Home  |  About JAPTR |  Editorial board  |  Search |  Ahead of print  |  Current issue  |  Archives |  Submit article  |  Instructions  |  Subscribe  |  Advertise  |  Contacts  |Login 
Users Online: 514   Home Print this page Email this page Small font sizeDefault font sizeIncrease font size

 Table of Contents  
Year : 2012  |  Volume : 3  |  Issue : 4  |  Page : 216-223  

Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride

Department of Pharmaceutics, G. Pulla Reddy College of Pharmacy, Osmania University, Hyderabad, India

Date of Web Publication14-Dec-2012

Correspondence Address:
P K Lakshmi
G. Pulla Reddy College of Pharmacy, Osmania University, Hyderabad 500 028
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-4040.104712

Rights and Permissions

Transdermal drug delivery has attracted much attention as an alternative to intravenous and oral methods of delivery. But the main barrier is stratum corneum. Terpenes classes of chemical enhancers are used in transdermal formulations for facilitating penetration of drugs. The aim of the study is to evaluate terpenes as skin penetration enhancers and correlate its relationship with permeation and lipophilicity. In this study, alfuzosin hydrochloride (AH) hydrogels were prepared with terpenes using Taguchi orthogonal array experimental design. The formulations contained one of eight terpenes, based on their lipophilicity (log P 2.13-5.36). The percutaneous permeation was studied in rat skin using diffusion cell technique. Flux, cumulative amount, lag time and skin content of AH were measured over 24 hours and compared with control gels. Nerolidol with highest lipophilicity (log P 5.36 ± 0.38) showed highest cumulative amount (Q 24 ) of 647.29 ± 18.76 μg/cm 2 and fluxrateof 28.16 ± 0.64 μg/cm 2 /hour. It showed decreased lag time of 0.76 ± 0.15 hours. Fenchone (2.5%) (log P 2.13 ± 0.30) produced the longest lag time 4.8 ± 0.20 hours. The rank order of enhancement effect was shown as nerolidol > farnesol > limonene > linalool > geraniol > carvone > fenchone > menthol. Lowest skin content was seen with carvone. Increase in lipophilicity of terpenes showed increase in flux, cumulative amount (Q 24 ), and enhancement ratio which was significant with P < 0.000. But lag time was decreased and no correlation was found between lipophilicity and skin content. Histological studies showed changes in dermis which can be attributed to disruption of lipid packing of stratum corneum due to effect of nerolidol within lipid lamellae. It was found that small alcoholic terpenes with high degree of unsaturation enhance permeation of hydrophilic drugs, liquid terpenes enhance better than solid terpenes and terpenes with high lipophilicity are good penetration enhancers.

Keywords: Alfuzosin hydrochloride, lipophilicity, taguchi robust design method, terpenes, transdermal permeation

How to cite this article:
Prasanthi D, Lakshmi P K. Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride. J Adv Pharm Technol Res 2012;3:216-23

How to cite this URL:
Prasanthi D, Lakshmi P K. Terpenes: Effect of lipophilicity in enhancing transdermal delivery of alfuzosin hydrochloride. J Adv Pharm Technol Res [serial online] 2012 [cited 2023 Mar 20];3:216-23. Available from: https://www.japtr.org/text.asp?2012/3/4/216/104712

   Introduction Top

Transdermal delivery is more advantageous over conventional modes of drug administration. It is

  • convenient,
  • bypasses first-pass metabolism,
  • provides a steady-state plasma concentration of the drug,
  • provides long term therapy in a single dose
  • and improves patient compliance.
However, the skin permeation of clinically useful drugs is generally poor with some exception (it has small molecular weight (< 300 Da) and lipophilic nature) because the stratum corneum functions as a barrier against foreign substances. [1] The most widely implemented approach to overcome this skin barrier has been the use of chemical penetration enhancers, which ideally alter the physiochemical nature of the stratum corneum safely and reversibly to facilitate the drug's delivery through the skin. [2] According to the lipid-protein-partitioning theory, penetration enhancers may increase the permeability of a drug by affecting the intercellular lipids of the stratum corneum via extraction or fluidization and/or by increasing the partitioning of the drug in the stratum corneum membranes, and/or by changing conformations within the keratinized protein component. [3]

