transdermal delivery of calcium channel blockers for hypertension

1. Introduction

2. Dihydropyridines

3. Phenylalkylamines

4. Benzothiazepines

5. Expert opinion

Review

Transdermal delivery of calciumchannel blockers for hypertensionAbdul Ahad†, Fahad I Al-Jenoobi, Abdullah M Al-Mohizea, Mohd Aqil &Kanchan Kohli†King Saud University, College of Pharmacy, Department of Pharmaceutics, Riyadh, Saudi Arabia

Introduction: Calcium channel blockers are a very important class of antihy-

pertensive drugs. Most calcium channel blockers (CCBs) exhibiting low oral

bioavailability are required to be taken more than once a day due to their

short half-lives which result in poor patient compliance. There is an inelucta-

ble requirement for improved drug-delivery devices for CCBs because of

the quantum of their utilization and shortcoming associated with their

conventional dosage forms.

Areas covered: There have been worthwhile research endeavors worldwide to

investigate the skin permeation and to develop transdermal formulations of

various categories of CCBs. This review explores the investigations on the

feasibility and applicability of systemic delivery of various CCBs via skin.

Expert opinion: Transdermal delivery of CCBs has been particularly acknow-

ledged as a potential drug-delivery route in the therapy of hypertension.

Several overtures have been made to enhance delivery of these drugs via

skin barrier. There have been remarkable research endeavors worldwide to

investigate the skin permeation and to develop transdermal systems of

various CCBs. Persistent advancement in this area holds promise for the

long-term success in technologically advanced transdermal dosage forms

being commercialized sooner rather than later.

Keywords: antihypertensive agent, calcium channel blockers, transdermal delivery, transdermal

therapeutic system

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

The skin is the largest organ of the human body with a main function to protect thebody against external aggression such as microorganisms, radiation, and to preventwater loss [1]. Its unique, highly organized structure comprises four distinct layers:stratum corneum (SC) a nonviable epidermis, viable epidermis, dermis, and subcu-taneous connective tissue (hypodermis) with various fully differentiated cell types [2].The SC, which is the outermost layer of the skin, is composed of dead, flattened,keratin-rich cells (corneocytes) embedded in a complex intercellular lipid mixture,particularly rich in ceramides, fatty acids, cholesterol, and cholesterol sulfate, orga-nized in bilayer arrays [3,4]. Therefore, the obstacle function of the skin is chiefly dueto the SC, which is responsible for the poor penetration of xenobiotics into theskin [5]. The biggest challenges in the development of transdermal therapeuticsystem (TTS) are to mitigate barrier property of skin without causing harmfuleffects, principally local irritation. The concept of TTS of drug delivery has beenwell known since 1924. It is only in the year of 1979, with FDA approval of scopol-amine transdermal systems for the treatment of motion sickness, the TTS havereceived broad impact on the scenario of novel dosage forms [6]. Subsequently,nitroglycerin patches were approved in 1981 for the management of angina pecto-ris. A number of TTS for different drugs are now in the market including those fornicotine, clonidine, testosterone, oxybutinin, fentanyl, lidocaine, and estradiol [7].

10.1517/17425247.2013.783562 © 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1All rights reserved: reproduction in whole or in part not permitted

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The global 2010 transdermal market for patches alonereached $9.5 billion, with advent of novel transdermal tech-nologies the worldwide transdermal market anticipated toexpand to $170 billion by 2015 [8]. TTS are easy to applyand remove as and when desired; furthermore, the transder-mal route has also provided the following advantages:i) avoidance of hepatic first-pass metabolism and other gastro-intestinal tract (GIT) issues such as presence of food and pHchanges; ii) sustained and controlled release over a long periodof time; iii) reduction of adverse effects; and iv) improvedpatient compliance [9-11].Hypertension is one of the main risk factors for other car-

diovascular diseases like myocardial infarction, congestiveheart failure, as well as kidney disorders. There is a direct rela-tionship between the level of blood pressure (BP) and the riskfor developing cardiovascular diseases such as coronary arterydisease and stroke [12,13]. Management of hypertension hasbeen indicated as an international health priority [14]. TheWorld Health Report 2002 named hypertension as thethird-ranked factor for disability-adjusted life years. Basedon a collective analysis of available national and regionaldata, it was expected that the burden of hypertension wouldrise by 60% to approximately 1.56 billion in the year2025 [15,16]. There are many classes of antihypertensives,which lower BP by different means; among the antihyperten-sive, most important and most widely used are the thiazidediuretics, the ACE inhibitors, calcium channel blockers(CCBs), b-blockers, and angiotensin II receptor antagonists.The CCBs are classified according to chemical structure

(Figure 1). Choice of antihypertensives is decided by individualpatient factors. Factors such as older age, angina, and arrhyth-mia associated with hypertension are the factors which favorthe use of CCBs [17], while choice amongst the differentCCBs depends on patient tolerability, comorbidity, and druginteractions [18]. All CCBs block the inward flow of calciumions into cells in vascular smooth muscle, myocardial cells,and cells within the sinoatrial and atrioventricular nodes which

can decrease the pumping strength of the heart and relax bloodvessels [19]. This causes the muscles to relax, lowering BP, slow-ing the heart rate, and decreasing oxygen demands of the heart.The effects of CCBs on heart and blood vessels are presentedin Figure 2. The dihydropyridines are more selective for vascu-lar sites than for myocardial sites and thus exhibit greater vaso-dilator effects with minimal effect on normal myocardialcells [20]. The dihydropyridines are mainly used for hyperten-sion and angina, and common side effects are associated withvasodilatation, such as flushing, headache, and ankle swelling.In contrast, phenylalkylamines- and benzothiazepines-typeCCBs preponderantly affect nonvascular smooth muscle andhave pronounced cardiac effects. They act on the myocardiumto reduce contractility and heart rate and are used in hyperten-sion and angina, but should not be used in heart failure [21].Therefore, side effects associated with phenylalkylamines aretypically nonvascular in nature (e.g., constipation and otherGIT effects). For transdermal product development, drugselection must be done based on the physicochemical proper-ties of the drug. The prerequisites for ideal drug candidate fortransdermal delivery are that the drug candidate must havelow molecular weight (< 400), logarithm partition coefficient(logP) value should be between 1 and 4, the drug should bepotent with a daily dose of the order of a few milligram perday, should have low oral bioavailability and short half-life,drug should be non-irritating and nonsensitizing to theskin, and drug candidates which degrade in the GIT or inacti-vated by hepatic first-pass effect are suitable candidates fortransdermal delivery [22,23].

The CCBs are generally well absorbed following oraladministration. However, all the CCBs undergo extensivefirst-pass metabolism, which significantly reduces bioavailabil-ity [24]. All CCBs are highly bound to plasma proteins. MostCCBs are inherently short acting due to a rapid eliminationhalf-life [25]. The conventional dosage forms of CCBs havemany limitations including hepatic first-pass metabolism,high incidence of adverse effects due to variable absorptionprofiles, higher frequency of administration, and poor patientcompliance [26]. Essentially, attempts have been made todevelop novel drug-delivery systems for various CCBs, includ-ing transdermal delivery systems, to circumvent the drawbacksof conventional drug delivery of CCBs. There have beenremarkable research endeavors worldwide at the laboratorylevel to investigate the skin permeation and to developtransdermal formulations of various CCBs such as dihydropyr-idines, for example, nifedipine (NFP), nicardipine hydrochlo-ride (NCP-HCl), nitrendipine (NTP), nimodipine (NMP),isradipine (IP), lacidipine (LP), felodipine (FP), and amlodi-pine (AP); phenylalkylamines like verapamil hydrochloride(VR-HCl); and benzothiazepines like diltiazem hydrochloride(DZ-HCl). This acceptability factor had encouraged research-ers and industries alike to take up challenging projects in thisparticular arena. This manuscript presents an outline of thetransdermal research in the area of CCBs reported in variouspharmaceutical journals. The advances and innovations in

Article highlights.

. The prevalence of hypertension is rapidly increasingworldwide. Amongst antihypertensive drugs, CCBs arevery important class of drugs.

. Conventional formulations of CCBs exhibit low oralbioavailability, and fluctuations in the plasma drugconcentrations, required to be taken more than once aday, result in poor patient compliance.

. The above limitation associated with conventionalformulations of these drugs can be circumvented bydelivering the drugs via transdermal route.

. This review explores the transdermal research of variousCCBs and will help the readers in the selection of asuitable antihypertensive drug candidate for improvingthe transdermal drug delivery for future endeavor.

This box summarizes key points contained in the article.

A. Ahad et al.

2 Expert Opin. Drug Deliv. [Early Online]

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the transdermal delivery of CCBs are discussed in the textand a summary is presented in Table 1.

2. Dihydropyridines

2.1 NifedipineNFP is extensively used for the treatment of cardiovasculardisease. NFP is firmly entrenched as a baseline treatment forhypertension and angina. It has a molecular weight of346.33 and logP of 2. NFP has a short biological half-life of2 h and bioavailability of 50 -- 70%. It undergoes high first-pass metabolism requiring high oral daily doses that must begiven frequently. These problems could be avoided if atransdermal patch with a surface area of 20 cm2 could bedesigned to deliver NFP through the skin at a target rate of0.033 mg/cm2/h [27,28]. Many overtures have been tried toenhance transdermal delivery of this difficult drug. Penetra-tion enhancers like sodium lauryl sulfate (SLS) and propyleneglycol (PG) have been failed to improve the permeability ofNFP to an acceptable level [29]. In another study, the effectof PG, oleic acid (OA), and dimethyl isosorbide on NFPflux was determined. It was observed that after 24 h, 57%

of the PG and 40% of the dimethyl isosorbide had permeatedthrough the skin. It was suggested that NFP flux was depen-dent on concomitant solvent permeation. It was mentionedthat both dimethyl isosorbide and PG readily permeate acrosshairless mouse skin, whereas OA showed no appreciable per-meation in the presence of these solvents. The synergisticacceleration of cosolvent flux was attributed to the effect ofOA on dimethyl isosorbide and PG permeation which, inturn, created conditions that favor partition of drug fromthe viable epidermis into the dermal layers [30]. Recently, elas-tic liposomes of NFP were also prepared for improved trans-dermal delivery of NFP. In comparison to conventionalliposomes higher entrapment efficiency was found in transfer-osomal formulation. In contrary, lower release rate of NFPwas found from elastic liposomes in comparison to rigid lipo-somes. Skin study showed that elastic liposomal formulationprovides higher skin permeation as compared to liposomaldispersion of NFP. Elastic liposomes were also found morestable as compared to liposomes. It was revealed that elasticliposomal formulations of NFP possess greater potential toenhance skin permeation, prolong drug release, and improvethe site specificity of NFP [31].

