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Current
Drug Delivery
ISSN: 1567-2018
Current Drug Delivery
Volume 5, Number 2, April 2008
Contents
Use of Microwave in Processing of Drug Delivery
Systems Pp. 77-84
T.W. Wong
[Abstract]
Stimuli-Responsive Molecularly Imprinted Polymers
for Drug Delivery: A Review Pp. 85-96
Francesco Puoci, Francesca Iemma and Nevio Picci
[Abstract]
Gelrite®
Microgels for Sustained Oral Drug Deliver Formulation
and Evaluation Pp. 97-101
R. Rastogi, M. Aqil, A. Ali and Y. Sultana
[Abstract]
Impregnation of an Intraocular Lens for Ophthalmic
Drug Delivery Pp. 102-107
Ana Rita C. Duarte, Ana Luisa Simplicio, Arlette Vega-González,
Pascale Subra-Paternault, Patrícia Coimbra, M.H. Gil,
Herminio C. de Sousa and Catarina M.M. Duarte
[Abstract]
Nasal Immunization Studies by Cationic, Fusogenic
and Cationic-Fusogenic Liposomes Encapsulated with Tetanus
Toxoid Pp. 108-113
M. Tafaghodi, M.R. Jaafari and S.A. Sajadi Tabassi
[Abstract]
Advanced Nebulizer Designs Employing Vibrating
Mesh/Aperture Plate Technologies for Aerosol Generation
Pp. 114-119
J.C. Waldrep and R. Dhand
[Abstract]
Novel Hydrophilic Drug Polymer Nano-Conjugates
of Cisplatin Showing Long Blood Retention Profile - Its Release
Kinetics, Cellular Uptake and Bio-Distribution Pp.
120-126
Anita K. Verma and K. Sachin
[Abstract]
Osmotically Regulated Flow of Flurbiprofen through
In Situ Formed Asymmetric Membrane Capsule
Pp. 127-132
Anil K. Philip
[Abstract]
Preparation and Evaluation of Buccal Bioadhesive
Tablets Containing Clotrimazole Pp. 133-141
S. Singh, S. Jain, M.S. Muthu and R.Tilak
[Abstract]
The Therapeutic Index of Locally Acting Inhaled
Drugs as a Function of their Fine Particle Mass and Particle
Size Distribution – A Literature Review Pp.
142-147
Marjolein Weda, Pieter Zanen, Anne H. de Boer, Dirk M.
Barends and Henderik W. Frijlink
[Abstract]
Transdermal Therapeutic System of Enalapril Maleate
Using Piperidine as Penetration Enhancer Pp. 148-152
M. Aqil, Bhavna, I. Chowdhary, Y. Sultana, S. Talegaonkar,
F.J. Ahmad and M.M. Ali
[Abstract]
Abstracts
[Back to top]
Use of Microwave in Processing of Drug Delivery Systems
T.W. Wong
Microwave has received a widespread application in pharmaceuticals
and food processing, microbial sterilization, biomedical therapy,
scientific and biomedical analysis, as well as, drug synthesis.
This paper reviews the basis of application of microwave to
prepare pharmaceutical dosage forms such as agglomerates,
gel beads, microspheres, nanomatrix, solid dispersion, tablets
and film coat. The microwave could induce drying, polymeric
crosslinkages as well as drug-polymer interaction, and modify
the structure of drug crystallites via its effects of heating
and/or electromagnetic field on the dosage forms. The use
of microwave opens a new approach to control the physicochemical
properties and drug delivery profiles of pharmaceutical dosage
forms without the need for excessive heat, lengthy process
or toxic reactants. Alternatively, the microwave can be utilized
to process excipients prior to their use in the formulation
of drug delivery systems. The intended release characteristics
of drugs in dosage forms can be met through modifying the
physicochemical properties of excipients using the microwave.
[Back to top]
Stimuli-Responsive Molecularly Imprinted Polymers for Drug
Delivery: A Review
Francesco Puoci, Francesca Iemma and Nevio Picci
Molecular imprinting is an efficient technique for introducing
regions with a highly specific molecular arrangement into
a polymeric matrix. The first example of a molecularly imprinted
polymer (MIP) was reported half a century ago; however, the
use of molecular imprinting has become a well established
practical tool only in the last decade. Recently, MIPs are
widely used, for example, in chromatographic applications
or enzyme antibody mimics.
MIPs have also been used in biological applications such as
drug delivery systems (DDS), and they have also been successfully
applied as excipients in controlled delivery systems. Their
huge potential could bring about intelligent drug release;
this refers to the release, in a predictable way, of therapeutic
agents in response to specific environmental stimuli (the
presence of another molecule, pH changes, temperature, etc.).
This review is focused on particular intelligent devices of
this type that exhibit selective recognition (traps for toxic
molecules) and release (of drugs in order to prolong the duration
of pharmacological action) in response to specific stimuli.
