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Current
Drug Delivery
ISSN: 1567-2018
Current Drug Delivery
Volume 5, Number 4, October 2008
Contents
Functional Polymeric Nano/Microparticles for Surface Adsorption
and Delivery of Protein and DNA Vaccines Pp. 230-242
Antonella Caputo, Katia Sparnacci, Barbara Ensoli
and Luisa Tondelli
[Abstract]
Pro-Drugs for Indirect Cannabinoids as Therapeutic
Agents Pp. 243-247
John Ashton
[Abstract]
Matrix Embedded Microspherules Containing Indomethacin
as Controlled Drug Delivery Systems Pp.
248-255
K.M. Lokamatha Swamy, B. Satyanath, S.M.
Shantakumar, D. Manjula, Hafsa Mohammedi and Ayesha
Farhana
[Abstract]
Novel pH-Sensitive Interpenetrating Network Hydrogel
Beads of Carboxymethylcellulose–(Polyacrylamide-Grafted-Alginate)
for Controlled Release of Ketoprofen: Preparation and Characterization
Pp. 256-264
Raghavendra V. Kulkarni and Biswanath
Sa
[Abstract]
Designing, Optimisation & Characterization
of Sustained Release Matrix Pellets Prepared by Extrusion
Spheronization Containing Mixture of Proteolytic Enzymes Pp.
265-274
Amit Ashok Chivate and Sushilkumar Sharatchandra
Poddar
[Abstract]
PEGylated Elastic Liposomal Formulation for Lymphatic
Targeting of Zidovudine 275-281
Subheet Jain, A.K. Tiwary and N.K. Jain
[Abstract]
Phase Transition System: Novel Oral In-Situ
Gel Pp. 282-289
Ramesh C. Nagarwal and J.K. Pandit
[Abstract]
Design and Evaluation of Chitosan Films for Transdemal
Delivery of Glimepiride Pp. 290-298
H.O. Ammar, H.A. Salama, S.A. El-Nahhas
and H. Elmotasem
[Abstract]
Targeted Delivery of Macromolecular Drugs: Asialoglycoprotein
Receptor (ASGPR) Expression by Selected Hepatoma Cell Lines
used in Antiviral Drug Development Pp. 299-302
Yan Li, Guifang Huang, James Diakur and Leonard I.
Wiebe
[Abstract]
Quantitation of Serrapeptase in Formulations by
UV Method in the Microplate Format Pp. 303-305
K.V. Sandhya, S. Gayathri Devi and
Sam. T. Mathew
[Abstract]
Pharmaceutical Development of Solid Dispersion
Based Osmotic Drug Delivery System for Nifedipine Pp.
306-311
Pritam Kanagale, Vineetkumar Patel, Natarajan
Venkatesan, Mukul Jain, Pankaj Patel and Ambikanandan
Misra
[Abstract]
Mucoadhesive Microspheres: A Promising Tool in
Drug Delivery Pp. 312-318
Sanjay B. Patil and Krutika K. Sawant
[Abstract]
Modification of the In Vitro Release
Profile of Cetrorelix by Complexation with Biophilic Partners
Pp. 319-323
Thomas Rattei, Jürgen Engel, Wolfgang
Naumann, Alexander Lang and Matthias Rischer
[Abstract]
Solid Lipid Nanoparticles and Nanostructured Lipid
Carriers – Innovative Generations of Solid Lipid Carriers
Pp. 324-331
S.S. Shidhaye, Reshma Vaidya, Sagar Sutar,
Arati Patwardhan and V.J. Kadam
[Abstract]
Gastroretentive Drug Delivery System of Ranitidine
Hydrochloride Based on Osmotic Technology: Development and
Evaluation Pp. 332-342
P. Kumar, S. Singh and B. Mishra
[Abstract]
Abstracts
[Back to top]
Functional Polymeric Nano/Microparticles for Surface
Adsorption and Delivery of Protein and DNA Vaccines
Antonella Caputo, Katia Sparnacci, Barbara Ensoli
and Luisa Tondelli
The use of particulate polymeric carriers holds great promise
for the development of effective and affordable DNA and protein
subunit vaccines. Rational development of such vaccine formulations
requires a detailed understanding of their physico-chemical
properties, cell-free and in vitro behaviour, in addition
to particle uptake and processing mechanisms to antigen presenting
cells capable of stimulating safe and effective immune responses.
