microscopy, and dynamic secondary ion mass spectroscopy showed significant differences in glass performance between vials and syringes. Pre-filled syringes outperform vials for most tests and conditions. The manufacturing conditions for vials lead to glass defects, not found in pre-filled syringes, which result in a less chemically resistant surface. The screening methodology presented in this work can be applied to assess suitability of primary containers for specific drug applications.
  • 3.

    【2hr】Evaluation of Granulated Lactose as a Carrier for DPI Formulations 1: Effect of Granule Size

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    机译 颗粒状乳糖作为DPI制剂载体的评估1：颗粒大小的影响
    摘要：The objective of this study was to investigate the effect of large granulated lactose carrier particle systems on aerosol performance of dry powder inhaler formulations. Granulated lactose carriers with average sizes ranging from 200 to 1,000 μm were prepared and subsequently fractionated into separate narrow size powders. The fractionated granulated lactose (GL) samples were characterized in terms of size, specific surface area, surface roughness, morphology, density, flowability, and solid-state. The in vitro aerosolization performance was performed on the different size fractions of GL samples from a commercial inhaler device (Aerolizer®) with a model formulation (2% w/w salbutamol sulfate). The cascade impaction parameters employed were 60 or 90 L/min with standard (aperture size, 0.6 mm) or modified piercing holes (aperture size, 1.2 mm) of the inhaler loaded capsules. It was shown that the largest size fraction formulation (850–1000 μm) had a slight improvement in the fine particle fraction (FPF) compared to immediately preceding size fractions, explained by a smaller adhesive force between drug and carrier. Compared to commercial piercing holes, enlarged piercing holes generated a slight decreasing trend of FPF as the lactose powder sizes increased from 200–250 μm to 600–850 μm, perhaps due to the reduced detachment force by flow forces. The size, surface roughness, density, and flowability of lactose carrier as well as device design all contributed to the aerosol dispersion performance of granulated lactose-based adhesive mixtures. It was concluded that poorer or enhanced redispersion performance is not an inherent property to the significantly large size of granulated lactose carriers as previously contended.
  • 4.

    【2hr】Lateral Drug Diffusion in Human Nails

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    机译 人指甲中的横向药物扩散
    摘要：The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm × 5 mm (25 mm2), 7 mm × 7 mm (49 mm2), and 9 mm × 9 mm (81 mm2) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.
  • 5.

    【2hr】An Application of Serially Balanced Designs for the Study of Known Taste Samples with the α-ASTREE Electronic Tongue

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    机译 串行平衡设计在α-ASTREE电子舌研究已知味觉样品中的应用
    摘要：The α-ASTREE e-Tongue instrument uses seven sensors to characterize taste signals associated with a liquid sample. The instrument was used to study eight test preparations (comprised of a blank, four preparations corresponding to four known tastes and Sodium Topiramate in three concentrations known to have a bitter taste) and eight washes. Serially balanced residual effects designs were used to order the samples to estimate residual and main effects. The design provided for eight repeated measurements per test preparation. The experimental results suggested the following: (1) The seven sensors can be separated into three groups according to the ability to discriminate test preparations, and three of the sensors contributed little or no information. Further investigation suggested the lack of differentiability might be due to the age of the sensors. (2) The sensors discriminated known tastes from blank. The residual effect due to test preparations might appear after repeated usage. (3) Exploratory principal component analysis of the data indicated that nearly 90% of the total variability across the seven sensors could be explained by a single principal component. (4) The four standard taste preparations did not correspond to orthogonal dimensions in the principal component axes. (5) The three Sodium Topiramate test preparations could neither be associated with the corresponding known bitter taste sample nor could the three doses be shown to follow a quantitative dose-response relationship on the e-Tongue measurement scale. The practical interpretation of the results of the statistical analysis indicates only poor discriminative ability of the e-Tongue to distinguish clearly between increasing concentrations of a known bitter compound such as Sodium Topiramate. No apparent linear relationship could be discerned over increasing concentrations that would allow the quantification of bitterness.
  • 6.