Calcium channelblockers

Benzothiazepines

Phenilalkylamines

Dihydropyridines

3rdgeneration

2ndgeneration

1stgeneration

Nifedipine

Nicardipine

Nitrendipine

Nimodipine

Isradipine

Lacidipine

Felodipine

Amlodipine

Verapamil

Diltiazem

Figure 1. Classification of CCBs according to chemical structure.

Transdermal delivery of calcium channel blockers for hypertension

Expert Opin. Drug Deliv. [Early Online] 3

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Microemulsions containing NFP were also prepared con-taining oil of ylang ylang, lavender oil, cinnamon oil, cineole,menthone, and menthol as skin penetration enhancers. Etha-nol was incorporated as emulsifying agent. Three vehicle sys-tems were prepared for developing microemulsion TTS ofNFP; first system containing 25% ethanol, second systemcontaining 50% ethanol, and third system consisting of solu-tions of penetration enhancers in 100% ethanol saturatedwith NFP. The concentrations of the penetration enhancerswere kept same in all preparation. The effects of microemul-sions containing 50 and 25% ethanol on the percutaneousabsorption of NFP were compared with formulations consist-ing of solutions of penetration enhancers in 100% ethanol.The authors claimed that among the permeation enhancercinnamon oil was found to be optimizing one and microe-mulsions containing 50% ethanol were found to be the bestvehicles for the percutaneous absorption of NFP [32]. Inanother study, in vitro skin permeation of NFP from microe-mulsions was investigated using the hairless mouse skin.Two microemulsions (N.1 and N.2) were prepared and thick-ened; they contained, respectively, 1.8 and 2.0% of NFPin solution. The fluxes of the NFP from the micro-emulsions were found to be 7.8 and 18.6 µg/cm2/h from for-mulations N.1 and N.2, respectively. The author also claimedthat the developed microemulsion also protects photolyticdegradation of NFP up to 6 months [33].

2.2 NicardipineNCP-HCl is widely used in the treatment of hypertension andangina pectoris [34]. NCP-HCl is rapidly and completelyabsorbed from the GIT but is subjected to hepatic first-passmetabolism. Because of the first-pass elimination, oral

bioavailability of NCP-HCl in human subjects has beenreported to be low as 30 -- 35%. The terminal half-life ofNCP-HCl after single dose (30 mg) in human subjects isbetween 2 and 4 h. It has logP of 4.34 [35,36]. NCP-HCl seemsto be a potential therapeutic transdermal system candidate, dueto its above-mentioned properties. It was reported thatethanol-water solvent system in the ratio of 70:30 v/v wasa suitable vehicle for the transdermal delivery of NCP-HCl [37]. However, it was necessary to improve the permeationrate of NCP-HCl by using suitable enhancers. In 2002,Krishnaiah et al. reported that the NCP-HCl permeability viaethylene-vinyl acetate (EVA) 2825 membrane coated withTACKWHITE 4A MED/skin composite was higher thanthat coated with MA-31 or MA-38. Thus, a new TTS forNCP-HCl was formulated using EVA 2825 membrane coatedwith a pressure-sensitive adhesive (PSA) TACKWHITE 4AMED and 2% w/w hydroxy propyl cellulose (HPC) gel as res-ervoir containing 4% w/w of limonene as a penetrationenhancer [38]. It was observed that the developed formulationprovided steady-state plasma concentration of the NCP-HCl with minimal fluctuations for 20 h with improvedbioavailability in comparison to immediate-release capsuledosage form. In another investigation, Krishnaiah et al.(2002) reported that 8% w/w of menthol in 2% w/w HPCgel provides the required permeability of NCP-HCl throughthe excised rat abdominal skin [39]. HPC gel formulations con-taining NCP-HCl and menthol (1 -- 12% w/w) were prepared,and evaluated for in vitro permeation of NCP-HCl throughexcised rat epidermis. It was observed that, as menthol concen-tration increased from 0 w/w to 8% w/w, the permeability ofNCP-HCl was also increased. On increasing the mentholconcentration further from 8 to 12% w/w, the increase in the

Superiorvena cava

AortaCCBs decrease heart rateand lower blood pressure

CCBs decrease SAnode automaticity

CCBs decrease AV nodeconduction velocity

CCBs decrease cardiaccontractility

SA node

AV node

Inferiorvena cava

CCBs dilate the arteriesand lower the BP

Figure 2. Effects of CCBs on heart and blood vessels.

A. Ahad et al.


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Table 1. Research advances in systemic delivery of CCBs via skin.

CCBs Characteristics Transdermal research Refs.

DihydropyridinesNFP BCS class II drug, undergoes

high first-pass metabolismMW: 346.33, logP = 2t1/2 = 2 hOral bioavailability = 50 -- 70%

SLS and PG have been failed to improve the permeability to anacceptable level

[29]

Effect of PG, OA, and dimethyl isosorbide on NFP flux wasdetermined. It was observed that NFP flux was dependent onconcomitant solvent permeation such as PG, OA, and dimethylisosorbide

[30]

Elastic liposomes showed greater potential to enhance skinpermeation of NFP

[31]

Cinnamon oil was found to be the best enhancer andmicroemulsions containing 50% ethanol were found to be thebest vehicles for the percutaneous absorption of NFP

[32]

NFP found stable from photolytic degradation in microemulsionup to 6 months

[33]

NCP-HCl BCS class II drug, oralbioavailability = 30 -- 35%Extensive hepatic first-passmetabolismt1/2 = 2 -- 4 h, logP = 4.34,MW: 479.52

Ethanol-water solvent system in the ratio of 70:30 v/v reportedas suitable vehicle for the transdermal delivery of NCP-HCl

[37]

TTS containing limonene (4% w/w) improved bioavailability ofNCP-HCl in comparison to immediate-release capsule dosageform

[38]

ER of 7.2 of NCP-HCl was observed from HPC gel containingmenthol (8% w/w)

[39]

Steady-state plasma concentration of NCP-HCl with improvedbioavailability was obtained from TTS prepared with EVA2825 membrane coated with TACKWHITE A 4MEDw/skin composite

[40]

Carvone (12% w/w) increased the permeability of NCP-HCl viathe rat epidermis by partial extraction of SC lipids

[41]

TTS prepared with HPMC and EC containing DMSO aspenetration enhancer increased the efficacy of NCP-HCl for thetherapy of hypertension

[46]

Microemulsion consisting of IPM (52%), Smix (35%), and water(13%) showed higher permeation rate of NCP-HCl via rat skin

[48]

NTP BCS class II drug, MW: 360.36,t1/2 = 3 h,logP = 3.21 undergoes extensivefirst-pass, oralbioavailability = 10 -- 20%

TTS of NTP comprising carvone (6% v/w) meets the target fluxof 19.10 µg/cm2/h

[52]

TTS was fabricated using synthesized acrylate PSAs containingd-limonene as permeation enhancer

[53]

OA was found to be the best enhancer for improved transdermaldelivery of NTP among the tested enhancer

[54]

Used Azone� as permeation enhancer for enhanced NTPtransdermal delivery

[55]

TTS of NTP was developed using polymeric combination ofE-RL 100:PVP K30 in a 4:6 ratio which showed maximum drugrelease (85.8%) and skin permeability coefficient (0.0142 cm/h)in 48 h

[56]

Developed SLN and NLC for transdermal delivery of NTP [57]

NMP BCS class II drug, extensivehepatic first-pass metabolism,logP =3.41, oralbioavailability = 13%t1/2 =1 -- 2 hMW: 418.44

HPMC gel as a reservoir system containing limonene (4% w/w)as enhancer, a transdermal flux of 126.59 µg/cm2/h wasobtained which was 1.3-fold greater than the required flux. Animprovement in bioavailability (705.56%) of NMP was alsoobserved

[63]

Maximum flux of NMP was observed (203 µg/cm2/h) with an ERof about 5.7 when limonene (4% w/w) was added in HPMC gel

[64]

AP: Amlodipine; BCS: Biopharmaceutics classification system; CCBs: Calcium channel blockers; DBP: Dibutyl phthalate; DMSO: Dimethyl sulfoxide;

DZ-HCl: Diltiazem hydrochloride; EC: Ethyl cellulose; ER: Enhancement ratio; EVA: Ethylene-vinyl acetate; FP: Felodipine; HPMC: Hydroxy propyl methyl cellulose;

IPM: Isopropyl myristate; IP: Isradipine; LP: Lacidipine; logP: Logarithm partition coefficient; MW: Molecular weight; NCP-HCl: Nicardipine hydrochloride;

NTP: Nitrendipine; NLC: Nanostructured lipid carrier; NMP: Nimodipine; NFP: Nifedipine; OA: Oleic acid; PG: Propylene glycol; PSAs: Pressure-sensitive adhesives;

PVP: Polyvinyl pyrrolidone; RSM: Response surface method; SC: Stratum corneum; SLN: Solid lipid nanoparticles; SLS: SodIum lauryl sulphate; Smix: Surfactant

mixture; t1/2: Half-life; TTS: Transdermal therapeutic system; VR-HCl: Verapamil hydrochloride.



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Table 1. Research advances in systemic delivery of CCBs via skin (continued).