We here provide an overview on functional polymeric nano-
and micro-particles designed for surface adsorption of proteins
and DNA antigens currently under investigation for the formulation
of new vaccines, including comments on their preparation method,
antigen delivery strategy, cell-free and in vitro behaviour.
In addition, we focus on their influence in activating antigen-specific
humoral and/or cellular immune responses and on their potential
for the development of new vaccines.
[Back to top]
Pro-Drugs for Indirect Cannabinoids as Therapeutic
Agents
John Ashton
Medicinal cannabis, cannabis extracts, and other cannabinoids
are currently in use or under clinical trial investigation
for the control of nausea, emesis and wasting in patients
undergoing chemotherapy, the control of neuropathic pain and
arthritic pain, and the control of the symptoms of multiple
sclerosis. The further development of medicinal cannabinoids
has been challenged with problems. These include the psychoactivity
of cannabinoid CB1 receptor agonists and the lack of availability
of highly selective cannabinoid receptor full agonists (for
the CB1 or CB2 receptor), as well as problems of pharmacokinetics.
Global activation of cannabinoid receptors is usually undesirable,
and so enhancement of local endocannabinoid receptor activity
with indirect cannabimimetics is an attractive strategy for
therapeutic modulation of the endocannabinoid system. However,
existing drugs of this type tend to be metabolized by the
same enzymes as their target endocannabinoids and are not
yet available in a form that is clinically useful. A potential
solution to these problems may now have been suggested by
the discovery that paracetamol (acetaminophen) exerts its
analgesic (and probably anti-pyretic) effects by its degradation
into an anandamide (an endocannabinoid) reuptake inhibitor
(AM404) within the body, thus classifying it as prodrug for
an indirect cannabimimetic. Given the proven efficacy and
safety of paracetamol, the challenge now is to develop related
drugs, or entirely different substrates, into prodrug indirect
cannabimimetics with a similar safety profile to paracetamol
but at high effective dose titrations.
[Back to top]
Matrix Embedded Microspherules Containing Indomethacin
as Controlled Drug Delivery Systems
K.M. Lokamatha Swamy, B. Satyanath, S.M.
Shantakumar, D. Manjula, Hafsa Mohammedi and Ayesha
Farhana
This work is focused on the development of controlled drug
delivery systems using different wax/fat embedded indomethacin
(IM). Discrete wax/fat embedded microspherules containing
indomethacin were prepared by using cetostearyl alcohol, paraffin
wax and stearic acid by employing emulsification-phase separation
method. These matrices have been used as barrier coatings
due to their hydrophobic nature. Chemically inert and tasteless
nature of wax/fats promotes their use as taste masking agents
for bitter drugs. Various waxes and fats are available having
different physicochemical properties to suit the needs of
formulation. Methyl cellulose (MC) 1% w/v, sodium alginate
(SA) 0.5% w/v and Tween–80 (TW) 1% w/v were used as
emulgents. The resulting microspherules were discrete, large,
spherical and also free flowing. It is revealed from the literature
that natures of wax/fat emulgents were found to influence
the rate of drug release. In the present work the drug content
in all the batches of microspherules were found to be uniform.
The rate of drug release corresponded best to first order
kinetics, followed by Higuchi and zero-order equations. The
release of the model drug from these wax/fat microspherules
was prolonged over an extended period of time and the drug
release mechanism followed anomalous (non-Fickian) diffusion
controlled as well as Super Case II transport. Among the three
matrix materials used, paraffin wax retarded the drug release
more than the other two. Surface characteristics of microspherules
have been studied by Scanning Electron Microscope (SEM). A
fair degree rank of correlation was found to exist between
the size and release retardation in all the three-wax/fat
emulgent combinations.
