利用平行人工膜比较硝苯地平缓释片的生物等效性

目的：采用平行人工膜对硝苯地平缓释片渗透速率进行研究,比较仿制药一致性评价前后样品的渗透速率,预测其人体生物等效性。方法：利用MacroFlux^TM药物渗透性测定仪,测定通过一致性评价的制剂和未通过一致性评价的制剂的渗透速率。结果：通过一致性评价的制剂渗透速率为84.3%～113.2%,累积渗透量为85.9%～110.9%;未通过一致性评价的制剂渗透速率为73.7%～94.1%,累积渗透量为71.8%～92.6%。结论：初步预测通过一致性评价的制剂与参比制剂生物等效,仿制药一致性评价工作提升了产品质量。     

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide

Pharmaceutical Research - Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While...     

Lipophilic Salts and Lipid-Based Formulations for Bridging the Food Effect Gap of Venetoclax

Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by ¹H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on ¹H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.     

The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

The purposes of this study were to assess the efficiency of different nifedipine amorphous solid dispersions (ASDs) in achieving and maintaining supersaturation and to investigate the solubility–permeability interplay when increasing the apparent solubility via ASD formulations. Spray-dried ASDs of nifedipine in three different hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), copovidone, and polyvinylpyrrolidone (PVP), were prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. The ability of these formulations to achieve and maintain supersaturation over 24 h was assessed. Then, nifedipine’s apparent intestinal permeability was investigated as a function of increasing supersaturation in the parallel artificial membrane permeability assay model and in the single-pass rat intestinal perfusion model. The efficiency of the different ASDs to achieve and maintain supersaturation of nifedipine was found to be highly polymer dependent; while a dispersion in HPMC-AS enabled supersaturation 20× that of the crystalline aqueous solubility, a dispersion in copovidone enabled 10×, and PVP allowed supersaturation of only 5× that of the crystalline solubility. Nifedipine flux across the intestine from supersaturated solutions was increased, and the apparent intestinal permeability was constant, irrespective of the degree of supersaturation or the polymer being used. In conclusion, while with other solubility-enabling approaches (e.g., surfactants, cyclodextrins, cosolvents), it is not enough to increase the apparent solubility, but to strike the optimal solubility–permeability balance, which limits the chances for successful drug delivery, the amorphous form emerges as a more advantageous strategy, in which higher apparent solubility (i.e., supersaturation) will be readily translated into higher drug flux and overall absorption.     

基于脂质前药的自组装药物传递系统

综述了脂质前药及自组装药物传递系统.药质体是基于脂质前药的自组装药物传递系统之一,对其概念、特点、制备方法和潜在应用性进行了简要介绍.     

Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat

The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation. C(max) was reduced and t(1/2) was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.     

基于平行人工膜渗透模型预测抗癌药甲磺酸仑伐替尼胶囊生物等效性

目的 采用平行人工膜渗透模型,预测自产甲磺酸仑伐替尼胶囊与参比制剂的体内生物等效性。方法 通过推测甲磺酸仑伐替尼的BCS分类,基于平行人工膜渗透模型,搭建甲磺酸仑伐替尼胶囊体外溶出-渗透速率测试模型,实时监测甲磺酸仑伐替尼胶囊和参比制剂在空腹条件模拟液以及餐后条件模拟液下的溶出度和渗透量,计算药物通过膜的通量、渗透总量。结果 在模拟空腹和餐后条件下,处方A的渗透速率和渗透量的几何均值比90%置信区间均在80.00%~125.00%范围内,处方B未落在此区间。结论 本研究方法可以预测甲磺酸仑伐替尼胶囊与参比制剂生物等效性,并具备一定的体内外相关性。     

Effect of Shear Strain on the Supercooled Itraconazole

This article investigated the effect of shear strain on the nematic itraconazole (ITR) from both elastic and plastic deformation regions. The rheo-dielectric technique was used for this purpose. It has been demonstrated that shear strain can change the sample color, liquid crystal alignment as well as its dielectric and thermal properties. The observed modifications depend on the shear strain value. One can distinguish four regions regarding the slope of ITR stress–strain dependence and caused changes. Proper alignment changes (obtained after the shearing procedure) can additionally affect the further recrystallization of ITR to other than the initial, i.e., second polymorphic form.     