HPMC gel TTS for NMP using EVA 2825 membrane coated withTACKWHITE 4A MED, containing menthol (8%) as a penetrationenhancer was developed

[65]

Cineole was found to be the best enhancer amongst the severalenhancers tested such as myristyl alcohol, caprylic acid,l-menthol, and OA for the transdermal delivery of NMP

[66]

ER of 4.56 of NMP was obtained across rat skin when carvone(10% w/w) was incorporated in HPMC gels

[67]

RSM was employed to observe combinatory effect of caprylicacid and cineol as permeation enhancers on NMP permeationacross human cadaver epidermis

[68]

IP BCS class II drug, MW: 371.4,logP = 4.28, oralbioavailability = 15 -- 24%,t1/2 = 8 h

Developed a matrix-type TTS for IP containing d-limonene(5% v/w) as permeation enhancer

[71]

LP BCS class IV drug, extensivehepatic first-pass metabolism,oral bioavailability = 10%t1/2 = 13 -- 19 h, MW: 455.54,logP = 5.20

Microemulsion was optimized using a three-factor,three-level Box-Behnken design and 3.5 times improvementin LP bioavailability was obtained

[75]

FP BCS class II drug, MW: 384.25,logP of 4.36, t1/2 = 7 -- 21 h,bioavailability = 13 -- 16%

d-Limonene (1%) significantly reduced the lag time FP to 1.4 has compared to control (lag time of 9.8 h)

[77]

Developed FP-metoprolol-TTS. Relative bioavailability of FP foundto be 275.37% compared to oral administration

[78]

Microemulsions containing benzyl alcohol found to be suitablevehicles for improved transdermal delivery

[79]

AP BCS class I drug, logP = 2.22,t1/2 = 30 -- 50 h, oralbioavailability = 60 -- 65%.Extensive hepatic metabolism,MW: 408.87

TTS containing SLS and PG as permeation enhancers found to befree of any skin irritation potential even after several days ofwear

[82]

The steady-state plasma level and improvement in bioavailability(88.8%) of (S)-AP in rats were obtained following transdermalapplication

[83]

Permeation of AP in the presence and absence of terpene andethanol was investigated

[84]

AP-base showed higher flux and permeability coefficient acrossrat skin than various complexes of AP such as AP-besilate,AP-adipate, AP-oxalate, and AP-maleate

[85]

Nanoemulsions prepared with OA, Tween-20, and Transcutol Pfound to be potential vehicles for improved transdermal deliveryof AP

[86]

PhenylalkylaminesVR-HCl BCS class I, II drug, oral

bioavailability = 20 -- 30%MW: 491.07, logP = 5.23,hepatic first-pass metabolism,t1/2 = 2 -- 7 h

Nerolidol was found to be the most promising enhanceramongst the other investigated terpenes

[89]

Developed TTS successful maintained steady and adequateplasma levels up to 24 h in rabbits

[90]

Azone enhanced the plasma levels of VR-HCl up to 10-fold, theeffect being greatly dependent on the amount of alcohols in theformulation

[91]

d-limonene showed improvement in VR-HCl permeation acrossthe skin

[93]







A. Ahad et al.


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permeability was insignificant. The flux of NCP-HCl wasfound to be 227.70 µg/cm2/h with an enhancement ratio(ER) of 7.12 when menthol was incorporated at a concentra-tion of 8% w/w in HPC gels in comparison with the control.In 2003, Krishnaiah et al. investigated the effect of variousPSAs (MA-31�, MA-38�, or TACKWHITE A 4MED�) onthe permeability of NCP-HCl through EVA 2825 membrane(28% w/w vinyl acetate) or EVA 2825 membrane/skin com-posite. It was observed that NCP-HCl permeability throughEVA 2825 membrane coated with TACKWHITE A4MEDw/skin composite was higher than that coated withMA-31� or MA-38�. In vivo studies in healthy human volun-teers indicated that the TTS of NCP-HCl designed providedsteady-state plasma concentration of the drug with minimalfluctuations for 26 h with improved bioavailability in compar-ison with immediate-release capsule dosage form [40]. Inanother report, the HPC gel formulations of NCP-HCl(1% w/w) containing terpene were developed [41]. Terpenesappear to be clinically acceptable permeation enhancers as indi-cated by high percutaneous enhancement ability, minimal per-cutaneous irritancy, and have been generally regarded as safe byFDA [42]. Moreover, a variety of terpenes have been shown to

increase percutaneous absorption of both hydrophilic and lipo-philic drugs [43,44]. It was revealed by the result of the study [41]

that transdermal flux of NCP-HCl across rat epidermis wasincreased markedly by the addition of carvone. A maximumflux of NCP-HCl was observed with an ER of 7.9 when car-vone was incorporated at a concentration of 12% w/w in theformulation. It was suggested that carvone increased the per-meability of NCP-HCl via the rat epidermis by partial extrac-tion of SC lipids. The results of another study [45] showed thatNCP-HCl permeability through EVA 2825 membrane coatedwith TACKWHITE A 4MED/skin composite was higher thanthat coated with MA-31 or MA-38. The bioavailability studiesin healthy human volunteers indicated that the prepared TTSof NCP-HCl (with 8% w/w of carvone) provided a steady-state plasma concentration of the drug for 23 h in comparisonwith the immediate-release capsule dosage form, and the rela-tive bioavailability from TTS was 301.20 ± 9.91%. The TTSpatch (containing 8% w/w of carvone) may be useful forlong-term constant drug delivery with minimum fluctuations.

Recently, matrix-type NCP-HCl TTS with different ratiosof hydrophilic and hydrophobic polymeric combinations bythe solvent evaporation technique was prepared. Three

Table 1. Research advances in systemic delivery of CCBs via skin (continued).


Matrix-type transdermal films were developed using Gum Copal,alone and in combination with PVP K-30Gum Copal seems to be a promising film former for transdermaldrug delivery

[94]

BenzothiazepinesDZ-HCl BCS class I drug, extensive

hepatic metabolism,logP = 3.09, oralbioavailability = 40%t1/2 = 3.5 h, MW: 414.51

In vivo study in rabbits showed that TTS sustained thetherapeutic activity over a study period of 24 h and provided afivefold increase in the bioavailability

[99,100]

In vivo studies showed that both matrix diffusion-controlled andmembrane permeation-controlled systems are capable ofachieving the effective plasma concentration over a prolongedperiod of time

[102]

Transdermal film composed of Damar Batu alone and incombination with E-RL100 was developed for enhancedtransdermal delivery of DZ-HCl

[103]

TTS containing IPM, isopropyl palmitate, or Tween-80 enhancethe transdermal fluxes of DZ-HCl approximately three times

[105]

Amongst several enhancers, polysorbate 80 was found to be thebest enhancer for enhanced transdermal delivery of DZ-HCl

[106]

Polymerized rosin in combination with PVP and DBP producessmooth flexible films with improved tensile strength and it canbe used in the development of a matrix-type TTS to prolong thedrug release

[108]

DZ-HCl can be successfully delivered through the skin using acombination of chemical enhancer (octaethylene glycolmonododecyl ether) and iontophoresis

[109]









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transdermal patch formulations (F1, F2, F3) consist ofhydroxy propyl methyl cellulose (HPMC) E5, and ethylcellulose (EC) in the ratios of 2:0, 0:2, and 1:1, respectivelywere prepared. All formulations carried dimethyl sulfoxide(DMSO) as penetration enhancer and dibutyl phthalate(DBP) as plasticizer in acetone and methanol (4:3) as solventsystem. The formulation F1 (HPMC E5 alone) showed max-imum release of 97.18% in 7 h, whereas F2 (EC alone)showed maximum release of 66.93% in 24 h. The formula-tion F3 with combination of polymers (1:1) showed maxi-mum release of 91.22% in 24 h, emerging to be idealformulations for NCP-HCl. It was concluded that thedeveloped transdermal patches increase the efficacy ofNCP-HCl for the therapy of hypertension [46].Aboofazeli et al. (2002) elucidate the mechanism of pene-

tration enhancement of NCP-HCl by solvents such as PG,OA, and dimethyl isosorbide. It was observed that noindividual solvent was capable of promoting NCP-HClpenetration. Among the systems studied, the ternary mixtureof PG/OA/dimethyl isosorbide and binary mixture of PG/OA showed excellent flux. The flux value of the ternary sys-tem was nearly three times higher than the correspondingvalues obtained for the binary solvent. The ternary mixturewas then selected as a potential absorption enhancementvehicle for the transdermal delivery of NCP-HCl. It wasdemonstrated that the choice of vehicle significantly affectsthe percutaneous absorption of NCP (as salt or base), acrossthe skin membrane [47].Microemulsions consisting of isopropyl myristate (IPM),

surfactant mixture (Smix) of Tween-80/Span 80 and/orTween-80/Span 20, co-surfactant (ethanol), and aqueousphase were prepared. Pseudo-ternary phase diagrams were con-structed using water titrationmethod. Themean droplet size ofNCP-HCl microemulsions ranged from 70 to 123 nm, anddroplet size was found to be indirectly proportional to the eth-anol concentration. NCP-HCl microemulsion had higher fluxat Smix with lower hydrophilic-lipophilic balance value andTween content. It was concluded that the microemulsion con-sisting of 52% IPM, 35% Smix, and 13% water showed higherpermeation rate via rat skin [48]. Maltose microneedles werealso prepared to improve delivery of NCP-HCl via skin. Itwas shown that prepared microneedles created microchannelsin the skin, which facilitated the transdermal delivery ofNCP-HCl [49].

2.3 NitrendipineNTP effectively reduces BP when given orally at doses of5 -- 20 mg/day. It is reported to be well absorbed followingoral administration, but undergoes extensive first-pass metab-olism; the oral bioavailability is reported to range from 10 to20% and half-life of 3 h; in addition, logP of NTPwas reported as 3.21 [50,51]; these properties make NTP apromising candidate for transdermal delivery.In 2007, Gannu et al. prepared matrix-type TTS of NTP

comprising carvone (6% v/w) as penetration enhancer by

solvent evaporation technique. Ten formulations composedof Eudragit (E) such as E-RL 100 and HPMC in the ratiosof 5:0, 4:1, 3:2, 2:3, and 1:4 in formulations A1, A2, A3,A4, A5, and E-RS 100 and HPMC in the same ratios in for-mulations B1, B2, B3, B4, and B5, respectively, were pre-pared. It was observed that the maximum drug release in24 h for A series formulations was 89.29% (A4) and86.17% for B series (B5), which are significantly differentfrom the lowest values (57.58 for A1 and 50.64 for B1). Againformulations A4 and B5 presented maximum skin permeationin the respective series. The flux obtained with formulationA4 and B5 meets the target flux, that is, 19.10 µg/cm2/h.Finally, it was suggested that NTP matrix-type TTS couldbe prepared with the required flux having suitable mechanicalproperties with investigated polymers [52]. A previous studyreported on fabrication of an acrylate-based TTS of NTPusing d-limonene as permeation enhancer [53]. In this study,transdermal patches were fabricated using synthesized acrylatePSAs: PSA1, PSA2, and commercially available PSA3 andPSA4 using d-limonene as permeation enhancer. DevelopedTTS in mentioned PSAs were evaluated for in vitro releaseand permeation kinetics through guinea pig skin. Cumulativerelease of drug in PSA1, PSA2, PSA3, and PSA4 was observedto be 45%, 40%, 25%, and 25%, respectively, up to 24 h.The NTP in PSA2 showed good rate-controlling propertyand presented comparatively high flux and could deliverdrug at high input rate through transdermal route; thus,PSA2 could be successfully used in transdermal delivery ofNTP. In addition to good adhesion and rate-controllingproperties, the synthesized PSA2 also have good skin compat-ible with desirable wear performance, and therefore could beuseful in fabrication of drug-in-adhesive transdermal systemof NTP. D-Limonene was found to be an effective perme-ation enhancer at 0.50% in PSA2. In 2008, Mittal et al. inves-tigated the effect of several penetration enhancers such asDMSO, IPM, SLS, Tween-20, myristic acid, lauric acid, cap-ric acid, Tween-80, span 80, thyme oil, palmarosa oil, petitl-grain oil, basil oil, and OA on permeation kinetics of NTPacross two different skin models. It was mentioned thatamongst all investigated enhancers, OA produces more distin-guished enhancing effect while DMSO was found to be theleast effective for transdermal delivery of NTP [54]. In earlierstudy, feasibility of polyisobutylene matrix comprisingAzone� as permeation enhancer was also reported for thedevelopment of TTS for enhanced transdermal delivery ofNTP [55]. In another study, NTP transdermal system wasdeveloped by the film casting technique. Drug release fromthe films followed anomalous transport. Polymeric combina-tion containing E-RL 100: polyvinyl pyrrolidone (PVP)K30 (4:6 ratio) showed the best effects. Maximum drugrelease and skin permeability coefficient in 48 h were foundto be 85.8% and 0.0142 cm/h, respectively [56].

