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a s i a n j o u rn a l o f p h a rma c e u t i c a l s c i e n c e s 9 ( 2 0 1 4 ) 2 6 0e2 6 7
Investigating the potential of essential oils aspenetration enhancer for transdermal losartandelivery: Effectiveness and mechanism of action
Indu Vashisth a,c, Abdul Ahad b, Mohd. Aqil a,*, Suraj P. Agarwal a
a Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University, New Delhi 110062, Indiab Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457,
Riyadh 11451, Saudi Arabiac Quality Assurance Unit, Fortis Clinical Research Ltd, New Delhi, India
a r t i c l e i n f o
Article history:
Received 13 March 2014
Received in revised form
23 June 2014
Accepted 26 June 2014
Available online 3 July 2014
Keywords:
Aloe vera oil
Essential oils
Losartan
Skin permeation
Transdermal
* Corresponding author. Tel.: þ91 9811798725;E-mail addresses: [email protected],Peer review under responsibility of Shenyan
Table 1 e Skin permeation parameters of LP using rat skin treated with ethanol: PBS mixture containing investigatedpenetration enhancer (Study 1) and pretreated rat skin with the penetration enhancers (Study 2).
Penetration enhancer Flux (mg/cm2/h) Pb � 10�5 (cm/h) Enhancement ratio % increase in flux Lag time (h)
Study 1a Study 2b Study 1a Study 2b Study 1a Study 2b Study 1a Study 2b Study 1a Study 2b
Controlc 255 ± 1.7d 220 ± 1.7d 41.57 35.86 1 1 e e 2.22 ± 0.5 2.26 ± 0.6
eNon-significant (P > 0.05).fSignificant (P < 0.05).a Study 1: Donor solution containing ethanol: PBS (1:9) and penetration enhancer.b Study 2: SC pretreated with the penetration enhancers for 2 h.c Respective controls were subjected to same treatment except penetration enhancer.d Mean ± SEM values of three observations.
a s i a n j o u rn a l o f p h a rm a c e u t i c a l s c i e n c e s 9 ( 2 0 1 4 ) 2 6 0e2 6 7 263
and time in (h). The permeability coefficient (kp) was calcu-
lated by dividing the flux by the initial drug concentration per
unit area of the skin (mg/cm2). The enhancement ratio (ER) was
calculated by dividing kp in presence of enhancer by kpwithout
enhancer (control).
Therapeutic transdermal daily dose (Td) of LP was calcu-
lated by the following equation [24].
Td ¼ Do � F=100
where, F is the bioavailability in percentage after oral
administration (33% for LP) and Do is the oral dose (25 mg
for LP).
The permeated daily dose (Dss) was calculated from the
following equation.
Dss ¼ J� Ta � t
where, J is the LP flux in mg/cm2/h, Ta is the area of diffusion
and t is the duration of treatment.
2.6. Statistics analysis
The data was subjected to one-way analysis of variance
(ANOVA) followed by Dunnett's test using GraphPad Prism
version 3.00 for Windows (San Diego, CA, USA). Statistical
significance will be assumed when P � 0.05.
Fig. 1 e Skin permeation profile of LP on concurrent
treatment of test penetration enhancers with saturated
solution of LP in the vehicle i.e. ethanol: PBS (1:9) (Study 1).
3. Results and discussion
3.1. In vitro skin permeation studies
The results of in vitro skin permeation studies revealed that
the flux of LP from saturated aqueous solution without
enhancer (control) was 220e255 mg/cm2/h (Table 1). This rate
of skin permeation would enable 6.45 mg of LP absorbed in
24 h which is well short of daily transdermal therapeutic dose
of LP (8.25 mg). In order to enhance the transdermal flux of LP
across the rat skin various essential oils namely TTO, CO, RO
were evaluated for their permeation enhancement potential.
