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  • 1.

    【2hr】Quality-by-Design II: Application of Quantitative Risk Analysis to the Formulation of Ciprofloxacin Tablets

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    机译 设计质量II：定量风险分析在环丙沙星片制剂中的应用
    摘要：Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.Electronic supplementary materialThe online version of this article (doi:10.1208/s12249-015-0349-2) contains supplementary material, which is available to authorized users.
  • 2.

    【2hr】Small-Scale Assays for Studying Dissolution of Pharmaceutical Cocrystals for Oral Administration

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    机译 用于研究口服给药药物共晶体溶解的小规模试验
    摘要：The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument. Two methodologies were used: (i) surface dissolution of pressed tablet (3 mm) in 20 mL running for fixed times at four pH stages (pH 1.8, pH 3.9, pH 5.4, pH 7.3) and (ii) powder dissolution (2.6 mg) in 2 mL at a constant pH (pH 2). Improved dissolution and useful insights into precipitation kinetics of poorly soluble compounds from the cocrystal form can be revealed by the small-scale dissolution assay. A clear difference in dissolution/precipitation behaviour can be observed based on the characteristics of the coformer used.
  • 3.

    【2hr】Microparticles Containing Curcumin Solid Dispersion: Stability, Bioavailability and Anti-Inflammatory Activity

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    机译 包含姜黄素固体分散体的微粒：稳定性，生物利用度和抗炎活性
    摘要：This work aimed at improving the solubility of curcumin by the preparation of spray-dried ternary solid dispersions containing Gelucire®50/13-Aerosil® and quantifying the resulting in vivo oral bioavailability and anti-inflammatory activity. The solid dispersion containing 40% of curcumin was characterised by calorimetry, infrared spectroscopy and X-ray powder diffraction. The solubility and dissolution rate of curcumin in aqueous HCl or phosphate buffer improved up to 3600- and 7.3-fold, respectively. Accelerated stability test demonstrated that the solid dispersion was stable for 9 months. The pharmacokinetic study showed a 5.5-fold increase in curcumin in rat blood plasma when compared to unprocessed curcumin. The solid dispersion also provided enhanced anti-inflammatory activity in rat paw oedema. Finally, the solid dispersion proposed here is a promising way to enhance curcumin bioavailability at an industrial pharmaceutical perspective, since its preparation applies the spray drying, which is an easy to scale up technique. The findings herein stimulate further in vivo evaluations and clinical tests as a cancer and Alzheimer chemoprevention agent.
  • 4.

    【2hr】Design and Evaluation of a Novel Felbinac Transdermal Patch: Combining Ion-Pair and Chemical Enhancer Strategy

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    机译 新型Felbinac透皮贴剂的设计和评估：结合离子对和化学增强剂策略
    摘要：The aim of this study was to design a novel felbinac (FEL) patch with significantly higher (P < 0.05) skin permeation amount than the commercial product SELTOUCH® using ion-pair and chemical enhancer strategy, overcoming the disadvantage of the large application area of SELTOUCH®. Six complexes of FEL with organic amines diethylamine (DEA), triethylamine (TEA), N-(2′-hydroxy-ethanol)-piperdine (HEPP), monoethanolamine (MEtA), diethanolamine (DEtA), and triethanolamine (TEtA) were prepared by ion-pair interaction, and their formation were confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction (pXRD), infared spectroscopy (IR), and proton nuclear magnetic resonance spectroscopy (1H-NMR). Subsequently, the effect of ion-pair complexes and chemical enhancers were investigated through in vitro and in vivo experiments using rabbit abdominal skin. Results showed that FEL-TEA was the most potential candidate both in isopropyl palmitate (IPP) solution and transdermal patches. Combining use of 10% N-dodecylazepan-2-one (Azone), the optimized FEL-TEA patch achieved a flux of 18.29 ± 2.59 μg/cm2/h, which was twice the amount of the product SELTOUCH® (J = 9.18 ± 1.26 μg/cm2/h). Similarly, the area under the concentration curve from time 0 to time t (AUC0-t) in FEL-TEA patch group (15.94 ± 3.58 h.μg/mL) was also twice as that in SELTOUCH® group (7.31 ± 1.16 h.μg/mL). Furthermore, the in vitro skin permeation results of FEL-TEA patch was found to have a good correlation with the in vivo absorption results in rabbit. These findings indicated that a combination of ion-pair and chemical enhancer strategy could be useful in developing a novel transdermal patch of FEL.
  • 5.

