Current Drug Delivery, Volume 1, No. 3, 2004
Polymer Based Drug Delivery Systems for
Mycobacterial Infections Pp. 195-201
Rajesh
Pandey and G.K. Khuller
Relevance of Multidrug Resistance Proteins on
the Clinical Efficacy of Cancer Therapy Pp. 203-212
V.
Merino, N.V. Jimenez-Torres and M. Merino-Sanjuan
Solvation of Drugs as a Key for Understanding Partitioning and Passive Transport Exemplified by NSAIDs Pp. 213-226
German
L. Perlovich and Annette Bauer-Brandl
Synthesis of Chitosan Microspheres Containing
Pendant Cyclodextrin Moieties and their Interaction with Biological Active
Molecules Pp. 227-233
Mocanu
Georgeta, About-Jaudet Elie, LeCerf Didier, Picton Luc, Carpov Adrian and
Muller Guy
Targeting Intracellular Targets Pp. 235-247
Jayanth
Panyam and Vinod Labhasetwar
Chronotherapeutic Approach to Design A
Thermoresponsive Membrane for Transdermal Drug Delivery Pp. 249-263
Shan-Yang
Lin
Controlled Release of Protein from
Hydrocolloid Gel Microbeads Before and After Drying Pp. 265-273
R.
Mukai-Correa, A.S. Prata, I.D. Alvim and C.R.F. Grosso
A Review on the Molecular Mechanisms Involved
in the Placental Barrier for Drugs Pp. 275-289
Jose
J.G. Marin, Oscar Briz1 and Maria A. Serrano
Drug Delivery to Captive Asian Elephants –
Treating Goliath Pp. 291-298
Ramiro
Isazaa, and Robert P. Hunterb
Drug Delivery Systems Using Immobilized Intact
Liposomes: A Comparative and Critical Review Pp. 299-312
Heidi
Brochu, Ange Polidori, Bernard Pucci and Patrick Vermette
[Back to top] Polymer Based Drug Delivery Systems for
Mycobacterial Infections
Rajesh Pandey and G.K. Khuller
In the last decade, polymer based technologies have found
wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide
or PLG) or natural (e.g. alginate, chitosan etc.), have the property of
encapsulating a diverse range of molecules of biological interest and bear
distinct therapeutic advantages such as controlled release of drugs, protection
against the premature degradation of drugs and reduction in drug toxicity.
These are important considerations in the long-duration treatment of chronic
infectious diseases such as tuberculosis in which patient non-compliance is the
major obstacle to successful chemotherapy. Antitubercular drugs, singly or in
combination, have been encapsulated in polymers to provide controlled drug
release and the system also offers the flexibility of selecting various routes
of administration such as oral, subcutaneous and aerosol. The present review
highlights the approaches towards the preparation of polymeric antitubercular
drug delivery systems, emphasizing how the route of administration may
influence drug bioavailability as well as the chemotherapeutic efficacy. In
addition, the pros and cons of the various delivery systems are also discussed.
[Back to top] Relevance of Multidrug Resistance Proteins on
the Clinical Efficacy of Cancer Therapy
V.
Merino, N.V. Jimenez-Torres and M. Merino-Sanjuan
Variations in drug uptake and efflux, as well as changes in intracellular drug entrapment and distribution may represent important resistance mechanisms to cancer therapy. A variety of ATP binding cassette transporters (ABC) localised in multiple cell membranes is implied in those phenomena, representing a mechanism of protection of cells against xenobiotics. Many cancer cell lines over express some ABC transporters, especially p-glycoprotein, MRP1 and BCRP. This over expression is related to worse cancer treatment outcome and, in some cases, reduced overall survival of cancer patients. This paper reviews the location and physiological role of the three transporters mentioned and also describes the drugs that are substrates of these proteins. The usefulness of animal and cellular models to evaluate the role of these transporters on the uptake and efflux of anticancer drugs is discussed. Finally, the results of preclinical and clinical studies about the utility of some inhibitors of these pumps, as well as the implications of polymorphism of ABC transporters on the efficacy and safety of anticancer therapeutics are reported.
