A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate

A novel solid particle system with a nanomatrix structure and without surfactant for the oral delivery of insoluble drugs was prepared. This used a combination of pH-sensitive polymethylacrylate and nano-porous silica, in order to improve the drug absorption using only pharmaceutical excipients and a relative simple process. The in vitro drug dissolution and in vivo oral bioavailability of this formulation, using fenofibrate as the model drug, were compared with other reference formulations such as a suspension, micronized formulation or self microemulsion drug delivery system (SMEDDS). The supersaturation stabilizing effect of different polymers was evaluated and the physicochemical characterization of the optimal formulation was conducted by SEM, TEM, surface area analysis, DSC, and XRD. The optimized formulation prepared with polymethylacrylate (Eudragit®L100-55) and silica (Sylysia®350) markedly improved the drug dissolution compared with other reference preparations and displayed a comparative oral bioavailability to the SMEDDS. Fenofibrate existed in a molecular or amorphous state in the nanomatrix, and this state was maintained for up to 1 year, without obvious changes in drug release and absorption. In conclusion, the nanomatrix formulation described here is a promising system to enhance the oral bioavailability of water-insoluble drugs.     

Using microemulsion formulations for oral drug delivery of therapeutic peptides

Peptide drugs are increasingly becoming a very important class of therapeutic agents with the rapid advances in the field of biotechnology engineering. However, these drugs are generally not suitable for oral administration. In this review, the main physico-chemical and biopharmaceutical characteristics of peptides are summarized. The obstacles to peptide drug absorption and the different possibilities for solving these difficulties are listed. Results using this formulation approach for oral drug delivery of peptides are apparently promising with some specific peptides such as cyclosporin. Various mechanisms are only beginning to be understood and further investigations need to be performed in this area to explain the results obtained with some peptides.     

Optimization and evaluation of lyophilized fenofibrate nanoparticles with enhanced oral bioavailability and efficacy

Abstract

The objective of this study was to enhance physiochemical properties as well as oral bioavailability of the poorly water soluble drug fenofibrate (FB), through preparation of amorphous solid dispersions (ASDs). ASDs were prepared via freeze drying using polyvinylpyrrolidone (PVP) K30 and poloxamer 188 as hydrophilic carriers. Formulations were optimized by 3² full factorial design (FFD) with PVP-K30 level (X₁) and poloxamer 188 level (X₂) as independent variables and particle size (Y₁), zeta potential (Y₂), drug content (Y₃) and dissolution rate (T90, [Y₄]) as dependent variables. Optimized FB nanoparticles were physicochemically evaluated and formulated into lyophilized sublingual tablets. Pharmacokinetic, pharmacodynamics and histological finding of optimized formulation were performed on rabbits. Y₁ and Y₄ were significantly affected by independent variables while Y₂ and Y₃ were not affected. Physicochemical characterization showed the drug was in amorphous state, nanometer range and pharmacophore of FB was preserved. Administration of optimized FB tablets to rabbits with fatty liver led to significant reduction (p?<?0.001) in serum lipids. Moreover, histological analysis of liver specimens confirmed the improved efficacy in animals with fatty liver. In this study, we confirmed that ASDs of FB had beneficial effects on managing fatty liver and serum lipids level in hyperlipidemic rabbits.     

In vitro dissolution and oral bioavailability study of fenofibrate nanomatrix system prepared by hot-melt extrusion

Solvent evaporation method for preparation of nanomatrix has the disadvantages, such as residual organic solvent, environmental pollution, explosion-proofing and so on. To overcome these shortcomings, a series of fenofibrate nanomatrix drug delivery system (NDDS) consisting of nano-porous silica Sylysia^®350 (S350) and pH sensitive material Eudragit^® L100-55 (EL100-55) were prepared using hot-melt extrusion (HME), and their in vitro dissolution and in vivo bioavailability were compared. Finally, the formulation with the highest in vivo bioavailability was selected as the optimized formulation for DSC and PXRD characterization. The results showed that the optimized NDDS showed a higher bioavailability than the reference formulation, although there was crystalline form drug remaining in NDDS. The relative bioavailability of the optimized formulation was 157.1% compared with the commercial product Lipanthyl^®. In addition, the relative bioavailability of the optimized formulation was 124.8% in comparison with the formulation prepared by solvent evaporation method, showing that the NDDS prepared by the HME method was effective in improving the bioavailability of fenofibrate. In conclusion, HME was a promising method to prepare NDDS.     