The “stimuli-responsive molecularly imprinted polymers”
reviewed in this paper are expected to contribute significantly
to the exploration and development of new generations of intelligent
and self-regulated drug delivery systems.
[Back to top]
Gelrite®
Microgels for Sustained Oral Drug Delivery-Formulation
and Evaluation
R. Rastogi, M. Aqil, A. Ali and Y. Sultana
Gelrite®
is an ion-activated polymer prepared by partial acetylation
of gellan gum, an exogeneous polysaccharide present in Pseudomonas
elodea. Its unique cation-dependent gelling property
at 33°C has been exploited for the formulation of in
situ gelling hydrogels for ophthalmic and oral drug delivery.
Gelrite®
based oral formulations are known to sustain the drug levels
at acidic pH due to the formation of 3D-lattice by cross-linking
of uronic acid groups with cations. An extrusion method for
formation of microspheres has been reported for Gelrite®.
The method cannot be successfully applied for encapsulation
of hydrophilic moieties and has thus been modified in the
present study. The microparticles prepared were optimized
for various encapsulation variables such as particle size,
shape, drug entrapment efficiency and in vitro drug
release. A maximum of 41.87 + 0.2 % drug loading was obtained
for the improved method. The drug release was found to be
sustained in acidic medium (50% in SGF pH 1.2) for a period
of 4 hours while burst release was observed in SIF pH 7.4.
The work thus, presents a simplified microencapsulation method
for hydrophilic drugs with higher entrapment efficiency for
Gelrite®,
taking rifampicin as the model drug.
[Back to top]
Impregnation of an Intraocular Lens for Ophthalmic Drug Delivery
Ana Rita C. Duarte, Ana Luisa Simplicio, Arlette Vega-González,
Pascale Subra-Paternault, Patrícia Coimbra, M.H. Gil,
Herminio C. de Sousa and Catarina M.M. Duarte
In this work the possibility of impregnating P(MMA-EHA-EGDMA)
with flurbiprofen using a clean and environmentally friendly
technology, namely supercritical fluid technology was evaluated.
P(MMA-EHA-EGDMA) has been proposed as a promising matrix to
be used for intraocular delivery of anti-inflammatory drugs
used in eye surgery and flurbiprofen is a non-steroidal anti-inflammatory
agent.
Fundamental studies like, the solubility of the drug in carbon
dioxide, as well as the sorption degree of this polymeric
matrix in the presence of carbon dioxide have been previously
carried out. The aim of this research was to evaluate the
effects of these two variables in the impregnation process.
Different experimental conditions were tested and the results
obtained suggest that the best impregnating conditions for
this system are low temperatures and pressures, which at the
same time correspond to a lower solubility of the drug in
the supercritical fluid and a low swelling of the polymeric
matrix.
Experiments performed also indicate that the batch impregnation
process leads to higher yields of impregnation and according
to the release profiles obtained the drug can be released
from the matrix up to three months, which presents great advantages
for post-surgical treatments.
[Back to top]
Nasal Immunization Studies by Cationic, Fusogenic and Cationic-Fusogenic
Liposomes Encapsulated with Tetanus Toxoid
M. Tafaghodi, M.R. Jaafari and S.A. Sajadi Tabassi
Particulate antigens are more effective than soluble
antigens in induction of systemic and mucosal immunity; possibly
because they are more efficiently endocytosed by mucosal-associated
lymphoid tissue (MALT) M cells. In this study, we determined
the systemic and mucosal immune responses in rabbits following
intranasal immunization with tetanus toxoid (TT) entrapped
in cationic, fusogenic and cationic-fusogenic liposomes. Liposomes
containing TT were prepared by dehydration-rehydration method.
The volume mean diameter of cationic, fusogenic and cationic-fusogenic
liposomes were 3.4 ± 0.6, 4.3 ± 2.3 and 3.4
± 1.5 μm,
respectively. Encapsulation efficiency of TT in cationic,
fusogenic and cationic-fusogenic liposomes was respectively
determined as 49.1 ± 8.4%, 48.5 ± 2.1% and 50.8
± 4.9%. After 3 months, the leaking of encapsulated
TT from liposomes ranged between 2.02 - 5.46%. Immunoreactivities
of encapsulated TT in all kinds of liposomes were completely
preserved, as studied by Sodium Dodecyl Sulfate – Polyacrylamide
Gel Electrophoresis (SDS-PAGE) and Enzyme-Linked Immunosorbent
Assay (ELISA). The highest serum immunoglobulin G (IgG) and
antitoxin titers were observed in groups immunized with solution
formulation (P< 0.001). However, the highest mucosal secretory
IgA (sIgA) titers were achieved by fusogenic liposomes (five
times more titers compared with TT solution, and 15 times
more titers compared with i.m. vaccine), followed by cationic-fusogenic
liposomes. No hemolysis was occurred on incubation of liposomes
and human erythrocytes. Also after nasal administration of
plain liposomes to human volunteers, no local irritation was
seen. This study suggests that intranasal administration of
fusogenic and cationic-fusogenic liposomes encapsulated with
vaccines could be an effective way for inducing mucosal immune
responses.
