Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro–in silico approach

Abstract

Consumption of alcoholic beverages with sustained-release oral dosage forms may pose a risk to patients due to potential alcohol-induced dose dumping (ADD). Regulatory guidances recommend in vitro dissolution testing to identify the risk of ADD, but the question remains whether currently proposed test conditions can be considered biopredictive. The purpose of this study was to evaluate different dissolution setups to assess ADD, and the potential of combined in vitro–in silico approach to predict drug absorption after concomitant alcohol intake for hydrophilic and lipophilic sustained-release tablets containing ibuprofen or diclofenac sodium. According to the obtained results, the impact of ethanol was predominantly governed by the influence on matrix integrity, with the increase in drug solubility being less significant. Hydrophilic matrix tablets were less susceptible to ADD than lipophilic matrices, although the conclusion on formulation ethanol-vulnerability depended on the employed experimental conditions. In silico predictions indicated that the observed changes in drug dissolution would not result in plasma concentrations beyond therapeutic window, but sustained-release characteristics of the formulations might be lost. Overall, the study demonstrated that in vitro–in silico approach may provide insight into the effect of ADD on drug clinical performance, and serve as a tool for ADD risk assessment.     

Predicting human exposure of active drug after oral prodrug administration,using a joined in vitro/in silico–in vivo extrapolation and physiologically-based pharmacokinetic modeling approach

Introduction: Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice. In this paper, a joined in vitro/in silico–in vivo extrapolation (IVIVE) and physiologically-based pharmacokinetic (PBPK) modeling approach is presented to predict active drug exposure in human after oral prodrug administration. Methods: Physico-chemical and in vitro assays as well as in silico predictions were proposed to characterize key pharmacokinetic properties (e.g. clearance, volume of distribution, conversion rates) of three marketed prodrugs. These data were used to parameterize a PBPK model for simulating human PK profiles of the active drugs after prodrug administration, which were compared to literature data by evaluating the accuracy and uncertainty of the predictions. Results: For mycophenate mofetil and midodrine the PK of their active moieties could be adequately predicted. The assumptions of the PBPK–IVIVE approach were valid, i.e. being hepatically cleared, converted in the gut lumen, blood and liver and not metabolized in the gut wall. However, the observed profiles after oral bambuterol administration clearly fell outside the prediction interval as the PBPK model failed to predict the observed bioavailability. Discussion: Adding quantitative information about prodrug conversion in the gut, liver and blood to a PBPK model for the absorption, distribution, metabolism and excretion (ADME) properties of prodrugs and their active moieties resulted, retrospectively, in reasonable predictions of the human PK when the ADME properties are well understood. Also in a prospective compound selection process, this integrative approach can improve decision making on prodrug candidates by putting relative differences in prodrug conversion of a large number of candidates into the perspective of their human PK profile, before conducting any in vivo experiments.     

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone.     

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     

Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug – an in vitro and an in vivo study

Abstract

The main objective of the study was to alter the dissolution profile of a practically insoluble Biopharmaceutics Classification System class II drug, aceclofenac, by formulating into lipid semisolid matrix (SSM) formulations using liquid filling technology in hard gelatin capsules, for both immediate and sustained release. SSM formulations of aceclofenac were prepared by melt fusion technique, using Gelucires (44/14, 50/13, 33/01 and 43/01), polyethylene glycols (4000 and 6000) and Poloxamer 188 at different levels. Role of additives like docusate sodium, Tween 80, Aerosil 200 and polyvinylpyrrolidone K-30 in enhancement of drug release was investigated. The optimized immediate and sustained SSM capsules were characterized in terms of assay, in vitro drug release, moisture uptake and differential scanning calorimetry. More than 80% of the drug was released within 15?min in various dissolution media studied, from Gelucire 44/14-based immediate release formulations. Incorporation of docusate sodium and Tween 80 provided further enhancement in drug dissolution when compared to plain drug and marketed tablet. SSM formulations based on Gelucire blends of 50/13 and 43/01 and 44/14 and 43/01 sustained the release of the drug for a period of 24?h following zero-order kinetics. The in vivo study of the optimized immediate release and sustained release formulations revealed significant enhancement in anti inflammatory activity (p?<?0.01) in rats. From these findings, liquid fill technique in hard gelatin capsules using Gelucire and their blends might be an efficacious approach for designing immediate or sustained drug release profiles for poorly soluble drugs like aceclofenac.     

