Upload
others
View
11
Download
0
Embed Size (px)
Citation preview
Review of literature
Suresh Gyan Vihar University, Jaipur Page 32
REVIEW OF LITERATURE
2.1 Status of polymers and drugs in transdermal delivery systems
Many drugs have been formulated in transdermal drug delivery systems e.g.,
nicotine, anti-histamines, beta-blockers, NSAIDS, calcium channel blockers,
contraceptives, anti-arrhythmic drugs, insulin, anti-viral drugs, hormones, A-
interferons and anti-cancer agents.
In 1969 first US Patent (US 3426754) on transderrnal drug delivery device
was issued to Bierenbaum et al., 1969 for the invention of breathable medical
dressing.
Stability and skin permeation of salbutamol base from adhesive matrix
transdermal patches containing antioxidants and skin permeation enhancers were
studied. Skin permeation was enhanced with increasing salbutamol and oleic acid
content in the patches. Accelerated stability study evaluation was carried out at 60C
for 15-days. The tentative period for 10% drug degradation was estimated to be 946
days, demonstrating that the patches were stable containing butylated hydroxy toluene
and thiourea had adequate stability profile reported (Kale et al., 1996).
Validation of a release diffusion cell for topical dosage form was
demonstrated. The methodology was followed to choose the agitation speed and
posterior validation of a new design of diffusion cell used in in vitro release studies of
naproxane, in transdermal dosage form. It was concluded that, the methodology was
precious, reproducible, repeatable and robust for select speed (600 rpm) provided that
the test temperature is controlled (Parera and Morell, 1996).
Permeation through skin of indomethacin from gel formed by fatty acid ester
and phospholipids was studied. Five fatty acid ester groups octanoate, isononanate,
myristate, palmitate and stearate were selected. The permeation rate of indomethacin
was proportional to its solubility from fatty acid ester suspension through excised
hairless rat skin. Gels were also formed by addition of phospholipids in esters. High
permeation rate from fatty acid esters gels in which side chains were present on both
fatty acid and alcohol moieties were observed and showed good and promising results
(Fuji et al., 1996).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 33
Transdermal delivery of prazocin HCl with non-ionic surfactants was
developed. The drug loaded and rate controlling membranes of ethylene vinyl acetate
copolymer 2806 (EVA) were prepared by adding 2%w/w of diethyl phthalate as
plasticizer. Non-ionic surfactants like Spans 20, 40, 60, 80 and Tween 20, 40, 60 and
80 were used. Tweens produced higher permeation than the spans (Rajendran et al.,
1997).
An attempt has been made to developed transdermal patches of verapamil
hydrochloride in a polymer matrix of sodium carboxy methyl guar, propylene glycol
as a plasticizer and aluminum foil as the backing membrane. A comparison of various
plasticizers and polymers were also made. In vitro release studies through mouse skin
showed that sodium carboxy methyl guar was a suitable polymer. The primary skin
irritancy tests showed that transdermal patches are non- irritant (Paranjothy and
Thampi, 1997).
The effects of interface transdermal nitroglycerine on occurrence of ischemia
after patch removal in patients with stable angina pectoris receiving calcium and β-
adrenergic antagonist or both were studied (Pepine et al., 1997).
The transdermal films of diltiazem hydrochloride and indomethacin were
formulated and evaluated. The formulation was developed using ethyl cellulose and
polyvinyl pyrrolidone containing diltiazem hydrochloride and indomethacin. It was
found that the films composed of polyvinyl pyrrolidone : ethyl cellulose: diltiazem
hydrochloride (2:8:2) and polyvinyl pyrrolidone: ethyl cellulose: indomethacin
(2:8:3) should be selected for the formulation of transdermal drug delivery system
(Rama Rao and Diwan, 1998).
The membrane controlled transdermal delivery system was developed for
isosorbide dinitrate (ISDM) was studied. The formulation was developed with
polyethylene (PE) and ethylene vinyl acetate copolymer (EVAC) membranes as rate
controlling membranes; in which a carbomer gel was used as the drug reservoir and
further results were compared with the marketed products. These results suggested
that transdermal therapeutic system that contains PE membrane as rate controlling
membrane, polyisobutylene adhesive and carbomer gel, as a reservoir can be
applicable for transdermal system of isosorbide dinitrate (Figen-Ocak and
Agabeyoglu, 1999).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 34
The effect of capsaicin and azone was studies on the permeation rate of
naproxane through human skin. It was concluded that both capsaicin and azone
enhanced the permeation rate with an enhancement ratio of up to 4 fold. The
magnitude of the effect was similar through human and rabbit skin. The result was
similar of permeation of naproxane from a saturated solution of the drug through skin
pretreated with azone with commercial preparation. Capsaicin had no effect on the
vasodilation of the blood vessels in the perfused rabbit ear, but inferring that the
penetration enhancement was a direct proposed of capsaicin influencing the barrier
function of skin (Degim et al., 1999).
In vitro permeation of naloxane through excised rat skin using a diffusion cell
was studied. The flux values varied from 6.5±0.72 mcg/cm2/h in control to
27.18±4.26 mcg/cm2/h in dimethyl formamide. The affinity of naloxane in the
presence of propylene glycol was decreased by 6.2 times with skin compared to
control. FTIR study was done the corresponding effect of various sorption promoters
on intercellular lipid pathways in skin (Jaiswal et al., 1999).
Topical formulation containing ciprofloxacin and tinidazole in lanoline
petrolatum base, emulsion base and PEG water soluble base were prepared and
evaluated for drug release. The anti-microbial activities of these formulations were
compared against marketed formulations, containing 1% (w/w) silver sulfadiazine
USP. It found that release of ciprofloxacin and tinidazole from the PEG base was
maximum through sigma membrane in phosphate buffer pH 6.0 and also observed
that the release of tinidazole was more than that of ciprofloxacin (Pandey et al., 1999).
The TDDS with natural polymer isolated from the roots of Salacia
macrosperma was developed. Both reservoir type and matrix type were prepared for
diltiazem. Influences of different excepient like PEG 400 and Eudragit RS and RL as
release modifiers were evaluated by in vitro tests using rat skin. In case of matrix
systems the drug release rate was inversely proportional to the polymer quantity. The
results are quite encouraging and suggest that the natural polymer from Salacia
macrosperma may be used for development of TDDS (Venkateswarlu et al., 1999).
A comparative in vitro study of percutaneous penetration of beta-blockers in
human skin was studied. The main permeation parameters like permeability
coefficient, flow and lag time were calculated and compared as measurement of
intrinsic permeability across human skin. A long lag time and low steady state flow
Review of literature
Suresh Gyan Vihar University, Jaipur Page 35
was found for all drugs assayed. Finally they concluded that lipophilicity was one of
the major factors in drug permeability through human skin (Modamino et al., 2000).
The dermal delivery of lignocaine, influence of ion pairing was studied. The
significance of ion pairing on the permeation on lignocaine was studied. The
polydimethylsiloxane and human skin at different pH values were used and indicated
that lignocaine hydrochloride flux significantly increased with amount of unionized
base (Valenta et. al., 2000).
Matrix type transdermal patches of aspirin were formulated and evaluated.
Matrix type patches of aspirin using polyvinyl alcohol with and without hydrolysis
inhibitor and a penetration enhancer were developed. Dimethyl formamide was added
as a penetration enhancer. Sodium fluoride was added to prevent the hydrolysis of
aspirin. The transdermal flux was studied using rat skin; volunteers resulted in
significant reduction in serum lipid peroxide levels and inhibition of platelet
aggregation (Krishna et al., 2000).
Nimesulide transdermal gels were prepared and evaluated. Using various
polymers like sodium alginate, HPMC, sodium CMC and methylcellulose formulated
the patches. In vitro release studies of the prepared formulation were performed using
dialysis membrane and it was found that sodium alginate containing gel showed better
release. In vivo anti-inflammatory activity was studied in carrageenan induced rat
paw edema and analgesic activity was studied in acetic acid induced writhing using
rats (Pandey et al., 2000).
Transdermal free films of atenolol were made using sodium CMC as
polymeric matrix and propylene glycol as the plasticizer. DMSO, PEG 400, Tween
20, Pluronic F12% and Brij 35 were used as permeation enhancers. The drug
diffusion studies were carried out using Keshary-Chein cell. A comparison of various
permeation enhancers on permeation rate of atenolol was done. Iontophoresis
increased the permeation rate of the drug to a greater extent compared to the
permeation enhancers (Bhaskaran and Harsha, 2000).
Preparation and evaluation of diclofenac sodium gels using an indigenously
valuable synthetic gelling agent acrypol 40G was studied. A simple lattice design for
preparation of the gel was employed. The amount of ethanol, propylene glycol and
polyethylene glycol 400 were chosen as the independent variables to study combined
Review of literature
Suresh Gyan Vihar University, Jaipur Page 36
effete of co-solvents. The release profiles obtained with rat skin and human cadaver
skin were found to be comparable (Gobel et al., 2000).
