Michael P. Danckwerts

Tuberculosis chemotherapy: current drug delivery approaches

Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance.

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side-effects. Conventional ophthalmic drug delivery systems such as topical eye-drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood-ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood-ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate-modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review.

Implantable Controlled Release Drug Delivery Systems: A Review

AbstractOrigins of rate controlled implantable drug delivery dates back to 1964 when silicone implants were used to prolong a drug effect. Despite much activity in the years since 1964, the progress to a safe, effective and acceptable implant system(s) has been slow. The critical factors in implant research which need to be addressed include: erodibility, reproducibility, lack of irritation and carcinogenicity, lack of dose dumping, duration and pulses. While it is possible to surgically implant and remove drug-containing devices or polymeric matrices, the requirement for such intervention could have a significant negative impact on the acceptability of a product candidate. In recent years, two implant systems have been approved for human use; (a) a silicone-based device (NorplantR), and (b) a system based on lactide/glycolide copolymers to release a luteinizing hormone - releasing hormone (LHRH) agonist for treatment of male reproductive tract tumours. This approach to drug delivery is very appealing for...

Design, biometric simulation and optimization of a nano-enabled scaffold device for enhanced delivery of dopamine to the brain.

This study focused on the design, biometric simulation and optimization of an intracranial nano-enabled scaffold device (NESD) for the site-specific delivery of dopamine (DA) as a strategy to minimize the peripheral side-effects of conventional forms of Parkinsons disease therapy. The NESD was modulated through biometric simulation and computational prototyping to produce a binary crosslinked alginate scaffold embedding stable DA-loaded cellulose acetate phthalate (CAP) nanoparticles optimized in accordance with Box-Behnken statistical designs. The physicomechanical properties of the NESD were characterized and in vitro and in vivo release studies performed. Prototyping predicted a 3D NESD model with enhanced internal micro-architecture. SEM and TEM revealed spherical, uniform and non-aggregated DA-loaded nanoparticles with the presence of CAP (FTIR bands at 1070, 1242 and 2926 cm(-1)). An optimum nanoparticle size of 197 nm (PdI=0.03), a zeta potential of -34.00 mV and a DEE of 63% was obtained. The secondary crosslinker BaCl(2) imparted crystallinity resulting in significant thermal shifts between native CAP (T(g)=160-170 degrees C; T(m)=192 degrees C) and CAP nanoparticles (T(g)=260 degrees C; T(m)=268 degrees C). DA release displayed an initial lag phase of 24 h and peaked after 3 days, maintaining favorable CSF (10 microg/mL) versus systemic concentrations (1-2 microg/mL) over 30 days and above the inherent baseline concentration of DA (1 microg/mL) following implantation in the parenchyma of the frontal lobe of the Sprague-Dawley rat model. The strategy of coupling polymeric scaffold science and nanotechnology enhanced the site-specific delivery of DA from the NESD.

Development of a zero-order release oral compressed tablet with potential for commercial tabletting production

Abstract The release of caffeine and ibuprofen as model drugs from a unique core-in-cup oral drug delivery system has been examined to determine their time exponent ( t n ) vs release profiles. The core-in-cup drug delivery system consisted of cores of various concentrations of two grades of hydroxypropylmethylcellulose (HPMC). HPMC K4M and HPMC K15M were used as the polymers in the core matrix. The flat disc-shaped core was then compressed with a previously compressed cup-shape tablet consisting of inert and impermeable carnauba wax and ethylcellulose. These drug delivery systems released active drug at a zero-order rate for periods of time between 8 and 23 h. The release rate was then compared to core only systems. The ( t n ) exponents varied from 0.477 for the lowest core system to 0.997 for a 5% w/w HPMC K4M in ibuprofen core-in-cup system. Because the core, the cup, and the core-in-cup are compressed on an automated tabletting press, this drug delivery system can be easily scaled up to commercial production.