    【2hr】Improved Aqueous Solubility and Antihypercholesterolemic Activity of Ezetimibe on Formulating with Hydroxypropyl-β-Cyclodextrin and Hydrophilic Auxiliary Substances

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    机译 依西替米贝在羟丙基-β-环糊精和亲水助剂配方中的水溶性和抗高胆固醇血症活性
    摘要：The purpose of this study was to improve the aqueous solubility, dissolution, and pharmacodynamic properties of a BCS class II drug, ezetimibe (Eze) by preparing ternary cyclodextrin complex systems. We investigated the potential synergistic effect of two novel hydrophilic auxiliary substances, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and l-ascorbic acid-2-glucoside (AA2G) on hydroxypropyl-β-cyclodextrin (HPBCD) solubilization of poorly water-soluble hypocholesterolemic drug, Eze. In solution state, the binary and ternary systems were analyzed by phase solubility studies and Job’s plot. The solid complexes prepared by freeze-drying were characterized by Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and scanning electron microscopy (SEM). The log P values, aqueous solubility, dissolution, and antihypercholesterolemic activity of all systems were studied. The analytical techniques confirmed the formation of inclusion complexes in the binary and ternary systems. HPBCD complexation significantly (p < 0.05) reduced the log P and improved the solubility, dissolution, and hypocholesterolemic properties of Eze, and the addition of ternary component produced further significant improvement (p < 0.05) even compared to binary system. The remarkable reduction in log P and enhancement in solubility, dissolution, and antihypercholesterolemic activity due to the addition of TPGS or AA2G may be attributed to enhanced wetting, dispersibility, and complete amorphization. The use of TPGS or AA2G as ternary hydrophilic auxiliary substances improved the HPBCD solubilization and antihypercholesterolemic activity of Eze.
  • 6.

    【2hr】Drop-on-Demand System for Manufacturing of Melt-based Solid Oral Dosage: Effect of Critical Process Parameters on Product Quality

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    机译 用于制造基于熔体的固体口服剂量的按需滴注系统：关键工艺参数对产品质量的影响
    摘要：The features of a drop-on-demand-based system developed for the manufacture of melt-based pharmaceuticals have been previously reported. In this paper, a supervisory control system, which is designed to ensure reproducible production of high quality of melt-based solid oral dosages, is presented. This control system enables the production of individual dosage forms with the desired critical quality attributes: amount of active ingredient and drug morphology by monitoring and controlling critical process parameters, such as drop size and product and process temperatures. The effects of these process parameters on the final product quality are investigated, and the properties of the produced dosage forms characterized using various techniques, such as Raman spectroscopy, optical microscopy, and dissolution testing. A crystallization temperature control strategy, including controlled temperature cycles, is presented to tailor the crystallization behavior of drug deposits and to achieve consistent drug morphology. This control strategy can be used to achieve the desired bioavailability of the drug by mitigating variations in the dissolution profiles. The supervisor control strategy enables the application of the drop-on-demand system to the production of individualized dosage required for personalized drug regimens.
  • 7.

    【2hr】Nanoparticle-Based Topical Ophthalmic Gel Formulation for Sustained Release of Hydrocortisone Butyrate

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    机译 基于纳米粒子的局部滴眼液凝胶制剂，可持续释放丁酸氢化可的松
    摘要：This study was conducted to develop formulations of hydrocortisone butyrate (HB)-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles (PLGA NP) suspended in thermosensitive gel to improve ocular bioavailability of HB for the treatment of bacterial corneal keratitis. PLGA NP with different surfactants such as polyvinyl alcohol (PVA), pluronic F-108, and chitosan were prepared using oil-in-water (O/W) emulsion evaporation technique. NP were characterized with respect to particle size, entrapment efficiency, polydispersity, drug loading, surface morphology, zeta potential, and crystallinity. In vitro release of HB from NP showed a biphasic release pattern with an initial burst phase followed by a sustained phase. Such burst effect was completely eliminated when nanoparticles were suspended in thermosensitive gels and zero-order release kinetics was observed. In HCEC cell line, chitosan-emulsified NP showed the highest cellular uptake efficiency over PVA- and pluronic-emulsified NP (59.09 ± 6.21%, 55.74 ± 6.26%, and 62.54 ± 3.30%, respectively) after 4 h. However, chitosan-emulsified NP indicated significant cytotoxicity of 200 and 500 μg/mL after 48 h, while PVA- and pluronic-emulsified NP exhibited no significant cytotoxicity. PLGA NP dispersed in thermosensitive gels can be considered as a promising drug delivery system for the treatment of anterior eye diseases.
  • 8.