    【2hr】Integrating Artificial and Human Intelligence into Tablet Production Process

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    机译 将人工智能和人类智能整合到片剂生产过程中
    摘要：We developed a new machine learning-based method in order to facilitate the manufacturing processes of pharmaceutical products, such as tablets, in accordance with the Process Analytical Technology (PAT) and Quality by Design (QbD) initiatives. Our approach combines the data, available from prior production runs, with machine learning algorithms that are assisted by a human operator with expert knowledge of the production process. The process parameters encompass those that relate to the attributes of the precursor raw materials and those that relate to the manufacturing process itself. During manufacturing, our method allows production operator to inspect the impacts of various settings of process parameters within their proven acceptable range with the purpose of choosing the most promising values in advance of the actual batch manufacture. The interaction between the human operator and the artificial intelligence system provides improved performance and quality. We successfully implemented the method on data provided by a pharmaceutical company for a particular product, a tablet, under development. We tested the accuracy of the method in comparison with some other machine learning approaches. The method is especially suitable for analyzing manufacturing processes characterized by a limited amount of data.
  • 7.

    【2hr】Optimization of Dexamethasone Mixed Nanomicellar Formulation

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    机译 地塞米松混合萘啶酮制剂的优化
    摘要：The purpose of this study was to develop a clear aqueous mixed nanomicellar formulation (MNF) of dexamethasone utilizing both d-α-tocopherol polyethylene glycol-1000 succinate (Vit E TPGS) and octoxynol-40 (Oc-40). In this study, Vit E TPGS and Oc-40 are independent variables. Formulations were prepared following solvent evaporation method. A three level full-factorial design was applied to optimize the formulation based on entrapment efficiency, size, and polydispersity index (PDI). A specific blend of Vit E TPGS and Oc-40 at a particular wt% ratio (4.5:2.0) produced excellent drug entrapment, loading, small mixed nanomicellar size and narrow PDI. Solubility of DEX in MNF is improved by ~6.3-fold relative to normal aqueous solubility. Critical micellar concentration (CMC) for blend of polymers (4.5:2.0) was found to be lower (0.012 wt%) than the individual polymers (Vit E TPGS (0.025 wt%) and Oc-40 (0.107 wt%)). No significant effect on mixed nanomicellar size and PDI with one-factor or multi-factor interactions was observed. Qualitative 1H NMR studies confirmed absence of free drug in the outer aqueous MNF medium. MNF appeared to be highly stable. Cytotoxicity studies on rabbit primary corneal epithelial cells did not indicate any toxicity suggesting MNF of dexamethasone is safe and suitable for human topical ocular drops after further in vivo evaluations.
  • 8.

    【2hr】Liquid Crystalline Systems for Transdermal Delivery of Celecoxib: In Vitro Drug Release and Skin Permeation Studies

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    机译 塞来昔布透皮给药的液晶系统：体外药物释放和皮肤渗透研究
    摘要：Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.
  • 9.

    【2hr】Synthesis of a Semi-Interpenetrating Polymer Network as a Bioactive Curcumin Film

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    机译 生物活性姜黄素膜的半互穿聚合物网络的合成。
    摘要：This study focused on the synthesis and characterization of a natural polymeric system employing the interpenetrating polymer network (IPN) comprising curcumin as a bioactive. Biopolymers and actives such as chitosan, hypromellose, citric acid, genipin, and curcumin were used to develop an effective, biodegradable, and biocompatible film employed therapeutically as a wound healing platform. The semi-IPN films were investigated for their physicochemical, physicomechanical, and biological properties by quantification by FTIR, DSC, and Young’s modulus. Following characterization, an optimum candidate formulation was produced whereby further in vitro and ex vivo studies were performed. Results revealed a burst release occurring at the first hour with 1.1 mg bioactive released when in contact with the dissolution medium and 2.23 mg due to bioactive permeation through the skin, thus suggesting that the lipophilic nature of skin greatly impacted the bioactive release rate. Furthermore, chemical and mechanical characterization and tensile strength analysis revealed that the degree of crosslinking and concentration of polymeric material used significantly influenced the properties of the film.
  • 10.

