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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).



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 nonirritant (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).


Suresh Gyan Vihar University, Jaipur 4

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



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



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).



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



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



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).



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



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).



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



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



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.



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



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



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).



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



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



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



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.



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



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,



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



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



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).



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



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.



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



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



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.



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



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).



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



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.



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.

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