Two different sets of skin permeation studies were carried
out. In study 1 (Fig. 1), 5% v/v of test enhancer was added to the
saturated solution of LP in the vehicle i.e. ethanol: PBS (1:9)
and themixturewas placed in the donor cell. In study 2 (Fig. 2),
SC was pretreated with test penetration enhancer and then
exposed to saturated solution of LP in the vehicle kept in the
donor cell. The two studies were conducted to compare the
effectiveness of the penetration enhancer pretreatment and
concurrent vehicle-enhancer treatment of SC.
In study 1 (Table 1), all the essential oils-vehicle treatments
produced significant differences (P < 0.05) in the LP flux over
the control with the exception of TTO (P > 0.05). Individual
comparison between the enhancer-vehicle treatments
revealed highly significant difference (P < 0.001) in case of
TTO-ethanol vs CO-ethanol, CO-ethanol vs RO-ethanol and
RO-ethanol vs TTO-ethanol.
The results of the study 2 (enhancer pretreatment) indi-
cated similar pattern of permeation enhancement. Highly
significant increment in LP flux (P < 0.001) was obtained by the
essential oils pretreatment over the control except TTO
(P > 0.05). On individual comparison between various pre-
treatments, highly significant difference (P < 0.001) was
observed between TTO vs CO., CO vs RO and RO vs TTO
(Table 1).
Inter study comparison presented a significant difference
(P < 0.05) between the LP flux obtained on concurrent vehicle-
Fig. 7 e Arrhenius plot of LP permeation across rat skin at
different temperatures.
Fig. 9 e Photomicrograph of test skin section (enhancer
treated) showing generally normal skin structure except
for absent keratin layer.
a s i a n j o u rn a l o f p h a rma c e u t i c a l s c i e n c e s 9 ( 2 0 1 4 ) 2 6 0e2 6 7266
free off hydrogen bonds near polar head group regions of lipid
bilayer [38]. Alteration of any of these processes may lead to
production of Eact for transdermal permeation. Accordingly,
reduction of Eact of LP permeation by AVO may be assigned to
the disruption of hydrogen bonding of drug molecule with SC
lipids or by creating pre volume in the lipid alkyl chain.
Moreover, very low Eact of LP transport (1.83 K cal/mol) in
presence of AVO suggests that AVO creates new polar path-
ways by interacting at polar head group region of SC lipids
bilayer.
3.2.4. Histopathological studiesFig. 8 shows the photomicrograph of the control (untreated)
skin with the well defined epidermal and dermal layers. SC is
presenting a layer of distinct keratinized cells (corneocytes).
Skin appendages (hair follicles) are clearly visible. On treating
the rat skin with the AVO, distinct changes in the keratinized
Fig. 8 e Photomicrograph of control skin section (not
treated with enhancer) showing normal skin structure.
Epidermal and dermal layers are well defined.
layer were observed (Fig. 9). Corneocytes were disrupted
losing the keratin and proteins. There was no effect on the
keratinized cells present in the follicles and the layers of
viable epidermis. Dermis and skin appendages were found to
be intact. The above observations clearly demonstrate the
possibility of transcellular skin transport of LP by AVO evi-
denced by dekeratinization of corneocytes present in the SC
(Fig. 9). There were no signs of skin irritation (e.g. edema, er-
ythema and inflammation) when the rat skin treated with the
AVO and the changes observed in the topmost layer (SC) could
be attributed to the action of the penetration enhancer (AVO)
only.
4. Conclusion
Findings of the above study demonstrate that it is possible to
achieve enhanced LP flux by test essential oils (RO, CO, TTO)
and AVO. However, only AVO pretreatment provided the
target flux required to deliver therapeutic dose of LP percu-
taneously. FTIR and DSC analysis confirm that all investigated
penetration enhancers enhance the permeation of LP by
extraction of lipid bilayers in SC. It is concluded that it is
feasible to deliver therapeutically effective dose of LP via
transdermal route using AVO as penetration enhancer.
r e f e r e n c e s
[1] Rao D. Trends in hypertension. Indian Heart J2012;64:132e133.