    【2hr】Characterization and Evaluation of 5-Fluorouracil-Loaded Solid Lipid Nanoparticles Prepared via a Temperature-Modulated Solidification Technique

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    机译 通过温度调节凝固技术制备的5-氟尿嘧啶固体脂质纳米颗粒的表征与评价
    摘要：The aim of this research was to advance solid lipid nanoparticle (SLN) preparation methodology by preparing glyceryl monostearate (GMS) nanoparticles using a temperature-modulated solidification process. The technique was reproducible and prepared nanoparticles without the need of organic solvents. An anticancer agent, 5-fluorouracil (5-FU), was incorporated in the SLNs. The SLNs were characterized by particle size analysis, zeta potential analysis, differential scanning calorimetry (DSC), infrared spectroscopy, atomic force microscopy (AFM), transmission electron microscopy (TEM), drug encapsulation efficiency, in vitro drug release, and in vitro cell viability studies. Particle size of the SLN dispersion was below 100 nm, and that of redispersed lyophilizates was ~500 nm. DSC and infrared spectroscopy suggested that the degree of crystallinity did not decrease appreciably when compared to GMS. TEM and AFM images showed well-defined spherical to oval particles. The drug encapsulation efficiency was found to be approximately 46%. In vitro drug release studies showed that 80% of the encapsulated drug was released within 1 h. In vitro cell cultures were biocompatible with blank SLNs but demonstrated concentration-dependent changes in cell viability to 5-FU-loaded SLNs. The 5-FU-loaded SLNs can potentially be utilized in an anticancer drug delivery system.
  • 11.

    【2hr】An Explanation for the Difference in the Percutaneous Penetration Behavior of Tamsulosin Induced by Two Different O-Acylmenthol Derivatives

    包量

    机译 两种不同的O-酰基薄荷醇衍生物诱导坦洛新的经皮渗透行为差异的解释
    摘要：Using tamsulosin (TAL) as a model drug, the aim of this study was to investigate and compare the percutaneous permeation behavior of two menthol derivatives, 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP) and 2-isopropyl-5-methylcyclohexyl decanoate (M-DEC). In vitro transdermal permeation study was carried out using porcine skin. The residual amount of enhancers in the skin after permeation experiment was determined by gas chromatographic (GC) method. The penetration depths of fluorescein were visualized by two-photon confocal laser scanning microscopy (2P-LSM) after the skin being treated with different enhancers. Furthermore, changes in the stretching frequency of functional group of ceramide were investigated by using attenuated total reflectance Fourier transform infrared (ATR-FTIR) technique. After M-HEP addition, the cumulative amount of TAL permeated in 8 h (Q8) reached 20.57 ± 0.54 μg/cm2 and the depth of fluorescein was 40 μm; the CH2 of ceramide symmetric stretching frequency was 4 cm−1 blue shifted. However, M-DEC has an opposite effect on TAL permeation compared with that of M-HEP. TAL is a crucial factor affecting permeation procedure, and microenvironment of lipid region determines promotion capability of the enhancers.
  • 12.

    【2hr】Preparation and Characterization of Fenofibrate-Loaded Nanostructured Lipid Carriers for Oral Bioavailability Enhancement