Terpenes classes of chemical enhancers are used in transdermal formulations for facilitating penetration of drugs. [4] Terpenes which are derived from plant essential oils are naturally occurring hydrocarbons based on combinations of the isoprene units. [5] They were reported to have less toxicity, high percutaneous enhancement abilities and low cutaneous irritancy at low concentrations (1-5%). [6] The effect of a specific terpene on skin depends upon its chemical structure and physicochemical properties, such as its lipophilicity, size and chiralty, boiling point and energy of vaporization and degree of unsaturation. [7] Terpenes can increase skin permeation by one or more of the mechanisms: interacting with stratum corneum lipids and/or keratin, and increasing the solubility of drug into stratum corneum lipids. [8]

Alfuzosin hydrochloride (AH) an alpha adrenoreceptor antagonist used for symptomatic relief of benign prostatic hyperplasia requires long term therapy in place of surgery. AH has molecular weight (425.9 daltons), log P (1.604), melting point (225-235°C), dose (2.5 to 10mg per day), half-life (3-5 hours) and undergoes hepatic metabolism to inactive metabolites. As AH possesses properties required for transdermal delivery and as it requires long term therapy, so it was aimed for transdermal delivery. [9]

Taguchi robust design is a statistical technique which studies all levels of input parameters with fewer experiments and optimizes the experiment having least variability. The variability of a property is expressed by signal to noise ratio (S/N ratio) and the experiment having maximum S/N ratio is considered as optimum condition. [10]

In the present study the influence of lipophilicity on permeation was studied by selecting eight terpenes of different lipophilicities. These terpenes were incorporated in hydrogels and their efficiency of permeating AH was optimized using Taguchi robust design method.

   Materials and methods Top


Alfuzosin hydrochloride (AH) was obtained as a gift sample from Dr. Reddy's Laboratories Ltd (Hyderabad, India). Acrypol-980 was purchased from Corel Pharma Ltd. (Ahmedabad, India). Nerolidol, farnesol, limonene, linalool, geraniol, carvone, fenchone and menthol were purchased from Alfa Aesar Ltd (USA). Propanol, glycerin and triethanolamine were purchased from S. D. Fine-Chem. Ltd. (India).

Preparation of Gels

AH gels were prepared using acrypol 980 (2%), propanol (5%), glycerin (5%), terpene (2.5, 5%), triethanolamine and distilled water (up to 100ml). Propanol, glycerin and water were mixed together and the mixture was divided into two equal parts. Acrypol 980 was added to one part and soaked for 1 hour. Drug AH (1%) and terpene was added to the other part and this solution was added to acrypol solution. Appropriate amounts of triethanolamine was added to the solution and mixed until the gel was formed. Terpenes were selected based on their lipophilicity given in [Table 1]. Terpene was added according to Taguchi L16 orthogonal array experimental design given in [Table 2].
Table 1: Log P of terpenes used as enhancers

Click here to view
Table 2: Taguchi L16 orthogonal array experimental design with independent variables and observed responses

Click here to view

Experimental Design

Taguchi L16 orthogonal array experimental design was constructed with type of terpene and concentration of terpene as independent variables. Cumulative amount permeated in 24 hours (Q 24 ) and flux was selected as dependent variables. The effect of independent variables on dependent variables was studied using SN ratio plots. MINITAB 16 software (Minitab Inc., PA, USA) was used for the generation and evaluation of the statistical experimental design. [11]

Solubility Studies

Saturated solubility of AH was evaluated by adding excess of drug to 10ml of propanol, glycerin and water (5:5:90) including appropriate quantity of terpene enhancer. The suspension was shaken using rotary shaker for 24 hours at room temperature, later it was centrifuged for 15 minutes at 3000 rpm, filtered and diluted with the vehicle and AH concentration was analyzed by UV-VIS double beam spectrophotometer (Chemito Spectrascan UV2600, India) at 245nm. The effect of terpene was determined by enhancement ratio which was calculated by dividing the solubility of AH in terpene to the solubility in control (no terpene).

Ex Vivo Permeation Studies

The experimental protocol was approved by the institutional animal ethical committee (IAEC) (Reference number: 320/CPCSEA ) .