Novel particulate carrier systems such as solid lipid nano-particles (SLN) and nanostructured lipid carrier (NLC) fortransdermal delivery of NTP were also investigated [57]. The

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antihypertensive activity of the carbopol SLN and carbopolNLC gels in comparison with that of oral NTP was studiedin desoxy corticosterone acetate-induced hypertensive rats. Itwas observed that both carbopol SLN (A1) and carbopolNLC (B1) gels significantly controlled hypertension fromthe first hour and increased the efficacy of NTP for the ther-apy of hypertension. Both the SLN and NLC dispersions andthe gels enriched with SLN and NLC possessed a sustaineddrug release over a period of 24 h, but the sustained effectwas more pronounced with the SLN gel and the NLC gel for-mulations than dispersion formulations. In a previous study,target flux of NTP (16.85 µg/cm2/h) was achieved by usingNLC and SLN formulations, NLC provided the greatestenhancement for NTP flux (21.485 µg/cm2/h, which wasfourfold over control, while SLN B produced flux of16.983 µg/cm2/h [58].

2.4 NimodipineNMP is used in the treatment of hypertension, cerebrovascu-lar disorders, and stroke [59,60]. It has a short biological half(1.7 -- 9 h) with favorable molecular weight (418.44) andlogP of 3.41. It is subjected to an extensive hepatic first-pass metabolism following oral administration with systemicbioavailability of 13% [61,62]. Because of its short eliminationhalf-life (1 -- 2 h), the drug has to be given frequently(30 mg three to four times daily). Thus, the conventionaltherapy may result in higher fluctuation in plasma concentra-tion of the drug resulting in unwanted side effects. Hence, thedevelopment of TTS for NMP would be beneficial as aneffective and safe therapy of hypertension.

In 2004, Krishnaiah et al. designed a membrane-moderatedTTS of NMP using 2% w/w HPMC gel as a reservoir systemcontaining 4% w/w of limonene as a penetration enhancer.The effect of PSAs such as TACKWHITE A 4MED� on thepermeability of NMP across EVA2825 membrane or mem-brane/rat skin composite was also investigated. The transder-mal permeability flux of NMP via EVA2825 membranecoated with TACKWHITE A 4MED�/rat skin compositewas found to be 126.59 µg/cm2/h, which is 1.3-fold greaterthan the required flux. The pharmacokinetic studies done onhealthy human volunteers showed that the TTS of NMPprovided steady-state plasma concentration of the drug withminimal fluctuations for 20 h with improved bioavailability(705.56%) in comparison with the immediate-release tabletdosage form [63].

In another report, the HPMC gel formulations containingNMP (1.5% w/w) and limonene (0 -- 8% w/w) as penetrationenhancers were developed, and in vitro permeation of thedrug through excised rat abdominal epidermis was evaluated.It was observed that the transdermal flux of NMP across ratepidermis was accentuated by the addition of limonene tothe HPMC gels. A maximum flux of NMP was observed(203 µg/cm2/h) with an ER of about 5.7 when limonene(4% w/w) was added in HPMC gel. Mechanistic study doneby Fourier transform infrared spectroscopy (FTIR) indicated

that limonene increased the permeability of NMP via the ratepidermis by partial extraction of lipids in the SC [64].

In another study, Krishnaiah and Bhaskar (2004) devel-oped a reservoir-type membrane-moderated TTS of NMPcontaining 2% w/w HPMC gel, menthol, and 60% v/vethanol-water as solvent system. The flux of NMP was exten-sively increased from 35.51 to 167.53 µg/cm2/h in thepresence of 8% w/w menthol as penetration enhancer toHPMC gel. There was an increase in the flux of NMP to152.05 µg/cm2/h via chosen EVA 2825 (with 28% w/wvinyl acetate content) copolymer membrane, and this fluxdecreased to 132.69 µg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. Theauthor claimed a new TTS for NMP using EVA 2825membrane coated with a PSA TACKWHITE 4AMED, and 2% w/w HPMC gel as reservoir containing8% w/w of menthol as a penetration enhancer. The resultsof in vivo evaluation in human volunteers showed that thementhol-based TTS patch of NMP provided steady plasmaconcentration of the drug with minimal fluctuations withenhanced bioavailability in comparison to immediate-releasetablet dosage form [65].

In an earlier report, cineole was found to be the bestenhancer amongst the several enhancers tested such as myris-tyl alcohol, caprylic acid, l-menthol, and OA for the transder-mal delivery of NMP [66]. The effect of terpene such ascarvone on the permeation of NMP across rat skin was alsoreported. An ER of 4.56 of NMP was obtained across ratskin when carvone was incorporated at a concentrationof 10% (w/w) in HPMC gels prepared with ethanol(60% v/v). The FTIR information presented that ethanolicsolution of carvone increased the transdermal permeabilityof NMP across the rat skin by partial extraction of lipids inthe SC. It was suggested that carvone (10% w/w) in ethanol(60% v/v), along with HPMC, may be useful for enhancingthe skin permeability of NMP from the membrane-moderated TTS [67]. In another study, the sustained actionof cineol on NMP skin permeability after 24 h was confirmedeither alone or in combination with caprylic acid. In thisstudy, response surface method (RSM) was employed toobserve the effect of the combination of two enhancers,namely caprylic acid and cineol on NMP permeation acrosshuman cadaver epidermis. By employing quadratic model itwas found that at 24 h the increase in NMP permeation wasmainly due to the effect of caprylic acid. On the contrary, itwas shown that at 48 and 72 h the combination of the twoenhancers contributed to the increase in NMP permeation.It was indicated that greater Qgel/Qcontrol values (illustratingthe relationship between the concentration of cineol (% v/v)and caprylic acid (% v/v) and the permeation rate of NMPat 24, 48, and 72 h) were found to be 2.62, 2.83, and2.99 at all time intervals, that is, 24, 48, and 72 h, respec-tively, when the concentrations of cineol and caprylic acidrange from 3.0 to 5.0% (v/v) and 8.0 to 9.5% (v/v),respectively [68].



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2.5 IsradipineIP has low molecular weight (371.4) with a favorable logP(4.28) [69]. IP is a dihydropyridine CCB that binds to calciumchannels with high affinity and specificity and inhibits cal-cium flux into cardiac and smooth muscle. IP is almostcompletely absorbed from the GIT following oral dose butundergoes extensive first-pass metabolism; the bioavailabilityis reported to be 15 -- 24%. The terminal elimination half-life is often stated to be about 8 h although a value of < 4 hhas also been reported [70]. All the above characteristicsmake IP a good candidate for transdermal delivery. However,only following report is found in the literature on the trans-dermal delivery of this drug.Tirunagari and others (2010) developed a matrix-

type controlled TTS for IP by employing E-RL100: HPMCand E-RS100: HPMC containing d-limonene (5% v/w) aspermeation enhancer. The skin permeation studies were car-ried out across excised rat skin using Franz diffusion cell.The authors revealed that the drug release from matrix filmsfollowed Higuchi model and the mechanism of drug releasewas diffusion mediated. Based on the physical evaluation,in vitro drug release and ex vivo permeation characteristics, itwas concluded that polymers selected were better suited forthe development of TTS of IP and prepared monolithicdrug matrix films, and may be suitable for the developmentof TTS of IP [71].

2.6 LacidipineLP is used in the treatment of hypertension and atherosclerosis.It also possesses antioxidant effect and is one of the most vascu-lar selective of the dihydropyridines [72,73]. LP undergoes exten-sive hepatic first-pass metabolism and has a meanbioavailability of about 10% (range 4 -- 52%) and half-life of13 -- 19 h. It has a favorable logP and molecular weight of5.20 and 455.54, respectively. LP is completely metabolizedin the liver by cytochrome P4503A4 to pharmacologicallyinactive metabolites [74]. In addition, its limited aqueous solu-bility contributes to its limited oral bioavailability, which inturn restricts its oral use; therefore, alternative mode of deliverysystem is desirable, to deliver the drug at effective concentra-tions to treat hypertension. Only following report is availableon transdermal delivery of LP. Gannu et al. (2010) developedand optimized the microemulsion-based TTS for LP. Themicroemulsion was optimized using a three-factor, three-level Box-Behnken design, and the independent variablesselected were IPM, Smix (Tween 80 and Labrasol), and water;dependent variables (responses) were cumulative amount per-meated across rat abdominal skin in 24 h (Q(24); Y(1)), flux(Y(2)), and lag time (Y(3)). The optimized gel formulationshowed a flux of 43.7 µg/cm2/h. The bioavailability of LPwas 3.5 times improved after transdermal administration ofmicroemulsion gel compared to oral suspension as revealedby the pharmacokinetic study. It was concluded that the statis-tical design microemulsion-based TTS of LP could provide aneffective treatment in the management of hypertension [75].

2.7 FelodipineFP is a dihydropyridine calcium antagonist which selectivelyrelaxes vascular smooth muscle. FP is indicated for the man-agement of hypertension. It has a favorable logP of 4.36 andterminal elimination half-life of FP ranged from 7 to 21 h fol-lowing single intravenous doses in normal volunteers, while amean value of 18 h was obtained after single intravenous dosesgiven to hypertensive patients. FP is well absorbed from theGIT but undergoes extensive first-pass metabolism, resultingin an absolute bioavailability of 13 -- 16% in fasted individu-als [76]. Above limitation associated with conventional formu-lations of FP can be circumvented by transdermal delivery.

The effect of different concentrations (0.5, 1, 5. and 10%)of d-limonene on the transdermal penetration of FP was eval-uated. The study was performed using a diffusion techniquein vitro, with the skin of the hairless rat. The authors claimedthat d-limonene (1%) significantly reduced the lag time to1.4 h as compared to control which showed a lag time of9.8 h. The d-limonene at (10%) higher concentrations didnot produce a significant decrease in the value of this param-eter. The presence of d-limonene in the formulae produces anincrease in the permeability constant as well as transdermalflux of FP [77].