    【2hr】Improved Skin Penetration Using In Situ Nanoparticulate Diclofenac Diethylamine in Hydrogel Systems: In Vitro and In Vivo Studies

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    机译 在水凝胶系统中使用原位纳米颗粒双氯芬酸二乙胺改善皮肤渗透性：体内和体外研究
    摘要：Delivering diclofenac diethylamine transdermally by means of a hydrogel is an approach to reduce or avoid systemic toxicity of the drug while providing local action for a prolonged period. In the present investigation, a process was developed to produce nanosize particles (about 10 nm) of diclofenac diethylamine in situ during the development of hydrogel, using simple mixing technique. Hydrogel was developed with polyvinyl alcohol (PVA) (5.8% w/w) and carbopol 71G (1.5% w/w). The formulations were evaluated on the basis of field emission scanning electron microscopy, texture analysis, and the assessment of various physiochemical properties. Viscosity (163–165 cps for hydrogel containing microsize drug particles and 171–173 cps for hydrogel containing nanosize drug particles, respectively) and swelling index (varied between 0.62 and 0.68) data favor the hydrogels for satisfactory topical applications. The measured hardness of the different hydrogels was uniform indicating a uniform spreadability. Data of in vitro skin (cadaver) permeation for 10 h showed that the enhancement ratios of the flux of the formulation containing nanosize drug (without the permeation enhancer) were 9.72 and 1.30 compared to the formulation containing microsized drug and the marketed formulations, respectively. In vivo plasma level of the drug increased predominantly for the hydrogel containing nanosize drug-clusters. The study depicts a simple technique for preparing hydrogel containing nanosize diclofenac diethylamine particles in situ, which can be commercially viable. The study also shows the advantage of the experimental transdermal hydrogel with nanosize drug particles over the hydrogel with microsize drug particles.
  • 9.

    【2hr】Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory

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    机译 基于弗洛里-哈金斯理论的非晶态固体分散体二元相图的构建和验证
    摘要：Drug–polymer miscibility is one of the fundamental prerequisite for the successful design and development of amorphous solid dispersion formulation. The purpose of the present work is to provide an example of the theoretical estimation of drug–polymer miscibility and solubility on the basis of Flory–Huggins (F–H) theory and experimental validation of the phase diagram. The F–H interaction parameter, χ d-p, of model system, aceclofenac and Soluplus, was estimated by two methods: by melting point depression of drug in presence of different polymer fractions and by Hildebrand and Scott solubility parameter calculations. The simplified relationship between the F–H interaction parameter and temperature was established. This enabled us to generate free energy of mixing (ΔG mix) curves for varying drug–polymer compositions at different temperatures and finally the spinodal curve. The predicted behavior of the binary system was evaluated through X-ray diffraction, differential scanning calorimetry, and in vitro dissolution studies. The results suggest possibility of employing interaction parameter as preliminary tool for the estimation of drug–polymer miscibility.
  • 10.

    【2hr】Gastroretentive Matrix Tablets of Boswellia Oleogum Resin: Preparation, Optimization, In Vitro Evaluation, and Cytoprotective Effect on Indomethacin-Induced Gastric Ulcer in Rabbits