Male Wistar rats (150-180 g) were used for permeation study. The animal was sacrificed by excessive ether anesthesia and hair was removed on abdomen using an animal hair clipper (Aesculap, Germany). Abdominal skin section was excised and observed for existence of cuts and wounds. The fat adhering on dermis was removed using scalpel and finally it was washed under tap water. The skin was stored at −20°C and used within a week.

For the permeation studies locally fabricated Keshary-Chein diffusion cells with an area of 4.9 cm 2 and 20ml receptor volume were used. The thawed rat skin was mounted onto diffusion cell such that the dermis side was in constant contact with receptor solution. 500mg of gel was applied to the stratum corneum facing the donor compartment and the hydrodynamics in the receptor compartment were maintained by stirring on magnetic stirrer at 600 rpm (Remi Equipments Ltd.). 1ml sample was withdrawn at predetermined time intervals for 24 hours and drug content was analyzed by UV-VIS double beam spectrophotometer (ChemitoSpectrascan UV2600, India) at 245nm. [12]

After 24 hours study drug retained in the skin was determined. For skin content studies, after study the skin was removed, washed with methanol and homogenized. The mixture was centrifuged at 7000 rpm for 30 minutes, filtered and analyzed for drug content spectrophotometrically at 245 nm.

Histopathological Studies

To determine the effect of terpene on skin, histopathological studies were conducted according to the protocol approved by institutional animal ethical committee (IAEC) (Reference number: 320/CPCSEA). The formulations placebo gel (without terpene) and optimized gel formulation (with terpene) were applied to wistar rats (hair was removed at application sites) for 6 hours. Then the animal was sacrificed by excessive ether anesthesia and application site was excised, stored in neutral formalin solution (50%). It was further subjected to histological processing such as dehydration and rehydration with alcohols, staining with Hematoxylin-eosin dye, paraffin blocks and slide preparation. H and E slides were evaluated using dark-light microscope by a blinded assessor.

Data Analysis

The cumulative amount permeated in 24 hours (Q 24 ) was calculated from permeation studies. Flux (J ss ) was calculated from slope of curve on plotting Q 24 Vs time and X-intercept of straight -line portion of the curve is Lag time. Flux divided by donor concentration resulted in apparent permeability coefficient (K p ). [13] Mean and standard deviation were calculated using Microsoft Excel 2003. The experiments were performed in triplicate (n = 3) and data was subjected to one-way ANOVA at a significance level of P ≤ 0.05 using MINITAB 16 software (Minitab Inc., PA, USA).

   Results and Discussion Top

Hydrogels of AH with terpenes as enhancers were prepared according to the formulations given by Taguchi L16 orthogonal array experimental design. Two factors mixed level with eight levels for factor one and two levels for factor two were selected as independent variables and responses, cumulative amount permeated in 24 hours and flux were selected as dependent variables for construction of Taguchi L16 orthogonal array experimental design. The formulations were optimized using SN ratio plots by Taguchi robust design method.

Effect of Terpene Type

Eight terpenes of different lipophilicities were selected as eight levels of factor, terpene type. Lipophilicities of decreasing order were selected for eight levels so nerolidol with log P 5.36 ± 0.38 was considered as first level and fenchone with log P 2.13 ± 0.30 as seventh level. Menthol with log P 3.20 ± 0.19 was considered as eight level even though its log P is greater than geraniol (log P 3.18 ± 0.30) as it is a solid terpene and researchers have reported liquid terpenes permeate better than solid terpenes. [14] To study the effect of physico-chemical properties of terpenes on permeation, such as lipophilicity, physical nature etc., different terpenes were selected. From the main effects SN Ratio plots shown in [Figure 1]a and [Figure 2]a it can be observed that type of terpene had a significant effect on cumulative amount permeated in 24 hours and flux (P < 0.005). As terpenes was selected based on decreasing order of lipophilicity, the permeated amount and flux also decreased showing a linear relationship between permeation and lipophilicity proving the influence of lipophilicity on permeation. Menthol a solid terpene of higher lipophilicity than carvone and fenchone enhanced permeation lesser than carvone and fenchone which shows liquid terpenes permeate better than solid terpenes. Of the eight terpenes Nerolidol with highest lipophilicity showed maximum permeation.
Figure 1: Mean effects plot for SN Ratios of (a) type of terpene and (b) terpene concentration for cumulative amount permeated in 24 hours

Click here to view
Figure 2: Mean effects plot for SN Ratios of (a) type of terpene and (b) terpene concentration for flux

Click here to view

Effect of Concentration

Two concentrations 2.5% and 5% were selected as two levels. Each terpene was evaluated at these two concentrations. SN Ratio plots shown in [Figure 1]b and [Figure 2]b indicate the effect of concentration on permeation was not significant (P > 0.05). But it was observed with each terpene as concentration increased the permeated amount also increased.

