Jan Steenekamp

Controlled Release of Dexamethasone from Microcapsules Produced by Polyelectrolyte Layer-by-Layer Nanoassembly

Purpose.In an effort to expand the application of core-shell structures fabricated by electrostatic layer-by-layer (LbL) self-assembling for drug delivery, this study reports the controlled release of dexamethasone from microcrystals encapsulated with a polyelectrolyte shell.Methods.The LbL self-assembly process was used to produce dexamethasone particles encapsulated with up to five double layers formed by alternating the adsorption of positively charged poly(dimethyldiallyl ammonium chloride), negatively charged sodium poly(styrenesulfonate) and depending on the pH positively or negatively charged gelatin A or B onto the surface of the negatively charged dexamethasone particles. The nano-thin shells were characterized by quartz crystal microbalance measurements, microelectrophoresis, microcalorimetry, confocal microscopy, and scanning electron microscopy. In vitro release of dexamethasone from the microcapsules suspended in water or carboxymethylcellulose gels were measured using vertical Franz-type diffusion cells.Results.Sonication of a suspension of negatively charged dexamethasone microcrystals in a solution of PDDA not only reduced aggregation but also reduced the size of the sub-micrometer particles. Assembly of multiple polyelectrolyte layers around these monodispersed cores produced a polyelectrolyte multilayer shell around the drug microcrystals that allowed for controlled release depending on the composition and the number of layers.Conclusions.Direct surface modification of dexamethasone microcrystals via the LbL process produced monodispersed suspensions with diffusion-controlled sustained drug release via the polyelectrolyte multilayer shell.

Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux

Introduction: While complementary and alternative medicine markets prosper with an increasing number of consumers of herbal medicines, there is an associated likelihood for herb–drug interactions to occur. Modulation of the activity of metabolic enzymes and/or active transporters by chemical constituents of herbal medicines may influence the therapeutic outcomes of coadministered allopathic medicines due to changes in their pharmacokinetic profiles. Although valuable information on herb–drug interactions is obtained by in vitro studies, such as the mechanisms of interaction, clinical significance of interactions is ultimately demonstrated by in vivo data. Areas covered: The authors outline the mechanisms of herb–drug pharmacokinetic interactions briefly and discuss pharmacokinetic interactions between different therapeutic classes of Western drugs and herbal medicines. Furthermore, the authors also discuss herb–drug interactions from both in vitro and in vivo studies with specific focus on recent findings. Expert opinion: Basic and clinical researches have contributed to the comprehension of the underlying mechanisms involved as well as the practical implications of herb–drug interactions. This provides a foundation for development of guidelines to inform patients about herb–drug interactions that can affect their health.

Cross-Linked Cationic Polymer Microparticles: Effect of N-Trimethyl Chitosan Chloride on the Release and Permeation of Ibuprofen

Microparticles made by cross-linking hydrophilic polymers, such as chitosan, have been used to modify the release rate of a loaded drug. In this study a polymer with fixed positive charges, N-trimethyl chitosan chloride (TMC), was used in combination with chitosan to formulate microparticles to investigate its effects on drug release rate and transport across intestinal epithelial cells. The microparticles were prepared by cross-linking these cationic polymer(s) using sodium citrate as the ionic cross-linker. This process was done under homogenization and ultrasonication to control the size of the particles. The addition of TMC to the chitosan microparticles resulted in an increase in particle size of the microparticles and an increase in ibuprofen release rate as compared to the microparticles containing chitosan alone. Permeation of ibuprofen across Caco-2 cell monolayers, after administration of a suspension of the microparticles to the apical side, was not significantly different for the microparticles containing TMC as compared to those consisting of chitosan alone. It was concluded that release of TMC molecules from the microparticles was probably not sufficient to interact with the intestinal epithelial cells in order to change the permeation of the released drug.

Eudragit® L100/N-trimethylchitosan chloride microspheres for oral insulin delivery.