Transdermal agomelatine microemulsion gel: pyramidal screening,statistical optimization and in vivo bioavailability

Agomelatine is a new antidepressant having very low oral drug bioavailability less than 5% due to being liable to extensive hepatic 1st pass effect. This study aimed to deliver agomelatine by transdermal route through formulation and optimization of microemulsion gel. Pyramidal screening was performed to select the most suitable ingredients combinations and then, the design expert software was utilized to optimize the microemulsion formulations. The independent variables of the employed mixture design were the percentages of capryol 90 as an oily phase (X₁), Cremophor RH40 and Transcutol HP in a ratio of (1:2) as surfactant/cosurfactant mixture ‘S_mix’ (X₂) and water (X₃). The dependent variables were globule size, optical clarity, cumulative amount permeated after 1 and 24?h, respectively (Q1 and Q₂₄) and enhancement ratio (ER). The optimized formula was composed of 5% oil, 45% S_mix and 50% water. The optimized microemulsion formula was converted into carbopol-based gel to improve its retention on the skin. It enhanced the drug permeation through rat skin with an enhancement ratio of 37.30 when compared to the drug hydrogel. The optimum ME gel formula was found to have significantly higher C_max, AUC _0–24?h and AUC_0–∞ than that of the reference agomelatine hydrogel and oral solution. This could reveal the prosperity of the optimized microemulsion gel formula to augment the transdermal bioavailability of agomelatine.     

Influence of polyvinylpyrrolidone quantity on the solubility,crystallinity and oral bioavailability of fenofibrate in solvent-evaporated microspheres

The objective of this study is to explore the influence of polyvinylpyrrolidone (PVP) quantity on the solubility, crystallinity and oral bioavailability of poorly water-soluble fenofibrate in solvent-evaporated microspheres. Numerous microspheres were prepared with fenofibrate, sodium lauryl sulphate (SLS) and PVP using the spray-drying technique. Their aqueous solubility, dissolution, physicochemical properties and pharmacokinetics in rats were assessed. The drug in the solvent-evaporated microspheres composed of fenofibrate, PVP and SLS at the weight ratio of 1:0.5:0.25 was not entirely changed to the amorphous form and partially in the microcrystalline state. However, the microspheres at the weight ratio of 1:4:0.25 provided the entire conversion to the amorphous form. The latter microspheres, with an improvement of about 115 000-fold in aqueous solubility and 5.6-fold improvement in oral bioavailability compared with the drug powder, gave higher aqueous solubility and oral bioavailability compared with the former. Thus, PVP quantity played an important role in these properties of fenofibrate in the solvent-evaporated microspheres.     

微粒化非诺贝特治疗高脂血症的临床观察

目的 观察微粒化非诺贝特对高脂血症的疗效与安全性。方法 用开放、随机对照方式,应用非诺贝特和多烯康治疗高脂血症12周,观察病人治疗前后有关检查结果及副作用。结果 非诺贝特组服药12周后血清胆固醇（TC）、甘油三脂（TG）、低胆固醇胆脂蛋白（LDL－C）水平与0周比较分别降低18．9％（P＜0．01）、44％（P＜0．001）、13％（P＜0．05）;多烯康组则分别降低11％、19％、13．7％（P＜0．05）。非诺贝特组与多烯康组服药12周时降低血脂的总有效率分别为79．1％和48．8％,非诺贝特组显著优于多烯康组（P＜0．01）。结论 非诺贝特为高脂血症的有效治疗药物,安全性好,疗效优于多烯康。     