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    机译 乳香树脂的胃滞留基质片剂：对吲哚美辛诱发的胃溃疡的制备，优化，体外评价和细胞保护作用
    摘要：Currently available anti-ulcer drugs suffer from serious side effects which limited their uses and prompted the need to search for a safe and efficient new anti-ulcer agent. Boswellia gum resin (BR) emerged as a safe, efficient, natural, and economic potential cytoprotective agent. Thus, it is of medical importance to develop gastroretentive (GR) formulations of BR to enhance its bioavailability and anti-ulcer efficacy. Early attempts involved the use of organic solvents and non-applicability to large-scale production. In this study, different tablet formulations were prepared by simple direct compression combining floating and bioadhesion mechanisms employing hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), pectin (PC), and/or carbopol (CP) as bioadhesive polymers and sodium bicarbonate (SB) as a gas former. The prepared tablets were subjected for assessment of swelling, floating, bioadhesion, and drug release in 0.1 N HCl. The optimized GR formulation was examined for its protective effect on the gastric ulcer induced by indomethacin in albino rabbits compared with lactose tablets. The obtained results disclosed that swelling, floating, bioadhesion, and drug release of the GR tablets of BR depend mainly on the nature of the matrix and the ratio of polymer combinations. Moreover, a combination of SCMC-CP in a ratio of 2:1 (SCP21) exhibited desirable floating, bioadhesion, swelling, and extended drug release. Also, a 6-h pretreatment with SCP21 tablets decreased the severity of inflammation and number of bleeding spots among ulcer-induced rabbits in comparison to those treated with lactose tablets.Electronic supplementary materialThe online version of this article (doi:10.1208/s12249-015-0351-8) contains supplementary material, which is available to authorized users.
  • 11.

    【2hr】Preparation and In Vitro–In Vivo Evaluation of Sustained-Release Matrix Pellets of Capsaicin to Enhance the Oral Bioavailability

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    机译 辣椒素的缓释基质微丸的制备和体内评价以增强口服生物利用度
    摘要：Capsaicin has multiple pharmacological activities including antioxidant, anticancer, and anti-inflammatory activities. However, its clinical application is limited due to its poor aqueous solubility, gastric irritation, and low oral bioavailability. This research was aimed at preparing sustained-release matrix pellets of capsaicin to enhance its oral bioavailability. The pellets comprised of a core of solid-dispersed capsaicin mixed with microcrystalline cellulose (MCC) and hydroxypropyl cellulose (HPMC) and subsequently coating with ethyl cellulose (EC) were obtained by using the technology of extrusion/spheronization. The physicochemical properties of the pellets were evaluated through scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). Besides, the in vitro release, in vivo absorption, and in vitro–in vivo correlation were also assessed. More importantly, the relative bioavailability of the sustained-release matrix pellets was studied in fasted rabbits after oral administration using free capsaicin and solid dispersion as references. The oral bioavailability of the matrix pellets and sustained-release matrix pellets of capsaicin was improved approximately 1.98-fold and 5.34-fold, respectively, compared with the free capsaicin. A good level A IVIVC (in vitro–in vivo correlation) was established between the in vitro dissolution and the in vivo absorption of sustained-release matrix pellets. All the results affirmed the remarkable improvement in the oral bioavailability of capsaicin owing to the successful preparation of its sustained-release matrix pellets.
  • 12.

    【2hr】Development and Optimization of a Novel Prolonged Release Formulation to Resist Alcohol-Induced Dose Dumping

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    机译 新型抗酒精诱导的剂量倾销延长释放配方的开发和优化
    摘要：Alcohol-induced dose dumping is a serious concern for the orally administered prolonged release dosage forms. The study was designed to optimize the independent variables, propylene glycol alginate (PGA), Eudragit RS PO (ERS) and coating in mucoadhesive quetiapine prolonged release tablets 200 mg required for preventing the alcohol-induced dose dumping. Optimal design based on response surface methodology was employed for the optimization of the composition. The formulations are evaluated for in vitro drug release in hydrochloric acid alone and with 40% v/v ethanol. The responses, dissolution at 120 min without alcohol (R1) and dissolution at 120 min with alcohol (R2), were statistically evaluated and regression equations are generated. PGA as a hydrophilic polymeric matrix was dumping the dose when dissolutions are carried in 0.1 N hydrochloric acid containing 40% v/v ethanol. ERS addition was giving structural support to the swelling and gelling property of PGA, and thus, was reducing the PGA erosion in dissolution media containing ethanol. Among the formulations, four formulations with diverse composition were meeting the target dissolution (30–40%) in both the conditions. The statistical validity of the mathematical equations was established, and the optimum concentration of the factors was established. Validation of the study with six confirmatory runs indicated high degree of prognostic ability of response surface methodology. Further coating with ReadiLycoat was providing an additional resistance to the alcohol-induced dose dumping. Optimized compositions showed resistance to dose dumping in the presence of alcohol.
  • 13.