The in vitro iontophoretic transdermal delivery of methotrexate across pigskin
was investigated. Cathodal iontophoresis considerably increased methotrexate skin
permeation as compared to the null and methotrexate in the vehicles. It was found
that methotrexate iontophoretic transport decreased with NaCl content. It also studied
the influence of current density. It was concluded that iontophoresis could be used to
improve the topical application of methotrexate for the treatment of psoriasis
(Alvarez-Figueroa et al., 2000).
The penetrations of non-steroidal anti-inflammatory agents through the skin
were analyzed. Most non-steroidal anti-inflammatory agents are carboxylic acids,
therefore, the pKa will be an important determinant in ionization and hence
permeation. The pH partition behavior into the skin has been considered together with
the relative impact of decreased permeation but increased solubility with degree of
ionization (Hadgraft et al., 2000).
Controlled delivery of Ketamine transdermal patch was prepared and
examined in postoperative analgesia after minor abdominal gynecological surgery
using Lidocaine epidural blockade with 52 patients were randomized to one of two
groups. Epidural anesthesia was performed with 25 ml 2% plain lidocaine and
investigated. At the end of the surgical procedure, a controlled delivery transdermal
patch containing either Ketamine (25mg / 24h) was applied. The time to first rescue
analgesic was longer in the Ketamine group (23012 min) compared with the placebo
group (9454 min); (P< 0.00001). It concluded that the Transdermal-controlled
delivery of Ketamine prolonged the duration of analgesia after minor gynecological
procedures (Vera et al., 2000).
To developed and evaluated pharmacodynamic performance in male Wistar
rats of acrylate based glibenclamide transdermal drug delivery system (TDDS). The
drug dispersed in a polymeric matrix of polymethyl methacrylate and ethylcellulose
was evaluated for its hypoglycemic activity in streptozotocin induced diabetic and
normal rats in comparison with its oral route. However, the reduction was slow and
sustained in case of transdermal drug delivery system when compared to oral route
where significantly hypoglycemic response was found in all the three studies
performed (Sridevi et al., 2000).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 37
To evaluate the possibility of sustained controlled delivery system of
therapeutically active ACE inhibitors in matrix type TDS and to enhance the
transdermal absorption by synthesis of prodrugs with improved matrix solubility and
lipophilicity, enalapril and captopril were selected and formulated using drug in
adhesive transdermal drug delivery system matrix. The TDDS containing enalapril
pro-drug exhibited a significantly higher penetration rate (Li et al., 2000).
Studies were performed to establish a correlation of skin permeability with
physico-chemical parameters using five hypertension antagonists. In vitro skin
permeation studies were performed in modified vertical type diffusion cells. When
steady state fluxes of the drugs were correlated with physico-chemical properties like,
good correlation was obtained with indirectly proportional of melting point; weak
correlation was obtained with partition coefficient, molecular weight and solubility.
However skin permeability versus solubility profiles revealed an interesting trend
(Ghosh and Reddy, 2001).
The in vitro topical absorption of apomorphine from microemulsions was
studied using the skin as a membrane. Two micro emulsions were formulated and
measure thickenness of both containing 3.9 gm of apomorphine hydrochloride.
Formation drug and polymer ion pairs increased the lipophilicity of the drug. The
flux of the drug from the micro emulsion through mouse skin was 100 mcg/h/cm2 and
88 mcg/h/cm2 from emulsions. It showed good stability up to 6 months (Peira et al.,
2001).
The effect of vehicles and enhancers on transdermal delivery of melatonin was
studied. The vehicles as ethanol, PEG 400 was used alone or mixed with phosphate
buffer. Binary vehicles ethanol/buffer with PEG/buffer showed different effects on
the permeation of melatonin and its skin permeation. The permeation enhancers like
lauric acid and unsaturated oleic acid dramatically enhanced the skin permeability
coefficient of melatonin. Finally, it concluded that oleic acid in a suitable vehicle
could more effectively enhance the skin permeation of melatonin and shorten its lag
time (Han-Joon et al., 2001).
To determine the feasibility of enhanced transdermal delivery of triprolidine
for pharmacokinetics and bioavailability of triprolidine, antihistamines from the poly
(4-methyl -1-penetene) (TPX) matrix system. The triprolidine Jpx matrix was applied
to abdominal skin of rabbit and plasma concentration of triprolidine were determined
Review of literature
Suresh Gyan Vihar University, Jaipur Page 38
by HPLC. The AUC was significantly higher in enhancer group that in control group.
The average Cmax was increased significantly as well as Tmax was also increased
significantly. It was concluded that matrix could be developed as a TDS for
providing consistent plasma concentration (Sang and Jun-Shik, 2002).
The applications of confocal laser scanning microscopy was examined of the
embedment and the release characteristics parameters of chemical permeation
enhancers from "drug-in-adhesive" type TDDS. Confocal laser scanning microscopy
was explained to be an excellent tool to study how enhancers are incorporated and
diffuse into a transdermal drug delivery system (Qvist et al., 2002).
To study the effect of different terpenes on imipramine hydrochloride
permeation in ethyl alcohol-water (2:1) system was investigated. It was found that the
contribution of diffusivity in enhanced permeation of imipramine hydrochloride was
much higher in comparison to partitioning of imipramine hydrochloride in rat skin
with terpene treatment (Panchangula et al., 2002).
To formulated transdermal patches of the diltiazem hydrochloride, using
different polymers ratios like povidone (PVP) and ethyl cellulose (EC) and evaluated
for the potential drug delivery employing hairless freshly excised abdominal mouse
skin. From that, it was found that the films contained of ethyl cellulose: povidone
(2:1) should be selected for the development of transdermal patches of the diltiazem
hydrochloride, employing a feasible adhesive layer and backing membrane, for
potential therapeutic use (Gupta and Mukherjee, 2003).
To developed matrix type transdermal drug delivery system of diltiazem
hydrochloride was studied to obtain a prolonged controlled drug delivery system.
Both the membrane permeation control and matrix diffusion control systems were
developed. The membrane permeation control systems were developed used the
natural polymer chitosan, whereas matrix diffusion control systems were developed
using various combinations of hydrophilic and lipophilic polymers. The drug release
from the matrix system increased by increasing the concentration of hydrophilic
polymer but the release from the membrane system decreased on cross linking the rate
controlling membrane and with drug reservoir gel on addition of citric acid to the
chitosan (Jain et al., 2003).
To in vitro skin permeation studied was carried out from transdermal
application of 2, 3, 5, 6-tetra methylpyrazine (TMP) in the systemic circulation in
Review of literature
Suresh Gyan Vihar University, Jaipur Page 39
rabbits. The results found that the observed drug concentration from transdermal drug
delivery by convolution method was in good agreement with the predicted drug
absorption profiles. Overall concluded that in vitro skin permeation tests could be
helpful to predict in vivo drug absorption profiles following transdermal drug delivery
(Qi et al., 2003).
The transdermal drug delivery system of metoprolol tartrate were prepared by
the film casting on a mercury substrate as monolithic matrix and characterized in
vitro skin permeation studied, drug release studied, and drug-excipients interaction
analysis. On the basis of in vitro skin permeation and drug release performance, it was
concluded that formulation MT-4 was found to be better than the other formulations
and it was selected as the optimized formulation (Aqil and Ali, 2003).
The different matrix, drug-in-adhesive and reservoir formulations of fentanyl
transdermal patches were designed and evaluated. Different types and amounts of
liquid, pressure- sensitive adhesives (PSAs) were used and evaluated with respect to
drug release and adhesive properties. A very simple but precise method, the simplified
peel 180° test, was developed to measure and compare adhesive properties of
transdermal patches. The results showed that release kinetics obeyed the square root
of time or Higuchi model, indicating the diffusion controlled release mechanism
(Mehdizadeh et al., 2004).
The in vitro drug release and permeation of caffeine from bioadhesive
transdermal patch was investigated and characterized the release kinetics of caffeine
from the patches. When drug loading is less (ie, caffeine is dissolved in the polymers
constituting the film), the control occupy in the skin. When caffeine loading surmount
its solubility in the film, the permeation profile is not linear, but shows a sort of
outburst effect in the earlytimes of permeation, probably owing to the presence of
solid drug and/or to a certain degree of „„conserved supersaturation‟‟ in the solid
phase (Nicoli et al., 2005).
Transdermal patch of clonidine was developed in KBD-transdermal
therapeutic system (TTS), for the treatment of attention shortage hyperactivity
disorder in children using ethylene vinylacetate as penetration rate controlled
membrane in the patch. The in vitro kinetic release rate of the clonidine from patch
significantly correlated with the in vivo absorption rate (Ke et al., 2005).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 40
The potential of proniosomal carrier system as a transdermal drug delivery for
captopril for the treatment of hypertension was developed that was capable of
efficiently delivering entrapped drug over an extended period of time. The potential of
proniosomes as a transdermal drug delivery system for captopril was investigated by
encapsulating the drug in various formulations of proniosomal gel composed of
various ratios of sorbitan fatty acid esters, cholesterol, lecithin prepared by
coacervation-phase separation method. In vitro studies showed prolonged release of
entrapped captopril. At refrigerated conditions, higher drug retention was observed
(Gupta et al., 2007).