多烯磷脂酰胆碱与非诺贝特联合治疗非酒精性脂肪性肝炎的疗效

目的：探讨多烯磷脂酰胆碱与非诺贝特联合治疗非酒精性脂肪性肝炎的临床效果。方法回顾性分析2013年2月~2014年7月我院收治的NAFLD患者114例并按治疗方法分为两组,研究组57例采用多烯磷脂酰胆碱与非诺贝特联合治疗,对照组57例单独应用多烯磷脂酰胆碱治疗。比较两组临床疗效,肝功能及血脂水平。结果研究组总有效率（85.96%）明显高于对照组（64.91%）,P＜0.05。研究组和对照组治疗后的ALT、AST、TbiL、GGT与治疗前比较均明显降低（P＜0.05）,两组治疗后比较差异无统计学意义（P＞0.05）。研究组和对照组治疗后的TC、TG、LDL-C较治疗前明显降低,而HDL-C则明显升高（P＜0.05）,研究组治疗后各指标升高或降低的幅度明显高于对照组（P＜0.05）。结论多烯磷脂酰胆碱与非诺贝特联合治疗非酒精性脂肪性肝炎疗效确切,优于单独应用多烯磷脂酰胆碱治疗,可明显提高临床总有效率,可以在临床推广应用。     

Improvement of cyclosporine A bioavailability by incorporating ethyl docosahexaenoate in the microemulsion as an oil excipient

The aims of this study were to determine the effect of ethyl docosahexaenoate (DHA-EE) on cyclosporine A (CsA) bioavailability, while also examining the effect of DHA-EE on CsA when DHA-EE was incorporated into a microemulsion formulation as an oil ingredient. The oral co-administration of DHA-EE and CsA increased the blood CsA concentration in a dose-dependent manner, and the AUC and C_max both increased by about 2-fold with 100 mg/kg DHA-EE. The microemulsion formulation of CsA consisted of Tween-20, ethanol, water, and DHA-EE (53.3/6.5/35.9/3.3 w/w%) (namely DHA-ME) was transparent and stable with an average particle size of 50 nm, which was similar to that of the control formulation incorporating vitamin E instead of DHA-EE (namely VE-ME). The permeabilities of CsA from DHA-ME, VE-ME and Neoral^® formulations across an artificial membrane were not significantly different. The C_max and AUC_0–∞ of CsA in rats administered DHA-ME significantly increased by approximately 2-fold in comparison to that of VE-ME. The relative oral bioavailability (F_r) of DHA-ME in comparison to Neoral^® was determined to be 114%, while the F_r of VE-ME was only 60%. It was, therefore, suggested that the use of DHA-EE as an oil excipient may be promising for the development of a microemulsion formulation of CsA with an improved oral bioavailability.     

辛伐他汀联合非诺贝特治疗混合性高脂血症的疗效观察

目的探讨辛伐他汀联合非诺贝特治疗混合性高脂血症的疗效及安全性。方法将146例混合性高脂血症患者随机分为两组,对照组73例给予辛伐他汀治疗,观察组73例在对照组的基础上加用非诺贝特,4周为1个疗程,观察两组患者降脂的疗效及不良反应发生情况。结果观察组临床效果总有效率为95.89%,对照组为78.08%(P<0.05);治疗后两组的TC、TG、LDL-C及HDL-C水平的变化均有显著性改善(P<0.05或P<0.01),但观察组的TG、LDL-C的改善情况优于对照组(P<0.05);观察组TC、TG、LDL-C的达标率分别为58.90%、45.21%、50.68%,3项达标率为36.99%,明显高于对照组的13.70%(P<0.05);两组总不良反应发生率比较差异无统计学意义(P>0.05)。结论辛伐他汀联合非诺贝特治疗混合性高脂血症可充分发挥药物互补、协同作用,有利于全面调节血脂异常,提高血脂水平的达标率,减少不良反应。     