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    机译 非诺贝特纳米结构脂质载体的制备和表征以提高口服生物利用度
    摘要：The aim of this study is to investigate the potential of nanostructured lipid carriers (NLCs) in improving the oral bioavailability of a lipid lowering agent, fenofibrate (FEN). FEN-loaded NLCs (FEN-NLCs) were prepared by hot homogenization followed by an ultrasonication method using Compritol 888 ATO as a solid lipid, Labrafil M 1944CS as a liquid lipid, and soya lecithin and Tween 80 as emulsifiers. NLCs were characterized in terms of particle size and zeta pote\ntial, surface morphology, encapsulation efficiency, and physical state properties. Bioavailability studies were carried out in rats by oral administration of FEN-NLC. NLCs exhibited a spherical shape with a small particle size (84.9 ± 4.9 nm). The drug entrapment efficiency was 99% with a loading capacity of 9.93 ± 0.01% (w/w). Biphasic drug release manner with a burst release initially, followed by prolonged release was depicted for in vitro drug release studies. After oral administration of the FEN-NLC, drug concentration in plasma and AUCt-∞ was fourfold higher, respectively, compared to the free FEN suspension. According to these results, FEN-NLC could be a potential delivery system for improvement of loading capacity and control of drug release, thus prolonging drug action time in the body and enhancing the bioavailability.
  • 13.

    【2hr】Development of Novel Ionic Liquid-Based Microemulsion Formulation for Dermal Delivery of 5-Fluorouracil

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    机译 用于5-氟尿嘧啶皮肤递送的新型离子液体基微乳液配方的开发
    摘要：The present study was aimed at synthesizing an imidazole-based ionic liquid 1-butyl-3-methylimidazolium bromide (BMIMBr) and subsequent development of a novel ionic liquid-in-oil (IL/o) microemulsion (ME) system for dermal delivery of a poorly permeating drug 5-fluorouracil (5-FU). A significant enhancement in the solubility of 5-FU was observed in BMIMBr. IL/o MEs of 5-FU were prepared using isopropyl myristate, Tween 80/Span 20, and BMIMBr. Results of ex vivo skin permeation studies through mice skin indicated that the selected IL/o ME exhibited 4-fold enhancement in percent drug permeation as compared to aqueous solution, 2.3-fold as compared to hydrophilic ointment, and 1.6-fold greater permeation than water in oil (w/o) ME. The results of in vivo studies against dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice skin carcinogenesis demonstrated that the IL/o ME could effectively treat skin cancer in 4 weeks. In addition, the side effects such as erythema and irritation associated with the conventional formulations were not observed. Histopathological studies showed that the use of IL/o ME caused no anatomic and pathological changes in the skin structure of mice. These studies suggest that the use of IL-based ME system can efficiently enhance the solubility and permeability of 5-FU and hence its therapeutic efficacy.
  • 14.

    【2hr】A Method to Evaluate the Effect of Contact with Excipients on the Surface Crystallization of Amorphous Drugs

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    机译 评价与赋形剂接触对无定形药物表面结晶影响的方法
    摘要：Amorphous drugs are used to improve the solubility, dissolution, and bioavailability of drugs. However, these metastable forms of drugs can transform into more stable, less soluble, crystalline counterparts. This study reports a method for evaluating the effect of commonly used excipients on the surface crystallization of amorphous drugs and its application to two model amorphous compounds, nifedipine and indomethacin. In this method, amorphous samples of the drugs were covered by excipients and stored in controlled environments. An inverted light microscope was used to measure in real time the rates of surface crystal nucleation and growth. For nifedipine, vacuum-dried microcrystalline cellulose and lactose monohydrate increased the nucleation rate of the β polymorph from two to five times when samples were stored in a desiccator, while d-mannitol and magnesium stearate increased the nucleation rate 50 times. At 50% relative humidity, the nucleation rates were further increased, suggesting that moisture played an important role in the crystallization caused by the excipients. The effect of excipients on the crystal growth rate was not significant, suggesting that contact with excipients influences the physical stability of amorphous nifedipine mainly through the effect on crystal nucleation. This effect seems to be drug specific because for two polymorphs of indomethacin, no significant change in the nucleation rate was observed under the excipients.
  • 15.