Solubility of AH in solvent mixture (propanol: glycerine: water (5:5:90)) of control gel was represented as unity [Table 3]. Major enhancement of solubility was not observed with terpenes. Nerolidol (5%) showed maximum enhancement of solubility by 1.23 fold followed by geraniol (2.5%) by 1.21 fold, fenchone (5%) and limonene (5%) by 1.18 fold, nerolidol (2.5%) by 1.17 fold, geraniol (5%) and carvone (5%) by 1.13 fold, limonene (2.5%) by 1.10 fold. Fenchone (2.5%) and farnesol (5%) showed similar solubility as control gel solvent mixture. But solubility was decreased by menthol (2.5 and 5%), carvone (2.5%), linalool (2.5 and 5%) and farnesol (2.5%). No significance was observed in the enhancement of solubility with lipophilicity of terpenes (P> 0.05).
Table 3: Solubility data and permeation parameters of AH formulations

Click here to view

The permeability coefficient (K p ), lag time, skin content and enhancement ratio of formulations with different terpenes as enhancers are listed in [Table 3].

Maximum permeability coefficient (K p ) of 5.63 ± 0.13 cm/ hour was obtained with Nerolidol 5% followed by farnesol 5% (5.51 ± 0.67 cm/hour), nerolidol 2.5% (5.03±0.04 cm/ hour), farnesol 2.5% (4.50 ± 0.06 cm/hour), limonene 5% (4.44 ± 0.03 cm/hour) etc. The lowest K p 2.86 ± 0.03 cm/hour was obtained with menthol 2.5%.

Nerolidol 5% showed lowest lag time of 0.76 ± 0.15 hours when compared with control (2.96 ± 0.35 hour). The highest lag time was observed with fenchone 2.5% (4.8 ± 0.20 hour) followed by fenchone 5% (4.6 ± 0.10 hour).

The amount of drug retained in skin after 24 hours study was calculated as skin content. Skin content of 1256.58 ± 64.39μg/g was obtained with control [Table 3]. When compared with control less amount of drug was retained in skin with terpenes. The lowest skin content was obtained with carvone 2.5% (80.85 ± 9.46 μg/g) next by carvone 5% (92.09 ± 17.52 μg/g). The highest skin content among terpenes was obtained with linalool 2.5% (408.67 ± 13.01 μg/g) and linalool 5% (387.25 ± 14.66 μg/g). With Nerolidol 2.5% and 5% (240.96 ± 9.35μg/g, 298.89 ± 14.00 μg/g) were obtained respectively. The effect of terpene enhancers on skin content was previously studied by Williams and Barry using differential scanning calorimetry (DSC). They have observed that no correlation exists between DSC results and enhancing abilities of the terpenes. [15]

The highest cumulative amount permeated in 24 hours (Q 24 ) was obtained with nerolidol 5% (647.29 ± 18.76 μg/ cm 2 ) followed by farnesol 5% (566.55 ± 7.49 μg/cm 2 ), and the lowest Q 24 among 5% concentration of terpenes was obtained with menthol 5% (365.65 ± 6.63 μg/cm 2 ) [Table 2]. The permeation profile with 2.5% and 5% terpenes is shown in [Figure 3] and [Figure 4] respectively.
Figure 3: Permeation profile of 2.5% concentration of different terpenes in gel formulations

Click here to view
Figure 4: Permeation profile of 5% concentration of different terpenes in gel formulations

Click here to view

With 2.5% terpenes concentration maximum permeation was obtained with Nerolidol followed by farnesol. Highest Q 24 and flux was obtained again with Nerolidol (561.02 ± 7.81 μg/cm 2 , 25.14 ± 0.18μg/cm 2 /hour) followed by farnesol (513.70 ± 9.65 μg/cm 2 , 22.48 ± 0.28μg/cm 2 /hour).With 5% concentration also highest flux was obtained with Nerolidol (28.16 ± 0.64μg/cm 2 /hour) and farnesol (27.58 ± 0.32μg/cm 2 /hour). Nerolidol and farnesol possessed considerably higher log P values than the others and hence, enhanced permeation maximum when compared with others.

