Bioavailability of water-soluble CoQ10 in beagle dogs

The bioavailability of a novel water-soluble inclusion complex of CoQ10, prepared in our laboratory was determined and compared with the bioavailability of commercially available oil-based form of CoQ10. Experimental work consisted of single dose comparative bioavailability study on seven beagle dogs, with a 14-day washout period between treatments. Identification and quantification of CoQ10 was done with HPLC-MS method using positive APCI ionization and SIM mode, M+ m/z 863.4. The bioavailability results confirm that the water-soluble formulation has nearly three times higher AUC(0-48 h), two times higher Cmax, and Tmax is shortened from 6 to 4 h.     

姜黄素-PLGA纳米粒提高口服给药生物利用度的研究

目的 研究乳酸/羟基乙酸共聚物（PLGA）纳米粒子提高姜黄素口服生物利用度。方法 采用乳液挥发法制备姜黄素-PLGA纳米粒;通过透射电镜（transmission electron microscope,TEM）观察纳米粒形态;采用动态光散射法（dynamic light scattering,DLS）测定纳米粒大小、表面电位（Zeta电位）;考察药物的体外稳定性以及药物释放行为;以大鼠口服灌胃给药方式考察姜黄素和姜黄素-PLGA纳米粒的体内药物生物利用度。结果 姜黄素-PLGA纳米粒粒度分布均匀,平均粒径大小约200 nm;姜黄素-PLGA纳米粒具有较高的载药量和包封率以及稳定性,体外药物释放实验结果显示具有一定的缓释效果;口服灌胃100 mg·kg^-1姜黄素和姜黄素-PLGA纳米粒,给药30 min之后,姜黄素-PLGA纳米粒给药组的血药浓度水平显著高于姜黄素组（P〈0.05）,药物生物利用度提高到原来的5.2倍。结论 姜黄素-PLGA纳米粒可以有效的提高姜黄素稳定性和口服给药生物利用度。     

Nanoemulsion for Improving the Oral Bioavailability of Hesperetin: Formulation Optimization and Absorption Mechanism

This study aimed to prepare a nanoemulsion vehicle to improve the oral bioavailability of hesperetin. The pseudo-ternary phase diagrams and the RSM were used to optimize nanoemulsion parameters. Compared with hesperetin suspension, the AUC_0-t and C_max of nanoemulsion were increased by 5.67-fold and 2.64-fold, respectively. The proportion of lymphatic transport reached 87.72%, the cumulative absorption amount of jejunum, ileum, and duodenum increased by 1.1-fold, 1.92-fold, and 1.5-fold, respectively. The results implied that hesperetin nanoemulsion could effectively improve the bioavailability of hesperetin by increasing lymphatic transport and enhancing intestinal permeability. Therefore, nanoemulsion is a potential method to improve the bioavailability of hesperetin, which has strong practicability.     

Glibenclamide Nanocrystals for Bioavailability Enhancement: Formulation Design,Process Optimization,and Pharmacodynamic Evaluation

The aim of this study is to improve the bioavailability of a poorly water-soluble drug glibenclamide (GLB), by preparing drug nanocrystals using wet milling by zirconia beads. To improve the dissolution characteristics, various formulation and process variables were identified and optimized by employing a 3² factorial design at two stages. Based on preliminary studies, the formulation variables selected were polymer-to-drug ratio and surfactant-to-drug ratio and the process variables selected were milling speed and milling time. The particle size, zeta potential, saturation solubility, and percentage drug released at 10 min were selected as dependent variables at both stages. F _ratio suggested that the predetermined response parameters were significantly dependent on the independent variables. An optimum desirability of 0.9925 was achieved using response profiler by Statistica® 8.0. The optimized formulation prepared as per levels obtained through desirability showed a close agreement between the predicted and expected values. X-ray diffraction studies concluded that the crystallinity of prepared nanocrystals was intact and the increased dissolution could be ascribed to conversion of unmilled drug to nanocrystals. In vivo studies carried out on male Wistar rats suggested a higher AUEC_(0–8h) for GLB nanocrystals as compared to pure GLB which could be ascribed to significant improvement of release from GLB nanocrystals as compared to pure GLB. It could be concluded that prepared GLB nanocrystals showed better bioavailability as compared to pure GLB and could offer improved drug therapy.     