A Novel Design of Artificial Membrane for Improving the PAMPA Model

PURPOSE: Since the first demonstration of PAMPA, the artificial membrane has been traditionally prepared by impregnating a porous filter with a solution of lipid mixture. While the lipid solution-based method is simple and seems to provide good predictability for many compounds, it is challenged by several shortcomings including reproducibility, stability, mass retention and the incorrect prediction of a group of highly permeable compounds including caffeine and antipyrine. Here we present the validation of a novel artificial membrane formed by constructing a lipid/oil/lipid tri-layer in the porous filter. METHODS: Permeability values obtained from traditional and new artificial membrane were compared for their correlation with Caco-2 and human absorption values. Mass retention, stability and organic solvent compatibility of the new artificial membrane were studied. RESULTS: The new artificial membrane correctly predicts the permeability of the traditionally under-predicted compounds and improves the correlation with Caco-2 and human absorption values. Furthermore, the new artificial membrane reduces the mass retention of compounds that are highly retained by the traditional artificial membrane. The new artificial membrane is also found to be robust enough to sustain long term storage and has good compatibility with organic solvents. CONCLUSIONS: The new artificial membrane provides an improved PAMPA model.     

Micelles Based on Polyvinyl Alcohol Substituted with Oleic Acid for Targeting of Lipophilic Drugs

Polymeric micelles based on polyvinyl alcohol substituted with oleic acid were used as vehicles for progesterone and folic acid. The ability of this amphiphilic polymer to entrap lipophilic drugs and to generate stable micelles in aqueous neutral medium makes it a good candidate for drug delivery. The release of the loaded drugs in acidic environments represents another important property of these systems. Size of micelles, their stability, and their drug-loading capacity were evaluated, as well as the in vitro controlled-release profiles at pH 7.4 and 5.5.     

Effects of Membrane Type and Liquid/Liquid Phase Boundary on In Vitro Release of Ketoprofen from Gel Formulations

The aim of this study was to test the hypothesis that the most appropriate model for studying the diffusional release of an active from a topical formulation is one in which the membrane offers minimal resistance to release and involves a receptor phase that presents the least possible interfacial discontinuity. Using ketoprofen as the active, a series of simple gels were prepared consisting of PEG400 thickened with Cabosil M5. Using Franz-type diffusion cells, three different types of membrane (two porous and one non-porous) were compared, as were receptor phases of PEG400 (component of formulation) and PBS. Of the membranes tested only 0.2 μm nylon provided consistent first order kinetics for a range of gel consistencies, indicating negligible influence of the membrane. The non-porous silicone membrane did not show first order kinetic profile confirming the diffusional nature of such a membrane. From the non-thickened formulations, diffusional release into a receptor phase of PEG400 was some 3× that into PBS, whereas from the formulation thickened with 5% Cabosil_® M5, diffusional release into a receptor phase of PEG400 was 6× lower than that into PBS. Diffusional release into PBS did not follow first order kinetics while diffusion into PEG400 did, suggesting that the existence of a discontinuity affected the release process. Although the importance of zero-resistance membranes is of perhaps obvious importance, it is often not stated in the literature. The existence of phase/hydrodynamic boundaries in release studies can be a source of significant inaccuracy.     

特比萘芬与伊曲康唑治疗甲真菌病的比较研究

目的：研究特比萘芬与伊曲康唑治疗甲真菌病的疗效及不良反应。方法：将本院2007年12月～2008年10月收治46例甲真菌病患者随机分为观察组（23例）及对照组（23例）。观察组采用特比萘芬治疗,而对照组采用伊曲康唑治疗,比较分析两组患者的疗效及不良反应。结果：两组患者的近期有效率、近期治愈率及远期治愈率比较,差异均无统计学意义,P〉0.05;两组患者不良反应发生率相比,差异亦无统计学意义,P〉0.05。结论：特比萘芬与伊曲康唑治疗甲真菌病均疗效满意,安全性高,临床上应选择两者中更为经济的药物推广使用。     

伊曲康唑与氟康唑治疗甲真菌病的临床比较研究

目的分析研究伊曲康唑与氟康唑治疗甲真菌病的临床疗效及不良反应。方法将56例甲真菌病患者随机分为观察组和对照组各28例。观察组采用伊曲康唑治疗,对照组采用氟康唑治疗,分析两组的疗效。结果两组患者近期总有效率、近期治愈率、不良反应发生率比较,差异均无统计学意义（P〉0.05）。结论伊曲康唑治疗甲真菌病能获得与氟康唑相似的治疗效果,且不良反应轻微,临床上应选择两者中更为经济的药物推广使用。     

