Current Drug Delivery, Volume 1, No. 4, 2004
In Vitro Evaluation of a Hydroxypropyl Cellulose Gel System for Transdermal Delivery of Timolol Pp.313-319
Pegylated Poly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible Applications in Drug Delivery Pp.321-333
Konstantinos Avgoustakis
HIV-1 Vpr: Enhancing Sensitivity of Tumors to Apoptosis Pp.335-344
Karuppiah Muthumani, Andrew Y. Choo, Daniel S. Hwang, Kenneth E. Ugen and David B. Weiner
Quinone Bioreductive Prodrugs as Delivery Agents Pp.345-350
Mohammed Jaffar, Nathalie Abou-Zeid, Li Bai, Ibrahim Mrema, Ian Robinson, Richard Tannerand Ian J. Stratford
Role of Cyclodextrins in Ophthalmics Pp.351-360
Indu Pal Kaur, Sonia Chhabra and Deepika Aggarwal
Drug Delivery Across the Blood-Brain Barrier Pp.361-376
Y. Chen, G. Dalwadi and H.A.E. Benson
Polymeric Radiotracers in Nuclear Imaging Pp.377-384
Xiaoxia Wen, Xianyi Cao, Marites J. Pasuelo, Richard Wendt and Chun Li
Mucosal Immunisation: Adjuvants and Delivery Systems Pp.385-396
P.M. Moyle, R.P. McGeary, J.T. Blanchfield and I. Toth
Skin Lipid Synthesis Inhibition: A Possible Means for Enhancing Percutaneous Delivery of Levodopa Pp.397-403
Kumar Babita and Ashok Kumar Tiwary
Dose Sparing of CpG Oligodeoxynucleotide
Vaccine Adjuvants by Nanoparticle Delivery Pp.405-412
Manish
Diwan, Praveen Elamanchili, Min Cao and John Samuel
[Back to top] In Vitro Evaluation of a Hydroxypropyl Cellulose Gel System for Transdermal Delivery of Timolol
D.F.
Stamatialis, H.H.M. Rolevink, M. Girones, D.C. Nymeijer and G.H. Koops
In this work, the development
of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system
is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the
permeability of TM from the gel through an artificial membrane (Polyfluxâ) and pig stratum corneum (SC) is studied.
For a constant TM
donor concentration, the TM transport across the Polyfluxâ membrane alone decreases when the
concentration of the gel increases due to increase of the gel viscosity. For
constant gel concentration, however, the TM permeation across the membrane
increases when the TM donor concentration increases. In addition, no effect of
the electrical current (iontophoresis, current density 0.5 mA cm-2)
on the TM permeation is found.
For the
combination of the Polyfluxâ membrane
with pig SC, the TM transport is much lower than for the membrane alone and the
SC fully controls the TM delivery. In this case, the application of electrical
current enhances the TM delivery 13-15 times in comparison to passive (no
current) transport. According to our estimation, the daily TM dose (10-60 mg)
can be delivered by an iontophoretic patch with Polyfluxâ membrane area of 6 - 36 cm2
containing 20 % (w/w) HPC gel and 15 mg cm-3 of TM.
[Back to top] Pegylated Poly(Lactide) and
Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation, Properties and Possible
Applications in Drug Delivery
Konstantinos
Avgoustakis
The preparation,
properties and potential applications in drug delivery of biocompatible and
biodegradable PLA-PEG and PLGA-PEG nanoparticles are discussed. PLA-PEG and PLGA-PEG nanoparticles have been produced by emulsification-solvent
evaporation, solvent displacement and salting out methods. The nanoparticles
can be stored as freeze-dried powders, but an adequate amount of a suitable
lyoprotectant should be added prior lyophilisation to prevent nanoparticle
aggregation and retain nanoparticle redispersibility. The nanoparticles have a
core-shell structure with a PLA core and a PEG coating. Their basic colloidal
properties and degradation depend on copolymer composition. The PLAPEG and PLGA-PEG nanoparticles exhibit prolonged blood circulation following
intravenous administration to animals. The composition of the nanoparticles
determine their biodistribution properties, probably through its effects on the
effectiveness of the PEG steric barrier and the size of the nanoparticles. The
ability of the PLA-PEG and PLGA-PEG nanoparticles to evade rapid phagocytocis
has extended the range of sites within the body that the nanoparticles can
reach, which has significant implications with regard to their application in
controlled drug delivery and targeting. The PLAPEG and PLGA-PEG nanoparticles
can be loaded with a variety of bioactive agents achieving satisfactory
loading, especially in the case of hydrophobic drugs. The nanoparticles have
been investigated for the treatment of infectious diseases and cancer, the
intravenous and mucosal delivery of proteins, and oligonucleotide and gene
delivery. The results have been encouraging and PLA-PEG and PLGA-PEG
nanoparticle formulations, improving the therapeutic potential of both
established and new drugs, may be expected to be available in the near future.