A matrix-type transdermal drug delivery system containing carvedilol with
different ratios of hydrophobic and hydrophilic polymeric combinations by the
solvent evaporation technique. The results advised no physicochemical interaction
between the drug and the polymers. The developed transdermal films that increase the
efficacy of carvedilol for the therapy of hypertension (Ubaidulla et al., 2007).
The therapeutic effect of nanoemulsion formulations for transdermal delivery
of celecoxib (CXB) as model drug. The in vitro drug skin permeation profile of
optimized formulations was compared with CXB gel. The finding indicated that
nanoemulsions are more effective vehicles for improved transdermal delivery of CXB
(Baboota et al., 2007).
Valdecoxib are highly a selective COX-2 inhibitor that produces serious side
effects when given orally. This has led to its secession. Transdermal drug delivery
system of valdecoxib was formulated and evaluated for its efficacy and safety.
Concentration of valdecoxib used in the preparation downplays the risk of systemic
effects, as shown by the rat plasma analysis of valdecoxib may be alternative to oral
preparations. The result showed no significant difference between bleeding and
clotting time before and after application (Kesavanarayanan et al., 2007).
The oral bioavailability of atenolol and metoprolol tartrate is inadequate,
different matrix-type transdermal patches of atenolol and metoprolol tartrates were
formulated to study the effect of polymers on transdermal drug release. The polymers
selected were PVP, cellulose acetate phthalate, HPMC, phthalate and ethyl cellulose.
These results suggested that maximum release was obtained at 48 h. The drug
permeation profile across cadaver skin showed about 27% of decrease in the amount
Review of literature
Suresh Gyan Vihar University, Jaipur Page 41
of drug release as that compared to rat abdominal skin was used (Agrawal and
Munjal, 2007).
The effects on the antihypertension activity and pharmacokinetics profile of a
novel transdermal patch of isosorbide dinitrate with bisoprolol. The in vitro
transdermal drug penetration profile of both isosorbide dinitrate and bisoprolol from
the patches showed a zero-order process. The transdermal patches of isosorbide
dinitrate with bisoprolol could be promising for prevention and treatment of
hypertension (Zhaoa et al., 2007).
The novel transdermal films as a matrix of metoprolol tartrate were prepared
by casting on mercury substrate using different ratios of polymers, ethyl cellulose and
polyvinyl pyrrolidone, employing dibutyl phthalate as a plasticizer. It was observed
that for potential therapeutic use, monolithic drug matrix films composed of ethyl
cellulose: polyvinyl pyrrolidone (3:2) may be suitable for the development of a matrix
type system of metoprolol tartrate (Bhatt et al., 2008).
Transdermal drug delivery system based on liquid crystals was prepared by
using liquid crystals in already prepared matrix based transdermal patch and evaluated
for physibility studies like drug content, moisture content, tensile strength, anisotropy,
water vapor transmission and In vitro drug release studied (Omray et al., 2008).
To developed a transdermal delivery based on metered dose spray formulation
of oxybutynin and evaluated in vitro characterization of the optimized formulation.
The results suggested that the metered dose transdermal formulation can be a
promising and advanced therapeutic system for the transdermal administration of
oxybutynin (Bajaj et al., 2008).
To developed transdermal drug delivery system of Aceclofenac in polymeric
matrix by the solvent evaporation technique of different ratios of hydrophilic
(hydroxyl propyl cellulose) and hydrophobic (ethyl cellulose) polymers using 15 %
w/w of dibutyl phthalate of the polymer weight, integrated as plasticizer. The results
followed the release profile of Aceclofenac followed first-order kinetics and mixed
zero-order in different formulation. These results indicated that the formulation
optimized containing 15% of oleic acid with 10% Isopropyl myristate increased
penetration of Aceclofenac through rat skin (Patel et al., 2009a).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 42
Transdermal drug delivery system of Diclofenac Sodium were formulated by
using different polymer combinations such as hydrophilic and mixture of hydrophilic
- lipophilic polymers. In vitro drug release study through cellophane membrane
indicates that hydrophilic polymer showed better release than the hydrophilic -
lipophilic mixtures. The results followed the release profile of Diclofenac Sodium
followed first order rate kinetic. Skin irritation study shows that the optimized films
are nonirritant (Jadhav et al., 2009).
Various penetration-enhancing approaches to improve drug permeation of the
skin (stratum corneum) have been attempted. These approaches are of two types:
chemical and physical. The chemical approaches are mainly effective in increasing
the skin permeation of low-molecular chemicals, whereas physical means are
effective for these chemicals but also high-molecules like peptides, proteins and
nucleotides (DNA or RNA). Marked development has been observed in these physical
means in the past decade. In addition, a recent development in tissue engineering
technologies enables the use of cultured skin containing keratinocytes and fibroblasts
as a TDDS. An effective “cell delivery system” may be a reality in the near future
(Sugino et al., 2009).
Transdermal film of metformin hydrochloride (MFH) was prepared and
evaluated using combinations of a hydrophobic polymer, ethyl cellulose and
hydrophilic polymer, polyvinyl pyrrolidone in different ratios by solvent evaporation
technique. The effect of storage on in vitro release and physiochemical parameters of
selected patch was found within the acceptable limits. The drug polymer interaction
study does not show any significant incompatibility among the drug and polymers
(Das et al., 2010).
Anti-inflammatory drug ketoprofen was encapsulated in formulation niosomes
for topical therapeutic applications. Noisome of ketoprofen were formulated using
cholesterol, surfactant, dicetyl phosphate & drug mixture in different weight ratios by
thin film hydration method. The formulated niosomes were characterized by various
physic-chemical parameters & drug release studied of ketoprofen in niosomes were
carried out by double beem UV Visible spectrophotometric method (Arora and
sharma, 2010).
Transdermal matrix patches can be formulated of Rosiglitazone maleate using
suitable Duro-Tak 87-2852 and Duro-Tak 387-2516 pressure-sensitive adhesive
Review of literature
Suresh Gyan Vihar University, Jaipur Page 43
polymers without any gelling agent. Moreover, Toxicity of drug due to the risk of
sudden high blood concentration in blood can avoid with sustained-release, and an
extended blood level of the drug is desirable for the treatment of Type 2 diabetic
patients (Damodharan et al., 2010).
The formulated transdermal patches of an anti-histaminic drug-
Chlorpheniramine maleate (CPM) in different bioadhesive polymers such as cellulose
acetate, polyvinyl pyrrolidon, and ethyl cellulose with different plasticizers such as
propylene glycol and polyethylene glycol 400. Patches were formulated by solvent
evaporation method, evaluated for their physic-mechnical parameters and then
carryout to stability study of optimized formulae to be evaluated in vitro and in vivo.
The results indicated that Chlorpheniramine maleate transdermal patch has better
bioavailability than an oral tablet of the same dose, with less administration frequency
and lower plasma fluctuation (Iman et al., 2010).
The developed and evaluated transdermal drug delivery system in polymer
matrix containing Ketotifen fumarate with different ratios of both hydrophilic and
hydrophobic polymeric proportions by the solvent evaporation method. The results
suggested Higuchi kinetics (r2), and the mechanism of drug release was diffusion
mediated. The developed transdermal patches increase the efficacy of Ketotifen for
the therapy of asthma and other allergic conditions (Shivaraj et al., 2010).
An attempted was made to formulated and evaluated the curcumin transdermal
drug delivery system by solvent casting method employing polymers like HPMC,
ethyl cellulose at various ratios and the yield was noted. This was done for three
formulations F1, F2, F3. It was found that formulation F1 showed the best
compatibility on the basis of all tests performed (Saraswathi et al., 2010).
The transdermal patches were prepared of Ketoprofen as matrix based by the
solvent evaporation method with Ficus reticulata fruit mucilage. The results observed
that the drug release from the patch prolonged as the proportion of Ficus reticulata
increased in controlled manner. The results was over that Ketoprofen can be
developed as transdermal patches for prolong release with Ficus reticulata fruit
mucilage (Swetha et al., 2010).
The studied of a suitable matrix type therapeutic of olanzapine in fused of two
different proportion of polymers, ethylcellulose (EC) and polyvinylpyrrolidone
(PVP). Best selected formulations were suggested to be suitable for formulating in
Review of literature
Suresh Gyan Vihar University, Jaipur Page 44
repect of physicochemical parameters and there was no significant interaction
observed between the drug and polymers used (Sharma et al., 2010).
The transdermal patches of ligustrazine were developed and evaluated for
good entrapment efficiency, rate of release, and topical absorption. Ligustrazine
ethosomes were prepared using acrylic resin, adding succinic acid as a crosslinking
agent and triethyl citrate as a plasticizer with entrapment efficiency as an indicator by
ethanol injection-sonication. The pharmacokinetic results concluded that the relative
bioavailability was increased (Liu et al., 2011).