[Back to top]
Novel pH-Sensitive Interpenetrating Network Hydrogel
Beads of Carboxymethylcellulose–(Polyacrylamide-Grafted-Alginate)
for Controlled Release of Ketoprofen: Preparation and Characterization
Raghavendra V. Kulkarni and Biswanath
Sa
Novel pH-sensitive carboxymethylcellulose–(polyacrylamide-grafted-sodium
alginate) interpenetrating network (IPN) hydrogel beads loaded
with ketoprofen were prepared using ionotropic gelation and
covalent crosslinking method. Polyacrylamide-grafted-sodium
alginate (PAAm-g-SA) copolymer was synthesized by free radical
polymerization using ammonium persulfate (APS) as free radical
initiator under the nitrogen atmosphere followed by hydrolysis
using sodium hydroxide. The grafting, alkaline hydrolysis
and crosslinking reactions were confirmed by Fourier transform
infrared spectroscopy (FTIR). Beads were characterized by
differential scanning calorimetric (DSC) analysis, thermogravimetric
analysis (TGA), X-ray diffractometry (XRD) and scanning electron
microscopy (SEM). The mechanical properties of the prepared
IPNs were investigated. The erosion was observed with the
beads containing only ionic crosslinks whereas it was negligible
with the beads containing both ionic and covalent crosslinks.
The swelling of the beads and drug release was significantly
increased when pH of the medium was changed from acidic to
alkaline (P<0.05).
The swelling and release data were fitted to an empirical
equation to determine the transport mechanism. Drug release
followed case II transport mechanism in acidic medium whereas
anomalous/non-Fickian transport mechanism was observed in
alkaline medium.
[Back to top]
Designing, Optimisation & Characterization of
Sustained Release Matrix Pellets Prepared by Extrusion Spheronization
Containing Mixture of Proteolytic Enzymes
Amit Ashok Chivate and Sushilkumar Sharatchandra
Poddar
A method for developing sustained release multiple unit dosage
form consisting of pellets of a proteolytic enzyme blend using
extrusion spheronization as a process is demonstrated in this
paper. Effect of Cellulose and Methacrylate based polymers
and plasticizers on stability of the enzyme blend are determined.
The effect of type & concentration of the sustained release
polymer, spheronization rpm and plasticizer on the yield &
sphericity of pellets is studied. The results indicated that
the SR pellets could be formulated for this enzyme blend using
both HPMC K15 and EUDRAGIT®
RSPO. The best rpm for spheronization turned out to be 1200
rpm. Use of plasticizer improved yield and sphericity. Triethyl
citrate was better over polyethylene glycol 400 and EUDRAGIT®
RSPO was better over HPMC K15 with respect to yield and sphericity
of pellets. The pellets could be suitably enteric coated for
protection of enzyme blend in lower pH of GIT. The in
vitro release profile indicated release extension could
be extended up to 12 hours in intestinal condition postulating
to an acceptable bioavaliablity in vivo.
[Back to top]
PEGylated Elastic Liposomal Formulation for Lymphatic
Targeting of Zidovudine
Subheet Jain, A.K. Tiwary and N.K. Jain
The present study was aimed at in vitro and in
vivo evaluation of PEGylated elastic liposomal formulation
for lymphatic targeting of zidovudine (AZT). PEGylated elastic
liposomal formulation was prepared and characterized for characteristic
in vitro, ex-vivo and in vivo parameters.
The plain and PEGylated elastic liposomal formulation showed
transdermal flux of 99.8±5.8
and 119.5±5.2
μg/cm2/hr,
respectively across the rat skin. Results of biodistribution
study indicated 27-fold higher accumulation of AZT in lymphoid
tissues after application of PEGylated elastic liposomes as
compared to free drug. The efficient localization of elastic
liposomal formulation in lymphatic system is of particular
interest for HIV therapy, taking in account that replication
of HIV mainly takes place in the lymphoid system. The Cellular
uptake studies showed significantly higher cellular uptake
in lymphoid cells (MT-2 cell line) from PEGylated elastic
liposomal formulation (88.9±8.7%)
in comparison to phosphate buffer saline (PBS, pH 7.4) solution
of drug (27.1±2.8%).
The entrapment of AZT into PEGylated elastic liposomes represents
a potential approach for overcoming the toxicity by its selective
uptake in lymphoid organs. This represents attractive approach
for sustained and targeted delivery of AZT.
[Back to top]
Phase Transition System: Novel Oral In-Situ
Gel
Ramesh C. Nagarwal and J.K. Pandit
Inspite of the various impediments in the bioavailability
of orally delivered drugs, oral dosage forms, both solid and
liquid, occupy a center stage in the therapeutic regimen of
diseases. However, liquid dosage forms are more prone to low
bioavailability because of their quick transit from the stomach/
duodenum. This could be a serious problem for drugs, which
are absorbed from these sites of the GIT. The gastric retention
of an oral liquid formulation could be successfully augmented
substantially through a strategy of liquid in-situ gelling
system. Natural polymers like alginate, gellan and chitosan
can undergo sol to gel transformation in the presence of either
divalent cations or due to a change in pH. The gel so formed,
being lighter than gastric fluids, floats over the stomach
contents and is retained there in for periods upto 24 hours.