Novel Modulation of Drug Delivery Using Binary Zinc-Alginate-Pectinate Polyspheres for Zero-Order Kinetics Over Several Days: Experimental Design Strategy to Elucidate the Crosslinking Mechanism

A Box-Behnken design was applied to mathematically establish whether different degrees of crosslinking were induced by Zn2 + and Ca2 + ions in polyspheres composed of alginate and/or pectin, and the model drug ibuprofen. Based on their different crystal structures and coordination numbers, a theoretical model was proposed demonstrating that Zn2 + ions preferentially crosslink alginate and pectin. In addition, the lower coordination number of Zn2 + (4–6) would significantly retard hydration of both polymers, as opposed to Ca2 + (7–9). The responses studied for 28 statistically derived polyspheres included drug encapsulation efficiency, physicomechanical behavior, and in vitro drug release potential. Single-tailed Students t-tests on data generated for the encapsulation efficiencies, primary facture values, and rupture energies indicated that Zn2 + was statistically superior (p < 0.05) in crosslinking alginate and pectin. Further textural analysis revealed a good correlation between the Brinell hardness number and fracture load, while an inverse relationship was found for matrix tensile strength. Viscosity studies demonstrated different in situ crosslinking thresholds for Zn2 +. The Durbin-Watson statistic and correlation coefficient revealed that the quadratic regression function was highly accurate in predicting the responses. Using a generalized reduced gradient algorithm on dissolution values obtained after 2 hours (t2h) provided optimized solutions for achieving zero-order release extending from 2 hours to 7 days. Mathematical simulations projected drug release from 25 to 50 days.

Experimental design for the formulation and optimization of novel cross-linked oilispheres developed for in vitro site-specific release ofMentha piperita oil

A Plackett-Burman design was employed to develop and optimize a novel crosslinked calcium-aluminum-alginatepectinate oilisphere complex as a potential system for the in vitro site-specific release ofMentha piperita, an essential oil used for the treatment of irritable bowel syndrome. The physicochemical and textural properties (dependent variables) of this complex were found to be highly sensitive to changes in the concentration of the polymers (0%–1.5% wt/vol), crosslinkers (0%–4% wt/vol) and crosslinking reaction times (0.5–6 hours) (independent variables). Particle size analysis indicated both unimodal and bimodal populations with the highest frequency of 2 mm oilispheres. Oil encapsulation ranged from 6 to 35 mg/100 mg oilispheres. Gravimetric changes of the crosslinked matrix indicated significant ion sequestration and loss in an exponential manner, while matrix erosion followed Higuchis cube root law. Among the various measured responses, the total fracture energy was the most suitable optimization objective (R2 =0.88, Durbin-Watson Index=1.21%, Coefficient of Variation (CV)=33.21%). The Lagrangian technique produced no significant differences (P>.05) between the experimental and predicted total fracture energy values (0.0150 vs 0.0107 J). Artificial Neural Networks, as an alternative predictive tool of the total fracture energy, was highly accurate (final mean square error of optimal network epoch≈0.02). Fused-coated optimized oilispheres produced a 4-hour lag phase followed by zero-order kinetics (n>0.99), whereby analysis of release data indicated that diffusion (Fickian constantk1=0.74 vs relaxation constantk2=0.02) was the predominant release mechanism.

A Timely Review of State-of-the-Art Chronopharmaceuticals Synchronized with Biological Rhythms