A time scaling approach to develop an in vitro–in vivo correlation (IVIVC) model using a convolution-based technique

In vitro–in vivo correlation (IVIVC) models prove very useful during drug formulation development, the setting of dissolution specifications and bio-waiver applications following post approval changes. A convolution-based population approach for developing an IVIVC has recently been proposed as an alternative to traditional deconvolution based methods, which pose some statistical concerns. Our aim in this study was to use a time-scaling approach using a convolution-based technique to successfully develop an IVIVC model for a drug with quite different in vitro and in vivo time scales. The in vitro and the in vivo data were longitudinal in nature with considerable between subject variation in the in vivo data. The model was successfully developed and fitted to the data using the NONMEM package. Model utility was assessed by comparing model-predicted plasma concentration-time profiles with the observed in vivo profiles. This comparison met validation criteria for both internal and external predictability as set out by the regulatory authorities. This study demonstrates that a time-scaling approach may prove useful when attempting to develop an IVIVC for data with the aforementioned properties. It also demonstrates that the convolution-based population approach is quite versatile and that it is capable of producing an IVIVC model with a big difference between the in vitro and in vivo time scales.     

Inhibition of IKKβ by celastrol and its analogues – an in silico and in vitro approach

Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions.

Objective: This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta_1-42 (Aβ_1-42) induced cytotoxicity and IKKβ activity, respectively.

Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1?μM) before treatment with Aβ_1-42 (IC₃₀ 10?μM) for 24?h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects.

Results: Celastrol (1?μM) inhibited Aβ_1-42 (10?μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol.

Discussion and conclusion: The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition.     

Toward a new paradigm for the efficient in vitro–in vivo extrapolation of metabolic clearance in humans from hepatocyte data

The objective of this study was to follow up a previous study on a comparative analysis of diverse in vitro–in vivo extrapolation (IVIVE) methods used for predicting hepatic metabolic clearance (CL) of drugs from intrinsic clearance (CL_int) data determined in microsomal incubations, but using hepatocyte data instead. Six IVIVE methods were compared: the “conventional and conventional bias‐corrected methods,” the “regression equation method,” the “direct scaling method,” the “Berezhkovskiy's method,” and the “novel IVIVE method of Poulin et al.” offering a new paradigm. A large and diverse dataset of 49 drugs were collected from the literature for hepatocyte data in human. Based on all statistical parameters, this study confirms that the novel IVIVE method of Poulin et al. shows the greatest prediction performance among the IVIVE methods tested by using hepatocyte data. The superior prediction performance of this novel IVIVE method is again most pronounced for (a) drugs highly bound in blood, (b) drugs bound to albumin, and (c) low CL drugs. Because the novel IVIVE method has been developed particularly to improve the prediction accuracy for drugs with such properties, this study confirms its utility. Furthermore, the results of the current comparative analysis performed using hepatocyte data confirm the findings of a previous analysis made with microsomal data. Overall, the proposed novel IVIVE method offers a new paradigm for the prediction of hepatic metabolic CL particularly for drugs, which have the aforementioned properties, and, hence, this would contribute to a more accurate CL prediction for small molecules in drug discovery and development, interspecies scaling, and can potentially be used for the optimization of driving factors of CL in an attempt to facilitate the simulation of drug disposition by using the physiologically based pharmacokinetics (PBPK) model. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3239–3251, 2013     

Prediction of metabolic drug clearance in humans: In vitro–in vivo extrapolation vs allometric scaling

