Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations

Abstract

The objective of this study was to develop self-emulsifying drug delivery system (SEDDS) to improve solubility and enhance the oral absorption of the poorly water-soluble drug, nevirapine. This lipid-based formulation may help to target the drug to lymphoid organs where HIV-1 virus resides mainly. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SEDDS were investigated in detail. Two SEDDS (F1 and F2) were prepared and characterized by morphological observation, droplet size and zeta potential determination, cloud point measurement and in vitro diffusion study. The influence of droplet size on the absorption from formulations with varying concentration of oil and surfactant was also evaluated from two self-emulsifying formulations. Oral bioavailability of nevirapine SEDDS was checked by using rat model. Results of diffusion rate and oral bioavailability of nevirapine SEDDS were compared with marketed suspension. The absorption of nevirapine from F1 and F2 showed 1.92 and 1.98-fold increase (p?<?0.05) in relative bioavailability, respectively, compared with that of the suspension. There was no statistical significant difference (p?<?0.05) between F1 and F2 in their AUC and C_max. This indicated that there was apparent poor correlation between the droplet size and in vivo absorption. However, nevirapine in SEDDS showed higher ex vivo stomach and intestinal permeability and in vivo absorption than the marketed suspension, suggesting that the SEDDS may be a useful delivery system for targeting nevirapine to lymphoid organs.     

[6]-Shogaol/β-CDs inclusion complex: preparation,characterisation, in vivo pharmacokinetics,and in situ intestinal perfusion study

Abstract

Aims: The aim was to improve the absorption and bioavailability of [6]-shogaol with β-cyclodextrin (β-CD) prior to in vitro and in vivo evaluation.

Methods: [6]-Shogaol/β-CDs inclusion complexes (6-S-β-CDs) were developed using saturated aqueous solution method and characterised with appropriate techniques. The absorption and bioavailability potential of [6]-shogaol was evaluated via in vivo pharmacokinetics and in situ intestinal perfusion.

Results: The results of characterisation showed that 6-S-β-CDs (drug loading, 7.15%) were successfully formulated. In vitro release study indicated significantly improved [6]-shogaol release. Pharmacokinetic parameters such as C_max, AUC_0–36?h, and oral relative bioavailability (about 685.36%) were substantially enhanced. The in situ intestinal perfusion study revealed that [6]-shogaol was markedly absorbed via passive diffusion in the intestinal segments, and duodenum followed by ileum and jejunum.

Conclusions: Cyclodextrin inclusion technology could enhance the intestinal absorption and oral bioavailability of hydrophobic drugs like [6]-shogaol.     

Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin

Abstract

Purpose: The present study was to formulate curcumin solid lipid nanoparticles (Cur-SLNs) with P-gp modulator excipients, TPGS and Brij78, to enhance the solubility and bioavailability of curcumin.

Methods: The formulation was optimized by Plackett–Burman screening design and Box–Behnken experiment design. Then physiochemical properties, entrapment efficiency and in vitro release of Cur-SLNs were characterized. In vivo pharmacokinetics study and in situ single-pass intestinal perfusion were performed to investigate the effects of Cur-SLNs on the bioavailability and intestinal absorption of curcumin.

Results: The optimized formulations showed an average size of 135.3?±?1.5?nm with a zeta potential value of ?24.7?±?2.1?mV and 91.09%?±?1.23% drug entrapment efficiency, meanwhile displayed a sustained release profile. In vivo pharmacokinetic study showed AUC_0→t for Cur-SLNs was 12.27-folds greater than curcumin suspension and the relative bioavailability of Cur-SLNs was 942.53%. Meanwhile, T_max and t_1/2 of curcumin for Cur-SLNs were both delayed comparing to the suspensions (p?<?0.01). The in situ intestinal absorption study revealed that the effective permeability (P_eff) value of curcumin for SLNs was significantly improved (p?<?0.01) comparing to curcumin solution.