Formulation Optimization and Bioavailability After Oral and Nasal Administration in Rabbits of Puerarin-Loaded Microemulsion

The main objective of the study was to investigate the efficacy of microemulsion (ME) to facilitate bioavailability of puerarin (PUE) after oral and nasal administration. The pseudo-ternary phase diagrams were constructed to screen the ME components and optimize the ME formulation. The optimized formulation for bioavailability assessment consisted of 20% Tween 80, 20% glycerin, and 1.6% ethyl oleate. The solubility (27.8 mg/mL) of PUE in ME was significantly improved compared to that (4.58 mg/mL) of crude PUE in water. The ME droplets were spherical with a mean particle diameter of 23.4 nm. After nasal (5 mg/kg) and oral (20 mg/kg) administration of a single dose of PUE as ME to fasted rabbits, the absolute bioavailability was 34.58% and 13.54%, respectively. It showed a shorter T_max (0.75 h) for nasal administration than that (1.0 h) for oral administration of PUE-loaded ME. The C_max of PUE-loaded ME was 0.55 μg/mL after nasal administration and 0.64 μg/mL after oral administration, respectively. The results showed that nasal administration might be a promising route to enhance the absorption of PUE in the form of ME.     

Nanostructured Lipid Carriers for Oral Bioavailability Enhancement of Exemestane: Formulation Design,In Vitro,Ex Vivo,and In Vivo Studies

Exemestane (EXE) is a novel oral steroidal aromatase inhibitor approved for the treatment of breast cancer. However, its oral clinical application is limited because of low aqueous solubility and low oral bioavailability. Here, we aim to design and fabricate nanostructured lipid carriers (NLCs) using Precirol^® ATO 5 and flaxseed oil as the solid lipid and liquid lipid, respectively. EXE-loaded NLCs were spherical in shape and with a hydrodynamic diameter of 131.3 ± 2.43 nm, polydispersity index 0.205 ± 0.06, and percentage entrapment efficiency 85.6 ± 1.20%. In vitro release study demonstrated a sustained release pattern for 24 h, with relative burst release at the initial time point. Differential scanning calorimetry and powder X-ray diffraction studies showed reduced crystallinity and complete encapsulation of drug within the lipid matrix. Ex vivo gut permeation study and confocal laser scanning microscopy revealed that NLCs comprising a lipid blend and surfactant enhanced intestinal permeability of EXE. Moreover, in vivo pharmacokinetic study on female Wistar rats found to augment 3.9-fold in oral bioavailability of EXE through NLCs compared with EXE suspension. Herein, we depict that loading of EXE into NLCs hold promising approach for the oral delivery of EXE in cancer therapy.     

Formulation Design and Photochemical Studies on Nanocrystal Solid Dispersion of Curcumin with Improved Oral Bioavailability

Considerable interest has been focused on curcumin due to its use to treat a wide variety of disorders, however, the therapeutic potential of curcumin could often be limited by its poor solubility, bioavailability, and photostability. To overcome these drawbacks, efficacious formulations of curcumin, including nanocrystal solid dispersion (CSD‐Cur), amorphous solid dispersion (ASD‐Cur), and nanoemulsion (NE‐Cur), were designed with the aim of improving physicochemical and pharmacokinetic properties. Physicochemical properties of the prepared formulations were characterized by scanning/transmission electron microscope for morphological analysis, laser diffraction, and dynamic light scattering for particle size analysis, and polarized light microscope, powder X‐ray diffraction and differential scanning calorimetry for crystallinity assessment. In dissolution tests, all curcumin formulations exhibited marked improvement in the dissolution behavior when compared with crystalline curcumin. Significant improvement in pharmacokinetic behavior was observed in the newly developed formulations, as evidenced by 12‐ (ASD‐Cur), 16‐ (CSD‐Cur), and 9‐fold (NE‐Cur) increase of oral bioavailability. Upon photochemical characterization, curcumin was found to be photoreactive and photodegradable in the solution state, possibly via type 2 photochemical reaction, whereas high photochemical stability was seen in the solid formulations, especially CSD‐Cur. On the basis of these observations, taken together with dissolution and pharmacokinetic behaviors, CSD strategy would be efficacious to enhance bioavailability of curcumin with high photochemical stability. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1871–1881, 2010     