[Back to top]
Advanced Nebulizer Designs Employing Vibrating Mesh/Aperture
Plate Technologies for Aerosol Generation
J.C. Waldrep and R. Dhand
Recent technological advances and improved nebulizer
designs have overcome many limitations of jet nebulizers.
Newer devices employ a vibrating mesh or aperture plate (VM/AP)
for the generation of therapeutic aerosols with consistent,
increased efficiency, predominant aerosol fine particle fractions,
low residuals, and the ability to nebulize even microliter
volumes. These enhancements are achieved through several different
design features and include improvements that promote patient
compliance, such as compact design, portability, shorter treatment
durations, and quiet operation. Current VM/AP devices in clinical
use are the Omron MicroAir, the Nektar Aeroneb, and the Pari
eFlow. However, some devices are only approved for use with
specific medications. Development of "smart nebulizers"
such as the Respironics I-neb couple VM technologies with
coordinated delivery and optimized inhalation patterns to
enhance inhaled drug delivery of specialized, expensive formulations.
Ongoing development of advanced aerosol technologies should
improve clinical outcomes and continue to expand therapeutic
options as newer inhaled drugs become available.
[Back to top]
Novel Hydrophilic Drug Polymer Nano-Conjugates of Cisplatin
Showing Long Blood Retention Profile - Its Release Kinetics,
Cellular Uptake and Bio-Distribution
Anita K. Verma and K. Sachin
The present study evaluates the efficacy of drug polymer self
folding nano-conjugates of pectin-cisplatin to enhance blood
circulating levels of cisplatin.
The binding of nano-conjugate was confirmed by a peak-shift
in UV-spectra. Physical characterization was done by DLS and
TEM. Pharmacokinetics and bio-distribution of the nano-conjugates
were performed at various time points in normal, Balb-c
mice.
Zeta Potential showed the shielding effect on the negative
potential of pectin that was ~7 times more than the pectin
chains when conjugated with cisplatin. TEM confirmed the formation
of a hydrophilic, easily re-dispersible nano-conjugate in
the size range of 100nm. Release kinetics in plasma showed
that the pectincisplatin conjugate is a stable, slow and sustained
system with no burst effect. Immuno-fluorescence analysis
of J-774, a mouse macrophage cell line, was assessed after
incubating the cells with pectin chains tagged with FITC as
well as Pectin-Cisplatin-FITC conjugates. With the cellular
uptake of these particles in J-774, 40% of the cells showed
an uptake post 30 min of incubation. However, Pectin chains
were clearly eliminated.
The plasma proteins facilitate the release of cisplatin with
85-89% of the drug being released in 17 days, and only 57%
of drug was released in ~ 30 days without plasma. The reduced
negative charge on the conjugate helps in adhesion to the
cell surface and subsequent uptake by cells as evidenced by
cell uptake studies on J-774 cell line. Nano-conjugates showed
long blood retention profile in mice and the cisplatin was
found in circulation even after 24 hrs. Pharmacokinetic study
clearly indicates that it can form a novel anticancer drug
that possesses good efficacy and has a safer profile than
cisplatin.
[Back to top]
Osmotically Regulated Flow of Flurbiprofen through In
Situ Formed Asymmetric Membrane Capsule
Anil K. Philip
An in situ formed non-disintegrating controlled
release asymmetric membrane capsular system, offering improved
osmotic effect, was used to deliver poorly water soluble drug
flurbiprofen (model drug) to demonstrate how controlled release
characteristics could be manipulated by design of polymeric
capsule with an asymmetric membrane. In situ formed
asymmetric membrane capsule was made by dry method via precipitation
of asymmetric membrane on the walls of hard gelatin capsule.
Effect of different formulation variables were studied based
on 23 factorial design, namely,
level of osmogen, ethylcellulose and pore former apart from
studying the effect of varying osmotic pressure on drug release.
Scanning Electron Microscopy showed an outer dense non porous
region and an inner lighter porous region for the prepared
asymmetric membrane inside and a gelatin layer outside. Statistical
test (Dunnett Multiple Comparison Test) was applied for in
vitro drug release at P>0.05. The best formulation
closely corresponded to the extra design checkpoint formulation
by a similarity (f2) value
of 96.88. The drug release was independent of pH but dependent
on the osmotic pressure of the dissolution medium. The release
kinetics followed Higuchi model and mechanism of release was
Fickian diffusion.