Conclusion: Cur-SLNs with TPGS and Brij78 could improve the oral bioavailability and intestinal absorption of curcumin effectively.     

Self-emulsifying drug delivery system and the applications in herbal drugs

Abstract

Herbal drugs have been used for thousands of years in the east and have had a recent resurgence in popularity among consumers in the west. However, most of herbal drug are poorly soluble and have hydrophobic properties and poor distribution, leading to reduced bioavailability and hence decreased treatment efficacy, requiring repeated administration or increased dose. In the past few decades, considerable attention has been focused on the development of self-emulsifying drug delivery system (SEDDS) for herbal drugs. SEDDS is isotropic and thermodynamically stable solutions consisting of oil, surfactant, co-surfactant and drug that can spontaneously form oil-in-water micro/nanoemulsion when mixed with water under gentle stirring. The formulation can be a viable alternative to classical formulations to take advantage of their lipophilic nature and to solve their problems of poor solubility, poor bioavailability, low oral absorption and instability. The mechanism of self-emulsification, solubility studies, construction of phase diagram, optimization and characterization of herbal drugs-loaded SEDDS formulation and in situ absorption evaluation of herbal drugs in rat intestine are presented in our article.     

Nonlinear Absorption Kinetics of Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Tocotrienols as Lipophilic Molecules: In Vivo and In Vitro Studies

Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60–85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann–Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.     

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC_0→24h, C_max and T_max, respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Preparation and evaluation of Vinpocetine self-emulsifying pH gradient release pellets

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.     

Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view

Self-emulsifying drug delivery system (SEDDS) is an isotropic mixture of lipid, surfactant and co-surfactant, which forms a fine emulsion when comes in contact of an aqueous medium with mild agitation. SEDDS is considered as a potential platform for oral delivery of hydrophobic drug in order to overcome their poor and irregular bioavailability challenges. In spite of fewer advantages like improved solubility of drug, bypassing lymphatic transport etc., SEDDS faces different controversial issues such as the use of appropriate terminology (self-microemulsifying drug delivery system; SMEDDS or self-nanoemulsifying drug delivery system; SNEDDS), presence of high amount of surfactant, correlation of in vitro model to in vivo studies, lack of human volunteer study and effect of conversion of SEDDS to final administrable dosage form on pharmacokinetic behavior of the drug. In this review, potential issues or questions on SEDDS are identified and summarized from the pharmacokinetic point of view. Primarily this review includes the conflict between the influences of droplet size, variation in correlation between in vitro lipolysis or ex-vivo intestinal permeation and pharmacokinetic parameters, variation in in vivo results of solid and liquid SEDDS, and potential challenges or limitation of pharmacokinetic studies on human volunteers with orally administered SEDDS. In the past decades, hundreds of in vivo studies on SEDDS have been published. In the present study, only the relevant article on in vivo pharmacokinetic studies with orally administered SEDDS published in past 5–6 years are analyzed for an up to date compilation.     

Effects of Structural Modifications on the Intestinal Permeability of Angiotensin II Receptor Antagonists and the Correlation of In Vitro,In Situ,and In Vivo Absorption

Purpose. The effects of structural modifications on the membrane permeability of angiotensin II (Ang II) receptor antagonists and the usefulness of in vitro and in situ intestinal absorption models in predicting in vivo absorption or bioavailability were investigated. Methods. Intestinal permeability was determined in vitro using Caco-2 cell monolayers and in situ using a perfused rat intestine method. Several physicochemical parameters were either measured or computed, and correlated with intestinal permeation. Results. Permeation coefficients (Pa) across Caco-2 cell monolayers correlated well with both in situ absorption rate constants (ka) and in vivo bioavailability or % absorption. For these Ang II antagonists, Pa values larger than 3 × 10^–6 cm sec^–1 and in situ ka values of 2 × 10^–4 min^–1 cm^–1 or above were associated with good in vivo absorption. Structural modifications at the R₅ position, where a COOH group was substituted with either a CHO or CH₂OH group, enhanced the permeability of the Ang II receptor antagonists up to 100-fold. There were good correlations between permeability and log P(octanol/buffer), log P_HPLCcharge, solvation/desolvation energy and assigned hydrogen bonding potential. Conclusions. The correlations obtained in this study indicate that both the Caco-2 cell model and the in situ perfused rat intestine could be used to predict intestinal absorption in vivo. Structural modifications of the Ang II antagonists had a significant impact on the intestinal permeability. Charge, solvation energy, and hydrogen bonding are predominant determinants of intestinal permeability and oral bioavailability of these compounds.     

Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: Case studies with fenofibrate

The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (∼70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65–72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in vitro digestion did not adversely impact fenofibrate bioavailability in vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.     

Oral bioavailability of ketoprofen in suspension and solution formulations in rats: the influence of poloxamer 188

Objectives The aim of the current study was to investigate the effect of poloxamer 188 (P‐188) on the bioavailability of the BCS class 2 drug ketoprofen in vivo. Methods Aqueous suspension and solution formulations of ketoprofen with and without P‐188 were orally administered to fasted male Wistar rats. The intrinsic dissolution rate and solubility of ketoprofen in simulated intestinal fluid, in both the presence and absence of P‐188, was measured. Key findings The AUC and C_max were found to be significantly enhanced when ketoprofen was administered as suspension and P‐188 was present in the formulation (Susp P‐188) as compared to the surfactant‐free formulation (～4‐fold higher AUC, 7‐fold higher C_max). While drug solubility appeared to be almost unaffected by P‐188, a significantly faster dissolution was observed. In addition, the influence of P‐188 on the drug absorption process was investigated by comparison of solution formulations with and without P‐188. Conclusions The in‐vivo performance of these solutions, a pure buffer solution and a P‐188‐containing buffer solution showed no significant difference, suggesting that the increase in bioavailability for Susp P‐188 was primarily a consequence of the dissolution rate‐enhancing effect.     

Optimized self-nanoemulsifying drug delivery system of atazanavir with enhanced oral bioavailability: in vitro/in vivo characterization

Background: Atazanavir (ATV) is a HIV protease inhibitor. Due to its intense lipophilicity, the oral delivery of ATV encounters several problems such as poor aqueous solubility, pH-dependent dissolution and rapid first-pass metabolism in liver by CYP3A5, which result in low and erratic bioavailability.

Objective: The current study aimed to develop self-nanoemulsifying drug delivery systems (SNEDDS) using long-chain triglycerides of ATV in an attempt to circumvent such obstacles.

Methods: Equilibrium solubility studies indicated the choice of Maisine 35-1 as lipid, and of Transcutol P and Span 20 as surfactants, for formulating the SNEDDS. Ternary phase diagrams were constructed to select the areas of nanoemulsions, and the amounts of lipid (X₁) and surfactant (X₂) as the critical factor variables. The SNEDDS were optimized (OPT) using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in situ single-pass intestinal perfusion studies of OPT formulation were investigated in Wistar rats.

Results: OPT formulation indicated marked improvement in drug release profile vis-à-vis pure drug. Cloud point determination and accelerated stability studies ascertained the stability of OPT formulation. Augmentation in the values of K_a (1.96-fold) and AUC (2.57-fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT formulation compared to pure drug. Successful establishment of in vitro/in vivo correlation Level A substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions.

Conclusion: The studies, therefore, indicate the successful formulation development of SNEDDS with distinctly improved bioavailability of ATV.     