[2] Ahad A, Al-Jenoobi FI, Al-Mohizea AM, et al. Transdermaldelivery of calcium channel blockers for hypertension.Expert Opin Drug Deliv 2013;10:1137e1153.
[3] Ahad A, Aqil M, Kohli K, et al. Role of novel terpenes intranscutaneous permeation of valsartan: effectiveness andmechanism of action. Drug Dev Ind Pharm 2011;37:583e596.
[4] Ahad A, Aqil M, Kohli K, et al. Interactions between novelterpenes and main components of rat and human skin:mechanistic view for transdermal delivery of propranololhydrochloride. Curr Drug Deliv 2011;8:213e224.
a s i a n j o u rn a l o f p h a rm a c e u t i c a l s c i e n c e s 9 ( 2 0 1 4 ) 2 6 0e2 6 7 267
[5] Ahad A, Aqil M, Kohli K, et al. Chemical penetrationenhancers: a patent review. Expert Opin Ther Pat2009;19:969e988.
[6] Hassan N, Ahad A, Ali M, et al. Chemical permeationenhancers for transbuccal drug delivery. Expert Opin DrugDeliv 2010;7:97e112.
[7] Aqil M, Ahad A, Sultana Y, et al. Status of terpenes as skinpenetration enhancers. Drug Discov Today2007;12:1061e1067.
[8] Patil UK, Saraogi R. Natural products as potential drugpermeation enhancer in transdermal drug delivery system.Arch Dermatol Res 2014.
[9] Aggarwal G, Dhawan S, Hari Kumar SL. Natural oils as skinpermeation enhancers for transdermal delivery ofolanzapine: in vitro and in vivo evaluation. Curr Drug Deliv2012;9:172e181.
[10] Tenjarla SN, Kasina R, Puranajoti P, et al. Synthesis andevaluation of N-acetylprolinate esters - novel skinpenetration enhancers. Int J Pharm 1999;192:147e158.
[11] Goa KL, Wagstaff AJ. Losartan potassium: a review of itspharmacology, clinical efficacy and tolerability in themanagement of hypertension. Drugs 1996;51:820e845.
[12] Zaiken K, Hudd TR, Cheng JW. A review of the use ofangiotensin receptor blockers for the prevention ofcardiovascular events in patients with essentialhypertension without compelling indications. AnnPharmacother 2013;47:686e693.
[13] Thakur R, Anwer MK, Shams MS, et al. Proniosomaltransdermal therapeutic system of losartan potassium:development and pharmacokinetic evaluation. J Drug Target2009;17:442e449.
[14] Baviskar DT, Parik VB, Gupta HN, et al. Design and evaluationof patches for transdermal delivery of losartan potassium.PDA J Pharm Sci Technol 2012;66:126e135.
[15] Shams MS, Alam MI, Ali A, et al. Pharmacodynamics of alosartan transdermal system for the treatment ofhypertension. Drug Dev Ind Pharm 2010;36:385e392.
[16] Shams MS, Alam MI, Ali A, et al. Pharmacokinetics of alosartan potassium released from a transdermal therapeuticsystem for the treatment of hypertension. Pharmazie2010;65:679e682.
[17] Ahad A, Aqil M, Ali A. Investigation of antihypertensiveactivity of carbopol valsartan transdermal gel containing 1,8-cineole. Int J Biol Macromol 2014;64C:144e149.
[18] Ahad A, Aqil M, Kohli K, et al. Enhanced transdermal deliveryof an anti-hypertensive agent via nanoethosomes: statisticaloptimization, characterization and pharmacokineticassessment. Int J Pharm 2013;443:26e38.
[19] Ahad A, Aqil M, Kohli K, et al. Formulation and optimizationof nanotransfersomes using experimental design techniquefor accentuated transdermal delivery of valsartan.Nanomedicine 2012;8:237e249.