In another study, a transdermal patch containing FP andmetoprolol was prepared. The permeation of FP and meto-prolol from the transdermal patch through excised rabbitskin showed zero-order kinetic pattern. The developed trans-dermal patch presented relatively constant, sustained bloodconcentration with minimal fluctuation and prolonged peaktime over a long period as compared to conventional oraldelivery. The relative bioavailability of FP and metoprololwas found to be 275.37 and 189.76% versus oral administra-tion, respectively. It was evident that the FP-metoprolol-TTSshowed well-controlled release properties that satisfied thedemands of original design that enhancing bioavailabilityand maintaining appropriate blood levels for a prolongedtime without adverse effects associated with frequent oraladministration [78]. In another study, microemulsions con-taining benzyl alcohol were found to be an interesting vehiclefor improved transdermal delivery of FP. The highest trans-dermal flux of FP from microemulsion was found to be10 -- 50 times higher than aqueous suspension [79].

2.8 AmlodipineAP belongs to the 1,4-dihydropyridine categories of CCBsand is structurally related to NFP. The clinical pharmacologyof the antihypertensive action of AP involves a direct relaxanteffect on vascular smooth muscle. AP is given orally (5 mgdaily), with peak plasma concentration occurring after6 -- 12 h. It has a favorable logP of 2.22 and half-life of30 -- 50 h and oral bioavailability of 60 -- 65% due to exten-sive hepatic metabolism [80,81]. Above limitation associatedwith conventional formulations of AP can be circumventedby transdermal delivery. In 1996, McDaid and Deasy exam-ined the effect of the penetration enhancers such as SLS

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(1%) and PG (20%) in a sodium carboxy methyl cellulose(3%) gel base. In addition, the influence of various rate-controlling membranes and a contact adhesive on drug per-meation was also observed. No local irritation was reportedat either application site, confirming that the device wasfound well tolerated on dermal application even after severaldays of wear. The author has claimed that an effective trans-dermal formulation system for the delivery of AP may bepossible [82].

Sun et al. (2009) developed a drug-in-adhesive transdermalpatch for (S)-AP free base and the effects of the type of adhe-sive and the content of permeation enhancers on (S)-AP freebase transport across excised rat skin were evaluated. It wasobserved that the plasma level of (S)-AP following transder-mal application could be maintained for 72 h, and the abso-lute bioavailability of 88.8% for (S)-AP free base wasobtained on transdermal administration to rats. It was sug-gested that the transdermal application of (S)-AP in a drug-in-adhesive transdermal patch may be used for the treatmentfor hypertension [83]. The possible enantioselectivity of per-meation of AP in the presence and absence of terpene and eth-anol was investigated [84]. It was mentioned that thepermeation of the enantiomers of AP from (RS)-AP reservoirshowed no significant differences in the presence and absenceof enhancers, but the permeation of (S)-AP from (S)-AP reser-voir was significantly higher than that of (RS)-AP from (RS)-AP reservoir at ethanol 30 and 50% concentrations andterpene enhancers could not influence the difference in per-meation between S-AP and RS-AP, but 75% ethanol couldreduce the difference. It was suggested that there was no enan-tioselectivity of the enantiomers of AP from (RS)-AP reservoirin the presence and absence of enhancers, but the differencesin physical properties between (S)-AP and (RS)-AP led tothe difference in permeation across rat skins. In another study,the influence of ion pairing on the skin permeation of AP wasinvestigated by Jiang et al. (2008). In vitro percutaneousabsorption of AP(base) and its complexes such as AP-besilate,AP-adipate, AP-oxalate, and AP-maleate was evaluatedthrough excised rat skin using two-chamber diffusion cells.The results showed that all four complexes of AP, viz.AP-besilate, AP-adipate, AP-oxalate, and AP-maleate pre-sented a lower flux and higher permeability coefficient thanAP base [85].

Recently, a novel oil-in-water nanoemulsion system fortransdermal delivery of AP was developed [86]. Various nano-emulsion formulations were prepared using OA (oil phase),Tween-20 (surfactant), and Transcutol P (co-surfactant). Itwas mentioned that the highest permeation rate and perme-ability coefficient were found at low oil and Smix concentra-tions. On increasing the same, fluxes were further decreased,probably due to increased globule size and decreased thermo-dynamic activity of drug at higher Smix concentration. Theoptimum nanoemulsion formulation consisted of 2% oil(OA), 20% surfactant (Tween 20), and 10% co-surfactant(Smix 2:1), and water showed highest skin permeation rate

and permeability coefficient. It was concluded that preparednanoemulsions were found to be potential vehicles forimproved transdermal delivery of AP.

3. Phenylalkylamines

3.1 VerapamilVR-HCl is widely used in the treatment of hypertension,angina, and supraventricular tachyarrhythmias [87]. It has afavorable logP (5.23) and low molecular weight (491.07).The plasma half-life of VR-HCl is 2 -- 7 h, which necessitatesmultiple dosing. It is approximately 90% absorbed from theGIT but is subjected to considerable hepatic first-pass metabolism and its bioavailability is around 20 -- 30%[88]. To improve the bioavailability of VR-HCl and reduceits frequency of administration, it was suggested to maketransdermal system of the drug. In 2008, Gungor et al. fabri-cated matrix-type transdermal patches of VR-HCl using pec-tin as a matrix agent and PG as a plasticizer. Terpenes such asnerolidol, d-limonene, eucalyptol, menthone, and mentholwere used as permeation enhancers. The authors claimedthat nerolidol was found to be the most promising enhanceramongst the investigated terpenes. Antihypertensive activityof the transdermal patches of VR-HCl containing nerolidolor d-limonene was evaluated in experimental hypertensiverats using tail cuff method. It was mentioned that VR-HCl transdermal patches significantly decreased the systolicBP after 30 min and transdermal patches containing nerolidoland d-limonene maintained the decrease in BP during theobservation of 360 min [89]. In another in vivo study, a matrixsystem of E-RL100, E-RS100, and HPMC to rabbits hadreported successful maintenance of steady and adequateplasma levels up to 24 h of administration [90]. In this report,transdermal patches of VR-HCl were prepared using four dif-ferent polymers such as E-RL100, E-RS100, HPMC, and EC.Different formulations were prepared in accordance with the23 factorial design. In vitro release studies presented zero-order release of the drug from all the patches, and the mech-anism of release was found to be diffusion mediated. Amongstseveral preparations, formulation (A12) which is composed ofE-RL100 (8%), HPMC (2%), and DBP (30% w/w of thepolymer), produced most satisfactory drug release and perme-ation via biological obstacles and found free of any skin irrita-tion potential [90]. Meanwhile, in another study, the in vitrorelease of VR-HCl progressively decreased from the transder-mal ointment on increasing the amount (from 20 to 50%) ofethanol-PG (2:1, v/v) into the gel ointment. Transdermalabsorption of the drug in vivo was also performed in rats usingazone as permeation enhancer. Azone enhanced the plasmalevels of VR-HCl up to 10-fold, the effect being greatlydependent on the amount of alcohols in the formulation.The author claimed that the gel ointment can be used fortransdermal drug delivery when an adequate absorptionpromoter is added [91]. It was reported that the steady-stateplasma concentration curve for total VR-HCl concentration



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was proportional to the surface area of the delivery system [92].TTS of VR-HCl using polyvinyl alcohol (PVA) and PVP anddifferent concentrations of d-limonene were developed. It wasdocumented that the incorporation of d-limonene as penetra-tion enhancer in sustained-release polymers shows definiteimprovement in drug permeation across the skin. The VR-HCl permeation across the skin has extensively increased byincorporation of PVA and PVP instead of using PVA orPVP alone [93].Recently, matrix-type transdermal films were developed

using Gum Copal alone and in combination with PVPK-30, to enhance transdermal delivery of VR-HCl. In vivostudy was done on Dawley rats using optimized formulationF5 containing Gum Copal: PVP K-30 (60:40). It wasobserved that the peak drug concentration of about244.94 ng/ml was achieved in 6 h after the application ofthe patch, and plasma drug concentration was maintainedtill 24 h. The author claimed that the developed transdermalpatch showed reasonably good mechanical properties, lowwater vapor transmission, and sustained release of drug.Hence, Gum Copal seems to be a promising film former fortransdermal drug delivery [94].

4. Benzothiazepines

4.1 DiltiazemDZ-HCl is widely used in the management of hypertensionand angina pectoris [95]. Because of its short biological half-life (3.5 h) and low oral bioavailability (40%) due to hepaticmetabolism leading to high-frequency drug dosing, continu-ous delivery of DZ-HCl is required [96,97]. Its physicochemicalproperties like logP (3.09) and molecular weight (414.51) alsomake it a good drug candidate for trandermal drug delivery.Therefore, development of TTS for DZ-HCl should be ofgreat interest [98]. In 1998 and 1999, Rao and Diwan formu-lated the EC-PVP films of DZ-HCl for transdermal adminis-tration. The film composed of EC/PVP at a ratio of8:2 loaded with 20% w/w DZ-HCl was selected as the poly-meric film for DZ-HCl transdermal patch. The in vivo studyin rabbits revealed that prepared DZ-HCl patch sustained thetherapeutic activity over a study period of 24 h after transder-mal administration and provided a fivefold increase in thebioavailability compared to oral administration [99,100]. Otherresearchers, Gupta and Mukherjee, 2003, also used EC andPVP as film former in 2:1 ratio [101], while Jain et al. (2003)developed the matrix diffusion-controlled TTS of DZ-HClusing various combinations of polymer such as E-E100 andE-L100 and PVP and polyethylene glycol 4000 [102]. Inthis study, matrix diffusion-controlled and membranepermeation-controlled systems were developed. The matrixdiffusion-controlled systems used various combinations ofhydrophilic and lipophillic polymers, whereas membranepermeation-controlled systems were developed using the nat-ural polymer chitosan. The in vitro release studies showed thatthe release from the matrix diffusion-controlled TTS follows

a nonfickian pattern and that from the membranepermeation-controlled TTS follow zero-order kinetics. Therelease from the matrix systems increased on increasing thehydrophilic polymer concentration, but the release from themembrane systems decreases on addition of glutaraldehyde(cross-linking agent) and citric acid (gelling agent) to the chi-tosan drug reservoir gel. The in vivo studies showed that bothsystems are capable of achieving the effective plasma concen-tration for a prolonged period of time.