The in-situ gel formation enhances the local or systemic bioavailability
of the administered drug. This concept is a redesign of liquid
oral dosage form, which fulfills the requirement for a sustained
release liquid preparation. This review discusses the various
aspects associated with the in-situ gelling systems and their
therapeutic applications.
[Back to top]
Design and Evaluation of Chitosan Films for Transdemal
Delivery of Glimepiride
H.O. Ammar, H.A. Salama, S.A. El-Nahhas
and H. Elmotasem
Glimepiride is a third generation oral antidiabetic sulphonylurea
drug frequently prescribed to patients of type 2 diabetes.
However, its oral therapy is encountered with bioavailability
problems due to its poor solubility leading to irreproducible
clinical response, in addition to adverse effects like dizziness
and gastric disturbances. As a potential for convenient, safe
and effective antidiabetic therapy, the rationale of this
study was to develop a transdermal delivery system for glimepiride.
Chitosan polymer was utilized in developing transdermal films
for glimepiride. Chitosan has film forming ability, bioadhesive
and absorption enhancing properties. Aiming at optimizing
the drug delivery and circumventing the skin barrier function,
inclusion complexation of glimepiride with beta-cyclodextrin
(β-CyD)
as well as the use of several conventional penetration enhancers
were monitored for augmenting the drug flux. The physical
and mechanical properties of the prepared films were investigated
using tensile testing, IR spectroscopy and X-ray diffractometry.
Release studies revealed adequate release rates from chitosan
films. Permeation studies through full thickness rat abdominal
skin were conducted. High flux values were obtained from films
comprising a combination of the drug with limonene and ethanol
as well as from films containing glimepiride-β-CyD
complex. In vivo studies on diabetic rats for selected
formulae revealed a marked therapeutic efficacy sustained
for about 48 hours. The above-mentioned results shed light
on feasibility of utilizing chitosan as an effective, safe
transdermal delivery system for glimepiride characterized
by increased patient compliance and better control of the
disease.
[Back to top]
Targeted Delivery of Macromolecular Drugs: Asialoglycoprotein
Receptor (ASGPR) Expression by Selected Hepatoma Cell Lines
used in Antiviral Drug Development
Yan Li, Guifang Huang, James Diakur and Leonard I.
Wiebe
The asialoglycoprotein receptor (ASGPR), an endocytotic
cell surface receptor expressed by hepatocytes, is triggered
by triantennary binding to galactose residues of macromolecules
such as asialoorosomucoid (ASOR). The capacity of this receptor
to import large molecules across the cellular plasma membrane
makes it an enticing target for receptor-mediated drug delivery
to hepatocytes and hepatoma cells via ASGPR-mediated endocytosis.
This study describes the preparation and characterization
of 125I-ASOR, and its utility
in the assessment of ASGPR expression by HepG2, HepAD38 and
Huh5-2 human hepatoma cell lines. ASOR was prepared from human
orosomucoid, using acid hydrolysis to remove sialic acid residues,
then radioiodinated using iodogen. 125I-ASOR
was purified by gel column chromatography and characterized
by SDS-PAGE electrophoresis. The ASOR yield by acid hydrolysis
was 75%, with ~87 % of the sialic acid residues removed. Electrophoresis
and gel chromatography demonstrated substantial differences
in 125I-ASOR quality depending
on the method of radioiodination. ASGPR densities per cell
were estimated at 76,000 (HepG2), 17,000 (HepAD38) and 3,000
(Huh-5-2). 125I-ASOR binding
to ASGPR on HepG2 cells was confirmed through galactose- and
EDTA- challenge studies. It is concluded that 125I-ASOR
is a facilely-prepared, stable assay reagent for ASGPR expression
if appropriately prepared, and that HepG2 cells, but not HepAD38
or Huh-5-2 cells, are suitable for studies exploiting the
endocytotic ASGPR.
