Hesham S. Al-Sallami

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study.

Gliclazide (G) is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D). In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA) mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients’ compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D.

Swelling, mechanical strength, and release properties of probucol microcapsules with and without a bile acid, and their potential oral delivery in diabetes

We have demonstrated a permeation-enhancing effect of deoxycholic acid (DCA), the bile acid, in diabetic rats. In this study, we designed DCA-based microcapsules for the oral delivery of the antilipidemic drug probucol (PB), which has potential antidiabetic effects. We aimed to further characterize these microcapsules and examine their pH-dependent release properties, as well as the effects of DCA on their stability and mechanical strength at various pH and temperature values. Using the polymer sodium alginate (SA), we prepared PB-SA (control) and PB-DCA-SA (test) microcapsules. The microcapsules were examined for drug content, size, surface composition, release, Micro-CT cross-sectional imaging, stability, Zeta potential, mechanical strength, and swelling characteristics at different pH and temperature values. The microencapsulation efficiency and production yield were also examined. The addition of DCA resulted in microcapsules with a greater density and with reduced swelling at a pH of 7.8 and at temperatures of 25°C and 37°C (p < 0.01). The size, surface composition, production yield, and microencapsulation efficiency of the microcapsules remained similar after DCA addition. PB-SA microcapsules produced multiphasic PB release, while PB-DCA-SA microcapsules produced monophasic PB release, suggesting more controlled PB release in the presence of DCA. The PB-DCA-SA microcapsules showed good stability and a pH-sensitive uniphasic release pattern, which may suggest potential applications in the oral delivery of PB in diabetes.

Microencapsulation as a novel delivery method for the potential antidiabetic drug, Probucol

Introduction In previous studies, we successfully designed complex multicompartmental microcapsules as a platform for the oral targeted delivery of lipophilic drugs in type 2 diabetes (T2D). Probucol (PB) is an antihyperlipidemic and antioxidant drug with the potential to show benefits in T2D. We aimed to create a novel microencapsulated formulation of PB and to examine the shape, size, and chemical, thermal, and rheological properties of these microcapsules in vitro. Method Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using the polymer, sodium alginate (SA), empty (control, SA) and loaded (test, PB-SA) microcapsules were prepared at a constant ratio (1:30). Complete characterizations of microcapsules, in terms of morphology, thermal profiles, dispersity, and spectral studies, were carried out in triplicate. Results PB-SA microcapsules displayed uniform and homogeneous characteristics with an average diameter of 1 mm. The microcapsules exhibited pseudoplastic-thixotropic characteristics and showed no chemical interactions between the ingredients. These data were further supported by differential scanning calorimetric analysis and Fourier transform infrared spectral studies, suggesting microcapsule stability. Conclusion The new PB-SA microcapsules have good structural properties and may be suitable for the oral delivery of PB in T2D. Further studies are required to examine the clinical efficacy and safety of PB in T2D.

Prediction of Fat-Free Mass in Children

BackgroundFat-free mass (FFM) is an important covariate for predicting drug clearance. Models for predicting FFM have been developed in adults but there is currently a paucity of mechanism-based models developed to predict FFM in children.ObjectiveThe aim of this study was to develop and evaluate a model to predict FFM in children.MethodsA large dataset (496 females and 515 males) was available for model building. Subjects had a relatively wide range of age (3–29xa0years) and body mass index values (12–44.9xa0kg/m2). Two types of models (M1 and M2) were developed to describe FFM in children. M1 was fully empirical and based on a linear model that contained all statistically significant covariates and their interactions. M2 was a simpler model that incorporated a maturation process. M1 was developed to provide the best possible description of the data (i.e. a positive control). In addition, a published adult model (M3) was applied directly as a reference description of the data. The predictive performances of the three models were assessed by visual predictive checks and by using mean error (ME) and root mean squared error (RMSE). A test dataset (90 females and 86 males) was available for external evaluation.ResultsM1 consisted of nine terms with up to second-level interactions. M2 was a sigmoid hyperbolic model based on postnatal age with an asymptote at the adult prediction (M3). For the index dataset, the ME and 95xa0% CI for M1, M2 and M3 were 0.09 (0.03–0.16), 0.24 (0.14–0.33) and 0.29 (0.06–0.51)xa0kg, respectively, and RMSEs were 1.12 (1.03–1.23), 1.58 (1.46–1.72) and 3.76 (3.54–3.97)xa0kg.ConclusionsA maturation model that asymptoted to an established adult model was developed for prediction of FFM in children. This model was found to perform well in both male and female children; however, the adult model performed similarly to the maturation model for females. The ability to predict FFM in children from simple demographic measurements is expected to improve understanding of human body structure and function with direct application to pharmacokinetics.

Release and swelling studies of an innovative antidiabetic-bile acid microencapsulated formulation, as a novel targeted therapy for diabetes treatment

Abstract In previous studies carried out in our laboratory, a bile acid formulation exerted a hypoglycaemic effect in a rat model of type 1 diabetes (T1D). When the antidiabetic drug gliclazide was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide–deoxycholic acid (G-DCA), with good structural properties, excipient compatibility and which exhibited pseudoplastic–thixotropic characteristics. The aim of this study is to test the slow release and pH controlled properties of this new formulation. The aim is also to examine the effect of DCA on G release kinetics at various pH values and different temperatures. Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared including: G-SA (control) and G-DCA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, 3, 7.4 and 7.8 and temperatures of 25u2009°C and 37u2009°C. The new formulation is further optimised by the addition of DCA. DCA reduced bead-swelling of the microcapsules at pH 7.8 and 3 at 25u2009°C and 37u2009°C, and even though bead size remains similar after DCA addition, the percentage of G release was enhanced at high pH values (pH 7.4 and 7.8, pu2009<u20090.01). The new formulation exhibits colon-targeted delivery and the addition of DCA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and DCA to the lower intestine.