Curcumin Enhances Oral Bioavailability and Anti-Tumor Therapeutic Efficacy of Paclitaxel upon Administration in Nanoemulsion Formulation

The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and therapeutic efficacy of paclitaxel (PTX) administered in nanoemulsion to SKOV3 tumor-bearing nu/nu mice. Oral administration of the mice with CUR at 50 mg/kg for 3 consecutive days resulted in a down regulation of intestinal P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2) protein levels. PTX, a Pgp and CYP3A2 substrate, was administered orally at 20 mg/kg in solution or nanoemulsion either as single agent or upon pretreatment with CUR at 50 mg/kg in tumor-bearing mice. Plasma AUC_0–∞ of PTX administered in nanoemulsion to CUR pretreated mice showed 4.1-fold increase relative to controls. Similarly, relative PTX bioavailability was increased by 5.2-fold, resulting in a 3.2-fold higher PTX accumulation in the tumor tissue. PTX administered in nanoemulsion to CUR pretreated mice also showed significantly enhanced anti-tumor activity. Preliminary safety evaluation showed that CUR + PTX combination did not induce any acute toxicity as measured by body weight changes, blood cell counts, liver enzyme levels, and liver histopathology. The results of this study suggest that combination of PTX and CUR, administered in nanoemulsions, could improve oral bioavailability and therapeutic efficacy in ovarian adenocarcinoma.     

不同粒径辅酶Q_(10)乳剂和脂质体小鼠药物动力学和组织分布

目的研究不同粒径辅酶Q10乳剂和脂质体小鼠药物动力学和组织分布。方法以市售辅酶Q10注射液(S)为对照,考察其60 nm乳剂(E60)、120 nm乳剂(E120)、60 nm脂质体(L60)和120nm脂质体(L120)小鼠尾静脉给药后的药物动力学及组织分布特征;采用DAS2.1.1药物动力学软件,进行房室模型和统计矩两种模式拟合;以组织相对摄取率(re)为指标,评价载体的粒径和种类对组织靶向性的影响。结果不同粒径辅酶Q10乳剂和脂质体体内分布均符合双隔室模型;E60、E120、L60和L120的统计矩AUC分别是S组的1.17、1.50、5.99和8.65倍;re结果显示,E60组在心、脾和脑的含量分别是S组的2.64、2.74和1.95倍,E120组在心、脾和脑的含量分别是S组的4.89、3.77和2.38倍;L60组在脑中的含量是S组的1.56倍,L120组在脑和肺的含量分布是S组的2.28和1.85倍。结论载体粒径和种类对辅酶Q10体内分布的影响十分明显,市售注射液组、乳剂组和脂质体组的AUC依次增大,且同一载体中,120 nm组较60 nm组的AUC高;相对市售注射液,乳剂组对心、脾和脑有一定的靶向性,而脂质体组主要靶向于脑和肺,同一载体内,120 nm组在多数组织的富集量多于60 nm组。     

Development of Taste Masked Oral Formulation of Ornidazole

Taste masked microspheres of ornidazole were prepared using amino alkyl methacrylate copolymers (Eudragit E-100) by solvent evaporation technique. Taste assessment of these microspheres was done by both spectrophotometric taste evaluation technique and panel testing. Compressed tablets of taste masked ornidazole microspheres which rapidly disintegrated in the oral cavity were prepared using microcrystalline cellulose as directly compressible filler and sodium starch glycolate as a super-disintegrant. These were subsequently evaluated for various pharmacopoeial tests, drug release, and disintegration time in the oral cavity. Sensory taste evaluation was carried by panel testing in 20 healthy human volunteers. Results indicate successful formulation of oral fast disintegrating tablets which disintegrated in the oral cavity in about 30 s and possessed good taste.     

Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for Immuno-Oncology

Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.     