[Back to top]
Preparation and Evaluation of Buccal Bioadhesive Tablets Containing
Clotrimazole
S. Singh, S. Jain, M.S. Muthu and R.Tilak
Buccal bioadhesive tablets of clotrimazole (CTZ) and
clotrimazole: hydroxypropyl-β-cyclodextrin
(CTZ-HPßCD) complex were prepared by using polymer xanthan
gum in combination with carbopol 974P. The prepared buccal
bioadhesive tablet formulations were evaluated for physicochemical
characteristics (weight, hardness, friability, diameter, and
drug content), swelling index, microenvironment pH, in-vitro
drug release, bioadhesion strength, residence time and duration
of antifungal activity (in-vitro). The dissolution
of CTZ from the prepared tablets into phosphate buffer (pH
6.8) was controlled up to 8 h. All the prepared tablets gave
reasonable in-vitro residence time (7.13 - 9.34 h).
X-ray diffraction (XRD) studies of the CTZ-HPβCD
complex, made by kneading and freeze-dried method, showed
no CTZ crystal signals, demonstrating the inclusion of CTZ
in the hydrophobic cavity of hydroxypropyl-β-cyclodextrin
(HPβCD)
and formation of amorphous inclusion complex. Duration of
the antifungal activity was measured by the inhibition zone
of Candida albicans by agar diffusion assay. It is
evident from the results obtained, the prepared buccal bioadhesive
tablets of CTZ would markedly prolong the duration of the
antifungal activity and may prove to be a viable alternative
to the conventional local oral medication.
[Back to top]
The Therapeutic Index of Locally Acting Inhaled Drugs as a
Function of their Fine Particle Mass and Particle Size Distribution
– A Literature Review
Marjolein Weda, Pieter Zanen, Anne H. de Boer, Dirk M.
Barends and Henderik W. Frijlink
The therapeutic index (TI) of locally acting inhaled
drug products depends on a number of parameters and processes:
the particle size distribution of the inhaled aerosol, the
dose-efficacy response curves at the deposition sites, the
amount of drug absorbed into the systemic circulation from
the lung as well as the gastrointestinal (GI) tract, and the
dose-effect curves for the different adverse drug reactions.
In this review, we present qualitative scenarios, combining
these effects and showing the possible influence of an envisaged
change in the particle size distribution in the inhaled dose
of a locally acting drug product on the TI. These scenarios
are a valuable tool in the development of inhalation drug
products. As a surrogate for the inhaled dose in vivo,
we use the fine particle mass (FPM), measured by in vitro
measurements. Using these scenarios, we reviewed the literature
on bronchodilators and corticosteroids for reported associations
between a change in the FPM and/or particle size distribution
within the FPM, and the TI. We conclude that decreasing the
particle size of an inhalation product may alter the TI both
in a positive as well as a negative sense. So, smaller particle
are not always better.
[Back to top]
Transdermal Therapeutic System of Enalapril Maleate Using
Piperidine as Penetration Enhancer
M. Aqil, Bhavna, I. Chowdhary, Y. Sultana, S. Talegaonkar,
F.J. Ahmad and M.M. Ali
The aim of this work was to formulate transdermal therapeutic
system (TTS) of an antihypertensive drug, enalapril maleate
(EM) using a new penetration enhancer, piperidine hydrochloride
(PH), belonging to the class of Dihydropyridines. The TTS
of EM was prepared by solvent evaporation technique using
polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying
ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w
PH as penetration enhancer. The TTS was evaluated for in-vitro
drug release using paddle over disc method and ex-vivo
skin permeation using modified Keshary and Chein diffusion
cell. The interaction studies were carried out by comparing
the results of assay, UV and TLC analysis for pure drug and
medicated and TTS formulation. Skin irritation potential of
TTS was assessed by visual examination of treated rat skin.
Stability studies were conducted according to ICH guidelines
at a temperature of 40±0.5
0 C and 75±5%
RH. The optimized formulation was evaluated for preclinical
bioavailability and antihypertensive efficacy using albino
rat model. The optimized formulation provided 87.3% drug release
in-vitro and a flux of 380 μg/cm2
/hr over a period of 48 hours. No chemical interaction
was found between the drug and excipients and there were no
signs of skin irritation on application of patch. The optimized
formulation was stable with a tentative shelf life of two
years. Significant fall in BP (p<0.001) was observed in
experimental hypertensive rats which was maintained for 2
days. There was 3 fold improvement in bioavailability with
TTS vis-à-vis marketed tablet (AUC0
to t : 1253.9 ng.h/ml vs.
422.88 ng.h/ml). These preclinicial studies indicate the feasibility
of matrix-type TTS of EM for 2 day management of hypertension.
Further studies on human beings are warranted to establish
clinical utility of the above TTS.
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