Comparing with control gel, permeation was enhanced by 3.57 fold by Nerolidol 5% followed by 3.49 fold by farnesol 5%, 3.19 fold by Nerolidol 2.5%, 2.85 fold by farnesol 2.5%. The lowest enhancement was seen with menthol 2.5% by 1.81 fold. The order of enhancement was nerolidol> farnesol>limonene >linalool >geraniol>carvone>fenchone>menthol. The activity of terpenes is related to their chemical structure and other factors such as lipophilicity, size and chiralty, boiling point and energy of vaporization, and degree of unsaturation. Terpenes with high lipophilicity, small size, low boiling point and low energy of vaporization are good sorption enhancers. Small alcoholic terpenes with high degree of unsaturation enhance permeation of hydrophilic drugs. [7] It has been reported from previous studies that hydrophilic terpenes enhance permeation of hydrophilic drugs more effectively than hydrophobic terpenes. [16],[17],[18],[19] Nerolidol has been reported as an effective enhancer for nicardipine hydrochloride, carbamazepine, [5] tamoxifen, [20] hydrocortisone [21] and diclofenac sodium. [19] Nerolidol also enhanced the permeation of 5-fluorouracil and its enhancement was reported by Cornwell and Barry [22] that its amphiphilic structure suitable for aligning within lipid lamellae attributed to disruption of highly organized lipid packing of stratum corneum.

Research studies have suggested properties for an ideal terpene enhancer such as they should be hydrophobic and liquid nature, should not be triterpene or tetraterpene and posses ester or aldehyde group. [14] Mono- and sesquiterpenes are better enhancers than di-, tri-, and tetra terpenes as their enhancement is attributed to increasing drug diffusivity within stratum corneum. [23],[24] In the present study terpenes studied were mono-and sesquiterpenes; hence, permeation was enhanced when compared with control. Terpenes selected are liquid in nature except menthol which is solid in nature. In the present study least enhancement was observed with menthol even though it is more lipophilic than carvone and fenchone, and in possessing an alcohol group which favors enhancement of hydrophilic drugs than ketone groups. This can be due to solid nature of menthol.

To study the effect of lipophilicity, log P of terpene was correlated with percutaneous parameters of AH. Log P of terpenes greatly influenced Q 24 and flux. The correlation coefficient for Q 24 with terpenes 2.5% and 5% is r 2 =0.772, P<0.0001 and r 2 =0.824, P<0.0001 [Figure 5] respectively and for flux with terpenes 2.5% is r 2 =0.764, P<0.0001, 5% is r 2 =0.871, P<0.0001 [Figure 6] indicating linear relationship with log P of terpenes at both 2.5% and 5% concentration.
Figure 5: Relationship between Log P of terpenes and cumulative amount permeated in 24 hours

Click here to view
Figure 6: Relationship between Log P of terpenes and flux

Click here to view

With lag time correlation coefficient for 2.5% is r 2 = −0.7195, P<0.0001 and 5% is r 2 = −0.7921, P < 0.0001 [Figure 7] respectively indicating a significant correlation between log P of terpenes and lag time.
Figure 7: Relationship between Log P of terpenes and lag time

Click here to view

With skin content coefficient values r 2 =0.077 for 5% and r 2 =0.000 for 2.5% indicated an insignificant correlation [Figure 8].
Figure 8: Relationship between Log P of terpenes and skin content

Click here to view

In the present study lipophilicity of enhancer played a major role and a linear relationship was observed which was also reported by Williams and Barry with 5-fluorouracil, [25] Kang et al., [14] El-Kattan et al. [21] and Rio-Sancho et al. [26]

H and E sections of skin when observed under 200× magnification in dark field light microscope showed hemorrhage and degeneration in dermis of skin treated with placebo gel (control formulation). Skin treated with optimized formulation TA2 showed presence of mononuclear cell infiltration, mild to moderate congestion, degeneration and fatty change in dermis. Degeneration and fatty change in dermis can be attributed to disruption of highly organized lipid packing of stratum corneum due to alignment of amphiphilic structure of nerolidol within lipid lamellae of stratum corneum. The changes observed in the skin samples showed the action of terpene on lipids and no local toxicity was seen. Photomicrographs of skin sections are shown in [Figure 9].
Figure 9: Histological section of skin a) control b) treated with placebo gel (without terpene) and c) treated with TA2 formulation

