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Current Drug Delivery
ISSN: 1567-2018
Current Drug Delivery
Volume 2, Number 2, April 2005
Contents
Transdermal Drug Delivery of Labetolol Hydrochloride: System
Development, In Vitro; Ex Vivo and In
Vivo Characterization Pp.125-131
M. Aqil, Saqib Zafar, Asgar Ali and Shoaib Ahmad
[Abstract]
Pharmaceutical Aspects of Hemoglobin-Based Oxygen Carriers
Pp.133-142
Vibhudutta Awasthi
[Abstract]
Design, Development and Optimization of Nimesulide-Loaded
Liposomal Systems for Topical Application Pp.143-153
Bhupinder Singh, Gaurav Mehta, Rajiv Kumar, Amit Bhatia,
Naveen Ahuja and O.P. Katare
[Abstract]
In Vitro and In Vivo Evaluation of Guar
Gum-Based Matrix Tablets of Rofecoxib for Colonic Drug Delivery
Pp.155-163
S.M. Al-Saidan, Y.S.R. Krishnaiah, V. Satyanarayana and
G.S. Rao
[Abstract]
Intranasal Drug Delivery for Brain Targeting Pp.165-175
Tushar K. Vyas, Aliasgar Shahiwala, Sudhanva Marathe and
Ambikanandan Misra
[Abstract]
Development of Novel Lyophilized Mixed Micelle Amphotericin
B Formulation for Treatment of Systemic Fungal Infection Pp.177-184
Sachin Naik, Mahavir Chougule, Bijay Kumar Padhi and Ambikanandan
Misra
[Abstract]
Synthesis and In Vitro Skin Permeation of Naproxen
Conjugates with α-Alkylamino
Acids Pp.185-189
Rosario Pignatello, Lucia Montenegro, Annalisa H.S. Stancampiano,
Antonina Puleo and Giovanni Puglisi
[Abstract]
Oral Delivery of Insulin with the eligen®
Technology: Mechanistic Studies Pp.191-197
Dmitry Malkov, Robert Angelo, Huai-zhen Wang, Elizabeth
Flanders, Heather Tang and Isabel Gomez-Orellana
[Abstract]
Decrease in Fungizone™ Toxicity Induced by the Use
of Lipofundin™ As a Dilutent: An In Vitro Study
Pp.199-205
Ivonete Batista de Araujo, Bolivar P.G.L. Damasceno, Tereza
Maria Dantas de Medeiros, Luiz Alberto Lira Soares and E.
Socrates Tabosa do Egito
[Abstract]
Abstracts
[Back to top]
Transdermal Drug Delivery of Labetolol Hydrochloride: System
Development, In Vitro; Ex Vivo and In Vivo
Characterization
M. Aqil, Saqib Zafar, Asgar Ali and Shoaib Ahmad
OBJECTIVE. The aim of the present work was
to develop and evaluate matrix type transdermal drug delivery
systems (TDDS) of labetolol hydrochloride (L-HCL) effective
for 48 hours.
EXPERIMENTAL. The TDDS were prepared by
solvent evaporation technique. Six formulations (carrying
Eudragit RL100:Eudragit RS 100 in 7.5:4.5, 5.0:5.0, 3.5:8.5
in formulations X-1, X-2, X-3 and Eudragit RL100:PVP K-30
in 9.0:2.0, 5.0:5.0, 4.0:7.0 in formulations Y-1, Y-2, Y-3,
respectively) were prepared. All formulations carried 36%
w/w of L-HCL, 10-12% w/w of enhancer dimethyl sulfoxide and
2.5-7.5% w/w of plasticizer PEG 400 in methanol-acetone solvent
system. The TDDS were evaluated by in vitro drug
release, ex vivo skin permeation, stability and in
vivo pharmacodynamic studies.
RESULTS. The maximum drug release for X-series
was 90.26% in 48 hours (X-1) and for Y-series, it was 83.24%
(Y-1). Again formulations X-1 (Kp = 0.221x10-2 cm hr-1) and
Y-1 (Kp = 0.210x10-2 cm hr-1) exhibited the best skin permeation
potential in the respective series. This might be due to higher
permeability characteristics of Eudragit RL100. A shelf life
of 2.38 years was predicted for the TDDS. Mean systolic BP
of the experimental hypertensive rats was significantly reduced
(p<0.01) on TDDS treatment.
CONCLUSION. The TDDS holds promise for clinical
trials.
[Back to top]
Pharmaceutical Aspects of Hemoglobin-Based Oxygen Carriers
Vibhudutta Awasthi
Oxygen delivery has evolved as a therapy of widespread interest
in the clinical setting, especially in emergency medicine
and anesthesiology. With the widespread recognition of blood-borne
infections during the last two decades and the looming shortage
of donor blood in future, efforts to formulate an artificial
substitute for oxygen carrying capacity of RBCs have increased.