In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system

In order to characterize the in situ intestinal permeability and in vivo oral bioavailability of celecoxib (CXB), a poorly water-soluble cyclooxygenase (COX)-2 inhibitor, various formulations including the self-emulsifying drug delivery system (SEDDS) and supersaturating SEDDS (S-SEDDS) were compared. The S-SEDDS formulation was obtained by adding Soluplus as a precipitation inhibitor to SEDDS, composed of Capryol 90 as oil, Tween 20 as surfactant, and Tetraglycol as cosurfactant (1:4.5:4.5 in volume ratio). An in situ single pass intestinal perfusion study in rats was performed with CXB-dissolved solutions at a concentration of 40 μg/mL. The effective permeability (P_eff) of CXB in the control solution (2.5 v/v% Tween 20-containing PBS) was 6.39 × 10^?5 cm/s. The P_eff value was significantly increased (P < 0.05) by the lipid-based formulation, yielding 1.5- and 2.9-fold increases for the SEDDS and S-SEDDS solutions, respectively, compared to the control solution. After oral administration of various formulations to rats at the equivalent dose of 100 mg/kg of CXB, the plasma drug level was measured by LC–MS/MS. The relative bioavailabilities of SEDDS and S-SEDDS were 263 and 355 %, respectively, compared to the CXB suspension as a reference. In particular, S-SEDDS revealed the highest C_max and the smallest T_max, indicating rapid and enhanced absorption with this formulation. This study illustrates the potential use of the S-SEDDS formulation in the oral delivery of poorly water-soluble compounds.     

Investigating a Modified Apparatus to Discriminate the Dissolution Capacity In Vitro and Establish an IVIVC of Mycophenolate Mofetil Tablets in the Fed State

In this study, a modified dissolution apparatus was developed by equipping a USP apparatus Ⅰ with an open-loop system to discriminate the dissolution capacity in vitro and establish an in vitro and in vivo correlation (IVIVC) for mycophenolate mofetil (MMF) tablets. MMF had strong pH-dependent solubility that could influence the dissolution rate in vivo after the meal. Dissolution tests involving reference (Cellcept®) and test formulations (F1 and F2) were conducted using pH 4.5 acetate buffer to simulate gastric fluids in the fed state. The dissolution profiles of the reference and test formulations were distinguished by using the modified dissolution apparatus and compared with those determined using the USP apparatuses Ⅱ and Ⅳ, and the dissolution capacities of the formulations were discriminated at different sampling time-points. The results of human bioequivalence (BE) studies in the fed state were consistent with in vitro evaluations that the maximum concentrations (C_{max, in vivo}) of both F1 and F2 fell below the acceptable range (80.00%). A level A IVIVC between the absorption fraction in vivo and dissolution in vitro, and a level C correlation between C_{max, in vivo} and C_{max, in vitro}, were established to guide the optimization of the tablet formulation containing MMF.     

Novel dietary lipid-based self-nanoemulsifying drug delivery systems of paclitaxel with p-gp inhibitor: implications on cytotoxicity and biopharmaceutical performance

Objectives: This work describes the development and characterization of novel self-nanoemulsifying drug delivery systems (SNEDDS) employing polyunsaturated fatty acids for enhancing the oral bioavailability and anticancer activity of paclitaxel (PTX) by coadministration with curcumin (Cu).

Methods: Preformulation studies endorsed sesame oil, labrasol, and sodium deoxycholate as lipid surfactants and cosurfactants based on their solubility for the drugs and spontaneity of emulsification to produce nanoemulsions. Further, phase titration studies were performed to identify a suitable nanoemulsion region for preparing the SNEDDS formulation.

Results: The prepared formulations were characterized through in vitro, in situ, and in vivo studies to evaluate the biopharmaceutical performance. In vitro drug release studies showed 2.8- to 3.4-fold enhancement in the dissolution rate of both drugs from SNEDDS as compared with the pure drug suspension. Cell line studies revealed 1.5- to 2.7-fold reduction in the cytotoxicity on MCF-7 cells by plain PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension. In situ intestinal perfusion studies revealed significant augmentation in permeability and absorption parameters of drug from PTX-Cu-SNEDDS over the plain PTX-SNEDDS and PTX-suspension (p < 0.001). In vivo pharmacokinetic studies also showed a remarkable improvement (i.e., 5.8- to 6.3-fold) in the oral bioavailability (C_max and AUC) of the drug from PTX-SNEDDS and PTX-Cu-SNEDDS vis-à-vis the PTX-suspension.