    【2hr】Enhancing the Antitumor Activity of Berberine Hydrochloride by Solid Lipid Nanoparticle Encapsulation

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    机译 固体脂质纳米粒包裹增强盐酸小ber碱的抗肿瘤活性
    摘要：Berberine hydrochloride (BH) is an isoquinolin alkaloid with promising anticancer efficacies. Nevertheless, further development and application of this compound had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism in the body. In this study, a solid lipid nanoparticle (SLN)-based system was developed for efficient incorporation and persistent release of BH. The drug-loading SLNs (BH-loaded SLNs) were stable, with a mean particle size of 81.42 ± 8.48 nm and zeta potential of −28.67 ± 0.71 mV. BH-loaded SLNs showed desirable drug entrapment efficiency and drug-loaded, and the release of BH from SLNs was significantly slower than free BH. Importantly, our in vitro study indicated that BH-loaded SLNs more significantly inhibited cell proliferation on MCF-7, HepG 2, and A549 cancer cells. Meanwhile, clone formation, cellular uptake, cell cycle arrest, and cell apoptosis studies also demonstrated that BH-loaded SLNs enhanced the antitumor efficacies of BH on MCF-7 cancer cells. Taken together, our results suggest that this SLN formulation may serve as a novel, simple, and efficient system for the delivery of BH.
  • 16.

    【2hr】Swellable Ciprofloxacin-Loaded Nano-in-Micro Hydrogel Particles for Local Lung Drug Delivery

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    机译 可溶环丙沙星的纳米微水凝胶颗粒用于局部肺部药物递送。
    摘要：Incorporation of drug-loaded nanoparticles into swellable and respirable microparticles is a promising strategy to avoid rapid clearance from the lung and achieve sustained drug release. In this investigation, a copolymer of polyethylene glycol grafted onto phthaloyl chitosan (PEG-g-PHCs) was synthesized and then self-assembled with ciprofloxacin to form drug-loaded nanoparticles. The nanoparticles and free drug were encapsulated into respirable and swellable alginate micro hydrogel particles and assessed as a novel system for sustained pulmonary drug delivery. Particle size, morphology, dynamic swelling profile, and in vitro drug release were investigated. Results showed that drug-loaded nanoparticles with size of 218 nm were entrapped into 3.9-μm micro hydrogel particles. The dry nano-in-micro hydrogel particles exhibited a rapid initial swelling within 2 min and showed sustained drug release. Preliminary in vivo pharmacokinetic studies were performed with formulations delivered to rats by intratracheal insufflation. Ciprofloxacin concentrations in plasma and in lung tissue and lavage were measured up to 7 h. The swellable particles showed lower ciprofloxacin levels in plasma than the controlled group (a mixture of lactose with micronized ciprofloxacin), while swellable particles achieved higher concentrations in lung tissue and lavage, indicating the swellable particles could be used for controlling drug release and prolonging lung drug concentrations.
  • 17.

    【2hr】Biologic Comparison of Inhaled Insulin Formulations: ExuberaTM and Novel Spray-Dried Engineered Particles of Dextran-10

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    机译 吸入式胰岛素制剂的生物学比较：ExuberaTM和新型喷雾干燥的Dextran-10工程颗粒
    摘要：Inhaled peptides and proteins have promise for respiratory and systemic disease treatment. Engineered spray-dried powder formulations have been shown to stabilize peptides and proteins and optimize aerosol properties for pulmonary delivery. The current study was undertaken to investigate the in vitro and in vivo inhalation performance of a model spray-dried powder of insulin and dextran 10 in comparison to Exubera™. Dextrans are a class of glucans that are generally recognized as safe with optimum glass transition temperatures well suited for spray drying. A 70% insulin particle loading was prepared by formulating with 30% (w/v) dextran 10. Physical characterization revealed a “raisin like” particle. Both formulations were generated to produce a similar bimodal particle size distribution of less than 3.5 μm MMAD. Four female Beagle dogs were exposed to each powder in a crossover design. Similar presented and inhaled doses were achieved with each powder. Euglycemia was achieved in each dog prior and subsequent to dosing and blood samples were drawn out to 245 min post-exposure. Pharmacokinetic analyses of post-dose insulin levels were similar for both powders. Respective dextran 10-insulin and Exubera exposures were similar producing near identical area under the curve (AUC), 7,728 ± 1,516 and 6,237 ± 2,621; concentration maximums (Cmax), 126 and 121 (μU/mL), and concentration–time maximums, 20 and 14 min, respectively. These results suggest that dextran-10 and other dextrans may provide a novel path for formulating peptides and proteins for pulmonary delivery.
  • 18.