[Back to top] Solvation of Drugs as a Key for Understanding
Partitioning and Passive Transport Exemplified by NSAIDs
German
L. Perlovich and Annette Bauer-Brandl
Passive transport properties of drug molecules are of
utmost importance for their pharmacological and biopharmaceutical
effectiveness. Diffusion in different media and through lipid bilayers is in
many cases the rate-determining step for the distribution in the body. In the
present review an attempt is made to demonstrate the importance of solvation of
drug molecules for the diffusion and partition/distribution in phases of
different lipophilicity. Different approaches known in the literature to
describe solvation of compounds with flexible conformation are discussed as
well as the experimental methods to directly measure the energy of solvation.
NSAIDs are chosen as an example of a class of drugs of different molecular
structures that have already been studied thoroughly in many aspects, and a set
of aliphatic alcohols can be used as a model for compartments of different
lipophilic/hydrophilic properties. Thermodynamic characteristics of solvation
of the drug molecules yielded by independent classical experimental methods
(Gibbs energy, enthalpic and entropic terms of Gibbs energy) are studied in
order to better understand diffusion and distribution properties. Correlations
between in-vitro-data (partition
coefficient, enthalpy of solvation) with biopharmaceutically relevant
characteristics (plasma half-life) are also discussed.
[Back to top] Synthesis of Chitosan Microspheres
Containing Pendant Cyclodextrin Moieties and their Interaction with Biological
Active Molecules
Mocanu
Georgeta, About-Jaudet Elie, LeCerf Didier, Picton Luc, Carpov Adrian and
Muller Guy
A new route to obtain chitosan derivatives containing
cyclodextrin moieties as pendant groups was developed. The chitosan
microspheres, obtained through crosslinking with glutaraldehyde of an acetic
acid solution of chitosan, in an organic suspension medium, were reacted with
chloroacyl cyclodextrins in organic basic solvents. The acyl cyclodextrin moieties
are linked to the chitosan microspheres through C-N bonds, with the elimination
of HCl; higher amounts of acyl cyclodextrin are linked to the microspheres with
a smaller crosslinking degree. The chitosan-cyclodextrin conjugates retain
higher amounts of bioactive substances (nalidixic acid, piroxicam) or of
p-nitrophenol (model substance) than their parent chitosan supports, both by
ionic forces and by the formation of inclusion complexes in the cyclodextrin
inner cavities. After these preliminary studies, one can appreciate that the
cyclodextrin-chitosan conjugates could be used as supports for chromatographic
separations or controlled release drug systems.
[Back to top] Targeting Intracellular Targets
Jayanth
Panyam and Vinod Labhasetwar
Many therapeutic agents have intracellular compartments as their site of action. Targeted delivery of these agents to their specific intracellular targets could result in enhanced therapeutic efficacy and reduced toxicity. Various carriers have been shown useful in targeted delivery of different classes of therapeutic agents. Among these carriers, biodegradable nanoparticles formulated from biocompatible polymers poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) have shown the potential for sustained intracellular delivery of different therapeutic agents. In this review, we discuss different intracellular targets, barriers to intracellular delivery, mechanism and pathways of intracellular delivery, and various carriers and approaches that have been investigated for intracellular drug delivery.
[Back to top] Chronotherapeutic Approach to Design A
Thermoresponsive Membrane for Transdermal Drug Delivery
Shan-Yang
Lin
In this review, the concepts of chronobiology, circadian
rhythm, chronopharmacology, homeostasis and chronotherapy are taken into
account to approach the optimal drug therapy, in which the timing of drug
administration plays an important role. Based on these considerations, our
laboratory has developed a thermo-responsive membrane by entrapping a single or
binary liquid crystal to achieve an on-off switching drug delivery for
transdermal application via the externally repeated cycle of temperature
change, which may simulate the dosing time of therapeutic needs for human body.
[Back to top] Controlled Release of Protein from
Hydrocolloid Gel Microbeads Before and After Drying
R.
Mukai-Correa, A.S. Prata, I.D. Alvim and C.R.F. Grosso
Casein entrapped within gel microbeads using alginate,
amidated LM pectin, gellan gum and a system containing a mixture of these
polysaccharides (pectin:gellan:alginate, 1/3: 1/3: 1/3), were obtained by ionic
gelation in a high-pressure capillary apparatus. Hydrogenated vegetable fat was
also added to produce the gel microbeads and protein release in all the systems
was measured, including from freeze-dried capsules containing protein and fat.