Transdermal patches were developed of Rivastigmine is a cholinesterase
inhibitor which improves cognitive function. The latter form is currently used for
most excellent compliance and few side effects. The most common cutaneous side
effects are irritative dermatitis. We found the second case of active sensitization by
the rivastigmine-patch in Alzheimer‟s dementia suffering patient (Grieco et al., 2011).
Transdermal patches containing Solid Lipid Nanoparticles of Repaglinide was
used to maintain the blood glucose level in diabetic patients. Antidiabetic drug -
Repaglinide was integrated in Solid lipid Nanoparticles (SLNs) using cephalin and
lecithin as lipids and Tween 80 as stabilizer by a hot homogenization method. Solid
lipid Nanoparticles loaded transdermal patches observed more suitable controlled
release kinetics for protein delivery (Vijayan et al., 2011).
The aim of this study was to developed an elemene transdermal drug delivery
system by choosing suitable drug-loaded matrices and permeation enhancers and to
observe their effects in this system. The amount of polyvinyl alcohol and sodium
carboxymethyl cellulose in the matrices had obvious effects on the penetration ability
of elemene. Types and concentration of the penetration enhancers had effect on the
permeability of elemene through skin (Zeng et al., 2011).
2.2 Polymer
A transdermal drug delivery system of flurbiprofen as matrix dispersion type
was designed and developed. The different conc. ratio and grades of hydroxy propyl
methyl cellulose (HPMC) were used. Patches of flurbiprofen were formulated using
varying concentration of HPMC K4M, HPMC K15M, HPMC K100M and containing
constant drug concentration (10mg per patch). The release followed Higuchi kinetics.
Review of literature
Suresh Gyan Vihar University, Jaipur Page 45
In vitro evaluation of patches was carried out on healthy rabbits and incomplete block
design are balanced (Verma and Murthy, 1997).
Matrix films of terbutaline sulphate were formulated as monophilic matrix
using polymers like HPMC, sodium carboxymethylcellulose, cellulose acetate and
ethyl cellulose were used. In vitro permeation studies were performed across isolated
skin of human cadaver using Keshary-Chien type diffusion cell. The formulations
also showed an appreciable release after 8 hours (Murthy, et al., 1997).
A matrix-dispersion-type transdermal delivery system was designed and
developed to improve bioavailability and achieve a smoother plasma-concentration
profile for propranolol as compared with oral administered, using different
concentration ratios of polymers like hydroxyl propyl methyl cellulose (HPMC) as
per viscosity grade K4M, K15M and K100M. The results observed that drug release
followed Higuchi kinetics rather than zero–order or first order kinetics (Verma and
Iyer, 2000).
Transdermal drug delivery system was designed and formulated of
theophylline and salbutamol sulphate employing hydroxypropylmethylcellulose
(HPMC). The T1/2 of the drugs were significantly extended rather than tablets.
During the period of 7 days no signs of erythema or oedema were observated in
volunteers (Murthy and Hiremath, 2001).
A matrix-dispersion-type transdermal delivery system of verapamil
hydrochloride was formulated employing four various polymers: Eudragit RL100,
Eudragit RS100 (ERS100), HPMCK15M and ethyl cellulose, different in degrees of
hydrophilicity and hydrophobicity. The invivo parameters estimated from blood levels
of the drug revealed a profile of typical of a controlled release formulation (Kusum
Devi et al., 2003).
The development a transdermal therapeutic system of a membrane moderated
of Nimodipine employing gel reservoir system of hydroxypropylmethylcellulose
(HPMC) containing 10% (w/w) of carvone as penetration enhancer in 60 % (v/v)
ethanol. Results indicated that the TTS of Nimodipine provided sustained plasma
concentration of the drug with minimal fluctuation (Krishnaiah et al., 2003).
The effect of limonene on in-vitro permeation of Nimodipine through the fresh
skin of rat abdominal from a 2% w/w hydroxyl propyl methylcellulose used as gel
reservoir system was studied. The results suggest the limonene is helpful for
Review of literature
Suresh Gyan Vihar University, Jaipur Page 46
increasing the skin permeability of Nimodipine from TTS containing HPMC gel as a
reservoir (Krishnaiah et al., 2004a).
The development of a limonene based membrane-moderated transdermal
therapeutic system of Nimodipine was formulated and evaluated. Here 2% w/w
hydroxy propyl methyl cellulose used as gel reservoir system using 4% w/w of
limonene as a penetration enhancer. The pharmacokinetic study indicated that the
TTS of Nimodipine provided constant plasma concentration of the drug with minimal
fluctuations for 20 h with improved bioavailability rather than the immediate release
tablet dosage form (Krishnaiah et al., 2004b).
The permeability of carvedilol from transdermal films, which is made by using
hydroxy propyl methylcellulose (HPMC) as polymeric matrix and PEG as plasticizer
and sodium lauryl sulphate (SLS), tween 20, dimethyl sulfoxide (DMSO) and
polyethylene glycol (PEG 400) were used as permeation enhancers were investigated.
The results suggested that the combination of permeation enhancers and ionto-
phoresis could be useful for enhancing the skin permeability of carvedilol through the
matrix TDDS (Ubaidulla et al., 2004).
The membrane was developed to controlled transdermal systems of
glibenclamide using carbopol gel as reservoir system and Eudragit RL-100, Eudragit
RS-100, ethyl cellulose, and Ethylene vinyl acetate (EVA) as rate controlling
membranes. The formulations containing different rate controlling membranes
verying in drug release/permeation profiles were observed. There are no changes in
the surface morphology after in vitro skin permeation studies of EVA membranes by
SEM. (Mutalik et al., 2005).
Matrix type transdermal systems were formulated containing the combinations
of ethyl cellulose/PVP and ERL-100/ERS-100. The different formulations verying in
drug permeation profiles were observed. The in vivo results indicated that the film
successfully prevented the severe hypoglycemia in the initial hours and they were also
effective on chronic application. The transdermal route showed negligible skin
irritation and produced better improvement with all the tested in vivo parameters
rather than oral administration (Mutalik et al., 2006).
Chitosan and hydroxypropylmethylcellulose fused in dissimilar compositions
have been by the solvent casting method. It may be concluded that a chitosan/HPMC
Review of literature
Suresh Gyan Vihar University, Jaipur Page 47
fused could be a promising approach for formulating a TDDS as they have good film
forming property (Siddaramaiah et al., 2006).
The activity of ampicillin sodium was developed as transdermal patch against
Escherichia coli. The E. coli stains were exposed to transdermal patch with different
kinds of polymers such as sodium alginate, cellulose acetate phthalate,
hydroxypropylmethylcellulose, chitosan and carboxymethylcellulose and the drug
releasing capacity was studied through colony-forming units (CFU). It was found out
that hydroxypropylmethylcellulose was the best polymer that gave less number of
CFU, followed by carboxyl methyl cellulose, chitosan, cellulose acetate phthalate and
sodium alginate ( Bagyalakshmi et al., 2006).
Transdermal drug delivery system of carvedilol using HPMC as drug reservoir
system was prepared by the solvent evaporation techniques. In this observation,
Eudragit RL100 and Eudragit RS100 membrane were cast to achieve steady state
release of the drug. The prepared films possessed satisfactory physic-chemical
characteristics. Moisture vapour transmission across the film followed zero-order
kinetics. The patches have no any sign of potentially hazardous skin irritation
(Tanwar et al., 2007).
To developed and evaluated transdermal therapeutic systems of ampicillin
sodium using different polymers like hydroxypropylmethylcellulose, cellulose acetate
phthalate, methylcellulose, sodium alginate, chitosan and sodium carboxy methyl
cellulose in an ethanol: buffer volatile systems pH 7.4 by the solvent evaporation
techniques with rate-controlling membrane for all the systems. Therefore, it can be
concluded that hydrophilic ampicillin sodium can be developed as a transdermal
therapeutic system with sodium alginate as compared to intravenous administration
(Bagyalakshmi, et al., 2007).
The present study was objective to evaluated the possibility with different
concentrations ratio and various polymeric grades of hydroxypropylmethylcellulose
(K4M, K15M and K100M) for transdermal systems of methotrexate. A significantly
in vitro/in vivo correlation was indicated when percent drug released profile was
correlated with serum drug concentration profile. The result can be concluded that the
selected formulations are best in their in vitro dissolution and pharmacokinetic
parameters and thus obtain potential for transdermal system (Verma, et al., 2008).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 48
Transdermal therapeutic systems of tramadol hydrochloride were developed of
a NSAI drug, using hydroxypropyl methylcellulose, ERL-100 and ERS-100
containing triethyl citrate as a plasticizer with dimethyl sulfoxide (DMSO) as a
penetration enhancer. The result can be concluded that the Eudragit produce
crystallization free patch (Shinde, et al., 2008).
The transdermal patches for nitrendipine were formulated by the film casting
techniques (glass ring) on mercury substrate. The results of this study indicated that
combination of Eudragit RL 100: PVP K 30 are better in a 4:6 ratio. FTIR and Thin
layer chromatigraphy studied indicated no drug and polymer interactions (Mittal, et
al., 2009).