[Back to top]
Quantitation of Serrapeptase in Formulations by UV
Method in the Microplate Format
K.V. Sandhya, S. Gayathri Devi and
Sam. T. Mathew
Serrapeptase is an anti-inflammatory, proteolytic enzyme isolated
from the microorganism, Serratia sp. HY-6. Very few methods
are available for the quantification of serrapeptase. The
activity of the enzyme is determined by an ELISA assay, colorimetric
method using casein as substrate or by HPLC method. These
methods are lengthy, time consuming and require a number of
reagents and solvents. Therefore an attempt was made to develop
a simple alternative method for regular estimation of drug
in formulations. Serrapeptase enzyme was estimated in formulations
by using microplate readers which uses the principle of vertical
photometry. Further this method was validated and the robustness
of this method was checked by estimating the drug in various
formulations including liposomes and marketed tablet formulations.
A linear relationship between drug concentration and absorbance
was observed between 1-4 μg/ml
at 230 nm (R2=0.9911). The
percentage recovery values of the drug in serrapeptase liposomes
were found to lie within the standard limit (97-98%) which
confirms the method is accurate and free from any positive
or negative interference of the excipient. The low value of
standard deviation obtained confirms the precision of the
method. (±0.020
- ±0.044).
The drug content values in marketed tablets values obtained
matched the label claim. The proposed microplate UV-method
for determination of serrapeptase in formulations is novel,
simple, inexpensive, fast, specific and robust. Thus this
method could be a better alternative for regular estimation
of drug in the various marketed formulations of serrapeptase.
[Back to top]
Pharmaceutical Development of Solid Dispersion Based
Osmotic Drug Delivery System for Nifedipine
Pritam Kanagale, Vineetkumar Patel, Natarajan
Venkatesan, Mukul Jain, Pankaj Patel and Ambikanandan
Misra
Elementary osmotic pumps (EOP) are well known for delivering
moderately soluble drugs at a zero order rate. A push-pull
osmotic system was developed and commercialized for poorly
water-soluble drugs [Procardia XL (Nifedipine), Glucotrl XL
(Glipizide)]. However, the technology is complex comprising
of bilayer compression and the suspension of drug formed in
the core has more viscosity and has to withstand the osmotic
pressure within the tablet, for which the membrane must be
thicker than that of EOP. The aim of the present study was
to develop a solid dispersion based EOP system for a poorly
water-soluble drug, nifedipine and deliver it in a zero order
fashion over an extended period of time. Solid dispersions
were prepared by hot melt technique using Poloxamer-188 at
various ratios of drug and polymer (1:1, 1:5 and 1:10, on
weight basis) and investigated for solubility study. Formation
of complex and decrease in crystallinity was confirmed from
differential scanning calorimetry (DSC) and X-ray crystallography
(XRD) study. Core tablets using solid dispersions were prepared
and coated with cellulose acetate and PEG-400. An orifice
was drilled manually to create passage for drug release. The
system was optimized for amount of osmogent, membrane weight
gain, amount of plasticiser and diameter of the orifice, to
achieve desired release profile. The osmotic system was found
to deliver nifedipine at a zero order rate for 20 h. The drug
release from the developed formulation was independent of
pH and agitational intensity.
[Back to top]
Mucoadhesive Microspheres: A Promising Tool in Drug
Delivery
Sanjay B. Patil and Krutika K. Sawant
Mucoadhesive polymers have recently gained interest among
pharmaceutical scientists as a means of improving drug delivery
by promoting the residence time and contact time of the dosage
form with the mucous membranes. Mucoadhesion is the process
whereby synthetic and natural polymers adhere to mucosal surfaces
in the body. If these materials are then incorporated into
pharmaceutical for-mulations, drug absorption by mucosal cells
may be enhanced or the drug will be released at the site for
an extended period of time. Microspheres, in general, have
the potential to be used for targeted and controlled release
drug delivery; however, coupling of mucoadhesive properties
to microspheres has additional advantages like, a much more
intimate contact with the mucus layer, efficient absorption
and enhanced bioavailability of the drugs due to a high surface
to volume ratio. The present review describes the potential
applications of mucoadhesive microspheres as a novel carrier
system to improve drug delivery by various routes of administration
like buccal, oral, nasal, ocular, vaginal and rectal, either
for systemic or for local effects. The mucoadhesive polymers,
methods of preparation of micro-spheres and their in vitro
and in vivo evaluation are also described.