Previously in vitro–in vivo extrapolation (IVIVE) with the Simcyp Clearance and Interaction Simulator® has been used to predict the clearance of 15 clinically used drugs in humans. The criteria for the selection of the drugs were that they are used as probes for the activity of specific cytochromes P450 (CYPs) or have a single CYP isoform as the major or sole contributor to their metabolism and that they do not exhibit non-linear kinetics in vivo. Where data were available for the clearance of the drugs in at least three animal species, the predictions from IVIVE have now been compared with those based on allometric scaling (AS). Adequate data were available for estimating oral clearance (CL_p.o.) in 9 cases (alprazolam, sildenafil, caffeine, clozapine, cyclosporine, dextromethorphan, midazolam, omeprazole and tolbutamide) and intravenous clearance in 6 cases (CL_i.v.) (cyclosporine, diclofenac, midazolam, omeprazole, theophylline and tolterodine). AS predictions were based on five different methods: (1) simple allometry (clearance versus body weight); (2) correction for maximum life-span potential (CL?×?MLP); (3) correction for brain weight (CL?×?BrW); (4) the use of body surface area; and (5) the rule of exponents. A prediction accuracy was indicated by mean-fold error and the Pearson product moment correlation coefficient. Predictions were considered successful if the mean-fold error was ≤2. IVIVE predictions were accurate in 14 of 15 cases (mean-fold error range: 1.02–4.00). All five AS methods were accurate in 13, 11, 10, 10 and 14 cases, respectively. However, in some cases the error of AS exceeded fivefold. On the basis of the current results, IVIVE is more reliable than AS in predicting human clearance values for drugs mainly metabolized by CYP450 enzymes. This suggests that the place of AS methods in pre-clinical drug development warrants further scrutiny.     

Inhibition of metastasis and angiogenesis in Hep-2 cells by wheatgrass extract – an in vitro and in silico approach

Metastasis is the major hindrance in the treatment of all cancers, including laryngeal squamous cell carcinoma. Intensive researches are under way to identify the effective natural polyphenols with anti-metastatic ability for cancer treatment. Wheatgrass, an herbal plant has been reported to show anticancer effects. Hence, in this study, we aimed to analyze the anti-metastatic effect of methanol extract of wheatgrass (MEWG). The levels of metastatic marker proteins were determined by western blot. PI3K and AKT levels were determined by real time (RT)-PCR analysis. In silico molecular docking was done to check the interaction of the 14 components (identified by HPLC/GCMS) of MEWG with PI3K and AKT. MEWG effectively decreased the metastatic protein expressions, namely VEGF, MMP-9 and COX-2 and increased TIMP-2. RT-PCR results showed reduced m-RNA levels of both PI3K and AKT when compared to control. Molecular docking studies revealed interaction of most of the identified compounds of the extract with the important residues of PI3K and AKT. These findings indicate that MEWG inhibits metastasis and angiogenesis in Hep-2 cells possibly via PI3K/AKT due to the cumulative effect of polyphenols and other constituent present in extract. The compounds of the extract were also found to be directly involved in inhibition of AKT/PI3K, thus could help to restrain metastasis.     

α-Glucosyl hesperidin induced an improvement in the bioavailability of pranlukast hemihydrate using high-pressure homogenization

The α-glucosyl hesperidin (Hsp-G)-induced improvement of both the dissolution and absorption properties of pranlukast hemihydrate (PLH) was achieved by means of a high-pressure homogenization (HPH) processing. The average particle size in the HPH-processed suspension was decreased significantly after 50 cycles of processing and reached a constant size of ca. 300 nm. The amount of dissolved PLH gradually increased with the pass number of HPH processing, and was extremely higher than the PLH solubility (0.8 μg/mL at 37°C) after the HPH processing. On a dissolution study of the freeze-dried sample of HPH-processed PLH/Hsp-G (1/10), the apparent solubility of PLH was at least 2.5-fold more than that of untreated PLH crystals. The transport study showed that the amount of PLH that had permeated through the Caco-2 cell monolayers was improved in the case of HPH-processed PLH/Hsp-G (1/10). The bioavailability of PLH from HPH-processed PLH/Hsp-G (1/10) showed a 3.9- and 2.2-fold improvement over the PLH crystal in terms of C(max) and AUC values, respectively. Hsp-G formed an associated structure in aqueous media. High-pressure homogenization provides a good opportunity for molecular-level interaction of PLH and the associated structure of Hsp-G to occur. The use of Hsp-G under HPH processing was a promising way to enhance the dissolution and absorption of PLH without using an organic solvent.     