Click here to view

   Conclusion Top

A linear relationship was established between log P of terpenes and Q 24 and flux of AH. As the concentration of each terpene increased the Q 24 and flux of AH also increased. From Taguchi Robust Design method TA2 formulation containing Nerolidol 5% was optimized which enhanced permeation by 3.57 fold. The effect of terpenes on solubility enhancement ratio was not significant attributing enhancement to diffusion and partitioning of drug into skin and disrupting lipid bilayer of stratum corneum which was supported with histological studies.

   References Top

1.Obata Y, Ashitaka Y, Kikuchi S, Isowa K, Takayama K. A statistical approach to the development of a transdermal delivery system for ondansetron. Int J Pharm 2010;399:87-93.  Back to cited text no. 1
2.Verma P, Pathak K. Therapeutic and cosmeceutical potential of ethosomes: An overview. J Adv Pharm Technol Res 2010;1:274-82.  Back to cited text no. 2
3.Bharkatiya M, Nema RK. Skin penetration enhancement techniques. J Young Pharm 2009;1:110-5.  Back to cited text no. 3
4.Liu CH, Chang FY, Hung DK. Terpenemicroemulsions for transdermal curcumin delivery: Effects of terpenes and co-surfactants. Colloids Surf BBiointerfaces 2011;82:63-70.  Back to cited text no. 4
5.Fox LT, Gerber M, Plessis JD, Hamman JH. Transdermal drug delivery enhancement by compounds of natural origin. Molecules 2011;16:10507-40.  Back to cited text no. 5
6.Dwibhashyam VS, Ratna VJ. Chemical penetration enhancers-an update. Indian Drugs 2010;47:5-18.  Back to cited text no. 6
7.Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today 2007;12:1061-7.  Back to cited text no. 7
8.Sapra B, Jain S, Tiwary AK. Percutaneous permeation enhancement by terpenes: Mechanistic view. AAPS J 2008;10:120-32.  Back to cited text no. 8
9.In: Moffat AC, editors. Clarke's analysis of drugs and poisons. [online] London: Pharmaceutical Press; Available from: http://www.medicinescomplete.com/2010 [Last accessed date 15/12/2010.]  Back to cited text no. 9
10.Kim KD, Choi DW, Choa YH, Kim HT. Optimization of parameters for the synthesis of zinc oxide nanoparticles by taguchi robust design method. Colloids Surf A Physicochem Eng Asp 2007;311:170-3.  Back to cited text no. 10
11.Kim KD, Han DN, Kim HT. Optimization of experimental conditions based on the taguchi robust design for the formation of nano-sized silver particles by chemical reduction method. Chem Eng J 2004;104:55-61.  Back to cited text no. 11
12.Rajan R, Vasudevan DT. Effect of permeation enhancers on penetration mechanism of transferosomal gel of ketoconazole. J Adv Pharm Technol Res 2012;3:112-6.  Back to cited text no. 12
13.Chudasama A, Patel VK, Nivsarkar M, Vasu K, Shishoo C. Investigation of microemulsion system for transdermal delivery of itraconazole. J Adv Pharm Technol Res 2011;2:30-8.  Back to cited text no. 13
14.Kang L, Yap CW, Lim PF, Chen YZ, Ho PC, Chan YW et al. Formulation development of transdermal dosage forms: Quantitative structure-activity relationship model for predicting activities of terpenes that enhance drug penetration through human skin. J Control Release 2007;120:211-9.  Back to cited text no. 14
15.Williams AC, Barry BW. Differential scanning calorimetry does not predict the activity of terpene penetration enhancers in human skin. J PharmPharmacol 1990;42:156P.  Back to cited text no. 15
16.Moghimi H, Williams A, Barry BW. A lamellar matrix for stratum corneum intercellular lipids. V. Effects of terpene penetration enhancers on the structure and thermal behavior of the matrix. Int J Pharm 1997;146:41-54.  Back to cited text no. 16
17.Gao S, Singh J. In vitro percutaneous absorption enhancement of lipophilic drug tamoxifen by terpenes. J Control Release 1998;51:193-9.  Back to cited text no. 17
18.Okabe H, Takayama K, Ogura A, Nagai T. Effect of limonene and related compounds on the percutaneous absorption of indomethacin. Drug Des Deliv 1989;4:313-21.  Back to cited text no. 18
19.Nokhodchi A, Sharabiani K, Rashidi MR, Ghafourian T. The effect of terpene concentrations on the skin penetration of diclofenac sodium. Int J Pharm 2007;335:97-105.  Back to cited text no. 19
20.El-Kattan AF, Asbill CS, Kim N, Michniak BB. The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities. Int J Pharm 2001;215:229-40.  Back to cited text no. 20
21.El-KattanAF, Asbill CS, Michniak BB. The effect of terpene enhancer lipophilicity on the percutaneous permeation of hydrocortisone formulated in HPMC gel systems. Int J Pharm 2000;198:179-89.  Back to cited text no. 21
22.Cornwell PA, Barry BW. Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5-fluorouracil. J Pharm Pharmacol 1991;46:261-9.  Back to cited text no. 22
23.Williams AC, Barry BW. Terpenes and the lipid protein partitioning theory of skin penetration enhancement. Pharm Res 1991;8:17-24.  Back to cited text no. 23
24.Cornwell PA, Barry BW. Determination of the mode of action of sesquiterpene skin penetration enhancers. J Pharm Pharmacol 1991;43:56P.  Back to cited text no. 24
25.Williams AC, Barry BW. The enhancement index concept applied to terpene penetration enhancers for human skin and model lipophilic (oestradiol) and hydrophilic (5-fluorouracil) drugs. Int J Pharm 1991;74:157-68.  Back to cited text no. 25
26.Rio-Sancho SD, Serna-Jimenez CE, Lalatayud-Pascual MA, Balaguer-Fernandez C, Femenia- Font A, Merino V et al. Transdermal absorption of memantine- effect of chemical enhancers, iontophoresis and role of enhancer lipophilicity. Eur J Pharm Biopharm 2012;82:164-70.  Back to cited text no. 26