[Back to top]
Modification of the In Vitro Release Profile
of Cetrorelix by Complexation with Biophilic Partners
Thomas Rattei, Jürgen Engel, Wolfgang
Naumann, Alexander Lang and Matthias Rischer
Cetrorelix is a GnRH antagonist of the third generation. Its
manifold therapeutic potential requires the adjustment of
its resorption rates and effect profiles. The method of non-covalent
complexation with suitable partner molecules enables the development
of customized depot formulations. Investigating new partners
and synthesis methods for Cetrorelix complexes we focused
on maximal biocompatibility of the complexes. Compared to
traditional depot forms the application of complexes aims
at decreased aggregation of the peptide and increased biophily
of the depots. The pharmacological properties of the new Cetrorelix
complexes were analyzed by standardized dynamical in vitro
liberation experiments. A new pharmacokinetic model has been
developed and successfully applied for the quantitative analysis
of the liberation profiles.
With aromatic carboxylic acids and dipeptides we could synthesize
stable complexes that have nearly linear release characteristics
in aggregating environments close to in vivo conditions.
The release rates were specific and very different for the
complex partners. Thus several complexes have a great potential
for a linear, characteristic release of the peptide in
vivo and can be the basis for new depot forms for Cetrorelix.
[Back to top]
Solid Lipid Nanoparticles and Nanostructured Lipid
Carriers – Innovative Generations of Solid Lipid Carriers
S.S. Shidhaye, Reshma Vaidya, Sagar Sutar,
Arati Patwardhan and V.J. Kadam
The first generation of solid lipid carrier systems in
nanometer range, Solid Lipid Nanoparticles (SLN), was introduced
as an alternative to liposomes. SLN are aqueous colloidal
dispersions, the matrix of which comprises of solid biodegradable
lipids. SLN are manufactured by techniques like high pressure
homogenization, solvent diffusion method etc. They exhibit
major advantages such as modulated release, improved bioavailability,
protection of chemically labile molecules like retinol, peptides
from degradation, cost effective excipients, improved drug
incorporation and wide application spectrum. However there
are certain limitations associated with SLN, like limited
drug loading capacity and drug expulsion during storage, which
can be minimized by the next generation of solid lipids, Nanostructured
lipid carriers (NLC). NLC are lipid particles with a controlled
nanostructure that improves drug loading and firmly incorporates
the drug during storage. Owing to their properties and advantages,
SLN and NLC may find extensive application in topical drug
delivery, oral and parenteral administration of cosmetic and
pharmaceutical actives. Cosmeceuticals is emerging as the
biggest application target of these carriers.
Carrier systems like SLN and NLC were developed with a perspective
to meet industrial needs like scale up, qualification and
validation, simple technology, low cost etc. This paper reviews
present status of SLN and NLC as carrier systems with special
emphasis on their application in Cosmeceuticals; it also gives
an overview about various manufacturing techniques of SLN
and NLC.
[Back to top]
Gastroretentive Drug Delivery System of Ranitidine
Hydrochloride Based on Osmotic Technology: Development and
Evaluation
P. Kumar, S. Singh and B. Mishra
Gastroretentive drug delivery systems (GRDDS) of Ranitidine
hydrochloride (RHC) has been designed based on the osmotic
technology, with the floating and swelling features in order
to prolong the gastric retention time. The developed system
consisted of osmotic core (containing drug, osmotic agent
and hydrophilic polymers), coated with semipermeable membrane
(SPM) which is then further coated with compression coating
of gelling agent (HPMC K4M) containing gas generating agent
(citric acid). All the developed formulations were evaluated
for floating lag time, duration of floating, drug content
and in-vitro drug release profile. Formulation variables
like levels of hydrophilic polymer (0-18.26%w/w), type of
plasticizer (PEG-400, Dibutyl phthalate), coat thickness of
SPM (60-100μm),
were found to affect the drug release from the developed formulations.
Drug release was directly proportional to hydrophilic nature
of plasticizer but inversely proportional to the levels of
hydrophilic polymer and coat thickness of SPM. Drug release
from developed formulations was independent of level of gas
generating agent in compression coat, pH and agitation intensities
of release media but dependent on osmotic pressure of the
release media. All the developed formulation showed floating
lag time of less than 2 min (desired) and were floated for
more than 12 hr. Floating lag time was inversely related to
level of citric acid in compression coat and directly related
to the density of the developed formulations. The manufacturing
procedure was found to be reproducible and formulations were
stable after 3 months accelerated stability study. Prediction
of steady state levels showed the plasma concentrations of
RHC to be within desired range.
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