CoQ10软胶囊在Beagle犬体内的相对生物利用度评价

目的:比较在 Beagle 犬体内3种辅酶 Q_(10)(CoQ_(10))制剂的相对生物利用度。方法:采用三制剂三周期(3×3拉丁方)自身对照交叉多剂量口服给药方式,周期间清洗1周。用高效液相色谱法测定6条健康 Beagle 犬口服 CoQ_(10)软胶囊(受试制剂A)、CoQ_(10)普通胶囊(参比制剂 B)和进口 CoQ_(10)软胶囊(参比制剂 C)后不同时间点血浆中 CoQ_(10)的浓度,扣除内源性 CoQ_(10)本底,绘制血药浓度-时间曲线,计算相对生物利用度。结果:受试犬口服 CoQ_(10)60mg 的受试制剂(A)和参比制剂(B,C)后,血浆中 CoQ_(10)AUC_(0-t)(μg·h·mL~(-1))分别为69.31±40.49,62.38±59.05,104.90±64.32。与参比制剂 B 与 C 相比,受试制剂中的相对生物利用度平均为(144.07±79.48)%和(78.60±54.28)%。结论:CoQ_(10)受试制剂 A 生物利用度高于参比制剂 B 而低于参比制剂 C。     

Paclitaxel-Loaded TPGS2k/Gelatin-Grafted Cyclodextrin/Hyaluronic Acid-Grafted Cyclodextrin Nanoparticles for Oral Bioavailability and Targeting Enhancement

The clinical applications of paclitaxel (PTX), a natural compound with broad-spectrum antitumor effects, have been markedly limited owing to its poor oral bioavailability and lack of targeting ability. Recently, several drug carriers, such as TPGS_2k, gelatin (Gel), cyclodextrin (CD), and hyaluronic acid (HA), have been identified as promising enhancers of drug efficacy. Therefore, Gel-grafted CD (GEL-CD) and HA-grafted CD (HA-CD) were synthesized via grafting, and PTX-loaded TPGS_2k/GEL-CD/HA-CD nanoparticles (TGHC-PTX-NPs) were successfully prepared using the ultrasonic crushing method. The mean particles size, polydispersity index, and Zeta potential of TGHC-PTX-NPs were 253.57 ± 2.64 nm, 0.13 ± 0.03, and 0.087 ± 0.005 mV, respectively. TGHC-PTX-NPs with an encapsulation efficiency of 61.77 ± 0.47% and a loading capacity of 6.86 ± 0.32% appeared round and uniformly dispersed based on transmission electron microscopy. In vitro release data revealed that TGHC-PTX-NPs had good sustained-release properties. Further, TGHC-PTX-NPs had increased the targeted uptake by HeLa cells as HA can specifically bind to the CD44 receptor at the cell surface, and its intestinal absorption is related to caveolin-mediated endocytosis. The pharmacokinetic results indicated that TGHC-PTX-NPs significantly enhanced the absorption of PTX in vivo compared to the PTX suspension, with a relative bioavailability of 227.21%. Such findings indicate the potential of TGHC-PTX-NPs for numerous clinical applications.     

Development and Evaluation of a Novel Microemulsion Formulation of Elacridar to Improve its Bioavailability

The study objective was to develop a formulation of elacridar to overcome its dissolution-rate-limited bioavailability. Elacridar is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted because of the poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol, and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in Madin-Darby canine kidney Il-transfected cells. Friend Leukemia Virus Strain B (FVB) mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally (i.p.) and orally (p.o.); and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Coadministration of elacridar microemulsion i.p. with p.o. erlotinib in FVB mice improved the erlotinib brain penetration threefold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp, in vitro and in vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood–brain barrier.     

Development of a Novel Amorphous Agomelatine Formulation With Improved Storage Stability and Enhanced Bioavailability

The present work describes the development of a novel formulation of amorphous agomelatine (AGM) that exhibits enhanced in vitro dissolution rate and bioavailability, as well as improved storage stability. AGM was loaded on a mixture of microcrystalline cellulose with a high specific surface area excipient, namely colloidal silicon dioxide, employing a wet granulation method, and the resultant AGM granules were subsequently formulated into immediate release film-coated tablets. Modulated temperature differential scanning calorimetry, hot-state light microscopy, powder X-ray diffraction, attenuated total reflectance FTIR, and micro-Raman spectroscopy revealed that the active pharmaceutical ingredient existed primarily in the amorphous state within the prepared formulations, with some crystals of polymorph I also present. Accelerated stability studies for up to 6 months in alu-alu blisters showed good physicochemical stability during storage. Finally, in vitro dissolution studies and clinical trials in healthy human volunteers showed a remarkable increase in the in vitro dissolution rate and a ～1.5-fold increase in bioavailability, respectively, compared to the marketed product.     