    【2hr】Caprylate-Conjugated Cisplatin for the Development of Novel Liposomal Formulation

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    机译 辛酸酯缀合的顺铂用于新型脂质体制剂的开发
    摘要：Cisplatin, first (platinum) compound to be evolved as an anticancer agent, has found its important place in cancer chemotherapy. However, the dose-dependent toxicities of cisplatin, namely nephrotoxicity, ototoxicity, peripheral neuropathy, and gastrointestinal toxicity hinder its widespread use. Liposomes can reduce the toxicity of cisplatin and provide a better therapeutic action, but the low lipid solubility of cisplatin hinders its high entrapment in such lipid carrier. In the present investigation, positively charged reactive aquated species of cisplatin were complexed with negatively charged caprylate ligands, resulting in enhanced interaction of cisplatin with lipid bilayer of liposomes and increase in its encapsulation in liposomal carrier. Prepared cisplatin liposomes were found to have a vesicular size of 107.9 ± 6.2 nm and zeta potential of −3.99 ± 3.45 mV. The optimized liposomal formulation had an encapsulation efficiency of 96.03 ± 1.24% with unprecedented drug loading (0.21 mg cisplatin / mg of lipids). The in vitro release studies exhibited a pH-dependent release of cisplatin from liposomes with highest release (67.55 ± 3.65%) at pH 5.5 indicating that a maximum release would occur inside cancer cells at endolysosomal pH. The prepared liposomes were found to be stable in the serum and showed a low hemolytic potential. In vitro cytotoxicity of cisplatin liposomes on A549 lung cancer cell line was comparable to that of cisplatin solution. The developed formulation also had a significantly higher median lethal dose (LD50) of 23.79 mg/kg than that of the cisplatin solution (12 mg/kg). A promising liposomal formulation of cisplatin has been proposed that can overcome the disadvantages associated with conventional cisplatin therapy and provide a higher safety profile.
  • 19.

    【2hr】Comparative Study on the Suitability of Two Techniques for Measuring the Transfer of Lipophilic Drug Models from Lipid Nanoparticles to Lipophilic Acceptors

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    机译 两种测量亲脂性药物模型从脂质纳米颗粒转移至亲脂性受体的适用性的比较研究
    摘要：Due to their particle size in the submicrometer range, lipid nanoparticles are suitable for parenteral administration. In order to obtain information on their potential in vivo performance, a simple and effective in vitro assay to evaluate the drug release behavior of such particles is required. This study compares the use of different experimental setups for this purpose. Lipid nanoparticles from trimyristin which were loaded with fluorescent lipophilic drug models (a temoporfin and Nile red) were used as donor particles. The transfer of the two drug models to multilamellar vesicles (MLV) and emulsion droplets as lipophilic acceptor compartments was examined. The determination of the transferred substance was performed either after separation by centrifugation or by an in situ flow cytometric technique. The transfer of temoporfin was slow to the acceptor MLV and very rapid to the acceptor emulsion. With both acceptors, the transfer of temoporfin stopped at a concentration much lower than the theoretical equilibrium values. The transfer of the less lipophilic drug Nile red was very rapid to both acceptors with equilibrium concentrations close to the expected values. The transfer results of temoporfin especially to the acceptor MLV obtained with the two detection techniques were comparable while the centrifugation technique indicated an apparently higher Nile red transfer rate than the flow cytometric technique. Both techniques are equally suitable to study the transfer of temoporfin, while the flow cytometric technique is advantageous to measure the very rapid transfer of Nile red.
  • 20.

    【2hr】Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation

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    机译 理化性质影响NSAID-环糊精络合的实验和计算研究
    摘要：The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (So) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and So of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.
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