    【2hr】Ilex paraguariensis Pellets from a Spray-Dried Extract: Development, Characterization, and Stability

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    机译 喷雾干燥提取物中的巴拉圭冬青小丸：发育，表征和稳定性。
    摘要：Several studies have shown the potential use of Ilex paraguariensis in developing products with the aim to protect biological systems against oxidative stress-mediated damages. In the same way, technological studies have demonstrated the feasibility of obtaining dry products, by spray-drying process, from aqueous extracts of I. paraguariensis in laboratory. The present work was designed to develop pellets by extrusion/spheronization process, from an I. paraguariensis spray-dried powder. The pellets were characterized with respect to their chemical, physical, and technological properties, and the thermal and the photostability of the main polyphenol constituents were investigated. The pellets exhibited adequate size, shape, and high process yield (78.7%), as well as a good recovery of the total polyphenols (>95%) and a good dissolution in water (89.44 to 100.05%). The polyphenols were stable against light when conditioned in amber glass bottles; unstable against heat when the samples were conditioned either in open glass bottles or in hermetically sealed glass bottles and demonstrated to be hygroscopic and sensible to the temperature, especially when stored in permeable flasks. These findings pointed to the relevance of reducing the residual moisture content of pellets as well as of conditioning them in opaque humidity tight packages under low temperatures. The feasibility of obtaining pellets from an I. paraguariensis spray-dried powder using extrusion/spheronization technique was, for the first time, demonstrated. This finding represents a novelty for the herbal products in both pharmaceutical and food fields.
  • 14.

    【2hr】A Quality by Experimental Design Approach to Assess the Effect of Formulation and Process Variables on the Extrusion and Spheronization of Drug-Loaded Pellets Containing Polyplasdone® XL-10

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    机译 通过实验设计的质量评估配方和工艺变量对含有Polyplasdone®XL-10的载药小球的挤出和球形化的影响
    摘要：Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported.
  • 15.

    【2hr】Effects of Temperature and Humidity on Laser Diffraction Measurements to Jet Nebulizer and Comparison with NGI

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    机译 温湿度对射流雾化器激光衍射测量的影响以及与NGI的比较
    摘要：Laser diffraction (LD) and next generation impactor (NGI) are commonly used for the evaluation of inhaled drug formulations. In this study, the effect of temperature and humidity on the assessment of the nebulizer particle size distribution (PSD) by LD was investigated, and the consistency between NGI and LD measurements was evaluated. There was an increase in particle size with higher temperature or lower humidity. The particle population with a diameter less than 1 μm was significant at a temperature of 5°C or at relative humidity >90%; however, the same particle population became undetectable when temperature increased to 39°C or at relative humidity of 30–45%. The results of the NGI and LD measurements of aerosol generated from three types of jet nebulizers were compared. A poor correlation between the NGI and LD measurements was observed for PARI LC (2.2 μm) (R 2 = 0.893) and PARI LC (2.9 μm) (R 2 = 0.878), while a relatively good correlation (R 2 = 0.977) was observed for the largest particle size nebulizer (PARI TIA (8.6 μm)). We conclude that the ambient environment and the nebulizer have significant impacts on the performance and consistency between these instruments. These factors should be controlled in the evaluation of inhaled aerosol drug formulations when these instruments are used individually or in combination.
  • 16.

    【2hr】An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions

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    机译 用于增强药物纳米悬浮液制备过程中的断裂动力学的强化振动研磨工艺
    摘要：As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 μm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 μm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 μm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 μm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.
  • 17.

    【2hr】Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

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    机译 含有冬凌草甲素/HP-β-环糊精包合物的纳米悬浮液可通过改善溶解度和通透性来增强口服生物利用度
    摘要：Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.
  • 18.

    【2hr】Development, Optimization, and Characterization of PEGylated Nanoemulsion of Prostaglandin E1 for Long Circulation