Enhancement of Oral Bioavailability of Tripterine Through Lipid Nanospheres: Preparation,Characterization, and Absorption Evaluation

Oral delivery of anticancer drugs remains challenging because of limited water-solubility and/or poor permeability. Here, we aimed to enhance the oral bioavailability of tripterine (TRI, a plant-derived anticancer compound) using lipid nanospheres (LNs) and to determine the mechanisms of oral absorption. TRI-loaded LNs (TRI-LNs) were prepared by rapid dispersion of an ethanol mixture of TRI, lecithin, sodium oleate, and soybean oil into water. The obtained LNs were 150 nm in size with a high value of entrapment efficiency (99.95%). TRI-LNs were fairly stable and the drug release was negligible (< 0.2%) in simulated physiological fluid. The pharmacokinetic results showed that LNs significantly enhanced the oral bioavailability of TRI with a relative bioavailability of 224.88% (TRI suspensions was used as a reference). The mechanistic studies demonstrated that improved intestinal permeability and post-enterocyte lymphatic transport were mainly responsible for the enhanced oral absorption. Our findings suggested that LNs may be a viable oral carrier for poorly bioavailable drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:171 1-1719, 2014     

Formulation Development and Dissolution Rate Enhancement of Efavirenz by Solid Dispersion Systems

The aim of this study was to enhance the dissolution rate of efavirenz using solid dispersion systems (binary and ternary). A comparison between solvent and fusion method was also investigated. Solid dispersions of efavirenz were prepared using polyethylene glycol 8000, polyvinylpyrrolidone K30 alone and combination of both. Tween 80 was incorporated to obtain a ternary solid dispersion system. Dissolution tests were conducted and evaluated on the basis of cumulative percentage drug release and dissolution efficiency. Physicochemical characterizations of the solid dispersions were carried out using differential scanning calorimetric, powder X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. Dissolution was remarkably improved in both systems compared to pure efavirenz (P<0.05). An optimum ratio was identified at a drug:polymer of 1:10. Incorporation of Tween 80 to 1:10 formulations formed using solvent method showed further improvement in the dissolution rate. Physicochemical characterization results suggested that efavirenz existed in the amorphous form in all the solid dispersion systems providing evidence of improvement in dissolution. No statistically significant difference (P>0.05) in dissolution was observed between the two methods. Binary and ternary solid dispersion systems both have showed a significant improvement in the dissolution rate of efavirenz. Formulations with only polyvinylpyrrolidone K30 showed best dissolution profile and 1:10 was identified as an optimum drug-polymer weight ratio.     

Bioavailability of Soil-Bound TCDD: Oral Bioavailability in the Rat

Bioavailability of Soil-Bound TCDD: Oral Bioavailability inthe Rat. SHU, H., PAUSTENBACH, D., MURRAY, F. J., MARPLE, L.,BRUNCK, B., DEI ROSSI, D., TEITELBAUM, P. (1988). Fundam ApplToxicol. 10, 648–654. The implications to the public healthof trace amounts of 2,3,7,8-TCDD in the environment are underevaluation by regulatory agencies in the United States and WesternEurope. One major consideration in such evaluations is the contributionto human exposure via ingestion of TCDD-contaminated soil. An80% figure is under consideration by some regulators for estimatedhuman exposure. A contractor for one agency has, in fact, useda value of 1007% bioavailability for estimating human bioavailability.Several studies have investigated the oral bioavailability ofTCDD from contaminated soil in animals. Most have reported estimatesof 25–50%, although one has reported <0.5 and 85%,depending on the source of the contaminated soil. This paperreports an oral bioavailability of approximately 43% in therat dosed with three environmentally contaminated soil samplesfrom Times Beach, Missouri. This figure did not change significantlyover a 500-fold dose range of 2 to 1450 ng TCDD/kg of body weightfor soil contaminated with approximately 2, 30, or 600 ppb ofTCDD. The relevance of animal oral bioavailability data forthe human remains to be evaluated. However, since regulatoryagencies use animal data for extrapolating to humans, the 43%or 25–50% figure would be more accurate than the 80 or100% estimates.