Effective oral delivery of protein and peptide drugs remains an active topic in scientific research. In this study, matrix type microspheres were prepared with Eudragit® L100 containing N-trimethylchitosan chloride to improve the permeation of insulin across the intestinal epithelium via the paracellular pathway. Insulin loaded microspheres were initially formulated in accordance with a factorial design (23) and manufactured by means of a single water-in-oil emulsification/evaporation method. Based on external and internal morphology two microsphere formulations were selected from the initial formulations for further investigation in terms of particle size, dissolution behaviour and in vitro insulin transport across excised rat intestinal tissue. The initial eight microsphere formulations exhibited drug loading capacities ranging from 27.9–52.4% with different shapes and internal structures. The two selected microsphere formulations had average particle sizes of 157.3 ± 31.74 µm and 135.7 ± 41.05 µm, respectively, and mean dissolution time values for insulin release of 34.47 and 42.63 min, respectively. In vitro transport of insulin across excised rat intestinal tissue from the two selected microsphere formulations was 10.67–fold and 9.68–fold higher than the control group (insulin alone). The microsphere delivery system prepared from Eudragit® L100 containing N-trimethylchitosan chloride is therefore a promising candidate for effective oral insulin delivery.

Excipients with specialized functions for effective drug delivery

Introduction: There is a growing need for the development of pharmaceutical excipients that could improve product performance and overcome the shortcomings of new drug moieties, such as their poor solubility and membrane permeability, as well as to aid with modern manufacturing processes. Areas covered: Different types of functional excipients are discussed in this paper, in terms of their roles in modern dosage forms to optimize drug delivery and manufacturability. Functions of specialized excipients that are covered in this article include the enhancement of drug membrane permeability, the improvement of drug solubility and stability, the regulation of drug release in response to feedback mechanisms and assistance with the production of dosage forms. Expert opinion: Modern drug delivery systems rely on sophisticated excipients with multiple functions to improve overall product performance. The excipient market is expected to grow substantially with emerging trends in the development of these advanced drug delivery systems.

Novel Non-Invasive Protein and Peptide Drug Delivery Approaches

Protein and peptide based therapeutics are typically administered by injection due to their poor uptake when administered via enteral routes of drug administration. Unfortunately, chronic administration of these drugs through multiple injections presents certain patient related problems and it is difficult to mimic the normal physiological release patterns via this mode of drug administration. A need therefore exists to non-invasively deliver these drugs by means of alternative ways such as via the oral, pulmonary, nasal, transdermal and buccal administration routes. Although some attempts of needle free peptide and protein drug delivery have progressed to the clinical stage, relatively limited success has been achieved in terms of commercially available products. Despite the low frequency of clinical breakthroughs with noninvasive protein drug delivery this far, it remains an active research area with renewed interest not only due to its improved therapeutic potential, but also due to the attractive commercial outcomes it offers. It is the aim of this review article to reflect on the main strategies investigated to overcome the barriers against effective systemic protein drug delivery in different routes of drug administration. Approaches based on chemical modifications and pharmaceutical technologies are discussed with reference to examples of drugs and devices that have shown potential, while attempts that have failed are also briefly outlined.

Effect of moisture content, temperature and exposure time on the physical stability of chitosan powder and tablets