Preparation of meloxicam–β-cyclodextrin–polyethylene glycol 6000 ternary system: characterization,in vitro and in vivo bioavailability

Ternary complexes of meloxicam (ML), a poorly water-soluble anti-inflammatory drug, with β-cyclodextrin (βCD) and polyethylene glycol (PEG) 6000 were prepared from an equimolar (ML–βCD) and 10% of PEG. Characterization of the ternary complex was carried out by differential scanning calorimetry and X-ray diffractometry. The solubility of ML increased as a function of increasing the concentration of βCD and PEG 6000. Ternary system increased significantly ML solubility in water. Ternary complexes improved drug release compared with ML and ML–βCD. The oral bioavailability of ML–βCD–PEG was investigated by administration to rat and compared with ML and ML–βCD. The results confirmed that the oral bioavailability of ML was significantly improved by complexation with βCD in the presence of PEG.     

In vitro and in vivo investigation of low molecular weight heparin–alginate beads for oral administration

Abstract

Low molecular weight heparin (LMWH) and standard heparin are widely used anticoagulants. However, they have very poor oral bioavailability and have to be administered by the parenteral route. Alginates are biodegradable, biocompatible and mucoadhesive polymers which can be used for advantage for the oral administration of LMWH. The aim of the study was to develop LMWH–alginate beads for oral delivery. Alginate beads were prepared based on the 2³ factorial design. In vitro characterization studies of the beads were carried out. In vivo studies were performed on rabbits. The LMWH solutions (5000?IU/kg, with and without 5% dimethyl-β-cyclodextrin), as well as the LMWH–alginate beads were administered to rabbits. The IV solution was also administered (100?IU/kg). The anti-Xa activity was measured in plasma. Area under curve (AUC) and C_max values were determined. Histological investigations were also carried out. The formulation consisting of a 1:2 drug/alginate ratio and cured using 0.5?M CaCl₂ for 15?min gave the best result in terms of encapsulation efficiency and the time for 50% of the drug to be released (t_50%). A significantly higher bioavailability was observed for LMWH–alginate beads than for LMWH solutions. It was concluded that, anticoagulant effectiveness was achieved using alginate beads containing LMWH after oral administration to the rabbits.     

Comparison of the intestinal absorption and bioavailability of γ-tocotrienol and α-tocopherol: in vitro, in situ and in vivo studies

The aim of this work was to compare the intestinal absorption kinetics and the bioavailability of γ-tocotrienol (γ-T3) and α-tocopherol (α-Tph) administered separately as oil solutions to rats in vivo. Also, to explain the significant difference in the oral bioavailability of the compounds: (1) the release profiles using the dynamic in vitro lipolysis model, (2) the intestinal permeability and (3) carrier-mediated uptake by Niemann-Pick C1-like 1 (NPC1L1) transporter were examined. Absolute bioavailability studies were conducted after oral administration of γ-T3 or α-Tph prepared in corn oil to rats. In situ rat intestinal perfusion with ezetimibe (a NPC1L1 inhibitor) was performed to compare intestinal permeability. The in vitro interaction kinetics with NPC1L1 was examined in NPC1L1 transfected cells. While the in vitro release studies demonstrated a significantly higher release rate of γ-T3 in the aqueous phase, the oral bioavailability of α-Tph (36%) was significantly higher than γ-T3 (9%). Consequent in situ studies revealed significantly higher intestinal permeability for α-Tph compared with γ-T3 in rats. Moreover, the NPC1L1 kinetic studies demonstrated higher Vmax and Km values for α-Tph compared with γ-T3. Collectively, these results indicate that intestinal permeability is the main contributing factor for the higher bioavailability of α-Tph. Also, these results emphasize the potentially important role of intestinal permeability in the bioavailability of γ-T3, suggesting that enhancing its permeability would increase its oral bioavailability.     

