Optimizing N,N,N-trimethyl chitosan synthesis: A design of experiments (DoE) approach.

This study aimed to optimize the synthesis of trimethyl chitosan (TMC) with a high degree of N,N,N-trimethylation (DTM) through a one-step procedure, minimizing reagent use, reaction time, and avoiding O-methylation, using the Design of Experiments (DoE) approach. Initially, sequential designs were done. Following the determination of the initial conditions a Fractional Factorial Design was used, investigating methyl iodide (MeI) and NaHCO3 molar ratios, temperature, and reaction time on DTM. MeI and NaHCO3 molar ratios were found to be significant (p-values equal to 0.02 and 0.02, respectively), the reaction temperature (p = 0.04) displayed a non-linear effect, while the reaction time was found to be non-significant (p = 0.93). Finally, a Full Factorial Design was done to optimize temperature and base addition methods. Incremental addition of the base was determined to be feasible without affecting the DTM, thereby preventing any viscosity-related problems. DTM was achieved up to 72 % in a one-step procedure, with no O-methylation. These optimized conditions offer a cost-effective, one-step synthesis method for TMC production, holding significant promise for industrial applications by avoiding multistep reactions, ensuring minimal reagent use, and preventing O-methylation. The findings mark a substantial advancement in TMC synthesis, presenting a streamlined and efficient approach with substantial practical implications for process development.

Incompatibility of antimalarial drugs: challenges in formulating combination products for malaria.

Lipophilic drugs require more advance formulation, especially if the intention is to make solutions or semisolid formulations. This also accounts for most antimalarial drugs. Although some of these antimalarial drugs are soluble in lipid vehicles, few of them, such as lumefantrine (LF), are also poorly soluble in oily vehicles. Trying to dissolve and formulate LF as a liquid formulation together with other antimalarial drugs is, therefore, a major task. When mixed in solution together with artemether (AR), precipitation occurs, sometimes with LF precipitating out on its own, and sometimes with AR precipitating out alongside LF. In this study, it was hypothesized that the use of fatty acids could lead to enhanced solubility in lipid formulation. Addition of the fatty acid solved the dissolution challenges, making LF soluble for over a year at room temperature (21-23 °C); but further research is needed to test the mechanism of action of the fatty acid. In addition, design of experiments (MODDE® 13) revealed that the amount of fatty acid in the formulation was the only significant factor for LF precipitation.

Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach.

Most of the individuals who die of malaria in sub-Saharan Africa are children. It is, therefore, important for this age group to have access to the right treatment and correct dose. Artemether-lumefantrine is one of the fixed dose combination therapies that was approved by the World Health Organization to treat malaria. However, the current recommended dose has been reported to cause underexposure or overexposure in some children. The aim of this article was, therefore, to estimate the doses that can mimic adult exposure. The availability of more and reliable pharmacokinetic data is essential to accurately estimate appropriate dosage regimens. The doses in this study were estimated using the physiological information from children and some pharmacokinetic data from adults due to the lack of pediatric pharmacokinetic data in the literature. Depending on the approach that was used to calculate the dose, the results showed that some children were underexposed, and others were overexposed. This can lead to treatment failure, toxicity, and even death. Therefore, when designing a dosage regimen, it is important to know and include the distinctions in physiology at various phases of development that influence the pharmacokinetics of various drugs in order to estimate the dose in young children. The physiology at each time point during the growth of a child may influence how the drug is absorbed, gets distributed, metabolized, and eliminated. From the results, there is a very clear need to conduct a clinical study to further verify if the suggested (i.e., 0.34 mg/kg for artemether and 6 mg/kg for lumefantrine) doses could be clinically efficacious.

Transdermal Drug Delivery of Tazarotene: Determining Tazarotene's Potential in Local Transdermal Therapy.

Retinoid-based drugs, while effective, are associated with systemic toxicity. Topical alternatives offer a safer option, and tazarotene, a third-generation synthetic retinoid, holds promise. This study investigates tazarotene's transdermal delivery potential, focusing on its application for joint-related conditions. The aim of this study was to investigate the suitability of tazarotene as a candidate for transdermal delivery into joints. In vitro permeation studies, using porcine skin, assessed tazarotene's transdermal drug delivery from solution and gel formulations. A tape-stripping analysis determined stratum corneum retention and a pilot study using porcine joints assessed tazarotene's ability to reach articular cartilage. Ultra Performance Liquid Chromatography coupled with a mass detector method was used to quantify tazarotene and tazarotenic acid permeation. The results validate that tazarotene can permeate porcine skin and accumulate in articular cartilage in detectable amounts. The detection of tazarotene and tazarotenic acid in both the in vitro permeation studies and the pilot study on porcine joints validate the drug's potential therapeutic use for hand osteoarthritis. This study lays the groundwork for future research, contributing insights into tazarotene's potential for transdermal drug delivery and guiding further exploration in topical retinoid applications.

Transdermal Drug Delivery: Determining Permeation Parameters Using Tape Stripping and Numerical Modeling.

The function of transdermal drug delivery (TDD) systems is complex due to the multiple layers necessary for controlling the rate of drug release and the interaction with the patient's skin. In this work, we study a particular aspect of a TDD system, that is, the parameters that describe the drug permeation through the skin layers. Studies of the diffusion of two compounds were carried out and supported by tape stripping and numerical modeling. The experimental studies are carried out for porcine skin in a Franz diffusion cell and tape stripping is used to quantify the concentration of drug in the stratum corneum. A multi-layered numerical model, based on Fickian diffusion, is used to determine the unknown parameters that define the skin's permeability, such as the partition between layers and the mass transfer coefficients due to the surface barrier. A significant correlation was found between the numerical modeling and experimental results, indicating that the partition and mass transfer effects at the interlayer boundary are accurately represented in the numerical model. We find that numerical modeling is essential to fully describe the diffusion characteristics.