To developed HPMC based transdermal delivery of pentazocine. Statistically,
a good correlation was observed between percent of drug absorbed from patches was
correlated with Cmax and AUC(s). A good correlation was also observed when
percent drug released vs the blood drug concentration obtained at the same time point.
The results can be concluded that the polymeric matrix films of pentazocine obtained
potential for transdermal delivery (Prasad Verma & Chandak, 2009).
The present study was objected to developed and evaluated transdermal drug
delivery systems of nicorandil with different polymeric grades of
hydroxypropylmethylcellulose (6cps, 15cps, and K4M) for an antianginal drug. The
best formulations were subjected for their ex vivo studies on porcine ear skin
(Jamakandi, et al., 2009).
Transdermal patch of reservoir system for delivery of ketorolac was studied. A
transdermal patch for delivery of ketorolac from reservoir system thus appears to be
feasible of delivering ketorolac across skin (Amrish and Kumar, 2009).
The potential applications of highly biocompatible of transdermal therapeutic
system (TTS) as a tropical drug carrier system for the transdermal delivery of
Ketoprofen. The films were formulated by employing hydroxypropylmethylcellulose
and polyethylene glycol 400. Results it can be concluded that, the formulated
transdermal films can be selected to achieve steady state release of the drug and
showed good skin tolerability (Somashekhara, et al., 2009).
Drug reservoir transdermal patches were formulated by solvent evaporation
methods using hydrophilic and hydrophobic polymers containing ethylcellose and
eudragit RS 100 polymers as drug reservoir were used to achieve controlled drug
Review of literature
Suresh Gyan Vihar University, Jaipur Page 49
release. On the basis of kinetic studies, the patch of both HPMC and Eudragit RS100
indicated satisfactory drug release patterns (Vijayan, et al., 2010).
Transdermal patches of Celecoxib were prepared with different polymers such
as hydroxyl propyl methyl cellulose, methyl cellulose, Polyvinylpyrolidone (PVP).
The in-vitro drug release from the patches was studied employing commercial semi
permeable membrane. The prepared formulation were subjected to various physic-
chemical characterization, in-vitro dissolution studies and kinetics studies shows
diffusion might be one of the outstanding mechanism influencing the drug release.
(Jayaprakash, et al., 2010).
Papaverine hydrochloride transdermal patches of were prepared by the solvent
casting method with different ratios of ethyl cellulose: Polyvinylpyrolidone, PVA:
Polyvinylpyrolidone and Eudragit RL100: Eudragit RS100. On the basis of kinetic
studies, patches containing the hydroplilic polymers indicated satisfactory drug
release patterns (Shah, et al., 2010).
A non-effervescent multiparticulate floating microballoons of famotidine
using Eudragit - L100 polymer prepared by emulsion solvent diffusion method for
improving the bioavailability. Thus microballoons of famotidine with acrylic polymer
Eudragit L-100 could to be an ideal novel floating dosage form for regulating the drug
delivery into the upper part of the intestine with assured enhancement in oral
bioavailability (Narayan, et al., 2010).
The present investigation was to objective that microencapsulated for the
Anti-Hypertensive drug with Eudragit-RS100 by solvent evaporation techniques.
Metoprolol Tartarte to provide Sustain Release and maintain constant the plasma
drug concentration and reduce the frequent administration and improve the Patient
compliance, unwanted side effects and Dose dumping (Karthikeyan, et al., 2010).
The recrystallized agglomerates was prepared using solvent change
technique with three solvents system for the enhancement of solubility, dissolution
rate and other physicochemical properties of roxithromycin (RTM). The effect of
various hydrophilic polymers like hydroxylpropylmethylcellulose, polyethylene
glycol and polyvinyl pyrrolidone (PVP) were observed on the solubility, rate of
dissolution and other physic-chemical parameters (Yadav and Yadav, 2010).
Buccal therapeutic systems for losartan potassium in the form of bioadhesive
films were developed and characterized using different bioadhesive polymers like
Review of literature
Suresh Gyan Vihar University, Jaipur Page 50
HPMC, Eudragit RS-100, Eudragit RL-100 and Ethylcellulose with glycerol as
plasticizer for improving bioavailability by solvent casting method. The results
indicated that, therapeutic level of losartan potassium can be achieved using this
buccoadhesive formulation (Shivhare, et al., 2010).
The matrix type TDDS for Lercanidipine hydrochloride (LRDP) were
formulated by solvent evaporation techniques with polymeric Eudragit RL100
(ERL) and hydroxypropylmethylcellulose. All the formulations exhibited
satisfactory physicochemical characteristics (Mamatha, et al., 2010).
The formulated floating hollow microspheres of Rosiglitazone Maleate
(RSM), which is soluble and shows better absorption in gastric pH using ethyl
cellulose, eudragit S100, polyethylene oxide and hydroxyproply methyl cellulose
(HPMC K15M) as polymers by modified Quasi-emulsion diffusion technique (
Gangadharappa, et al., 2011)
The transdermal patch containing Glibenclamide and Atenolol was designed
and developed using fused of different polymeric ratio such as
hydroxypropylmethylcellulose, Polyvinylpyrolidone and carbopol. The developed
transdermal patch containing Glibenclamide & Atenolol might be a milestone in the
combinational therapy of diabetes and hypertension (Mohamed, et al., 2011).
The physical properties of polymers used for modified-release coating of
pharmaceutical dosage forms are governed by several variables such as
plasticization, temperature and humidity. Eudragit® RS100 and eudragit® RL 100
polymer films would become brittle without the addition of plasticizers (Asnani &
Parashar, 2011).
The objective of this study was to designed a prolonged release dosage form
to be used for targeted and controlled release drug delivery using ethyl cellulose and
Eudragit RS100 provide a potentially useful means of drug delivery because they are
stable, both physic-chemically amenable to preparation in large batches. The
optimized formulation exhibited highest drug entrapment efficiency and the release
of drug was also sustained for more than 24 hours (Senthil, et al., 2011).
Multiparticulate floating drug delivery system of aceclofenac was to
prepared and evaluated using eudragit RS 100 as a release rate controlling polymer
by emulsification solvent evaporation technique. The developed floating
microspheres of aceclofenac may be used for prolonged drug release for at least 12 h
Review of literature
Suresh Gyan Vihar University, Jaipur Page 51
for maximizing the therapeutic efficacy along with patient compliance (Kancharla,
et al., 2011).
2.3 Drug
A simple, selective, rapid, precise and economical RP-HPLC method has been
developed for the simultaneous estimation of nebivolol and hydrochlorthiazide from
pharmaceutical formulation with a mobile phase consisting of acetonitrile: 50mM
ammonium acetate at a flow rate of 1.0 ml/min was used. The proposed method was
validated in terms of accuracy, precision, linearity, limit of detection, limit of
quantitation and solution stability (Meyyanathan et al., 2008).
A simple, specific, accurate and stability indicating reversed phase liquid
chromatographic method was developed for the determination of nebivolol
hydrochloride in tablet dosage forms with mobile phase containing methanol:
acetonitrile: 0.02 M potassium dihydrogen phosphate (60:30:10, v/v/v; pH 4.0) was
used. The retention time of nebivolol hydrochloride was 2.6 min. The linearity for
nebivolol hydrochloride was in the range of 0.2-10 μg/ml. The recovery was found to
be in the range of 98.68-100.86%. The detection limit and quantification limit were
found to be 0.06 μg/ml and 0.2 μg/ml, respectively. The proposed method was
validated and successfully applied to the estimation of nebivolol hydrochloride in
tablet formulations (Shah et al., 2008).
Nebivolol hydrochloride and Amlodipine besylate in combination are
available as tablet dosage forms in the ratio of 1: 1. Two simple, sensitive, accurate,
and reproducible methods have been developed for simultaneous estimation of both
using methanol as solvent. Estimation of Amlodipine besylate was done directly from
its absorbance at 238 nm and 360 nm for method I and II respectively. While
estimation of nebivolol hydrochloride is done by the equations derived. The method is
validated statistically. The recovery studies confirmed the accuracy of the proposed
methods (Mishra et al., 2009).
A Simple, rapid, precise, accurate, specific and sensitive ion-paired reverse
phase liquid chromatographic method has been developed for the simultaneous
estimation of nebivolol hydrochloride and valsartan in their capsule formulation
mobile phase consisting of methanol: water (80:20 v/v) with addition of 0.1 percent 1-
hexanesulfonic acid monohydrate sodium salt as an ion-pairing reagent was selected.
Review of literature
Suresh Gyan Vihar University, Jaipur Page 52
The method was validated and produced accurate and precise results for estimation of
the two drugs (Kokil & Bhatia 2009).
Quantitative estimation of poorly water-soluble drugs involves use of organic
solvents. Major drawbacks of organic solvents include high cost, volatility and
toxicity. In the present investigation, hydrotropic solubilization is employed to
enhance the aqueous solubilities of poorly water-soluble drugs Nebivolol
hydrochloride in one-component tablet formulation for simultaneous
spectrophotometric determination. For simple, accurate and economical procedures
employed are simultaneous equation method, calibration method. The hydrotropic
agent and additives used in the manufacture of tablets did not interfere in the analysis.