Such blood substitutes, defined more correctly as oxygen therapeutics,
are particularly valuable in circumstances such as war and
trauma situations where properly matched blood may not be
immediately available or is not accepted by the recipients
for religious reasons. Several elegant formulations of hemoglobin,
both free and encapsulated, have evolved recently and are
collectively referred to as hemoglobin-based oxygen carriers
(HBOCs). Few HBOCs have successfully entered into the clinical
phase. This review discusses formulation requirements of HBOCs
from a physiological viewpoint. Physico-pharmaceutical parameters,
such as colloidal oncotic pressure, osmolality, viscosity,
sterility, apyrogenicity and shelf-stability are traditionally
a concern for large volume parenterals meant for resuscitation
purposes. At the same time, properties such as oxygen affinity,
hemoglobin content and in vivo efficacy of oxygen carriers
are specific to HBOCs. Owing to the presence of a very active
and functional protein (hemoglobin), requirements for adequate
performance of HBOCs significantly differ from those of other
large-volume parenterals, such as lactated Ringer’s solution,
and plasma expanders, such as dextran or albumin solutions.
[Back to top]
Design, Development and Optimization of Nimesulide-Loaded
Liposomal Systems for Topical Application
Bhupinder Singh, Gaurav Mehta, Rajiv Kumar, Amit Bhatia,
Naveen Ahuja and O.P. Katare
Nimesulide, a non-steroidal anti-inflammatory drug, was
incorporated into multilamellar liposomes to improve its performance
on topical administration. The drug was loaded onto liposomes
employing thin film hydration technique. Various process and
formulation variables were investigated to obtain the liposomal
products of desired quality. Liposomes were monitored for
percent drug entrapment, after separating the unentrapped
drug by mini column centrifugation, for vesicular properties
(such as size distribution profile, morphological attributes
and agglomeration tendency), drug diffused through synthetic
semipermeable membrane, and drug leakage. Systematic optimization
studies were carried out using 32 factorial design to select
the optimized liposomal composition with reference to percent
drug entrapment, drug diffusion and leakage. The optimized
batch of liposomes was subjected to drug permeation and drug
retention studies employing rat skin and human cadaver skin.
In comparison to methanolic solution of pure nimesulide, liposomal
formulations were found to retain higher amounts of nimesulide
in the skin. Anti-inflammatory studies, using carragenan-induced
rat paw edema model, indicated significantly better performance
of liposomally entrapped nimesulide in comparison to the marketed
gel formulation and the Carbopol gel containing nimesulide.
[Back to top]
In Vitro and In Vivo Evaluation of Guar
Gum-Based Matrix Tablets of Rofecoxib for Colonic Drug Delivery
S.M. Al-Saidan, Y.S.R. Krishnaiah, V. Satyanarayana and
G.S. Rao
The present study was carried out to develop and evaluate
guar gum-based matrix tablets of rofecoxib for their intended
use in the chemoprevention of colorectal cancer. Matrix tablets
containing 40% (RXL-40), 50% (RXL-50), 60% (RXL-60) or 70%
(RXL-70) of guar gum were prepared by wet granulation technique,
and were subjected to in vitro drug release studies. Guar
gum matrix tablets released only 5 to 12% of rofecoxib in
the physiological environment of stomach and small intestine.
The matrix tablets RXL-40 disintegrated completely within
10 h in a dissolution medium without rat caecal contents (control
study), and hence not studied further. When the dissolution
study was continued in simulated colonic fluids (rat caecal
content medium), the matrix tablets RXL-50 were acted upon
by colonic bacterial enzymes releasing the entire quantity
of drug wherein there was no appreciable difference when compared
to that released in control study. The matrix tablets RXL-60
released another 88% of rofecoxib whereas matrix tablets RXL-70
released only 57% of rofecoxib in simulated colonic fluids
indicating the susceptibility of the guar gum formulations
to the rat caecal contents. The guar gum matrix tablets RXL-70
were subjected to in vivo evaluation in human volunteers to
find their ability of targeting rofecoxib to colon. The delayed
Tmax, prolonged absorption time (ta), decreased Cmax and decreased
ka indicated that rofecoxib was not released significantly
in stomach and small intestine, but was delivered to colon
resulting in a slow absorption of the drug and making it available
for local action in human colon.