Encapsulation efficiency, capsule size and morphology were evaluated as well as
the protein release profile. Encapsulation efficiencies from 83.7 to 90.7% were
obtained for the protein capsules and from 71.8 to 95.4% for those containing
protein and fat. Greater release was observed from gel microbeads without fat
where alginate presented the greatest diffusion (100%) and the system with a
mixture of polyssacharides, the best barrier, with protein retention of 90%
after 240 min in solution. The fat containing gel microbeads presented good
percent retentions and both the gel microbeads and the dry microbeads showed
similar percentages for release. The majority of the systems studied showed a
burst effect on release. Gel microbeads size distribution was similar, both
with and without fat, and independent of the matrix material, the mean size
being 150mm.
The morphological observations showed that the gel microbeads were spheroidal
with a homogenous distribution of fat droplets in the microcapsules.
Agglomeration occurred on drying but many particles maintained a partially spheroidal
form, with a configuration of solid material.
[Back to top] A Review on the Molecular Mechanisms Involved
in the Placental Barrier for Drugs
Jose
J.G. Marin, Oscar Briz1 and Maria A. Serrano
The placenta has traditionally been considered as a highly
permeable organ for a large variety of substances with diverse molecular
structures that are readily able to cross it from the maternal blood to reach
the foetus. This has recommended limiting the use of drugs during pregnancy as
far as possible. However, our present knowledge points to the existence of
different systems, including plasma membrane carriers, biotransforming enzymes,
and export pumps, that determine the selectivity and efficacy of the so-called
placental barrier. A good understanding of the molecular bases of these
processes and their regulation is crucial: i) to predict interactions between
drug-drug, drug-endogenous substances and drug-food components, ii) to analyse
the relevance of polymorphisms in the inter-individual variability of conceptus sensitivity to drugs, and iii)
to develop novel pharmacological strategies aimed at delivering medicinal drugs
to pregnant women, simultaneously minimising the risk of foetal exposure to
active agents, and to specifically target drugs to the placenta and/or foetus.
The present review does not attempt to offer a complete list of the available
medicinal compounds and their ability to cross the placenta but instead to
provide the reader with an up-to-date overview of the mechanisms involved in
carrying out or preventing the transfer of active drugs across the placenta.
[Back to top] Drug Delivery to Captive Asian Elephants –
Treating Goliath
Ramiro
Isazaa, and Robert P. Hunterb
Captive Asian elephants have been maintained in captivity by humans for over 4000 years. Despite this association, there is little published literature on the treatment of elephant diseases or methods of drug administration to these animals. Elephants in captivity are generally healthy and require few therapeutic interventions over the course of their lifetime. However, when they become acutely ill, treatment becomes a serious issue. The successful and consistent administration of therapeutics to elephants is formidable in an animal that presents significant limitations in drug delivery options. The single most important factor in administering drugs to an elephant is the animal’s cooperation in accepting the medication. Working around elephants can be very dangerous and this is magnified when working around sick or injured animals where the elephant is subject to increased stress, pain, and unusual situations associated with treatment. The large body size of the Asian elephant produces a separate set of issues. In this paper, methods of drug administration and their associated limitations will be reviewed. Considerations of medicating such large animals can serve to highlight the problems and principles of treatment that are inherent in these species.
[Back to top] Drug Delivery Systems Using Immobilized Intact Liposomes: A Comparative
and Critical Review
Liposomes sustain considerable interest to develop ways to fabricate drug delivery systems that would provide a good release without inducing any systemic reactions into the host. However, in many cases, liposomes injected into the blood stream are rapidly cleared from the system and only a fraction reaches the target site even when poly(ethylene glycol) (PEG)-coated liposomes are used. Composite drug delivery systems with liposomes i.e., liposomes linked to other substrates can be good candidates for certain type of drug release to achieve a localised treatment.
This paper reviews the fundamental phenomena of the
interactions between liposomes and solid substrates. Then, we address various
techniques that have been used to immobilize intact liposomes onto and into
different substrates. Finally, properties of liposomes used as drug delivery
systems are briefly reviewed.