The results of analysis have been validated statistically and by recovery studied
(Sharma et al., 2010).
Simultaneous quantification of nebivolol hydrochloride (NEB-H) and
hydrochlorothiazide (HCT) in tablets by UV spectroscopy, RP-HPLC and HPTLC
methods were developed. Recovery studies of 98.88-102.41%, percentage relative std
deviation of not more than 0.8 and correlation coefficient (linearity range) of 0.9954-
0.9999 shows that developed methods were accurate and precise (Dhandapani et al.,
2010).
Two simple spectrophotometric methods have been developed for
simultaneous determination of Amlodipine besylate and Nebivolol hydrochloride in
tablet formulation. The first method is Absorbance correction and second method is
based on Absorbance ratio in which wavelengths selected. The methods were
validated in terms of accuracy, precision, ruggedness and specificity. The methods
can be routinely adopted for quality control of these drugs in tablet (Chandnani et al.,
2010).
Simple, sensitive and specific spectrophotometric method was developed and
validated for quantification of nebivolol in tablet dosage form. The percentage
recovery was found to be 99.3% and showed good repeatability with relative standard
deviation less than 2. So, the proposed method can be applied for the routine analysis
of nebivolol from formulations (Parambi et al., 2010).
The goal of this investigation was to developed new spectrophotometric
methods viz. AUC method and first derivative spectroscopy method, for simultaneous
determination of Nebivolol hydrochloride (NEB) and Hydrochlorothiazide (HCT) in
Review of literature
Suresh Gyan Vihar University, Jaipur Page 53
bulk and in combined tablet dosage form, which were used for the validation of
linearity, accuracy and precision. Both the drugs obey linearity with absorbance in the
concentration ranges employed for these methods. These methods were found to be
simple, sensitive, rapid, accurate, reproducible and economical. The methods have
been validated statistically and by recovery studies (Shah et al., 2010).
A sensitive, selective, precise and stability indicating high-performance thin-
layer chromatographic method of analysis of Amlodipine besylate and Nebivolol
hydrochloride both as a bulk drug and in formulations containing these two in
combination was developed and validated. The method was validated for linearity,
accuracy, specificity, LOD, LOQ, precision and robustness. The statistical analysis
proved that the method is repeatable and selective for the estimation of the said drugs.
As the method could effectively detect the drugs in the presence of their degradation
products, it can be employed as a stability indicating one (Dhangi et al., 2010).
A simple high-performance liquid chromatography RP-HPLC and two
reproducible UV spectrophotometric methods were developed and validated for the
estimation of nebivolol HCl and valsartan simultaneously in combined
pharmaceutical solid dosage form. The accuracy of these methods evaluated by
recovery measurements and good recovery results obtained from 98.28% to 102.25%
for all the methods and the relative standard deviation of below 3% were achieved
(Birajdar et al., 2011).
A simple, rapid, accurate and precise RP-HPLC methods was developed and
validated for rapid assay of Nebivolol in tablet dosage form. Separation of Nebivolol
was performed by Chromatographic methods using a C18 column with stationary
phase as a mobile phase containing 0.05 M of potassium dihydrogen phosphate,
methyl alcohol (30:70 V/V) at flow rate of 1.0 ml/min and U.V detection at 225 nm.
The limits of detection and quantification were found to be 0.15 and 0.5ppm
respectively. The linearity of Nebivolol is in the range of 10-50 ppm/ml. The recovery
was calculated by standard addition method. The proposed method was found to be
accurate, precise and rapid for the analysis of Nebivolol in formulation (Krishnaveni
& Satyannarayana, 2011).
Nebivolol is a novel β1-blocker with a greater degree of selectivity for β1-
adrenergic receptors possessing an ancillary vasodilating effect. The haemodynamic
and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind,
Review of literature
Suresh Gyan Vihar University, Jaipur Page 54
placebo-controlled cross-over study. Plasma concentrations of the separate
enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive
patients were similar to those in healthy subjects (Himmelmann, et al., 1996).
Nebivolol is a new β1-blocker with a greater degree of selectivity for β1-
adrenergic receptors than other agents in this class and a nitric oxide (NO)-
potentiating, vasodilatory effect that is unique among beta-blockers currently
available to clinicians (nebivolol is approved in Europe and is currently under review
in the US). A NO-potentiating agent such as nebivolol may have an important role in
hypertensive populations with reduced endothelial function such as diabetics, African-
Americans and those with vascular disease. Nebivolol is a racemic mixture with beta-
blocker activity residing in the d-isomer; in contrast, l-nebivolol is far more potent in
facilitating NO release. The efficacy of nebivolol has been tested successfully in
clinical trials against other agents including other beta-blockers, angiotensin-
converting enzyme-inhibitors and calcium channel antagonists in patients with
hypertension, angina, and congestive heart failure. The tolerability of nebivolol has
been shown to be superior to that of atenolol and metoprolol (Robert Weiss, 2006).
Nebivolol is a third generation β-blocker, which can be distinguished from
other beta-blockers by its hemodynamic profile. It combines beta-adrenergic blocking
activity with a vasodilating effect mediated by the endothelial L-arginine nitric oxide
(NO) pathway. Endothelium-derived NO is important in the regulation of large
arterial stiffness, which in turn is a major risk factor for cardiovascular disease.
Treatment with nebivolol increases the release of NO from the endothelium and
improves endothelial function, leading to a reduction in arterial stiffness. Decreased
arterial stiffness has beneficial hemodynamic effects including reductions in central
aortic blood pressure. Unlike first generation beta-blockerrs, vasodilator beta-
blockerrs such as nebivolol have favorable hemodynamic effects, which may translate
into improved cardiovascular outcomes in patients with hypertension (John 2007).
Nebivolol appears to be well tolerated with an adverse event profile that is at
least similar, if not better, than that of other beta-adrenergic blockers. Studies suggest
that long-term therapy with nebivolol improves left ventricular function, exercise
capacity, and clinical endpoints of death and cardiovascular hospital admissions in
patients with stable heart failure. To date, it is one of the only beta-adrenergic
blockers that have been exclusively studied in elderly patients. Additionally, the
Review of literature
Suresh Gyan Vihar University, Jaipur Page 55
unique mechanism of action of nebivolol makes it a promising agent for treatment of
chronic heart failure in high-risk patient populations, such as African Americans
(Veverka et al., 2007).
Nebivolol produces unlike nitric oxide (NO)-potentiating, vasodilatory effect
that is unique among beta-blockers, lacks intrinsic sympathomimetic activity and
possesses a tolerability profile similar to that of other beta blockers (Hilas et al.,
2009).
Nebivolol showed antiepileptic effects along with antihypertensive effect,
which could be assigned to action of the two drugs across different mechanisms or
due to drug interaction that may be pharmacodynamic or pharmacokinetic needing
elucidation (Goel et al., 2009).
Nebivolol treatment of untreated hypertensive patients led to a significant
improvement in endothelial function compared with bisoprolol treatment, despite the
similar effect on BP with either therapeutic agent (Simova et al., 2009).
Nebivolol to improve artery stiffness to a greater extent than older β-blockers.
Because endothelial dysfunction and increased arterial stiffness play an important role
in the early atherosclerotic processes and are associated with poor outcomes and
independently of blood pressure, increased mortality, consequently improve
endothelial function and arterial stiffness and the ability of nebivolol to enhance
release of endothelium-derived nitric oxide, may have significant clinical
implications for the use of this agent in the treatment of hypertension and
cardiovascular diseases (Jhon 2007, Rosei et al., 2009).
Observation such as urine analysis, blood sugar, lipid profile, kidney function
test, and ECG were performed before starting the treatment. Any adverse effects
during the treatment were noted. Adverse effects such as dizziness, fatigue and
headache were reported with both drugs (Sahana et al., 2010).
Heart failure is a common and disabling condition with morbidity and
mortality that increase dramatically with advancing age. The effects of nebivolol on
left ventricular function in elderly patients with chronic heart failure (ENECA) and
the study of effects of nebivolol intervention on outcomes and rehospitalization in
seniors with heart failure (SENIORS) have been specifically aimed to assess the
efficacy of beta-blockade in elderly heart failure patients. The results of these two
trials demonstrate that nebivolol is well tolerated and effective in reducing mortality
Review of literature
Suresh Gyan Vihar University, Jaipur Page 56
and morbidity in older patients, and that the beneficial clinical effect is present also in
patients with mildly reduced ejection fraction. However, further targeted studies are
needed to better define the efficacy as well as safety profile in frail and older patients
with comorbid diseases (Sindaco et al., 2010).
Nebivolol prevented salt-induced kidney injury and associated proteinuria in
SHR through a blood pressure-independent mechanism. Its protective effects may be
related to reduction in oxidative stress, increases in neuronal NOS and restoration of
angiotensin II type 1/mas receptor balance (Varagic et al., 2010).