Abstract Context: Chitosan does not rank highly regarding its employment as tablet filler due to certain limitations. Undesirable properties that limit its utilization as excipient in solid dosage forms include its hydration propensity that negatively affects tablet stability, strength and disintegration. Objective: The objective of this study was to investigate the physical stability of chitosan powder, mixtures, granules and tablets under accelerated conditions such as elevated temperatures and humidity over different periods of time. Methods: Selected physico-chemical properties of pure chitosan powder, physical mixtures of chitosan with Kollidon® VA64 (BASF, Ludwigshafen, Germany), chitosan granules, as well as tablets were evaluated under conditions of elevated humidity and temperature. Results and discussion: The physical stability of chitosan tablets exhibited sensitivity towards varying exposure conditions. It was furthermore evident that the presence of moisture (sorbed water) had a marked influence on the physical stability of chitosan powder and tablets. It was evident that the presence of Kollidon® VA64 as well as the method of inclusion of this binder influenced the properties of chitosan tablets. The physical stability of chitosan powder deteriorated to a greater extent compared to that of the chitosan tablets, which were subjected to the same conditions. Conclusion: It is recommended that tablets containing chitosan should be stored at a temperature not exceeding 25 °C as well as at a relatively low humidity (<60%) to prevent deterioration of physical properties. Direct compression of chitosan granules which contained 5%w/w Kollidon® VA64 produced the best formulation in terms of physical stability at the different conditions.

More good news about polymeric plant- and algae-derived biomaterials in drug delivery systems

Natural polymers are continuously investigated for use in pharmaceutical and tissue engineering applications due to the renewability of their supply. Besides the conventional use of natural materials in dosage form design such as fillers, they are progressively investigated as functional excipients in specialised dosage forms. The hydrophilic nature of natural polymers together with their non-toxic and biodegradable properties make them useful in the design of modified release dosage forms. Matrix type tablets and beads made from natural gums and mucilages often exhibit sustained drug release through erosion in combination with swelling. Natural polymers are used to reach different pharmaceutical objectives, for instance, inulin and pectin are plant derived polymers that have suitable properties to produce colon-specific drug delivery. Alginate is an example of a natural polymer that has been used in the formulation of gastro-retentive dosage forms. Different cellulose derived polymers have been investigated as coating materials for dosage forms. Natural polymers can be chemically modified to produce molecules with specific properties and formation of co-polymers or polymer mixtures provide new opportunities to develop innovative drug delivery systems.

Cross-linked chitosan matrix-based multiple-unit drug delivery systems

Matrix-based multiple-unit drug delivery systems were manufactured by the compression of conventional and cross-linked chitosan into mini-matrices, which were then loaded into hard gelatin capsules. Three different types of mini-matrices were manufactured by direct compression of chitosan powder (not cross-linked), cross-linked chitosan microparticles or cross-linked chitosan granules and were characterized in terms of their physical properties such as hardness, friability, dimensions as well as their swelling and dissolution characteristics. The mini-matrices were film coated with Eudragit polymers (i.e. Eudragit L100, S100 and L100-55) to allow for drug release to start at different pH values. Several combinations of the coated mini-matrices were loaded into hard gelatin capsules to provide for rapid release as well as for delayed-onset sustained release from each multiple-unit drug delivery system. Release kinetics of the matrices consisting of cross-linked chitosan microparticles are presented as well as the in vitro release profiles of the multiple-unit drug delivery systems.

In vitro oral drug permeation models: the importance of taking physiological and physico-chemical factors into consideration

ABSTRACT Introduction: The assessment of intestinal membrane permeability properties of new chemical entities is a crucial step in the drug discovery and development process and a variety of in vitro models, methods and techniques are available to estimate the extent of oral drug absorption in humans. However, variations in certain physiological and physico-chemical factors are often not reflected in the results and the complex dynamic interplay between these factors is sometimes oversimplified with in vitro models. Areas covered: In vitro models to evaluate drug pharmacokinetics are briefly outlined, while both physiological and physico-chemical factors that may have an influence on these techniques are critically reviewed. The shortcomings identified for some of the in vitro techniques are discussed in conjunction with novel ways to improve and thereby overcome some challenges. Expert opinion: Although conventional in vitro methods and theories are used as basic guidelines to predict drug absorption, critical evaluations have identified some shortcomings. Advancements in technology have made it possible to investigate and understand the role of physiological and physico-chemical factors in drug delivery more clearly, which can be used to improve and refine the techniques to more closely mimic the in vivo environment.