Conclusions: Overall, the studies corroborated superior biopharmaceutical performance of PTX-Cu-SNEDDS.     

Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.KEY WORDS: Pharmacokinetics, Lipolysis, IVIVC, Efflux transporters, Lymphatic delivery, Food effectAbbreviations: ADME, absorption/distribution/metabolism/elimination; AUC, area under the curve; BCS, biopharmaceutics classification system; BDDCS, biopharmaceutics drug disposition classification system; CACO, human epithelial colorectal adenocarcinoma cells; C_max, maximum plasma concentration; CMC, critical micellar concentration; CYP, cytochrome; DDS, drug delivery systems; FaSSGF, fasted-state simulated gastric fluid; FaSSIF, fasted-state simulated intestinal fluid; FeSSIF, fed-state simulated intestinal fluid; GIT, gastrointestinal tract; IVIVC, in vitro in vivo correlation; LCT, long chain triglyceride; LFCS, lipid formulation classification system; log P, n-octanol/water partition coefficient; MCT, medium chain triglyceride; MDCK, Madin–Darby canine kidney cells; NCE, new chemical entity; P-app, apparent permeability; P-gp, permeability glycoprotein; SCT, short chain triglyceride; SEDDS, self-emulsifying drug delivery system; SIF, simulated intestinal fluid; SMEDDS, self-microemulsifying drug delivery system; SNEDDS, self-nanoemulsifying drug delivery system; Vit E, vitamin E     

消炎痛缓释胶囊的生物利用度研究

消炎痛普通制剂口服吸收迅速,可出现不必要的高血药浓度,导致不良反应。为此我们对三种消炎痛缓释胶囊(A,B,C)和一种常用片剂(D)作了体外溶出试验和体内生物利用度比较。胶囊制剂由丙烯酸类树脂材料E₃₀D包衣的药物小丸制成,其体外溶出行为显示缓慢释放图象。在8名成年男性交叉实验中,不同胶囊制剂和普通片剂之间的Tmax,Cmax和AUC_0～12h经方差分析无统计学差异,但是在给药后4至12小时的血清浓度—时间曲线,均比普通片剂高而平滑。在第12小时,三种胶囊产生的血清浓度显著高于普通片剂(P<0.1)。根据体外溶出行为和体内生物利用度发现T₅₀或Tmax和包衣厚度呈良好线性关系。     

Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound

Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsifi-cation was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37°C), producing dispersions with mean droplet diameters of less than 3 µm. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (C _max) and the time to reach the maximum concentration (t _max). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.     

Self-Emulsifying Drug Delivery Systems for Improving Oral Absorption of Ginkgo Biloba Extracts

Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. We found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. Ginkgo biloba extract (GBE) has become a widely used herbal remedy for increasing cognitive function in elderly people. The main purpose of our work is to prepare SEDDS for improving oral absorption of GBE. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsification region, and particle size distributions of resultant emulsions were determined. The optimized formulation for bioavailability assessment consisted of 45% Tween 80-Cremophor EL35 (1:1, w/w), 10% 1, 2-propanediol, and 45% ethyl oleate. The mean droplet size distribution of the optimized SEDDS was ～100 nm when diluted with 500-fold volume of the distilled water. The in vitro dissolution rates of the active components of GBE SEDDS form were significantly faster than those of the GBE tablets. After single oral administration of 800 mg GBE as SEDDS or tablets to fasted dogs, the relative bioavailability of SEDDS for bilabolide and ginkgolide A and B was 162.1, 154.6, and 155.8% compared with the reference tablets, respectively. Our results suggested the potential and promising use of SEDDS for the efficient delivery of the sparingly soluble drugs or traditional Chinese medicines, such as GBE by oral administration.