Study of the in vitro–in vivo correlation of Danshensu and protocatechuic aldehyde in a two-step release system

A two-step release system (TSRS) for the compound Danshen, which has drug-release behavior that is in accordance with the circadian rhythms of cardiovascular disease, was developed by combining an effervescent osmotic pump tablet and a pulsed-released tablet into one hard capsule by our lab. An in vivo study indicated that after oral administration of TSRS, two peaks of the plasma concentration of both Danshensu (DS) and protocatechuic aldehyde (PA) were observed, which suggested that the drug plasma concentration–time curve could meet the requirements for chronotherapy of cardiovascular disease after the bed-time administration of such a device. High performance liquid chromatography using an ultraviolet (UV) detector was used to simultaneously determine the concentrations of DS and PA in plasma. This method was simple, convenient, and appropriate for the quality control of DS and PA. A linear correlation model was established based on the percent absorbant data and percent in vitro dissolution data. Because the drugs were released from the device in an osmotic pressure-dependent manner and absorbed rapidly, a reasonable linear regression relationship was observed between the in vitro and in vivo performances. The current study highlights the potential use of such a device for chronopharmaceutical drug delivery.     

Preparation,optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat

The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat (FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone (PVPP) and magnesium stearate (MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat (CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer (pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC_0-24h of CXT and FXT were 22,245.96 ± 7342.92 µg⋅h/l and 12,249.70 ± 2024.04 µg⋅h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC_0-24h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.     

Enhanced ocular bioavailability of fluconazole from niosomal gels and microemulsions: formulation,optimization, and in vitro–in vivo evaluation

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span^® 60 and cholesterol (CH) using 1% w/w carbopol^® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween^® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit’s. Nanoscopic niosomes (63.67–117.13?nm) and microemulsions (57.05–59.93?nm) showed respective negative zeta potential ranges of ?45.37 to ?61.40 and ?20.50 to ?31.90?mV and sustained release up to 12?h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span^® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween^® 80-PEG 400 mixture significantly (p?<?0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.     

A population approach to in vitro–in vivo correlation modelling for compounds with nonlinear kinetics

Developing an In Vitro–In Vivo Correlation (IVIVC) model is becoming an important part of the drug development process. Traditional methods such as deconvolution and convolution make the assumption of linearity of the system being studied and are, therefore, unsuitable for use with compounds exhibiting nonlinear kinetics. This study proposes the use of a compartmental approach which may be based on systems of differential equations, a method which can comfortably accommodate nonlinearity. This technique can easily be implemented using existing NONMEM libraries and is an accurate, fast and straightforward method of developing an IVIVC model.     

Preparation of meloxicam-β-cyclodextrin-polyethylene glycol 6000 ternary system: characterization, in vitro and in vivo bioavailability

Ternary complexes of meloxicam (ML), a poorly water-soluble anti-inflammatory drug, with β-cyclodextrin (βCD) and polyethylene glycol (PEG) 6000 were prepared from an equimolar (ML-βCD) and 10% of PEG. Characterization of the ternary complex was carried out by differential scanning calorimetry and X-ray diffractometry. The solubility of ML increased as a function of increasing the concentration of βCD and PEG 6000. Ternary system increased significantly ML solubility in water. Ternary complexes improved drug release compared with ML and ML-βCD. The oral bioavailability of ML-βCD-PEG was investigated by administration to rat and compared with ML and ML-βCD. The results confirmed that the oral bioavailability of ML was significantly improved by complexation with βCD in the presence of PEG.