A novel film-forming biomaterial, Damar Batu alone andin combination with E-RL100, was evaluated for its potentialapplication in the preparation of unilaminate transdermaladhesive matrix systems for enhanced transdermal deliveryof DZ-HCl [103]. Damar Batu is the gum which comes outfrom the hard wood tree and falls into the ground. It isobtained from Shorea species like S. lamellata Foxw., S. vires-cens Parijs, S. retinodes Sloot., S. guiso, and S. robusta, familyDipterocarpaceae. DB is mainly used as an emulsifier and sta-bilizer for the production of color, paints, inks, and aromaticemulsions in food and cosmetic industries. The polymer ofDB was identified as polycadinene and is said to containabout 40% a-resin (alcohol soluble part), 22%b-resin (alcohol insoluble part), 23% dammarol acid, and2.5% water; in addition it also contains a small sesquiterpe-noid fraction [104]. Developed transdermal patches of DZ-HCl were evaluated for thickness uniformity, weight unifor-mity, folding endurance, and drug content. On the basis ofin vitro drug release and in vitro skin permeation profileof formulation, F5 composed of Damar Batu:E-RL100 (60:40) and carrying 20% w/w DZ-HCl wasselected as an optimized formulation for in vivo study. Thein vivo study results showed that F5 achieved the Cmax ofabout 269.76 ng/ml in 6 h and sustained the release of thedrug till 24 h. The authors claimed that developed transder-mal patch is nonsensitizing and non-irritating. It was con-cluded that by applying suitable adhesive layer and backingmembrane, Damar Batu: E-RL100 (60:40) transdermalpatches can be of potential therapeutic use [103].

In 2008, Limpongsa and Umprayn developed the TTS ofDZ-HCl using hydrophilic (HPMC) and hydrophobic (EC)film formers. It was observed that addition of EC intoHPMC film produced lower-tensile strength transdermalfilm. However, addition of EC up to 60% resulted in toohard film. Plasticization with DBP produced higher strengthbut lower elongation as compared to triethyl citrate. The10:0 and 8:2 HPCM/EC films showed the comparablepermeation-time profiles, and had higher flux values andshorter lag time as compared to 6:4 HPMC/EC film. Addi-tion of IPM, isopropyl palmitate, or Tween-80 could enhancethe fluxes for approximately three times, while Tween-80 alsoshorten the lag time. In conclusion, the film composed of8:2 HPMC/EC, DBP (30%), and IPM (10%), isopropyl pal-mitate, or Tween-80 loaded with 25% DZ-HCl should beselected for manufacturing transdermal patch by using asuitable adhesive layer and backing membrane [105].

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In another study, the release characteristic of DZ-HCl fromHPMC gels containing 0.5% (w/w) permeation enhancerslike SLS, DMSO, polysorbate 80, PG, N-methylpyrrolidone,fatty acids (OA, caprylic acid, and myristic acid), and IPMwas investigated. Amongst the permeation enhancers, polysor-bate 80 showed highest permeation flux (57.1 µg/cm2/h)compared with the rest of the enhancers, and myristic acidproduced more flux (18.4 µg/cm2/h) among all fatty acidsbecause of a decrease in the gel’s viscosity. Enhancers likeN-methylpyrrolidone and IPM increased the permeationflux from the second day onward, and they increased thegel’s viscosity, while SLS decreased the viscosity of the geland the drug’s permeation flux because of its binding withthe drug, PG decreased the permeation flux by increasingthe gel viscosity, and DMSO increased the permeation fluxwithout altering the viscosity. It was suggested that toformulate DZ-HCl into a HPMC gel, the enhancers ofchoice should be polysorbate 80, myristic acid, DMSO,N-methylpyrrolidone, and IPM or combinations thereof [106].

The polymerized rosin for its use as a film former in thedevelopment of TTS was already reported [107]. It was men-tioned that polymerized rosin exhibits excellent film-formingproperty with sustained-release applications. Polymerizedrosin patches were prepared with PVP using DZ-HCl as adrug model [108]. It was reported that polymerized rosin incombination with PVP and with incorporation of DBP(30% w/w) produces smooth flexible films with improvedtensile strength and percentage elongation. The release rateof drug from films and permeation across skin increase withincrease in drug and PVP loading but are independent offilm thickness. Patches containing polymerized rosin: PVP(7:3) show promise for pharmacokinetic and pharmacody-namic performance. It was concluded from the above resultsthat polymerized rosin can be used in the design of amatrix-type TTS to prolong the drug release.

Recently, three nonionic ether-monohydroxyl surfactantslike ethylene glycol monododecyl ether (C12E1), pentaethy-lene glycol monododecyl ether (C12E5), and octaethylene gly-col monododecyl ether (C12E8) as skin permeation enhancerswere evaluated for transdermal delivery of DZ-HCl andondansetron hydrochloride, formulated as hydrogel. Theenhancers are used alone, or in combination with iontophore-sis. It was observed that the nonionic ether-monohydroxylsurfactants tested were effective as skin penetration enhancersfor the transdermal drug delivery of DZ-HCl. The enhance-ment effects observed were dependent on the penetrationmodifier and on the drug used. C12E5 produced the highestflux values and cumulative amounts of drug permeatedobserved in the passive transdermal studies of DZ-HCl(ER = 9.4). The combined use of the chemical penetra-tion enhancers and iontophoresis (0.3 mA -- 8 h) significantlyincreased the amount of drug permeated. The highest drugpermeation was obtained with the combination of iontopho-resis and the enhancer C12E8 (ER = 200, compared to passivepermeation without enhancer pretreatment) for DZ-HCl.

Skin integrity evaluation studies did not show significantchanges in the tissue morphology when compared to theuntreated samples, suggesting that these compounds arepromising candidates for use in transdermal formulations. Itwas suggested that DZ-HCl can be successfully deliveredthrough the skin using a combination of chemical enhancerand iontophoresis, attaining plasma levels comparable tothose obtained with oral formulations [109].

5. Expert opinion

Hypertension is the most common cardiovascular diseaseworldwide; it is a progressive disorder, which if not effectivelymanaged results in a greatly increased probability of coronarythrombosis, strokes, and renal failure. Hypertension is sus-tained elevation of resting systolic BP (‡ 140 mm Hg), dia-stolic BP (‡ 90 mm Hg), or both. Essential hypertensionwith no known cause is most common than secondary hyper-tension. BP increases with age. About two thirds of people> 65 years of age have hypertension, and people with a normalBP at age 55 have a 90% lifetime risk of developing hyperten-sion. Because hypertension becomes so common with age, theage-related increase in BP may seem innocuous, but higherBP increases morbidity and mortality risk. Management ofhypertension involves lifestyle changes and drugs, includingCCBs, diuretics, b-blockers, ACE inhibitors, and angiotensinII receptor blockers. CCBs were developed in the 1970s andare now widely used. CCBs are a key therapeutic choice inthe major guidelines for the treatment of hypertension.CCBs encourage heart health by reducing the power of theheart’s pump, thus promoting healthier, more relaxed bloodflow. CCBs avert too much calcium ion from getting by thebloodstream and into the heart. They may be employed tomitigate a variety of conditions, such as hypertension, cardiacarrhythmia, and chest pain. Most CCBs are very low in costbut extremely effective. Low- to moderate-cost options areavailable at apothecary’s shop. Decreasing BP as a result ofCCBs use can be life-saving. Moreover, CCBs have beendetermined by some groups to be safer than medicationsused for similar purposes, such as ACE inhibitors andb-blockers. The conventional dosage forms of CCBs havemany limitations including hepatic first-pass metabolism,high incidence of adverse effects due to variable absorptionprofiles, higher frequency of administration, and poor patientcompliance. These findings suggest that despite the availabil-ity of a plethora of therapeutically effective CCB molecules,inadequate patient welfare is observed; this arguably presentsan opportunity to deliver CCBs through a different route.The transdermal route has been utilized since ancient timesto transport a range of therapeutically active molecules intothe systemic circulation. TTS have been accepted as a poten-tial noninvasive route of drug administration, with advantagesof avoidance of the first-pass effect, sustained therapeuticaction, and better patient compliance. Hence, deliveryof drugs via transdermal route has been particularly



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acknowledged as a potential drug-delivery route in the ther-apy of chronic diseases like hypertension. Though, its preva-lent use is restricted due to excellent impervious nature ofskin. Skin barrier is the greatest challenge for researchersthat have to be surmounted for maximized transdermal drugdelivery to achieve systemic therapeutic concentration. Severalovertures have been made to defeat this barrier and enhancethe SC permeability. Such strategies include physical, bio-chemical, and chemical methods. There have been remarkableresearch endeavors worldwide to investigate the skin perme-ation and to develop transdermal systems of various CCBs,still there is a scope of transdermal delivery of CCBs otherthan those discussed above, including mebudipine, dibudi-pine, aranidipine, barnidipine, benidipine, cilnidipine,clevidipine, nisoldipine, and so on, depending on their

physicochemical properties. Future research may harnesstransdermal vesicular system, and nanocarriers such as SLNand NLC, the most recent and promising techniques forenhanced percutaneous absorption of CCBs. More workand further clinical trials are needed to establish in vivo effi-cacy, and long-term safety data of transdermal systems ofCCBs. Persistent advancement in this area holds promise forthe long-term success in technologically advanced transdermaldosage forms being commercialized sooner rather than later.

Declaration of interest

The authors are thankful to the College of Pharmacy ResearchCenter and the Deanship of Scientific Research at King SaudUniversity for financial assistance.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Chuong CM, Nickoloff BJ, Elias PM,

et al. What is the ‘true’ function of skin?

Exp Dermatol 2002;11:159-87

2. Menon GK. New insights into skin

structure: scratching the surface.

Adv Drug Deliv Rev 2002;54:S3-17

3. Wertz PW. Lipids and barrier function

of the skin. Acta Derm Venereol

2002;208:7-11

4. Madison KC. Barrier function of the

skin: “la raison d’etre” of the epidermis.

J Invest Dermatol 2003;121:231-41

5. Elias PM. Stratum corneum defensive

functions: an integrated view.

J Invest Dermatol 2005;125:183-200

6. Prausnitz MR, Langer R. Transdermal

drug delivery. Nat Biotechnol

2008;26:1261-8

7. Aqil M, Sultana Y, Ali A. Transdermal

delivery of beta-blockers. Expert Opin

Drug Deliv 2006;3:405-18.. Review article demonstrates the

transdermal research on various beta-

blockers.

8. Advances in the transdermal drug

delivery market: market size, leading

players, therapeutic focus and innovative

technologies, in: business Insights.