[Back to top] HIV-1 Vpr: Enhancing Sensitivity of Tumors to
Apoptosis
Karuppiah
Muthumani, Andrew Y. Choo, Daniel S. Hwang, Kenneth E. Ugen and David B. Weiner
Cancers can adapt
several evasive functions including apoptosis evasion, self-sufficiency in growth
signals, insensitivity to anti-growth signals, sustained angiogenesis,
limitless replication potential, tissue invasion and metastasis. The invariable
hurdle for development of therapies against such aberrant conditions requires
both selective and potent cytotoxicity. Analysis of HIV-1 Vpr’s apoptotic and
anti-proliferative activity have revealed potentially important implications
for cancer therapy. Accordingly, we have reviewed the properties of Vpr that
will likely contribute to its efficacious function as an anti-tumor agent.
Among these are its ability to induce cell cycle arrest, inhibit inflammation,
provoke p53 independent apoptosis, and selective killing of rapidly dividing
cells.
[Back to top] Quinone Bioreductive Prodrugs as Delivery
Agents
Mohammed
Jaffar, Nathalie Abou-Zeid, Li Bai, Ibrahim Mrema, Ian Robinson, Richard
Tannerand Ian J. Stratford
Quinone
bioreductive prodrugs were developed to target the hypoxic or the reductase-
rich population of solid tumours. The mechanism of their selective activation
is based on their ability to convert the quinone sub-structure to their
activated semiquinone or hydroquinone species affording the active species.
Recent studies on their biochemical activation process have resulted in their
development as delivery agents that can effectively release a potent (but not
necessarily a cytotoxic) agent under hypoxic/reductive conditions. This
technology platform is currently being used to design / identify, and
synthesise novel quinone bioreductive delivery agents to target cancer and
other diseses where hypoxia and/or reductive enzymes play a major
pathophysiological role.
[Back to top] Role of Cyclodextrins in Ophthalmics
Indu
Pal Kaur, Sonia Chhabra and Deepika Aggarwal
Cyclodextrins are
oligosaccharides having outer hydrophilic surface and central hydrophobic
cavity. These agents form inclusion complexes with poorly water-soluble drugs;
hence they show an important implication for use in ophthalmics because of
their applications in solubilising and stabilising the ocular drugs. Most of
the drugs being used in ophthalmics were not tailor-made for the eye and
considering the poor bioavailability of <1% from the corneal surface,
presentation of the drug in a soluble form and at high concentration is
important. Provision of a high drug concentration at the corneal surface
increases the percent drug permeation indicating the usefulness of
cyclodextrins as penetration enhancers. A decrease in irritation potential of
some drugs upon incorporation of cyclodextrins is also reported.
Polymercyclodextrin multicomponent systems further extend the role of
cyclodextrins in improving the solubility and bioavilability of ocular drugs.
Large hydrophilic cyclodextrins like hydroxypropyl-b-cyclodextrin and sulphobutylether-b-cyclodextrin are safe for the use in aqueous
eye drop solutions especially since they do not cross the lipophilic cornea.
Various aspects about
the applications of cyclodextrins in ophthalmics, the formulation
considerations and expected toxicity of cyclodextrins (especially if high
concentration is used) is discussed in this review. Strategies like use of
polymers to reduce the effective concentration of cyclodextrin required without
compromising solubility are also included. Further the concept of incorporating
the drug-cyclodextrin complexes into liposomes or niosomes for a better
targeting of the drug at appropriate tissue destination is discussed as a
possible future option.
[Back to top] Drug Delivery Across the Blood-Brain Barrier
Y.
Chen, G. Dalwadi and H.A.E. Benson
The brain is
protected and isolated from the general circulation by a highly efficient
blood-brain barrier. This is characterised by relatively impermeable
endothelial cells with tight junctions, enzymatic activity and active efflux
transport systems. Consequently the blood-brain barrier is designed to permit
selective transport of molecules that are essential for brain function. This
creates a considerable challenge for the treatment of central nervous system
diseases requiring therapeutic levels of drug to enter the brain. Some small
lipophilic drugs diffuse across the blood-brain barriersufficiently well to be
efficacious. However, many potentially useful drugs are excluded. This review
provides an insight into the current research into technologies to target small
molecules, peptides and proteins to the brain. A brief review of the nature of
the blood-brain barrier and its transport mechanisms is provided. Strategies to
target and improve transport across the blood-brain barrier include the
prodrug-lipidisation approach, sequential metabolism chemical delivery systems,
drug-vectors, liposomes and nanoparticles. Included is the discussion of
techniques to minimise clearance from the circulation by the
reticuloendothelial system in order to extend circulation residence time and
optimise the opportunity for interaction between the drug delivery system and
the blood-brain barrier.
[Back to top] Polymeric Radiotracers in Nuclear Imaging
Xiaoxia
Wen, Xianyi Cao, Marites J. Pasuelo, Richard Wendt and Chun Li
Water-soluble
polymers have been used in the last two decades to modify the pharmacokinetics
and physicochemical properties of targeted therapeutic agents. Non-invasive
imaging techniques such as nuclear imaging can be used to assess the drug
delivery efficiency of novel formulations in a cost-effective fashion and
thereby facilitate their development process. Polymeric radiopharmaceuticals
have also been investigated on their own right as potential nuclear imaging
agents. Clinical applications of polymeric radiopharmaceuticals include
blood-pool imaging and targeted molecular imaging. In the latter case,
water-soluble polymers are often used to modify the pharmacokinetics and
biodistribution pattern of ligands that target receptors or antigens at disease
sites. As advances are continue to be made in the emerging field of molecular
imaging, nuclear imaging will play an increasingly important role in the
development of polymeric drug delivery systems. Similarly, polymer technology
will also be integrated into the development of molecularly targeted
radiopharmaceuticals. Here, we review various aspects of polymeric radiotracers
and their applications in nuclear imaging.