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    机译 长期流通的前列腺素E1聚乙二醇纳米乳液的开发，优化和表征
    摘要：Lipo-PGE1 is the most widely used formulation of PGE1 in clinic. However, PGE1 is easier to leak out from lipo-PGE1 and this will lead to the phlebophlogosis when intravenous injection. The stability of lipo-PGE1 in storage and in vivo is also discounted. The aim of this study is to develop a long-circulating prostaglandin E1-loaded nanoemulsion modified with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) to improve the stability and pharmacokinetics profiles of lipo-PGE1. PEGylated PGE1 nanoemulsion was prepared using a dispersing-homogenized method. The stability of nanoemulsion in 1 month was investigated. Pharmacokinetic studies were employed to evaluate the in vivo profile of the optimized nanoemulsion. The optimized nanoemulsion PGE1-PEG2000(1%)-NE showed an oil droplet size <100 nm with a surface charge of −14 mV. Approximately, 97% of the PGE1 was encapsulated in the nanoemulsion. The particle size, zeta potential, and drug loading of PGE1-PEG2000(1%)-NE were stable in 1 month. After PGE1-PEG2000(1%)-NE was intravenously administered to rats, the area under curve (AUC) and half-life of PGE1 were, respectively, 1.47-fold and 5.98-fold higher than those of lipo-PGE1 (commercial formulation). PGE1-PEG2000(1%)-NE was an ideal formulation for prolonging the elimination time of PGE1. This novel parenteral colloidal delivery system of PGE1 has a promising potential in clinic use.
  • 19.

    【2hr】pH-Dependent Solubility and Dissolution Behavior of Carvedilol—Case Example of a Weakly Basic BCS Class II Drug

    包量

    机译 卡维地洛的pH依赖性溶解度和溶解行为-弱碱性BCS II类药物的案例
    摘要：The objective of this study was to investigate the pH-dependent solubility and dissolution of weakly basic Biopharmaceutical Classification Systems (BCS) class II drugs, characterized by low solubility and high permeability, using carvedilol, a weak base with a pK a value of 7.8, as a model drug. A series of solubility and in vitro dissolution studies was carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH range of the GI from 1.2 to 7.8. The effect of ionic strength, buffer capacity, and buffer species of the dissolution media on the solubility and dissolution behavior of carvedilol was also investigated. The study revealed that carvedilol exhibited a typical weak base pH-dependent solubility profile with a high solubility at low pH (545.1–2591.4 μg/mL within the pH range 1.2–5.0) and low solubility at high pH (5.8–51.9 μg/mL within the pH range 6.5–7.8). The dissolution behavior of carvedilol was consistent with the solubility results, where carvedilol release was complete (95.8–98.2% released within 60 min) in media simulating the gastric fluid (pH 1.2–5.0) and relatively low (15.9–86.2% released within 240 min) in media simulating the intestinal fluid (pH 6.5–7.8). It was found that the buffer species of the dissolution media may influence the solubility and consequently the percentage of carvedilol released by forming carvedilol salts of varying solubilities. Carvedilol solubility and dissolution decreased with increasing ionic strength, while lowering the buffer capacity resulted in a decrease in carvedilol solubility and dissolution rate.
  • 20.

    【2hr】Solid-State Characterization and Interconversion of Recrystallized Amodiaquine Dihydrochloride in Aliphatic Monohydric Alcohols

    包量

    机译 脂肪族一元醇中重结晶的氨二喹二盐酸盐的固相表征和相互转化
    摘要：Amodiaquine dihydrochloride monohydrate (AQ-DM) was obtained by recrystallizing amodiaquine dihydrochloride dihydrate (AQ-DD) in methanol, ethanol, and n-propanol. Solid-state characterization of AQ-DD and AQ-DM was performed using X-ray powder diffractometry, Fourier transform infrared spectroscopy, thermogravimetry, and differential scanning calorimetry. All recrystallized samples were identified as AQ-DM. Crystal habits of AQ-DD and AQ-DM were shown to be needle-like and rhombohedral crystals, respectively. When AQ-DD and AQ-DM were exposed to various relative humidity in dynamic vapor sorption apparatus, no solid-state interconversion was observed. However, AQ-DM showed higher solubility than AQ-DD when exposed to bulk water during solubility study, while excess AQ-DM was directly transformed back to a more stable AQ-DD structure. Heating AQ-DM sample to temperatures ≥190°C induced initial change to metastable amorphous form (AQ-DA) which was rapidly recrystallized to AQ-DD upon ≥80%RH moisture exposure. AQ-DD was able to be recrystallized in alcohols (C1-C3) as AQ-DM solid-state structure. In summary, AQ-DM was shown to have different solubility, moisture and temperature stability, and interconversion pathways when compared to AQ-DD. Thus, when AQ-DM was selected for any pharmaceutical applications, these critical transformation and property differences should be observed and closely monitored.
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