Extensive research into circadian rhythms and their influence on biological systems has given rise to the science of chronobiology and subsequently chronotherapy, the science of delivering drugs in synchrony with biological rhythms. The field of chronotherapeutics paves the way for advances and complexities in current drug delivery technology. The ultimate goal of current chronopharmaceutical research strives to design ideal chronotherapeutic drug delivery systems that respond to such therapeutic needs. Considering the fact that physiological events such as heart rate, blood pressure, plasma concentration of hormones, plasma proteins and enzymes display constancy over time, drug delivery systems with constant release profiles have thus been favored. However, due to circadian rhythms, the conventional paradigm of constant drug delivery may not be what is needed. Instead, precisely timed drug delivery systems are required in order to correlate drug delivery with circadian rhythms to provide maximum therapeutic efficacy for chronotherapeutic diseases when most needed. The aim of this review paper is to outline the concepts in designing chronopharmaceuticals from a clinical viewpoint of major chronotherapeutic diseases such as asthma, allergic rhinitis, cardiovascular disorders, rheumatoid arthritis and cancer as well as relatively minor niche areas of interest such as in glaucoma, diabetes, immunity, pain, gastric ulcers, epilepsy and even HIV/AIDS that would require chronotherapy. In addition this review paper attempts to concisely assimilate and explicate the role of circadian rhythms in these various disease states and provide a focused overview of the current state-of-the-art in designing strategies for chronopharmaceutical formulations employed for treating chronotherapeutic diseases.

A Crosslinked Calcium-Alginate-Pectinate-Cellulose Acetophthalate Gelisphere System for Linear Drug Release

This study proposes a novel binary crosslinked ternary multiple-unit system, collectively referred to as calcium-alginate-pectinate-cellulose acetophthalate gelispheres (CAPCA), for the purpose of obtaining linear, controlled drug release. This polymeric system, composed of sodium alginate, pectin, and cellulose acetophthalate, was developed through a binary crosslinking reaction in a composite aqueous system consisting of calcium and acetate ions. The crosslinking reaction was optimized in terms of maximizing drug release suppression and could be obtained by exposing the gelispheres for 24 hours to a combined aqueous solution of 15% w/v acetic acid and 2% w/v calcium chloride. The highly acidic nature of this solution (pH 1.9) was desirable for enhancing the drug entrapment efficiency of the gelispheres. Synchronization of matrix swelling and erosion appeared to be responsible for the attainment of zero-order drug release. However, such perfect synchronization was only achievable through application of the ternary polymeric combination presented in this work. The main advantages of the ternary system shown in this study over the previously presented binary calcium-alginate-pectinate system (CAP) proposed by Pillay and Fassihi (1999a, 1999b), was provision of extended drug release over 18 hours, minimization of late-phase drug release tapering, and provision of superior linearity in drug release profiles. Kinetic modeling of dissolution data using various power law equations highlighted the significance of matrix relaxation and erosion in modulation of drug release rate. In all cases of model fitting excellent correlation (r 2 > 0.98) was obtained between observed and predicted data. Textural profiling of crosslinked gelispheres reflected a significantly lower reduction in matrix resilience as the concentration of cellulose acetophthalate was increased in the gelisphere formulation. This may be attributed to the concentration-dependent matrix plastic-transforming property of cellulose acetophthalate.

Intraoral drug delivery

The oral availability of many drugs is poor because of the pH of the stomach, the presence of enzymes, and extensive first-pass metabolism. Traditionally, these drugs have been administered as parenteral drug delivery systems, which invariably leads to poor patient compliance. This has made the pharmaceutical industry look for alternative routes of drug delivery.One possible route is via the oral cavity. This review compares the many different and novel drug delivery systems that have been developed for absorption through the oral cavity as well as those that undergo quick disintegration or dissolution in the oral cavity. Systems for oral delivery include mucoadhesive patches, films and tablets, as well as quick-disintegrating wafers, tablets and films. There are many examples of drugs that have been formulated into intraoral absorptive drug delivery systems as well as quick-disintegrating drug delivery systems.The fact that most of the research being conducted on intraoral drug delivery systems is driven by pharmaceutical manufacturers demonstrates the need for such drug delivery systems. As we begin to discover more about oral mucosal drug delivery, and develop much more sophisticated drug delivery systems, many more drugs will be formulated as intraoral systems. There is no doubt that the need for these systems is real, and many classes of drugs could benefit from this noninvasive type of drug delivery. The challenge now is to synthesize drug moieties that exhibit increased absorption across the oral mucosa and are more potent in their action. Intraoral drug delivery systems are possibly one of the very few drug delivery systems that seem to be ahead of the development of new drug compounds that are effectively absorbed across tissue membranes.