Insulin resistance is associated with obesity and may be accompanied by left
ventricular diastolic dysfunction and myocardial remodeling. Decreased insulin
metabolic signaling and increased oxidative stress may promote these maladaptive
changes. We hypothesized that nebivolol would attenuate diastolic dysfunction and
myocardial remodeling by blunting myocardial oxidant stress and promoting insulin
metabolic signaling in a rodent model of obesity, insulin resistance, and hypertension
(Zhou et al., 2010).
Recently, it was reported that nebivolol also acts as an oestrogen receptor (ER)
agonist. To investigate the neuroprotective potential of oestrogens, we assessed the
oestrogenic effects of nebivolol induces oestrogen-dependent gene transcription, and
protects neuronal cells against oxidative stress. Moreover, nebivolol modulates
processing of APP in mouse neuronal N2Aswe cells by increasing α-secretase
activity, ultimately leading to enhanced release of soluble non-amyloidogenic sAPPα
(Manthey. 2010).
Atenolol, nebivolol have been showed metabolic adverse effects is the better
choice whenever β-blockers have to be used in essential hypertension (Badar et al.,
2011).
Nebivolol is a beta blocker with a unique function which distinguishes it from
other beta blockers. It increases the release of nitric oxide (NO) which produces
vasodilatation and thereby improves arterial compliance and reduces peripheral
vascular resistance. It also reduces heart rate without improving maximal exercise
tolerance. These effects are beneficial in hypertension and angina pectoris (Sahana et
al., 2011).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 57
2.4 Evaluation of Transdermal Drug Delivery Kinetics
The release and skin permeation kinetics of drug from different TDDS can be
evaluated using a two-compartment diffusion cell assembly under identical
conditions. This is carried out by individually mounting a skin specimen excised from
either a human cadaver or a live animal on a vertical diffusion cell, such as the Franz
diffusion cell and its modifications, or a horizontal diffusion cell, such as the Valia-
Chein skin permeation cell. The skin permeation profile of the drug is followed by
sampling the receptor solution at predetermined intervals until the steady-state flux is
established and assayed drug concentrations in the samples by a sensitive analytic
method, such as high-performance thin layer chromatography (HPTLC). The release
profiles of the drug from these TDD systems can also be investigated in the same
diffusion cell assembly without a skin specimen.
2.4.1 In vitro drug release kinetics
The aim of in vitro experimentation in transdermal delivery (TDD) is to
understand and/or predict the delivery and penetration of a molecule from the skin
surface into the body via the skin of a living animal. The in vitro technique involves
placing a piece of excised skin in a diffusion chamber applying compounds to one
side of the skin and then assaying for compound in the collection vessel on the other
side of the skin (Treager, 1996).
Thus, two factors are important in vitro percutaneous absorption studies:
1. Skin
2. Diffusion cell
2.4.1.1 Skin
Ideally human skin should be used to have a model that best describes the
actual situation of the use of the transdermal patch. But it has been difficult to obtain
human skin on regular basis thus excised skin from a variety of animals including rat,
mice (normal and hairless), rabbits, guinea pigs, hamsters, pigs, hairless dogs and
monkeys has been used in diffusion cells (Bronaugh and Stewart, 1986). The primary
problem with these skin models is that it can over estimate permeation relative to that
of human skin (Wester and Noonan, 1980; Bronaugh et al., 1982; Catz and Friend,
1990). The problem of over estimation using animal models may be partly due to
differences of the skin. The primary differences between human and animal skin is the
Review of literature
Suresh Gyan Vihar University, Jaipur Page 58
lipid composition and organization in the Stratum corneum. Over estimation of
permeation is also associated with the efforts of hydration wherein prolonged
exposure of rodent skin to aqueous phase brings about a marked diminution in the
barrier properties of the skin. Allowing for the different compounds used in each
studies to rank the species and the difference in origin of the skin sample (back,
forearm), the studies generally shows that the skin of common laboratory animals
(rabbit, rat and guinea pig) is more generally approximates the permeability of human
skin (Durrheim et al., 1980).
The in vitro permeation of scopolamine studies through rat, rabbit and human
skin was investigated. The results indicated that human skin is the least permeable of
the three species tested and the relative order of rat and rabbit skin permeabilities
depends both on skin location and the method used to remove the hair.
Skin permeation of benzoic acid and testosterone was studied and data
indicated a very close correspondence between the two species (monkey and human)
and these suggested that monkey skin as a good substitute for human skin in
permeability experiments.
The faster rates of penetration with rats and rabbits are due to largely the
thinner epidermis in these animals and to the much larger number of hair follicles,
which provide a significant shunt pathway for diffusion (Zatz, 1985).
A reliable model for human skin has been a highly desirable goal for a number
of years. Human keratinocytes cultures grown at the air liquid interface have been
found to develop substantial barrier properties to water diffusion (Mak et al., 1991).
2.4.1.2 Diffusion cell
The permeation, diffusion and partitioning of drug are influenced by the
hydrodynamic characteristics of the in vitro system used, which affect heart and mass
transfer. Only an in vitro skin permeation system with precisely defined
hydrodynamics and thermal characteristics can provide a reliable and reproducible
means for the determination of drug release and skin permeation rates. Various types
of in vitro apparatus for measuring drug permeation profiles across the skin have been
reported (Akhter and Barry, 1985).
Broadly these can be classified as
A) Diffusion system without a membrane.
Review of literature
Suresh Gyan Vihar University, Jaipur Page 59
B) Diffusion cell without a rate limiting membrane.
C) Diffusion cell incorporating a rate limiting membrane.
A) Diffusion system without a membrane
In these systems, the formulation is immersed in immiscible, agitated receptor
liquid maintained at constant temperature. These systems have limited applicability
because they lack similiarty to in vitro. In these studies, researchers have packed
topical formulation into jars or dishes that were invented or immersed into liquid
receptor phases. The method for in vitro evaluation of transdermal system included in
USP XXII 1990 includes dissolution apparatus with some modifications, is also an
example of such type of diffusion system (Ong and Manoukian, 1988).
B) Diffusion cell without a rate limiting membrane
In these systems, the donor vehicle is retained within an open glass jar
petridishes by cellulose or similar porous membrane, but will prevent dispersion of
formulation into receptor phase without influencing the movement of the drug
molecules into the liquid. Modified jars have been used extensively as donor
formulation containers (Ashton and Hadgraft, 1986; Gilbert et al., 1986).
C) Diffusion cell incorporating a rate limiting membrane
To obtain a clear approximation of complexities of transdermal drug
absorption, some form of rate limiting barrier to diffusion should be included in cell
apparatus. Such Type of cells are usually classified according to physical design as
horizontal, vertical and flow through type. Franz diffusion cell and Keshary Chein cell
exemplify vertical skin permeation system, as these permeation cells are the most
commonly used permeation systems.
D) Franz diffusion cell
The vertical type skin permeation system developed by Franz and
commercialized by Crown glass has been frequently used for studying the kinetics of
percutaneous absorption. The cell has a receptor compartment with an effective
volume of approximately 10-12 ml and an effective surface area for permeation
varying from 1.57-4.71 cm2. The solution in the receptor compartment is stirred by a
rod shaped magnet at 600 rpm. The temperature in the bulk of the solution can be
Review of literature
Suresh Gyan Vihar University, Jaipur Page 60
maintained at a constant level by circulating thermostated water through the water
jacket surrounding the receptor compartment. However, variations in the receptor
solution temperature results because the donor compartment (at which the skin is
positioned) is not thermal controlled (Keshary and Chien, 1984).
E) Modified Franz diffusion cell
Owing to poor solution hydrodynamics of Franz cell, set forth to modify the
Franz diffusion cell improve its efficiency of fluid mixing. The modified cell (K-C
cell) has an effective receptor solution volume of 12 ml and a skin surface area of
3.14 cm2. The receptor solution is stirred by a star head magnet at constant speed of
600 rpm (Chien, 1987).
F) Horizontal type skin permeation system, small cell volume
A horizontal type small volume skin permeation system (The V cell) was
developed. Each half-cell had a volume of 3.5 ml and membrane area of 0.64 cm2.
Both the donor and receptor solutions are agitated by a matched set of star head
magnets (diameter 8mm) at 600 rpm (Chien and Valia, 1984).
G) Horizontal type membrane permeation system, large solution volume
A flow through cell, which offers several advantages over static cells
particularly automation sampling and maintenance of skin conditions designed
(Bronaugh and Stewart, 1985; Tojo et al., 1985).
2.4.2 Skin irritation studies
Dermal irritation is the production of reversible inflammatory changes in the
skin following the application of a test substance. The skin is a complex body organ
that can exhibit a bewildering variety of pharmacological, pathological and
toxicological responses. Contact dermatitis reactions may be immediate or delayed,
chronic or acute, irritant or allergic. An additional cofactor in the development of
cutaneous reactions may be ultraviolet reaction (UVR). UVR has the capacity to
energize molecules and in this photoactive state, these molecules can produce
phototoxic (photo-allergic) reactions. In transdermal drug delivery systems the
adhesives used to produce intimate contact with the skin may be a source of cutaneous
reactivity. An additional problem of TDDS is that the physical process of removal
Review of literature
Suresh Gyan Vihar University, Jaipur Page 61
from the skin can induce mechanical trauma to the skin surface leading to erythema
and edema that may further lead to altered barrier function of the skin which, in turn,
could enhance the percutaneous penetration of materials at or near the skin surface.