HPLC法测定非诺贝特缓释片中非诺贝特

目的采用HPLC法测定非诺贝特缓释片中非诺贝特。方法采用Dikma C18色谱柱(200 mm×4.6 mm,5μm);流动相:甲醇–水(90∶10);检测波长:288 nm;柱温:25℃;体积流量:1.0 mL/min;进样量10μL。结果非诺贝特在2.0~12.0μg/mL与其峰面积呈良好的线性关系(r=0.999 9);检测限和定量限分别为10、30 ng/mL;平均回收率为99.86%,RSD值为0.72%(n=9)。结论该方法准确、简便,可用于非诺贝特缓释片中非诺贝特的质量控制。     

Oral microemulsions of paclitaxel: In situ and pharmacokinetic studies

The overall goal of this study was to develop cremophor-free oral microemulsions of paclitaxel (PAC) to enhance its permeability and oral absorption. The mechanism of this enhancement, as well as characteristics of the microemulsions relevant to the increase in permeability and absorption of the low solubility, low permeability PAC was investigated. Phase diagrams were used to determine the macroscopic phase behavior of the microemulsions and to compare the efficiency of different surfactant-oil mixtures to incorporate water. The microemulsion region on the phase diagrams utilizing surfactant-myvacet oil combinations was in decreasing order: lecithin: butanol: myvacet oil (LBM, 48.5%) > centromix CPS: 1-butanol: myvacet oil (CPS, 45.15%) > capmul MCM: polysorbate 80: myvacet oil (CPM, 27.6%) > capryol 90: polysorbate 80: myvacet oil (CP-P80, 23.9%) > capmul: myvacet oil (CM, 20%). Oil-in-water (o/w) microemulsions had larger droplet sizes (687-1010 nm) than the water-in-oil (w/o) microemulsions (272-363 nm) when measured using a Zetasizer nano series particle size analyzer. Utilizing nuclear magnetic resonance spectroscopy (NMR), the self-diffusion coefficient (D) of PAC in CM, LBM and CPM containing 10% of deuterium oxide (D₂O) was 2.24 × 10⁻¹¹, 1.97 × 10⁻¹¹ and 0.51 × 10⁻¹¹ m²/s, respectively. These values indicate the faster molecular mobility of PAC in the two w/o microemulsions (CM and LBM) than the o/w microemulsion - CPM. The in situ permeability of PAC through male CD-IGS rat intestine was 3- and 11-fold higher from LBM and CM, respectively, than that from the control clinical formulation, Taxol^® (CE, cremophor: ethanol) in a single pass perfusion study. PAC permeability was significantly increased in the presence of the pgp/CYP3A4 inhibitor cyclosporine A (CsA). This enhancement may be attributed to the pgp inhibitory effect of the surfactants, oil and/or the membrane perturbation effect of the surfactants. The oral disposition of PAC in CM, LBM and CPM compared to CE was studied in male CD-IGS rats after a single oral dose (20 mg/kg). The area-under-the-curve of PAC in CM was significantly larger than LBM, CPM and CE. Oral microemulsions of PAC were developed that increased both the permeability and AUC of PAC as compared to CE.     

Formulation of parenteral microemulsion containing itraconazole

The aim of this study was to develop an aqueous parenteral formulation containing itraconazole (ITZ) using an o/w microemulsion system. A mixture of benzyl alcohol and medium chain triglyceride (3/1) was chosen as the oil phase. Pseudoternary phase diagrams of the microemulsion formations were constructed in order to determine the optimum ratio of oils, the concentration range of surfactant and cosurfactant and the optimum ratio between them. Consequently, the suitability of the chosen microemulsion system as a parenteral formulation was evaluated using droplet size analysis and hemolysis tests. Among the surfactants and cosurfactants screened, a mixture of polyoxyethylene (50) hydrogenated castor oil and ethanol (3/1) showed the largest o/w microemulsion region in the phase diagram. The average droplet size of the microemulsions was < 150 nm, and the hemolysis test showed this formulation to be nontoxic to red blood cells. The pharmacokinetic profiles of the ITZ-microemulsion for itraconazole and its major metabolite, hydroxyitraconazole, were compared with those of a PEG 400 solution and cyclodextrin formulations in rats. Overall, these results highlight the potential of an ITZ-microemulsion formulation for the parenteral route.     