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 Effects of terpenes in the treatment of visceral leishmaniasis: a systematic review of preclinical evidence
Vagner Dias Raimundo, Renner Philipe Rodrigues Carvalho, Mariana Machado-Neves, Eduardo de Almeida Marques da Silva
Pharmacological Research. 2022; : 106117
[Pubmed] | [DOI]
2 Bioactive properties of the aromatic molecules of spearmint (Mentha spicata L.) essential oil: a review
Lu-Lu Zhang, Yan Chen, Zhi-Jian Li, Xiao Li, Gang Fan
Food & Function. 2022;
[Pubmed] | [DOI]
3 Using Chitosan-Coated Polymeric Nanoparticles-Thermosensitive Hydrogels in association with Limonene as Skin Drug Delivery Strategy
Estefânia V. R. Campos, Patrícia L. F. Proença, Tais G. da Costa, Renata de Lima, Leonardo F. Fraceto, Daniele R. de Araujo, Vesa-Pekka Lehto
BioMed Research International. 2022; 2022: 1
[Pubmed] | [DOI]
4 Preparation and Characterization of Blank and Nerolidol-Loaded Chitosan–Alginate Nanoparticles
Rahaf M. Ahmad, Yaser E. Greish, Hesham F. El-Maghraby, Loay Lubbad, Yahia Makableh, Fayez T. Hammad
Nanomaterials. 2022; 12(7): 1183
[Pubmed] | [DOI]
5 The Potential of Pharmaceutical Hydrogels in the Formulation of Topical Administration Hormone Drugs
Aneta Ostrózka-Cieslik
Polymers. 2022; 14(16): 3307
[Pubmed] | [DOI]
6 Preparation and Characterization of 5-Fluorouracil Loaded Nanogels for Skin Cancer Treatments: In Vitro Drug Release, Cytotoxicity and Cellular Uptake Analysis
Swati Rathore, Vaibhav Rajoriya, Varun Kushwaha, Sanyog Jain, Sushil K. Kashaw
Current Nanomedicine. 2021; 11(2): 127
[Pubmed] | [DOI]
7 Evaluation of the antioxidant, antibacterial, and antibiofilm activity of the sesquiterpene nerolidol
Danielle Feijó de Moura,Tamiris Alves Rocha,Dayane de Melo Barros,Marllyn Marques da Silva,Marcielle dos Santos Santana,Beatriz Mendes Neta,Isabella Macário Ferro Cavalcanti,René Duarte Martins,Márcia Vanusa da Silva
Archives of Microbiology. 2021;
[Pubmed] | [DOI]
8 Permeability Enhancers in Transdermal Delivery System Technology (Review)
M. N. Anurova,N. B. Demina,E. O. Bakhrushina
Pharmaceutical Chemistry Journal. 2021; 54(11): 1162
[Pubmed] | [DOI]
9 Development of a novel nanoemulgel formulation containing cumin essential oil as skin permeation enhancer
Katayoun Morteza-Semnani,Majid Saeedi,Jafar Akbari,Mohammad Eghbali,Amirhossein Babaei,Seyyed Mohammad Hassan Hashemi,Ali Nokhodchi
Drug Delivery and Translational Research. 2021;