[Back to top]
Intranasal Drug Delivery for Brain Targeting
Tushar K. Vyas, Aliasgar Shahiwala, Sudhanva Marathe and
Ambikanandan Misra
Many drugs are not being effectively and efficiently delivered
using conventional drug delivery approach to brain or central
nervous system (CNS) due to its complexity. The brain and
the central nervous system both have limited accessibility
to blood compartment due to a number of barriers. Many advanced
and effective approaches to brain delivery of drugs have emerged
in recent years. Intranasal drug delivery is one of the focused
delivery options for brain targeting, as the brain and nose
compartments are connected to each other via the olfactory
route and via peripheral circulation. Realization of nose
to brain transport and the therapeutic viability of this route
can be traced from the ancient times and has been investigated
for rapid and effective transport in the last two decades.
Various models have been designed and studied by scientists
to establish the qualitative and quantitative transport through
nasal mucosa to brain. The development of nasal drug products
for brain targeting is still faced with enormous challenges.
A better understanding in terms of properties of the drug
candidate, nose to brain transport mechanism, and transport
to and within the brain is of utmost importance. This review
will discuss some pertinent issues to be considered and challenges
to brain targeted intranasal drug delivery. A few marketed
and investigational drug formulations will also be discussed.
[Back to top]
Development of Novel Lyophilized Mixed Micelle Amphotericin
B Formulation for Treatment of Systemic Fungal Infection
Sachin Naik, Mahavir Chougule, Bijay Kumar Padhi and Ambikanandan
Misra
The purpose of the study was to develop a stable, controlled
release Amphotericin B ( Amph B) lyophilized mixed micelle
(MM) formulation using hydrogenated soya phosphatidylcholine
(HSPC) and bile salts in monomeric form and evaluate it for
therapeutic performance and side effects. The MM formulations
of Amph B were prepared using sodium deoxycholate (NDC)/sodium
taurocholate (NTC)/sodium cholate (NC), and HSPC. The optimization
of bile salt: HSPC ratio in the MM formulation was done using
24 factorial designs. MM formulations were lyophilized using
sucrose as a cryoprotectant and analyzed for per cent micelle
yield, per cent drug loading and per cent entrapment efficiency.
Comparative in vitro diffusion studies, hemolytic activity,
and minimum inhibitory concentration (MIC) of developed MM
formulations and marketed formulation (Fungizone) were evaluated
using cellophane membrane, human red blood cells and Candida
albicans respectively. In vivo studies of MM formulations
were also carried out on Candida albicans infected
white albino rats and compared with Fungizone. The optimized
molar ratio of bile salt: HSPC was found to be 8:11. Among
all MM formulations prepared, NDC/ HSPC formulation found
to have maximum per cent drug loading (4.96±0.8%),
per cent entrapment efficiency (93.2±1.5%) and per
cent micelle yield (96.4±1.4%). The in vitro
drug diffusion studies of developed MM formulations show close
to zero-order diffusion kinetics. All MM formulations show
improved therapeutic index and reduced side effects compared
to reference formulation Fungizone. The NDC/HSPC MM formulation
was found to have least hemolytic activity, MIC and mortality
rate at all dosage levels. Improved antifungal activity and
reduced toxicity of Amph B solubilized in MM may be due to
higher cellular uptake of the drug by fungal cells of infected
tissues from MM formulations. Hence, Amph B MM formulation
could be a safe and effective viable alternative in the treatment
of systemic fungal infections.
[Back to top]
Synthesis and In Vitro Skin Permeation of Naproxen
Conjugates with α-Alkylamino
Acids
Rosario Pignatello, Lucia Montenegro, Annalisa H.S. Stancampiano,
Antonina Puleo and Giovanni Puglisi
Novel amide conjugates of the NSAID naproxen (NAP, 1)
with short-chain α-alkylamino
acids (C4 to C6 alkyl chain) were synthesized through a carbodiimide
(EDAC)-assisted coupling reaction and evaluated as dermal
prodrugs of NAP. The 2-α-aminobutyl
derivative (2) showed lipophilicity similar
to that of NAP, while the higher homologues (3)
and (4) were more lipophilic than the parent
drug, as assessed by CLogP and HPLC methods.
The chemical and enzymatic hydrolysis of these compounds
was evaluated in aqueous buffer solution (pH 7.4) and 80%
human plasma. All compounds showed a good chemical stability
(t½
= 88-133 h) but underwent a rapid enzymatic hydrolysis to
NAP (t½_around
3 h). The bioconversion of prodrugs into NAP was confirmed
by an in vivo test, since i.p. administration of
compounds 2-4 to mice gave a similar analgesic
response than the parent drug.
In vitro skin permeation experiments were performed
using adult human SCE samples mounted in Franz-type diffusion
cells. The butyl derivative 2 that showed
an increased aqueous solubility compared to NAP gave a 5-fold
improvement of skin permeation compared to NAP. In conclusion,
the conjugate 2 could be regarded as a good
candidate to improve NAP topical delivery and will be further
studied as a prodrug for topical administration of this drug.