[Back to top] Mucosal Immunisation: Adjuvants and Delivery
Systems
P.M.
Moyle, R.P. McGeary, J.T. Blanchfield and I. Toth
The mucosal
administration of vaccines is an area currently receiving a high level of
interest due to potential advantages offered by this technique. These
advantages include the ability to administer vaccines without need for needles,
thus improving patient compliance with vaccination schedules, and the capacity
to induce immune responses capable of preventing infections at the site of
acquisition. Despite these advantages a number of limitations exist which
currently inhibit our ability to successfully develop new mucosal vaccines. As
such, much research is currently focused on developing new adjuvants and
delivery systems to overcome these difficulties. However, despite high levels
of interest in this area, relatively few mucosal vaccine candidates have
successfully progressed to human clinical trials. In the review that follows,
we aim to provide the reader with an overview of the immune system with respect
to induction of mucosal immune responses. Furthermore, the review provides an
overview of a number of microbial (bacterial toxins, CpG DNA,
cytokines/chemokines, live vectors, and virus like particles) and synthetic
(microspheres, liposomes, and lipopeptides) strategies that have been
investigated as adjuvants or delivery systems for mucosal vaccine development,
with a focus on the delivery of vaccines via the oral route.
[Back to top] Skin Lipid Synthesis Inhibition: A Possible
Means for Enhancing Percutaneous Delivery of Levodopa
Kumar
Babita and Ashok Kumar Tiwary
Skin perturbation
with ethanol followed by application of b-chloroalanine
(b-CA) or atorvastatin (AVN) was employed for
delaying the recovery of sphingosine (a precursor of ceramide) and cholesterol,
respectively in epidermis of rats. Dose optimization studies revealed 600 mg of
b-CA and 750 µg of AVN significantly (p <
0.05) inhibited the synthesis of sphingosine and cholesterol, respectively and
prevented their replenishment to normal levels till 48 hr in viable rat skin.
Co-application of calcium chloride (0.1 mM) inhibited the synthesis of both
micro constituents of epidermis to a greater magnitude, whereas verapamil
reduced this effect. The in vitro permeation of levodopa across treated
skin portions was directly correlated with percentage of sphingosine and
cholesterol inhibited by the treatments. The in vitro permeation of
levodopa across skin excised after treatment with b-CA or AVN was enhanced 3-fold. Effective
plasma concentration (1.58 µg/ml) of levodopa in rats was achieved within 2 hr
and maintained till 12 hr after AVN treatment, and increased to 36 hr with the
co-application of calcium chloride. However, when the skin was treated with b-CA, Ceff was achieved after 4 hr
and was maintained till 36 hr. The inclusion of calcium chloride maintained Ceff
for 48 hr. Hence, synthesis inhibition of skin lipids seems to offer a feasible
means to enhance the systemic delivery of
polar drugs like levodopa.
[Back to top] Dose Sparing of CpG Oligodeoxynucleotide Vaccine Adjuvants by
Nanoparticle Delivery
Manish
Diwan, Praveen Elamanchili, Min Cao and John Samuel
The main objective
of these studies was to investigate whether the nanoparticle delivery has any immunopotentiation
effect at modest doses of a few micro- or nanograms of CpG oligodeoxynucleotide
(CpG ODN) and what would be the influence on T cell responses at such low
doses. Various doses (5 to 0.05 µg) of a model CpG ODN adjuvant (#1826) along
with 2 Lf tetanus toxoid (TT) were formulated in either nanoparticles using
poly(D,L-lactic-coglycolic acid) (PLGA) 50:50 co-polymer, or saline. Strong
antigen specific ex vivo T cell proliferation was observed for the
Balb/c mice receiving immunogens in nanoparticles. At 5 µg dose of CpG ODN, the
T cell stimulation index (SI) was 241 as compared with 74 for the same dose
when given in saline. Comparable SI value of 78 was observed at 100-fold lower
dose (0.05 µg) using nanoparticles. Similarly, significantly higher (P<0.01)
cytokine secretion was observed for nanoparticles groups. A ten-fold lower dose
(0.5 µg instead of 5 µg) of CpG ODN in nanoparticles was adequate to obtain
levels of IFN-g, TNF-a,
and IL-2 comparable to those observed following immunisations in saline. The
immunopotentiation effect of the particulate delivery on antibody response
(total IgG and subtypes) was not so marked. These studies emphasise that
antigen delivery in biodegradable nanoparticles can facilitate induction of
strong T cell responses, particularly of the Th1 type, at extremely lower doses
of CpG ODN. Such reduction in the effective dose would be advantageous for
minimising the potential side effects of these novel adjuvants.