[20] Jain R, Aqil M, Ahad A, et al. Basil oil is a promising skinpenetration enhancer for transdermal delivery of labetololhydrochloride. Drug Dev Ind Pharm 2008;34:384e389.
[21] Rizwan M, Aqil M, Ahad A, et al. Transdermal delivery ofvalsartan: I. Effect of various terpenes. Drug Dev Ind Pharm2008;34:618e626.
[22] Bhatia KS, Singh J. Effect of linolenic acid/ethanol orlimonene/ethanol and iontophoresis on the in vitro
percutaneous absorption of LHRH and ultrastructure ofhuman epidermis. Int J Pharm 1999;180:235e250.
[23] Jalalizadeh H, Souri E, Farsam H, et al. A high-performanceliquid chromatographic assay for the determination oflosartan in plasma. Iran J Pharmacol Ther 2003;2:18e21.
[24] Vaddi HK, Ho PC, Chan SY. Terpenes in propylene glycol asskin-penetration enhancers: permeation and partition ofhaloperidol, Fourier transform infrared spectroscopy, anddifferential scanning calorimetry. J Pharm Sci2002;91:1639e1651.
[25] Vaddi HK, Ho PC, Chan YW, et al. Terpenes in ethanol:haloperidol permeation and partition through human skinand stratum corneum changes. J Control Release2002;81:121e133.
[26] Vaddi HK, Wang LZ, Ho PC, et al. Effect of some enhancers onthe permeation of haloperidol through rat skin in vitro. Int JPharm 2001;212:247e255.
[27] Aqil M, Sultana Y, Ali A, et al. Transdermal drug deliverysystems of a beta blocker: design, in vitro, and in vivocharacterization. Drug Deliv 2004;11:27e31.
[28] Kunta JR, Goskonda VR, Brotherton HO, et al. Effect ofmenthol and related terpenes on the percutaneousabsorption of propranolol across excised hairless mouseskin. J Pharm Sci 1997;86:1369e1373.
[29] Gao S, Singh J. In vitro percutaneous absorptionenhancement of a lipophilic drug tamoxifen by terpenes. JControl Release 1998;51:193e199.
[30] El-Kattan AF, Asbill CS, Kim N, et al. The effects of terpeneenhancers on the percutaneous permeation of drugs withdifferent lipophilicities. Int J Pharm 2001;215:229e240.
[31] Wilfried F, Petra H, Paul M. Intradermal-penetration agentsfor topical local anesthetic administration. U. S 6,746,689;June 8, 2004.
[32] Cotte M, Dumas P, Besnard M, et al. Synchrotron FT-IRmicroscopic study of chemical enhancers in transdermaldrug delivery: example of fatty acids. J Control Release2004;97:269e281.
[33] Golden GM, Guzek DB, Harris RR, et al. Lipid thermotropictransitions in human stratum corneum. J Invest Dermatol1986;86:255e259.
[34] White SH, Mirejovsky D, King GI. Structure of lamellar lipiddomains and corneocyte envelopes of murine stratumcorneum. An X-ray diffraction study. Biochemistry1988;27:3725e3732.
[35] Yamane MA, Williams AC, Barry BW. Terpene penetrationenhancers in propylene glycol/water co-solvent systems:effectiveness and mechanism of action. J Pharm Pharmacol1995;47:978e989.
[36] Chu HL, Lin SY. Temperature-induced conformationalchanges in amyloid beta (1-40) peptide investigated bysimultaneous FT-IR microspectroscopy with thermal system.Biophys Chem 2001;89:173e180.
[37] Krishnaiah YS, Satyanarayana V, Karthikeyan RS. Effect ofthe solvent system on the in vitro permeability ofnicardipine hydrochloride through excised rat epidermis. JPharm Pharm Sci 2002;5:123e130.
[38] Narishetty ST, Panchagnula R. Transdermal delivery ofzidovudine: effect of terpenes and their mechanism ofaction. J Control Release 2004;95:367e379.