Relative bioavailability of two oral formulations of navelbine in cancer patients

A study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two-way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (C_max) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0–∞) AUC.     

利多卡因——卵磷脂微乳处方的初步研究

目的 :以卵磷脂微乳为载体 ,制备利多卡因透皮给药系统。方法 :伪三元相图考察油包水型微乳形成区域 ;测定微乳黏度 ,正交分析法筛选微乳处方 ;紫外分光光度法直接测定微乳中盐酸利多卡因浓度。结果 :助表面活性剂的种类和Km(表面活性剂 /助表面活性剂用量比 )对微乳形成区域有显著性影响 ,正丙醇和异丙醇所形成的微乳区较大 ;低纯卵磷脂微乳形成区域较高纯卵磷脂大 ;醇的种类对微乳的黏度均有显著的影响 ,Km 对微乳的黏度有较大影响。选定紫外检测波长为 2 6 2nm ,盐酸利多卡因浓度在 0 .0 2～ 0 .5mg/mL范围内线性关系良好 (R =0 .9999)。平均回收率 ( 10 0 .17± 0 .16 ) %。日内差与日间差分别为 0 0 137±0 0 12 1,0 0 119± 0 0 115。结论 :选择混合表面活性剂利于制备微乳 ,醇的种类与用量对于利多卡因透皮微乳体系处方的选择具有重要意义。     

非诺贝特致甲状腺功能减低患者横纹肌溶解症1例

1例37a男性患者,因血脂高,给予非诺贝特缓释胶囊250mg,口服,每晚1次。服药前查：TG17.17mmol·L-1,CK45U·L-1,LDH98U·L-1,AST30IU·L-1,ALT21IU·L-1。服药第9天后患者出现右侧小腿肌肉酸痛、无力,急查CK2900.05U·L-1,LDH432U·L-1,AST121IU·L-1,ALT65.5IU·L-1,确诊为横纹肌溶解症。立即停用非诺贝特,给予碱化尿液、保护细胞膜等治疗。查甲状腺功能示：TT30.3nmol·L-1,TT47.5nmol·L-1,FT31.9pmol·L-1,FT47.8pmol·L-1,TSH237μIU·mL-1。甲状腺B超示甲状腺弥漫性病变。确诊为甲状腺功能减低,遂加用口服左甲状腺素钠片治疗。停非诺贝特3d后患者症状消失,27d后血CK、转氨酶基本恢复。     

Pharmacokinetics,bioavailability and withdrawal period of antibiotic oxytetracycline in catfish Pangasianodon hypophthalmus

The antibiotic oxytetracycline (OTC) has been widely used for therapeutic and preventive management of bacterial diseases in finfish and shellfish. In the present study the bioavailability, pharmacokinetics, and withdrawal period of the OTC have been determined following in-feed administration in intensively cultured catfish Pangasianodon hypophthalmus. Furthermore, the pharmacokinetic parameters of oral route were also compared with parenteral route. Drug concentrations were measured in various tissues at different time intervals by LC-MS/MS. The study revealed the drug kinetics best followed the enterohepatic circulation model with very poor bioavailability and low blood concentration after oral administration. In the withdrawal study, after 10-days of in-feed administration at the therapeutic dose the drug reached very high concentrations in the liver and kidneys but did not attain minimum inhibitory concentrations (MICs) in blood or flesh. OTC concentration also did not exceed the recommended MRL value in flesh; however, considering high amounts of the chemical in the liver and kidneys a withdrawal period of 4 days (at 28 ± 1.5 ^oC) is recommended for consumer safety. Poor bioavailability and non-attainment of minimum therapeutic concentration in blood and flesh do not warrant in-feed administration of OTC for control of bacterial diseases in P. hypophthalmus.Availability of data and materialsAll data generated and analyzed during this study are included in this article. Raw data may be shared upon reasonable request.     