2010. Available from: http://www.

marketresearch.com/Business-Insights-

v893/Advances-Transdermal-Drug-

Delivery-size-2890473/

9. Ahad A, Aqil M, Kohli K, et al.

Chemical penetration enhancers: a patent

review. Expert Opin Ther Pat

2009;19:969-88.. An excellent review, demonstrates

patent status of various chemical

permeation enhancer for

transdermal use.


Transdermal drug delivery: the inherent

challenges and technological

advancements. Asian J Pharm Sci

2010;5:276-88.. Demonstrates various novel

transdermal penetration

enhancement technologies.


Interactions between novel terpenes and

main components of rat and human

skin: mechanistic view for transdermal

delivery of propranolol hydrochloride.

Curr Drug Deliv 2011;8:213-24.. Indicates the effectiveness of various

novel terpenes on skin delivery of

antihypertensive drug.

12. Ahad A, Aqil M, Kohli K, et al. Role of

novel terpenes in transcutaneous

permeation of valsartan: effectiveness and

mechanism of action. Drug Dev

Ind Pharm 2011;37:583-96.. Indicates the effectiveness of various

novel terpenes on skin delivery of

lipophilic drug.

13. Campbell N, Young ER, Drouin D,

et al. A framework for discussion on how

to improve prevention, management, and

control of hypertension in Canada.

Can J Cardiol 2012;28:262-9

14. Ralston RA, Lee JH, Truby H, et al.

A systematic review and meta-analysis of

elevated blood pressure and consumption

of dairy foods. J Hum Hypertens

2012;26:3-13

15. Kearney PM, Whelton M, Reynolds K,

et al. Worldwide prevalence of

hypertension: a systematic review.

J Hypertens 2004;22:11-19

16. Chockalingam A, Campbell NR,

Fodor JG. Worldwide epidemic of

hypertension. Can J Cardiol

2006;22:553-5

17. Zweifler AJ, Esler M. Factors influencing

the choice of antihypertensive agents.

Postgrad Med 1976;60:81-5

18. Epstein BJ, Vogel K, Palmer BF.

Dihydropyridine calcium channel

antagonists in the management of

hypertension. Drugs 2007;67:1309-27

19. Schwartz A, Triggle DJ. Cellular action

of calcium channel blocking drugs.

Annu Rev Med 1984;35:325-39

20. Nordlander M, Abrahamsson T,

Akerblom B, et al. Vascular versus

myocardial selectivity of dihydropyridine

calcium antagonists as studied in vivo

and in vitro. Pharmacol Toxicol

1995;76:56-62

21. Sweetman SC. Martindale: the complete

drug reference. Pharmaceutical Press,

London, UK; 2007

22. Thomas BJ, Finnin BC. The transdermal

revolution. Drug Discov Today

2004;9(16):697-703

23. Keleb E, Sharma RK, Mosa EB, et al.

Transdermal drug delivery system- design

and evaluation. Int J Adv Pharm Sci

2010;1:201-11

A. Ahad et al.


Exp

ert O

pin.

Dru

g D

eliv

. Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f N

otre

Dam

e A

ustr

alia

on

04/3

0/13

For

pers

onal

use

onl

y.

http://www.marketresearch.com/Business-Insights-v893/Advances-Transdermal-Drug-Delivery-size-2890473/




24. Talbert RL, Bussey HI. Update on

calcium-channel blocking agents.

Clin Pharm 1983;2:403-16

25. Nayler WG. Calcium antagonists: past,

present and future -- a personal view.

J Clin Basic Cardiol 1999;2:155-61

26. Ram CV, Fenves A. Clinical

pharmacology of antihypertensive drugs.

Cardiol Clin 2002;20:265-80

27. Squillante E, Needham T, Zia H.

Solubility and in vitro transdermal

permeation of nifedipine. Int J Pharm

1997;159:171-80

28. Squillante E, Maniar A, Needham T,

et al. Optimization of in vitro nifedipine

penetration enhancement through hairless

mouse skin. Int J Pharm

1998;169:143-54

29. McDaid DM, Deasy PB. An

investigation into the transdermal

delivery of nifedipine. Pharm Acta Helv

1996;71:253-8

30. Squillante E, Needham T, Maniar A,

et al. Codiffusion of propylene glycol

and dimethyl isosorbide in hairless

mouse skin. Eur J Pharm Biopharm

1998;46:265-71

31. Manvir A, Rana AC, Nimrata S, et al.

Elastic liposome mediated transdermal

delivery of an anti-hypertensive agent:

nifedipine. J Drug Deliv Ther

2012;2:55-60

32. Thacharodi D, Rao KP. Transdermal

absorption of nifedipine from

microemulsion of lipophilic skin

penetration enhancers. Int J Pharm

1994;111:235-40

33. Boltri L, Morel S, Trotta M, et al. In

vitro transdermal permeation of

nifedipine from thickened

microemulsions. J Pharm Belg

1994;49:315-20

34. Graham DJ, Dow RJ, Hall DJ, et al.

The metabolism and pharmacokinetics of

nicardipine hydrochloride in man. Br J

Clin Pharmacol 1985;20:23S-8S

35. Dow RJ, Graham DJ. A review of the

human metabolism and pharmacokinetics

of nicardipine hydrochloride. Br J


36. Whiting RL, Dow RJ, Graham DJ. An

overview of the pharmacology and

pharmacokinetics of nicardipine.

Angiology 1990;41:987-91

37. Krishnaiah YS, Satyanarayana V,

Karthikeyan RS. Effect of the solvent

system on the in vitro permeability of

nicardipine hydrochloride through

excised rat epidermis. J Pharm Pharm Sci

2002;5:123-30.. indicates the efficacy of an

antihypertensive drug applied with a

transdermal therapeutic system.


Bhaskar P. Influence of limonene on the

bioavailability of nicardipine

hydrochloride from

membrane-moderated transdermal

therapeutic systems in human volunteers.

Int J Pharm 2002;247:91-102


Karthikeyan RS. Penetration enhancing

effect of menthol on the percutaneous

flux of nicardipine hydrochloride through

excised rat epidermis from hydroxypropyl

cellulose gels. Pharm Dev Technol

2002;7:305-15.. Shows the efficacy of an

antihypertensive drug applied with a

transdermal therapeutic system.


Bhaskar P. Influence of menthol and

pressure-sensitive adhesives on the in vivo

performance of membrane-moderated

transdermal therapeutic system of

nicardipine hydrochloride in human

volunteers. Eur J Pharm Biopharm

2003;55:329-37


Bhaskar P. Enhanced percutaneous

permeability of nicardipine hydrochloride

by carvone across the rat abdominal skin.

Drug Dev Ind Pharm 2003;29:191-202

42. Akhtar N, Ahad A, Khar RK, et al. The

emerging role of P-glycoprotein

inhibitors in drug delivery: a patent

review. Expert Opin Ther Pat

2011;21:561-76.. An excellent review demonstrates the

role of P-glycoprotein inhibitors in

various classes of drugs.

43. Aqil M, Ahad A, Sultana Y, et al. Status

of terpenes as skin penetration enhancers.

Drug Discov Today 2007;12:1061-7.. An excellent review on the utility of

terpenes as permeation enhancers for

transdermal drug delivery.

44. Hassan N, Ahad A, Ali M, et al.

Chemical permeation enhancers for

transbuccal drug delivery. Expert Opin

Drug Deliv 2010;7:97-112.. An excellent review on the application

of various chemical permeation

enhancers for transbuccal

drug delivery.


Bhaskar P. Formulation and in vivo

evaluation of membrane-moderated

transdermal therapeutic systems of

nicardipine hydrochloride using carvone

as a penetration enhancer. Drug Deliv

2003;10:101-9

46. Kavitha K, Kumar PD. Development of

transdermal patches of nicardipine

hydrochloride: an attempt to improve

bioavailability. Int J Res Pharma

Biomed Sci 2011;1:285-93

47. Aboofazeli R, Zia H, Needham TE.

Transdermal delivery of nicardipine:

an approach to in vitro permeation

enhancement. Drug Deliv 2002;9:239-47

48. Wu PC, Lin YH, Chang JS, et al. The

effect of component of microemulsion

for transdermal delivery of nicardipine

hydrochloride. Drug Dev Ind Pharm

2010;36:1398-403

49. Kolli CS, Banga AK. Characterization of

solid maltose microneedles and their use

for transdermal delivery. Pharm Res

2008;25:104-13

50. Kann J, Krol GJ, Raemsch KD, et al.

Bioequivalence and metabolism of

nitrendipine administered orally to

healthy volunteers.

J Cardiovasc Pharmacol 1984;6:S968-73

51. Goa KL, Sorkin EM. Nitrendipine.

A review of its pharmacodynamic and

pharmacokinetic properties, and

therapeutic efficacy in the treatment of


52. Gannu R, Vishnu YV, Kishan V, et al.

Development of nitrendipine transdermal

patches: in vitro and ex vivo

characterization. Curr Drug Deliv

2007;4:69-76

53. Tipre DN, Vavia PR. Acrylate-based

transdermal therapeutic system of

nitrendipine. Drug Dev Ind Pharm

2003;29:71-8

54. Mittal A, Sara UV, Ali A, et al. The

effect of penetration enhancers on

permeation kinetics of nitrendipine in

two different skin models.

Biol Pharm Bull 2008;31:1766-72

55. Ruan LP, Liang BW, Tao JZ, et al.

Transdermal absorption of nitrendipine

from adhesive patches. J Control Rel

1992;20:231-6

56. Mittal A, Sara UV, Ali A. Formulation

and evaluation of monolithic matrix



Exp

ert O

pin.

Dru

g D

eliv

. Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f N

otre

Dam

e A

ustr

alia

on

04/3

0/13

For

pers

onal

use

onl

y.

polymer films for transdermal delivery of

nitrendipine. Acta Pharm

2009;59:383-93

57. Bhaskar K, Krishna MC, Lingam M,

et al. Development of SLN and NLC

enriched hydrogels for transdermal

delivery of nitrendipine: in vitro and

in vivo characteristics. Drug Dev

Ind Pharm 2009;35:98-113

58. Bhaskar K, Krishna MC, Lingam M,

et al. Development of nitrendipine

controlled release formulations based on

SLN and NLC for topical delivery:

in vitro and ex vivo characterization.


59. Hassan N, Ali M, Ali J. Development

and evaluation of novel buccoadhesive

wafers of nimodipine for treatment of

hypertension. Drug Deliv 2010;17:59-67

60. Hassan N, Ali M, Ali J. Novel buccal

adhesive system for anti-hypertensive

agent nimodipine. Pharm Dev Technol

2010;15:124-30. Demonstrates that transbuccal delivery

of nimodipine gives

encouraging results.