[Pubmed] | [DOI]
10 Volatile molecules for COVID -19: A possible pharmacological strategy?
Cristiano Colalto
Drug Development Research. 2020;
[Pubmed] | [DOI]
11 Composition and Antibacterial Effect of Mint Flavorings in Candies and Food Supplements
Karmen Kapp,Anne Orav,Mati Roasto,Ain Raal,Tőnu Püssa,Heikki Vuorela,Päivi Tammela,Pia Vuorela
Planta Medica. 2020; 86(15): 1089
[Pubmed] | [DOI]
12 Chemical composition, anti-nociceptive and anti-inflammatory activities of essential oil of Bougainvillea glabra
Isiaka A. Ogunwande,Opeyemi N. Avoseh,Kazeem N. Olasunkanmi,Oladipupo A. Lawal,Roberta Ascrizzi,Guido Flamini
Journal of Ethnopharmacology. 2019; 232: 188
[Pubmed] | [DOI]
13 The combination of Nanomicelles with Terpenes for Enhancement of Skin Drug Delivery
Emine Kahraman,Neset Nesetoglu,Sevgi Güngör,Duri Sehvar Ünal,Yildiz Özsoy
International Journal of Pharmaceutics. 2018;
[Pubmed] | [DOI]
14 Effect of pH on weakly acidic and basic model drugs and determination of their ex vivo transdermal permeation routes
Pranitha Akula,Lakshmi P.K.
Brazilian Journal of Pharmaceutical Sciences. 2018; 54(2)
[Pubmed] | [DOI]
15 a-Bisabolol improves 5-aminolevulinic acid retention in buccal tissues: Potential application in the photodynamic therapy of oral cancer
Nathany Prado Quintanilha,Irina dos Santos Miranda Costa,Mônica Freiman de Souza Ramos,Nádia Campos de Oliveira Miguel,Maria Bernadete Riemma Pierre
Journal of Photochemistry and Photobiology B: Biology. 2017;
[Pubmed] | [DOI]
16 Solid-in-oil nanodispersions for transdermal drug delivery systems
Momoko Kitaoka,Rie Wakabayashi,Noriho Kamiya,Masahiro Goto
Biotechnology Journal. 2016;
[Pubmed] | [DOI]
17 Nerolidol: A Sesquiterpene Alcohol with Multi-Faceted Pharmacological and Biological Activities
Weng-Keong Chan,Loh Tan,Kok-Gan Chan,Learn-Han Lee,Bey-Hing Goh
Molecules. 2016; 21(5): 529
[Pubmed] | [DOI]
18 Investigating Transdermal Delivery of Vitamin D3
Ahmed Alsaqr,Mohammed Rasoully,Florin Marcel Musteata
AAPS PharmSciTech. 2015;
[Pubmed] | [DOI]
19 Formulation Optimization of Arecoline Patches
Pao-Chu Wu,Pi-Ju Tsai,Shin-Chen Lin,Yaw-Bin Huang
The Scientific World Journal. 2014; 2014: 1
[Pubmed] | [DOI]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Materials and me...
    Results and Disc...
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded512    
    Comments [Add]    
    Cited by others 19    

Recommend this journal