非诺贝特咀嚼片治疗高脂血症的疗效观察

目的观察非诺贝特咀嚼片治疗高脂血症的有效性和安全性。方法在北京五所医院选择血浆甘油三酯水平≥2．26mmol／L的患者100例,按随机号分为咀嚼片组和胶囊组2组,分别给予非诺贝特咀嚼片及非诺贝特胶囊200mg／d,共治疗8周。治疗前后测定血脂及安全参数并进行分析,记录药物不良反应情况。结果与治疗前比,治疗8周后2组患者的甘油三酯水平均有显著的下降,高密度脂蛋白胆固醇水平明显升高。咀嚼片组与胶囊组降低甘油三酯及升高高密度脂蛋白胆固醇效果相似,差异无统计学意义（分别为44．88％与45．11％及16．51％与13．35％,P〉0．05）,2组总体疗效接近（84．1％与86．7％,P〉0．05）。结论非诺贝特咀嚼片降低甘油三酯及升高高密度脂蛋白胆固醇效果理想,安全性较好。     

Effect of powder processing on performance of fenofibrate formulations

In this study, the effect of the order in which powder blending and jet-milling were performed for the production of the bulk powders on the performance of 200-mg dose orally disintegrating tablets (ODTs) of fenofibrate was evaluated. Bulk powders composed of fenofibrate, mannitol, copovidone S630, and docusate sodium in a 10:10:2:1.2 ratio were prepared by the following three processes: process A: fenofibrate+excipients-->blending; process B: fenofibrate-->jet-milling-->blending with excipients; process C: fenofibrate+excipients-->blending-->jet-milling. The bulk powders were granulated followed by blending and tableting. The materials were tested for Differential Scanning Calorimetry (DSC), drug particle sizing post-reconstitution, dissolution, optical micrography, Scanning Electron Microscopy (SEM), Energy Dispersive X-ray Spectroscopy (EDS) and disintegration of the ODTs. It was found that the crystallinity of fenofibrate was not impacted by the blending and jet-milling processes. Process A produced materials having poorer fenofibrate reconstitution as compared to processes involving jet-milling. It was discovered that milling a blend of fenofibrate/excipient (process C) was advantageous over milling the raw drug alone (process B). Process C yielded bulk powder that showed rapid dissolution and ODTs which exhibited rapid disintegration.     

Formulation design of microemulsion for dermal delivery of penciclovir

The purpose of the present study was to evaluate the potential application of microemulsions as a dermal drug delivery loading penciclovir. The pseudo-ternary phase diagrams were developed for various microemulsion formulations composed of oleic acid (oil phase), Cremorphor EL (surfactant) and ethanol (cosurfactant). Composition of microemulsion systems was optimized using simplex lattice mixture design including the concentrations of surfactant, cosurfactant and water (independent variables) and the solubility and the cumulative amount of penciclovir permeated through excised mouse skins per unit area (response variables). The physicochemical properties of the optimized microemulsion and the permeating ability of penciclovir from microemulsions were also investigated. The results showed that the optimized microemusion formulation was composed of oleic acid (5%, w/w), Cremorphor EL (20%, w/w), ethanol (30%, w/w) and water (45%, w/w). The mean particle diameter was 36.5nm and solubility of penciclovir in the emulsion was 7.41 mg g(-1). The cumulative amount of penciclovir permeated through excised mouse skins from microemulsion was about 3.5 times that of the commercial cream. The conclusion was that the permeating ability of penciclovir was significantly increased from the microemulsion formulation compared with commercial cream.