61. Kirch W, Ramsch KD, Duhrsen U, et al.

Clinical pharmacokinetics of nimodipine

in normal and impaired renal function.

Int J Clin Pharmacol Res 1984;4:381-4

62. Kumana CR, Kou M, Yu YL, et al.

Investigation of nimodipine

pharmacokinetics in Chinese patients

with acute subarachnoid haemorrhage.

Eur J Clin Pharmacol 1993;45:363-6

63. Krishnaiah YS, Bhaskar P,

Satyanarayana V. Formulation and

evaluation of limonene-based membrane-

moderated transdermal therapeutic

system of nimodipine. Drug Deliv

2004;11:1-9


Satyanarayana V. In vitro percutaneous

permeability enhancement of nimodipine

by limonene across the excised rat

abdominal skin. Pharmazie

2004;59(12):942-7

65. Krishnaiah YS, Bhaskar P. Studies on the

transdermal delivery of nimodipine from

a menthol-based TTS in human

volunteers. Curr Drug Deliv

2004;1(2):93-102

66. Giannakou SA, Dallas PP, Rekkas DM,

et al. Development and in vitro

evaluation of nimodipine transdermal

formulations using factorial design.

Pharm Dev Technol 1998;3:517-25


Satyanarayana V. Penetration-enhancing

effect of ethanol-water solvent system and

ethanolic solution of carvone on

transdermal permeability of nimodipine

from HPMC gel across rat abdominal

skin. Pharm Dev Technol 2004;9:63-74

68. Giannakou SA, Dallas PP, Rekkas DM,

et al. In vitro evaluation of nimodipine

permeation through human epidermis

using response surface methodology.

Int J Pharm 2002;241:27-34

69. Moffat AC, David O, Brian W. Clarke’s

analysis of drugs and poisons.

Pharmaceutical Press, London; 2005

70. Sweetman SC. Martindale: The complete


London, UK; 2005

71. Tirunagari M, Jangala VR, Khagga M,

et al. Transdermal therapeutic system of

isradipine: effect of hydrophilic and

hydrophobic matrix on in vitro and

ex vivo characteristics. Arch Pharm Res

2010;33:1025-33

72. Lee CR, Bryson HM. Lacidipine.

A review of its pharmacodynamic and

pharmacokinetic properties and

therapeutic potential in the treatment of


73. Salako BL, Kadiri S, Walker O, et al.

Evaluation of lacidipine (a calcium

blocker) in the treatment of hypertension

in black African people: a double-blind

comparison with hydrochlorothiazide.

Afr J Med Med Sci 1998;27:73-5

74. McCormack PL, Wagstaff AJ.

Lacidipine: a review of its use in the

management of hypertension. Drugs

2003;63:2327-56

75. Gannu R, Palem CR, Yamsani VV, et al.

Enhanced bioavailability of lacidipine via

microemulsion based transdermal gels:

formulation optimization, ex vivo and

in vivo characterization. Int J Pharm

2010;388:231-41.. Indicates that microemulsion based

transdermal gel significantly improved

bioavailability of dihydropyridine type

antihypertensive drug.

76. Saltiel E, Ellrodt AG, Monk JP, et al.

Felodipine. A review of its

pharmacodynamic and pharmacokinetic

properties, and therapeutic use in


77. Diez I, Peraire C, Obach R,

Domenech J. Influence of d-limonene on

the transdermal penetration of felodipine.

Eur J Drug Metab Pharmacokinet

1998;23(1):7-12

78. Wang WG, Yun LH, Wang R, et al.

Preparation of transdermal drug delivery

system of felodipine-metoprolol and its

bioavailability in rabbits. Yao. Xue. Xue.

Bao 2007;42:1206-14

79. Trotta M, Morel S, Gasco MR, et al.

Effect of oil phase composition on the

skin permeation of felodipine from o/w

microemulsions. Pharmazie 1997;52:50-3

80. Williams DM, Cubeddu LX. Amlodipine

pharmacokinetics in healthy volunteers.

J Clin Pharmacol 1988;28:990-4

81. Chhabra G, Chuttani K, Mishra AK,

et al. Design and development of

nanoemulsion drug delivery system of

amlodipine besilate for improvement of

oral bioavailability. Drug Dev Ind Pharm

2011;37:907-16

82. McDaid DM, Deasy PB. Formulation

development of a transdermal drug

delivery system for amlodipine base.

Int J Pharm 1996;133:71-83

83. Sun Y, Fang L, Zhu M, et al.

A drug-in-adhesive transdermal patch for

S-amlodipine free base: in vitro and

in vivo characterization. Int J Pharm

2009;382:165-71

84. Zeng A, Wang C, Yuan B, et al. The

influence of chirality, physicochemical

properties, and permeation enhancers on

the transdermal permeation of

amlodipine across rat skin. Drug Dev

Ind Pharm 2010;36:724-34

85. Jiang Y, Fang L, Niu X, et al. The effect

of ion pairing on the skin permeation of

amlodipine. Pharmazie 2008;63:356-60

86. Kumar D, Aqil M, Rizwan M, et al.

Investigation of a nanoemulsion as

vehicle for transdermal delivery of

amlodipine. Pharmazie 2009;64:80-5

87. Paranjothy KLK, Thampi PP.

Transdermal drug delivery systems.

Indian J Pharm Sci 1997;59:1-4

88. Follath F, Ha HR, Schutz E, et al.

Pharmacokinetics of conventional and

slow-release verapamil. Br J


89. Gungor S, Bektas A, Alp FI, et al.

Matrix-type transdermal patches of

verapamil hydrochloride: in vitro

permeation studies through excised rat

skin and pharmacodynamic evaluation in

rats. Pharm Dev Technol 2008;13:283-9

A. Ahad et al.


Exp

ert O

pin.

Dru

g D

eliv

. Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f N

otre

Dam

e A

ustr

alia

on

04/3

0/13

For

pers

onal

use

onl

y.

90. Kusum DV, Saisivam S, Maria GR, et al.

Design and evaluation of matrix

diffusion controlled transdermal patches

of verapamil hydrochloride. Drug Dev

Ind Pharm 2003;29:495-503

91. Sekine T, Machida Y, Nagai T. Gel

ointment of verapamil for percutaneous

absorption. Drug Des Deliv

1987;1:245-52

92. Shah HS, Tojo K, Chien YW, et al.

Transdermal controlled delivery of

verapamil: characterization of in vitro

skin permeation. Int J Pharm

1992;86:167-73

93. Jain GK, Sharma AK, Agrawal SS.

Transdermal controlled administration of

verapamil-enhancement of skin

permeability. Int J Pharm

1996;130:169-77

94. Mundada AS, Avari JG. In vitro and

in vivo characterization of novel

biomaterial for transdermal application.

Curr Drug Deliv 2011;8(5):517-25

95. Basile J. The role of existing and newer

calcium channel blockers in the

treatment of hypertension.

J Clin Hypertens 2004;6:621-9

96. Mazzo DJ, Obetz CL, Shuster J.

Diltiazem hydrochloride. In: Florey K,

editor. Analytical profiles of drug

substances and excipients. Academic

Press; 1994. pp 53-98

97. Gilman AG, Goodman LS, Rall TW,

et al. The pharmacological basis of

therapeutics. McGraw-Hill, New York;

1996

98. Sweetman SC. Martindale: the complete


London, UK; 2006

99. Rao PR, Diwan PV. Formulation and

in vitro evaluation of polymeric films of

diltiazem hydrochloride and

indomethacin for transdermal

administration. Drug Dev Ind Pharm

1998;24:327-36

100. Rao PR, Diwan PV. Comparative in vivo

evaluation of diltiazem hydrochloride

following oral and transdermal

administration in rabbits.

Indian J Pharmacol 1999;31:294-8. Demonstrates that transdermal delivery

of an antihypertensive drug gives

encouraging results.

101. Gupta R, Mukherjee B. Development

and in vitro evaluation of diltiazem

hydrochloride transdermal patches based

on povidone-ethylcellulose matrices.


102. Jain SK, Chourasia MK, Sabitha M,

et al. Development and characterization

of transdermal drug delivery systems for

diltiazem hydrochloride. Drug Deliv

2003;10:169-77

103. Mundada AS, Avari JG. Novel

biomaterial for transdermal application:

in vitro and in vivo characterization.

Drug Deliv 2011;18(6):424-31

104. Mundada AS, Avari JG. Permeability

studies of damar batu free films for

transdermal application. Chem Ind &

Chem Eng Quart 2009;15(2):83-8

105. Limpongsa E, Umprayn K. Preparation

and evaluation of diltiazem hydrochloride

diffusion-controlled transdermal delivery

system. AAPS PharmSciTech

2008;9:464-70

106. Karakatsani M, Dedhiya M,

Plakogiannis FM. The effect of

permeation enhancers on the viscosity

and the release profile of transdermal

hydroxypropylmethylcellulose gel

formulations containing diltiazem HCl.

Drug Dev Ind Pharm

2010;36(10):1195-206

107. Fulzele SV, Satturwar PM, Dorle AK.

Polymerized rosin: novel film forming

polymer for drug delivery. Int J Pharm

2002;249:175-84

108. Satturwar PM, Fulzele SV, Dorle AK.

Evaluation of polymerized rosin for the

formulation and development of

transdermal drug delivery system:

a technical note. AAPS PharmSciTech

2005;6:E649-54

109. Silva SM, Hu L, Sousa JJ, et al.

A combination of nonionic surfactants

and iontophoresis to enhance the

transdermal drug delivery of ondansetron

HCl and diltiazem HCl. Eur J

Pharm Biopharm 2012;80:663-73

AffiliationAbdul Ahad†1 MPharm PhD,

Fahad I Al-Jenoobi2 PhD,

Abdullah M Al-Mohizea2 PhD,

Mohd Aqil3 MPharm PhD &

Kanchan Kohli4 MPharm PhD†Author for correspondence1Assistant Professor,

King Saud University, College of Pharmacy,

Department of Pharmaceutics, P.O. Box 2457,

Riyadh 11451, Saudi Arabia

Tel: +966557124812;

E-mail: [email protected],

[email protected] Professor,

King Saud University, College of Pharmacy,

Department of Pharmaceutics, P.O. Box 2457,

Riyadh 11451, Saudi Arabia3Assistant Professor,

Jamia Hamdard (Hamdard University), Faculty

of Pharmacy, Department of Pharmaceutics,

M. B. Road, New Delhi 110062, India4Associate Professor,

Jamia Hamdard (Hamdard University), Faculty

of Pharmacy, Department of Pharmaceutics,

M. B. Road, New Delhi 110062, India



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transdermal delivery of calcium channel blockers for hypertension

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