The resulting dermatitis can be a source of considerable discomfort and
inconvenience and limit the usefulness of a TDDS. Thus, they may evoke a number of
unwanted side effects in the long term that can be divided into traumatic reactions and
allergic reactions. Allergic reactions to TDDS are usually caused by hypersensitively
in some patients due to one or several compounds in the adhesive layer or to the drug
itself. Using hypoallergic compounds in the adhesive layer can minimize these
reactions. Traumatic reactions to these systems are mainly induced by maceration of
the occluded skin but are strictly limited to the application site and do not increase in
intensity with repeated induction.
A number of test procedures to test for primary irritancy levels both in the
animals and in human have been reported. Some of them are described below
Draize rabbit patch test (Draize et al., 1945)
This is the most commonly used test for measurements. Patch of the test
materials are applied in a single dose to the skin of rabbits occluded for 24 h and then
removed for screening of irritancy, erythema or edema.
Signs for recording degree of patch test reaction are following.
Table 1. Signs for recording degree of patch test reaction
No reaction -
Erythema +
Erythema, papules ++
Erythema, papules and vesicles +++
Marked edema and vesicles ++++
2.4.3 In vivo methodology
The in vivo evaluation of transdermal drug delivery system represents a crucial
stage in the development of a therapeutic device. The in vivo skin permeation studies
are undertaken for the following purposes.
1. To verify and quantify the cutaneous bioavailability of a topically applied
drug.
Review of literature
Suresh Gyan Vihar University, Jaipur Page 62
2. To verify and quantify the systemic bioavailability of a transdermally
delivered drug.
3. To establish bioequivalence of different topical formulations of the same drug
substance and
4. To determine incidence and degree of systemic toxicological risk following
the topical application of a specific drug/drug product.
The penetration potential of a compound is to be evaluated by in vivo human
models. However, many compounds are potentially too toxic to test in vivo in humans
and so their percutaneous absorption must be done in animals. Likewise, in vivo
human studies are costly and not all investigators have access to human volunteers
therefore, animal models are needed for the development of conceptual insights and to
investigate mechanisms.
2.4.3.1 Animal models
If the objective is prediction of percutaneous absorption in man, the rate and
extent of skin absorption in animal model should be:
a. Quantitatively the same in man
b. Consistently related to the absorption in man by a constant ratio.
c. The animal chosen for the studies must respond to the treatment in the
same way and to roughly the same degree as in man.
Numerous species have been used in such percutaneous absorption studies that
include mouse, rat, guinea pig, rabbit, dog, pig and monkey.
2.4.4 Stability testing of TDDS
The purpose of the stability testing is to provide evidence how the quality of
the drug substance or drug product varies with time under the influence of a variety of
environment factors such as temperature, humidity and light and to establish a re-rest
period for the drug substance or the self-life for the drug product and recommended
storage conditions. Accelerated stability testing may be defined as a study in which
the formulation under investigation is subjected to conditions that accelerate changes
in the formulation aiming to predict the stability of formulation. According to
International Conference on Harmonization (ICH) Q1AR2 guidelines, accelerated
Review of literature
Suresh Gyan Vihar University, Jaipur Page 63
stability testing has a supportive role in submission of long-term stability evaluation
data. Conditions that are used in accelerated stability testing, more or less, try to
simulate the conditions a drug product may experience during its distribution chain.
ICH specifies stability guidelines for various dosage forms in which conditions and
test parameters to be evaluated are provided (Anony, 2000).
Table 2. Protocol for stability testing as per ICH (Q1AR) guidelines
Study Storage Condition Time period
Long term 25 ± 2º C / 60± 5 % RH 12 months
Intermediates 30 ± 2º C/ 60± 5 % RH 6 months
Accelerated 40 ± 2º C/ 75 ±5% RH 6 months
2.5 Literature review of clinical studies on transdermal system
Feldmann and Maibach, (1967) reported quantitative data on the percutaneous
penetration of hydrocortisone in man. Cunningham et al., (1989) conducted two
sequential studies on the pharmacokinetics of testosterone administered as a
transdermal patch in 12 male patients with hypogonadism. Gourlay et al., (1989)
studied the pharmacokinetic and pharmacodynamic effects of transdermal
administration of Fentanyl in 13 patients. Roy et al., (1995) studied transdermal
delivery of ketorolac trimethamine in humans. Wilding et al., (1996) studied
pharmacokinetics evaluation of transdermal buprenorphine in man. Krishna et al.,
(2000) studied transdermal delivery of aspirin in human volunteers and its influence
on platelet aggregation and serum lipid peroxidase.
WHO Technical Report Series, (1995) gives certain guidelines for good
clinical practice (GCP) for trials on pharmaceutical products. These guidelines
includes the following terms:
2.5.1 Clinical Trial
A systematic study on pharmaceutical products in human subjects (including
patients and other volunteers) in order to discover or verify the effects of and/or
identify any adverse reaction to investigational products, and/or to study the
absorption, distribution, metabolism and excretion of the products with the object of
ascertaining their efficacy and safety (Williams, 2003).
Review of literature
Suresh Gyan Vihar University, Jaipur Page 64
Clinical trials are generally classified into Phases I to IV. It is not possible to
draw distinct lines between the phases, and diverging opinions about details and
methodology do exist. A brief description of the individual phases, based on their
purposes as related to clinical development of pharmaceutical products, are given
below:
Phase I
These are the first trials of a new active ingredient or new formulations in
man, often carried out in healthy volunteers. Their purpose is to establish a
preliminary evaluation of safety, and a first outline of the pharmacokinetic and, where
possible, a pharmacodynamic profile of the active ingredient in humans.
Phase II
These trials are performed in a limited number of subjects and are often, at a
later stage, of a comparative (e.g., placebo-controlled) design. Their purpose is to
demonstrate therapeutic activity and to assess short-term safety of the active
ingredient in patients suffering from a disease or condition for which the active
ingredient is intended. This phase also aims at the determination of appropriate dose
ranges or regimens and (if possible) clarification of dose-response relationships in
order to provide an optimal background for the design of extensive therapeutic trials.
Phase III
Trials in larger (and possibly varied) patient groups with the purpose of
determining the short and long term safety/efficacy balance of formulation(s) of the
active ingredient, and of assessing its overall and relative therapeutic value.
The pattern and profile of any frequent adverse reactions must be investigated
and special features of the product must be explored (e.g., clinically relevant drug
interactions, factors leading to differences in effect such as age). These trials should
preferably be of a randomized double-blind design, but other designs may be
acceptable, e.g., long-term safety studies. Generally, the conditions under which these
trials are carried out should be as close as possible to normal conditions of use.
Phase IV
Studies performed after marketing of the pharmaceutical product. Trials in
phase IV are carried out on the basis of the product characteristics on which the
marketing authorization was granted and are normally in the form of post-marketing
surveillance or assessment of therapeutic value or treatment strategies. Although
Review of literature
Suresh Gyan Vihar University, Jaipur Page 65
methods may differ, these studies should use the same scientific and ethical standards
as applied in premarketing studies.
After a product has been placed on the market, clinical trials designed to
explore new indications, new methods of administration or new combinations are
normally considered as trials for new pharmaceutical products.
2.5.2 Ethics Committee
An independent body (a review board or a committee, institutional, regional or
national), constituted of medical professionals and non-medical members, whose
responsibility is to verify that the safety, integrity and human rights of the subjects
participating in a particular trial are protected and to consider the general ethics of the
trial, thereby providing public reassurance. Ethics committees should be constituted
and operated, so that their tasks can be executed free from bias and from any
influence of those who are conducting the trial.
2.5.3 Good Clinical Practice (GCP)
A standard for clinical studies which encompasses the design, conduct,
monitoring, termination, audit, analyses, reporting and documentation of the studies
and which ensures that the studies are scientifically and ethically sound and that the
clinical properties of the pharmaceutical product (diagnostic, therapeutic or
prophylactic) under investigation are properly documented.
2.5.4 Informed Consent
A subject's voluntary confirmation of willingness to participate in a particular
trial, and the documentation thereof. This consent should only be sought after all
appropriate information has been given about the trial including an explanation of its
status as research, its objectives, potential benefits, risks and inconveniences,
alternative treatment that may be available and of the subject‟s rights and
responsibilities in accordance with the current revision of the Declaration of Helsinki
in world medical association 2013.
Review of literature
Suresh Gyan Vihar University, Jaipur Page 66
2.5.5 Pharmaceutical product
Any substance or combination of substances which has a therapeutic,
prophylactic or diagnostic use, or is intended to modify physiological functions, and is
presented in a dosage form suitable for administration to humans.
2.5.6 Protocol
A document, which states the background, rationale and objectives of the trial
and describes its design, methodology and organization, including statistical
considerations, and the conditions under which it is to be performed and managed.
The protocol should be dated and signed by the investigator, the institution involved
and the sponsor. It can also function as a contract.