The time course of drug effects

This review aims to introduce the concepts and principles underpinning the time course of drug effects. Models describing the time course of drug concentrations (pharmacokinetic models) and the ensuing concentration-effect (pharmacodynamics models) as well as the linked time-effect (pharmacokinetic-pharmacodynamic models) are introduced. Different types of drug time-effects models are discussed with examples which aim to explain the time course of onset, duration, and maximal effect that occurs from any given dosing schedule. These drug effects are also described in relation to disease progression models.

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6u2009±u20090.25% PB content, and zeta potential of −66u2009±u20091.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (pu2009<u20090.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85u2009±u20095 and 92u2009±u20092%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules.

Falsely elevated vancomycin plasma concentrations sampled from central venous implantable catheters (portacaths).

Vancomycin is a glycopeptide antibiotic used to treat infections caused by gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The monitoring of steady-state vancomycin plasma concentrations is recommended to reduce the risk of ototoxicity and nephrotoxicity and to ensure that target therapeutic plasma concentrations are achieved [1–3]. Most current recommendations suggest that vancomycin doses should be adjusted to achieve trough plasma concentrations from 5–20 mg l−1, depending on the severity of the infection and the pathogen being treated [1, 3]. Clinicians therefore rely on accurate plasma concentrations to aid dose adjustments and to ensure optimal patient care. n nWe present two cases of spurious vancomycin plasma concentrations drawn from central venous implantable catheters (portacaths). Whereas a previous report described spurious vancomycin plasma concentrations drawn from a central catheter [4], this problem does not appear to have been described for vancomycin sampled from portacaths.

Between-subject variability: should high be the new normal?

The pharmacokinetics of numerous drugs are said to be predictable [1–5]. This is often seen as an advantage and implies the ease of dosing or dose adjustments of these drugs. However, predictability requires both accuracy and precision. In the context of pharmacokinetics, precision refers to the ability to achieve a specified target concentration in different individuals. Precision is the inverse of between-subject variance (BSV), i.e. the greater the BSV, the less precise/predictable a parameter is across a patient population. BSV in pharmacokinetic (PK) parameters is usually quantified by the coefficient of variation (CV%). The current conventionis that BSVin PK parameters is considered “low” (CV%≤10 %), “moderate” (CV%∼25 %), or “high” (CV%>40 %) [6]. We contend that the average CV% in PK parameters in the population is normally high. In other words, we hypothesise that a CV% of 40 % is actually normal and a CV%≤10 % is abnormally low. A literature review of population PK studies from various data sources was conducted. We reviewed the range of BSV values of PK parameters reported for patient populations of preselected drug classes. Drug classes studied included psychotropics, immunosuppressants, cardiovascular drugs, and antibiotics. Estimates of clearance (CL), volume of distribution (V), absorption rate constant (ka), and their corresponding CV% were recorded. PK studies in healthy volunteers were excluded from the review. A total of 182 studies involving 95 drugs were found (see “Appendix”). For the purpose of illustration, we report on the values of CL and Vonly. We extracted BSV values from the final PK models that accounted for covariates and report here as CV%. The meanCV% in CL was 40.3±24% and in V was 51.3±40.4%. ThemeanCV% in CL in predominately renally cleared drugs was 31 %a nd in those predominately hepatically cleared drugs was 47.4 %. For the nonintravenously administered drugs, the BSV refers to the between-subject variability in apparent oral clearance. Additionally, drugs with low bioavailability ( 50 %. Clinically, this meansthatanormallevel ofvariability in CL would resultina 4- to 5-fold variability in steady state average plasma concentrations and, therefore, for all drugs with a low therapeutic index, monitoring of plasma concentration or response and dose-individualisation will be essential. We have shown that a CV% in PK parameters of ∼40 % should be considered normal. This is not intended to be alarming, rather a reflection of the actual variability inherent in patient populations. Using the loaded term “predictability” in describing the PK of a drug is not helpful, and instead the BSV in PK parameters of the drug needs to be stated.

The influence of dosing time, variable compliance and circadian low-density lipoprotein production on the effect of simvastatin: simulations from a pharmacokinetic-pharmacodynamic model.

The aim of this study was to explore the influence of simvastatin dosing time, variable compliance and circadian cholesterol production on the reduction of low-density lipoprotein (LDL). A published pharmacokinetic-pharmacodynamic (PKPD) model for simvastatin was identified and evaluated. A model for circadian LDL production was incorporated into the PKPD model. Reduction in LDL from baseline was simulated stochastically from the full model at dose levels of 10, 20, 40 and 80 mg daily for 30 days. Simulated dosing times for each data set were morning (8.00 a.m.), evening (22.00 p.m.), evening with reduced compliance and evening for a hypothetical bioequivalent generic. Differences in LDL reduction from baseline between evening (33-43%) and morning dosing (31-43%) were negligible across a range of doses. Any differences were negated when variable compliance was considered. In addition, differences in simvastatin effect between morning and evening dosing were found to be within the range of LDL concentrations that would be permissible for a bioequivalent generic (at the lower limit) and hence are not likely to be important clinically. The results of this study suggest that taking simvastatin in the evening is not superior to morning dosing.