A numerical framework for drug transport in a multi-layer system with discontinuous interlayer condition.

Discontinuous boundary conditions arise naturally when describing various physical phenomena and numerically modelling such conditions can prove difficult. In the field of pharmaceutical sciences, two such cases are the partitioning of a compound between different materials and a flux rate membrane controlling mass transfer between materials which both result in a discontinuous jump in concentration across adjacent materials. In this study, we introduce a general one-dimensional finite element drug delivery framework, which along with diffusion, reversible binding and dissolution within material layers, incorporates the partitioning and mass transfer conditions between layers of material. We apply the framework to construct models of experiments, which along with experimental data, allow us to infer pharmacokinetic properties of potential material for drug delivery. Understanding such material properties is the key to optimising the therepeutic effect of a targeted drug delivery system.

Experimental design for determining quantitative structure activity relationship for antibacterial chitosan derivatives.

Experimental design approach was successfully used to guide the synthesis and determine the structure-activity relationship for antimicrobial derivatives of the biopolymer chitosan. Specialized software with D-optimal design capabilities was used to create a library of chitosan derivatives with optimal structural variation in order to conduct a detailed investigation of the structure-activity relationship. The derivatives contain three substituents: N,N,N-trimethylamine, N-acetyl and N-stearoyl at different degrees of substitution (DS) on the 2-amino group of chitosan. The design matrix consisted of 14 target materials that were synthesized in 'one-pot synthesis' using TBDMS-chitosan as the precursor to allow precise control of the DS. The antibacterial activity (MIC) towards the Gram positive bacteria Staphylococcus aureus and the Gram negative bacteria Escherichia coli, hemolytic activity (HC50) towards human red blood cells and solubility of the chitosan derivatives were used as the responses in the model. The response surface model was refined by removing the interaction terms to improve the statistical significance and predictive power of the model. The investigation showed that materials with DS for trimethylation in the range 0.45-0.65, acetylation in the range 0.08-0.33 and stearoylation in the range 0.22-0.29 were capable of showing high antimicrobial activity, high solubility and low hemolytic activity.

Numerical modelling of transdermal delivery from matrix systems: parametric study and experimental validation with silicone matrices.

A model is presented for transdermal drug delivery from single-layered silicone matrix systems. The work is based on our previous results that, in particular, extend the well-known Higuchi model. Recently, we have introduced a numerical transient model describing matrix systems where the drug dissolution can be non-instantaneous. Furthermore, our model can describe complex interactions within a multi-layered matrix and the matrix to skin boundary. The power of the modelling approach presented here is further illustrated by allowing the possibility of a donor solution. The model is validated by a comparison with experimental data, as well as validating the parameter values against each other, using various configurations with donor solution, silicone matrix and skin. Our results show that the model is a good approximation to real multi-layered delivery systems. The model offers the ability of comparing drug release for ibuprofen and diclofenac, which cannot be analysed by the Higuchi model because the dissolution in the latter case turns out to be limited. The experiments and numerical model outlined in this study could also be adjusted to more general formulations, which enhances the utility of the numerical model as a design tool for the development of drug-loaded matrices for trans-membrane and transdermal delivery.

Numerical modelling and experimental investigation of drug release from layered silicone matrix systems.

Medical devices and polymeric matrix systems that release drugs or other bioactive compounds are of interest for a variety of applications. The release of the drug can be dependent on a number of factors such as the solubility, diffusivity, dissolution rate and distribution of the solid drug in the matrix. Achieving the goal of an optimal release profile can be challenging when relying solely on traditional experimental work. Accurate modelling complementing experimentation is therefore desirable. Numerical modelling is increasingly becoming an integral part of research and development due to the significant advances in computer simulation technology. This work focuses on numerical modelling and investigation of multi-layered silicone matrix systems. A numerical model that can be used to model multi-layered systems was constructed and validated by comparison with experimental data. The model could account for the limited dissolution rate and effect of the drug distribution on the release profiles. Parametric study showed how different factors affect the characteristics of drug release. Multi-layered medical silicone matrices were prepared in special moulds, where the quantity of drug in each layer could be varied, and release was investigated with Franz-diffusion cell setup. Data for long-term release was fitted to the model and the full depletion of the system predicted. The numerical model constructed for this study, whose input parameters are the diffusion, effective dissolution rate and dimensional solubility coefficients, does not require any type of steady-state approximation. These results indicate that numerical model can be used as a design tool for development of controlled release systems such as drug-loaded medical devices.

Experimental design for optimizing drug release from silicone elastomer matrix and investigation of transdermal drug delivery.

Silicone elastomers are commonly used for medical devices and external prosthesis. Recently, there has been growing interest in silicone-based medical devices with enhanced function that release drugs from the elastomer matrix. In the current study, an experimental design approach was used to optimize the release properties of the model drug diclofenac from medical silicone elastomer matrix, including a combination of four permeation enhancers as additives and allowing for constraints in the properties of the material. The D-optimal design included six factors and five responses describing material properties and release of the drug. The first experimental object was screening, to investigate the main and interaction effects, based on 29 experiments. All excipients had a significant effect and were therefore included in the optimization, which also allowed the possible contribution of quadratic terms to the model and was based on 38 experiments. Screening and optimization of release and material properties resulted in the production of two optimized silicone membranes, which were tested for transdermal delivery. The results confirmed the validity of the model for the optimized membranes that were used for further testing for transdermal drug delivery through heat-separated human skin. The optimization resulted in an excipient/drug/silicone composition that resulted in a cured elastomer with good tensile strength and a 4- to 7-fold transdermal delivery increase relative to elastomer that did not contain excipients.