伊曲康唑对双氯芬酸在比格犬体内药动学的影响

摘 要 目的：研究伊曲康唑对双氯芬酸钠在比格犬体内药动学参数的影响。方法: 采用随机交叉试验方法,一组口服双氯芬酸钠,另一组同时口服双氯芬酸钠和伊曲康唑,清洗期1周后,两组交叉服用药物。用HPLC法测定比格犬合用伊曲康唑前后双氯芬酸的血药浓度,并对其药动学参数进行分析。结果: 较单独给予双氯芬酸钠,合用伊曲康唑使双氯芬酸钠血药浓度曲线下面积(AUC_0-∞)与最大血药浓度C_max分别降低31%和42%。而达峰时间和半衰期并无显著差异(P>0.05)。结论:伊曲康唑可能通过影响双氯芬酸的胃肠道吸收过程,来影响AUC_0–∞和C_max。     

采用平行人工膜测定螺内酯片体外渗透速率的研究

目的:采用平行人工膜对药物体外渗透速率进行研究,预测口服固体制剂药物螺内酯片的人体生物等效性.方法:使用MacroFLUX药物渗透速率测定仪,模拟空腹和饱腹条件对螺内酯片的渗透速率进行测定.结果:模拟空腹和饱腹条件,螺内酯片的体外渗透速率模拟空腹结果为114.6％～119.6％,模拟饱腹结果为101.5％～107.5％...     

Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a-1h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans- stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the anti-angiogenic and anti-fungal activities of itraconazole.     

The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations

An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.     

Membrane Binding Proteins are the Major Determinants for the Hepatocellular Transmembrane Flux of Long-Chain Fatty Acids Bound to Albumin

Purpose The hepatic transmembrane flux of long-chain fatty acids (LCFA) occurs through passive and fatty acid transport protein facilitated processes from blood. The extent that these transport processes can be related to the unbound and protein-bound fractions of LCFA in blood is not clear. Methods We used hepatocyte suspensions, hepatoma monolayers, and perfused rat livers to quantitate the transport of purified [³H]palmitate ([³H]PA) and 12-(N-methyl)-N-[(7-nitrobenz-2oxa-1,3-diazol-4yl-)amino]octadecanoicacid (12-NBDS) from solutions with a constant unbound LCFA concentration with varying bovine serum albumin (BSA) concentrations and in the presence and absence of antisera raised against cytosolic liver fatty acid binding protein (L-FABP). Results In the absence of L-FABP antisera, using an unbound ligand concentration that was adjusted to remain constant at each BSA concentration, hepatocyte [³H]PA and 12-NBDS uptake rates increased linearly with an increase in BSA concentration (p < 0.0001). In the presence of L-FABP antisera, [³H]PA uptake showed a greater reduction in the presence of 100 μM BSA than 5 μM BSA. The calculated permeability surface area product (PS) confirmed that both unbound and bound fractions of LCFA contributed to the overall flux, but only the PS for the protein-bound fraction was reduced in the presence of L-FABP antisera. In situ rat liver perfusion studies showed that the only rate process for the disposition of [³H]PA in the liver inhibited by L-FABP antisera was that for influx, as defined by PS, and that it reduced PS in the perfused liver by 42%. Conclusion These results suggest that, at physiological albumin concentrations, most of the LCFA uptake is mediated from that bound to albumin by a hepatocyte basolateral membrane transport protein, and uptake of unbound LCFA occurring by passive diffusion contributes a minor component.     

Effect of Concentration and Degree of Saturation of Topical Fluocinonide Formulations on In Vitro Membrane Transport and In Vivo Availability on Human Skin

Purpose. The thermodynamic acitvity of drugs in topical vehicles is considered to significantly influence topical delivery. In vitro diffusion across a synthetic membrane was shown to be correlated to the degree of saturation of the drug in the applied vehicle and therefore offers a potential for increased topical drug delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound to investigate in vitro and in vivo availability from formulations with different degrees of saturation. Methods. Sub-, as well as, supersaturated drug solutions were prepared using PVP as an antinucleant agent. In vitro membrane diffusion experiments across silicone membrane and in vivo pharmacodynamic activity assessments, using the human skin blanching assay, were carried out. Results. Over the concentration range studied, the in vitro membrane transport of fluocinonide was proportional to the degree of saturation of the respective formulations. The in vivo pharmacodynamic response in the human skin blanching assay was related to the concentration of the drug in the vehicle irrespective of the degree of saturation. Conclusions. From the membrane permeation experiment it can be concluded, that the drug flux might be increased supra-proportionally with increasing donor concentration, drug (super-)saturation (proportional), beyond what would be anticipated based on ideal donor concentration and partition coefficient considerations only. These findings could not be confirmed in the in vivo investigation, probably due to additional vehicle effects (e.g., enhancement, irritation, drug binding) which have to be expected and could have altered the integrity of the stratum corneum and therewith topical bioavailability of the drug.