[Back to top]
Oral Delivery of Insulin with the eligen®
Technology: Mechanistic Studies
Dmitry Malkov, Robert Angelo, Huai-zhen Wang, Elizabeth
Flanders, Heather Tang and Isabel Gomez-Orellana
The development of oral insulin using the eligen®
technology represents a significant advance in insulin
administration which is expected to improve the quality of
life of diabetic patients. As clinical studies progress, a
great deal of interest has focused on the process by which
this technology enables insulin absorption from the intestinal
lumen into the bloodstream. The eligen®
technology employs low molecular weight compounds (termed
drug delivery agents or carriers) which interact weakly and
non-covalently with insulin, increasing its lipophilicity
and thereby its ability to cross the gastrointestinal epithelium.
In this study we investigated the mechanism of insulin absorption
across caco-2 cell monolayers with one of these drug delivery
agents, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC). Our
results show that SNAC increases insulin permeability approximately
ten fold across cell monolayers and does so without affecting
mannitol permeability or disrupting cell membranes. Confocal
microscopy and immunocytochemistry revealed that insulin is
transported transcellularly without detectable alteration
of the tight junctions between adjacent cells. SNAC also appears
to play some role in protecting insulin from proteolytic degradation,
potentially allowing for more intact insulin to be available
at the site of absorption.
[Back to top]
Decrease in Fungizone™ Toxicity Induced by the Use
of Lipofundin™ As a Dilutent: An In Vitro Study
Ivonete Batista de Araujo, Bolivar P.G.L. Damasceno, Tereza
Maria Dantas de Medeiros, Luiz Alberto Lira Soares and E.
Socrates Tabosa do Egito
The aim of this work was to develop an in vitro
experimental protocol for the evaluation of toxicity and efficacy
of an amphotericin B (AmB) micelle system, Fungizone™,
which was previously diluted with a lipid based emulsion for
parenteral use, named Lipofundin™ LCT/MCT-20%. Two cell
models were used for the experiments: Red Blood Cells (RBC)
from human donnors and Candida tropicalis (Ct).
These models were used to perform the toxicity and activity
of the Fungizone™/ Lipofundin™ admixture (AmB-LP)
and the Fungizone™ (AmB-M) alone. While potassium (K+)
and hemoglobin leakage from RBC were the parameters used to
evaluate the acute and chronic toxicity, respectively, the
efficacy of AmB-LP and AmB-M were assessed by K+
leakage or cell survival rate (CSR) from Ct. The
results show that the toxicity of AmB-LP to RBC was concentration
dependent concerning the K+ leakage; while at high
concentrations, 5 and 50 mg.mL-1, the leakage was
50.91 ± 2.09% and 95.71 ± 0.64%, respectively,
at a concentration of 0.5 mg.mL-1 this value was
17.16 ± 1.57% and the value tended to zero for the
lowest concentration studied, 0.05 mg.mL-1. Surprisingly,
AmB-LP induced very low hemoglobin leakage for all concentrations
studied. At the highest concentration, 50 mg.mL-1,
this value was around 3%. When the cell model was Ct,
the results changed completely. Not only high concentrations
of AmB-LP, but also lower ones were able to induce a K+
permeability of around 100%. The CSR parameter showed an inverse
correlation with the concentration; high values, between 50
and 5 mg.mL-1, resulted in a CSR of around 8%.
On the other hand, for lower concentration values, 0.05 and
0.5 mg.mL-1, this one was around 80%. The same
profile of activity against Ct was found for AmB-M.
Only a small variation was found for the K+ leakage
at 0.05 mg.mL-1 that presented a value of 96.99
± 2.53%. However, AmB-M seemed to be much more toxic
than AmB-LP. Its induction of hemoglobin leakage started at
0.5 mg.mL-1 and reached the 100% at 5 mg.mL-1.
K+ leakage results were worse. The intermediate
concentrations of study, 0.5 and 5 mg.mL-1, presented
a significant increase compared to AmBLP. All together these
results reveal that the activity of AmB is not only concentration
dependent, but also depends on the drug carrier in which this
compound was inserted. The AmB-LP preparation showed the same
efficacy as AmB-M, but with a low toxicity. Therefore, AmB-LP
presented a higher therapeutic index that permits the administration
of high concentration of AmB without revealing side effects.
However, the simple mixture of two complex pharmaceutical
entities, as micelles and emulsions, should be analyzed carefully
to assure that physicochemical stability is not reduced and
thereby cause a different biodistribution in vivo.
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