Synthesis and Assessment of a New Tetrahydrogeraniol Derivative as Penetration Enhancer for Transdermal Drug Delivery

Background: Skin is one the most important sites for administration of drugs to obtain desired pharmacological effects either locally or through systemic bioavailability; and this has placed the transdermal route of drug delivery as an attractive and as one of the most innovative areas for conducting drug delivery research. However the stratum corneum in skin creates hurdles and acts as significant barrier for the permeation of drugs through skin. Penetration enhancers play a pivotal role to overcome such barriers and help enhance the permeation of drug through skin. However, penetration enhancement technology is challenging development and needs to be properly and skillfully addressed. Objective: The present investigation aimed to study the penetration enhancing effect of a newly synthesized alcohol derivative of an acyclic monoterpene (Tetrahydrogeraniol-THG). Methodology: The new derivative, 5,9-Dimethyl-1-Decanol (DIMDOL), has been synthesized by a chemical reaction of the THG with Grignard reagent and ethylene oxide. Permeation enhancing effect of the synthesized derivative was explored for better transdermal penetration of the two model drugs viz. tramadol hydrochloride and 5-fluorouracil (5-FU) through the excised rat skin by conducting in-vitro permeation experiments employing Franz diffusion cells apparatus. The standard enhancers Azone and THG were used to compare penetration enhancing effect of the enhancers. Results: It was revealed that DIMDOL could effectively enhance the permeability of both the drugs by 18.60 and 73.19 folds across the skin used with a lag time of 3.35 and 1.20 h, respectively. The newly synthesized derivative was found to significantly increase the partition coefficient and diffusion coefficient values. Conclusion: The results obtained suggest that DIMDOL can more effectively enhance the permeation of these model drugs, expectedly by affecting the stratum corneum and interacting with both lipid-rich layers and keratin-rich layers of the excised rat skin. DOI : 10.14302/issn.2572-5424.jgm-16-1170 Freely Available Online www.openaccesspub.org | JGM CC-license DOI : 10.14302/issn.2572-5424.jgm-16-1170 Vol-1 Issue 1 Pg. no.46 Introduction Transdermal drug delivery is the delivery of drugs across epidermis to achieve systemic effects. It is a non-invasive method for drug administration with an improved approach and is capable of maintaining therapeutic plasma drug level for prolonged and extended period of times [1]. Properly designed and developed transdermal drug delivery systems (TDDS) may offer better solutions to the problems associated with other drug delivery systems currently in vogue. The systems have thus been developed as an alternative to oral and parenteral pharmaceutical forms. However, many drugs are unsuitable for use as transdermal therapeutic systems because of their low permeability through the human skin. The improvement of permeability using penetration enhancers may therefore be desirable [2]. During the last few years various penetration enhancers including aprotic solvents, several surfactants and Azone have been extensively studied by different investigators in order to explore their penetration enhancing effect. The exact mechanism of penetration enhancing effect of these enhancers over the skin is not very clear, however, the lipophilicity of such enhancers is considered to play an important role in this regard. It has been found that mostly the longchain primary alcohols could be of greater value in this connection, apart from being cheaper and alos non-toxic in nature [3] and the number of carbon atoms in the chain may influence the enhancing effect. In our series of research work, previously we reported the synthesis of 5,9-Dimethyl-2-Decanol (DICNOL) and its evaluation as a potential percutaneous penetration enhancer. The purpose of the present work is to synthesize 5,9-Dimethyl-1-Decanol (DIMDOL), another new derivative of Tetrahydrogeriniol (THG) and to investigate its enhancing effects on the penetration and transport of 5-Fluorouracil and Tramadol HCI through excised rat skin. Materials and Methods


Introduction
Transdermal drug delivery is the delivery of drugs across epidermis to achieve systemic effects. It is a non-invasive method for drug administration with an improved approach and is capable of maintaining therapeutic plasma drug level for prolonged and extended period of times [1]. Properly designed and developed transdermal drug delivery systems (TDDS) may offer better solutions to the problems associated with other drug delivery systems currently in vogue. The systems have thus been developed as an alternative to oral and parenteral pharmaceutical forms. However, many drugs are unsuitable for use as transdermal therapeutic systems because of their low permeability through the human skin. The improvement of permeability using penetration enhancers may therefore be desirable [2]. During the last few years various penetration enhancers including aprotic solvents, several surfactants and Azone have been extensively studied by different investigators in order to explore their penetration enhancing effect. The exact mechanism of penetration enhancing effect of these enhancers over the skin is not very clear, however, the lipophilicity of such enhancers is considered to play an important role in this regard. It has been found that mostly the longchain primary alcohols could be of greater value in this connection, apart from being cheaper and alos non-toxic in nature [3] and the number of carbon atoms in the chain may influence the enhancing effect.
In our series of research work, previously we reported the synthesis of 5,9-Dimethyl-2-Decanol (DICNOL) and its evaluation as a potential percutaneous penetration enhancer 4 . The purpose of the present work is to synthesize 5,9-Dimethyl-1-Decanol (DIMDOL), another new derivative of Tetrahydrogeriniol (THG) and to investigate its enhancing effects on the penetration and transport of 5-Fluorouracil and Tramadol HCI through excised rat skin.

Drug Permeation Studies
Permeation studies were conducted using an established procedure [4,8].

Hydrochloride in skin
For this purpose the exposed skin was removed after the experiment was over. In order to remove excess drug on the surface, it was carefully washed with water for several time followed by dry blotting, weighing and cutting into many small pieces. The tissue was processed with 4 ml of ethyl acetate for three times in a homogenizer. The homogenates so obtained were mixed, vacuum filtered and ethyl acetate evaporated to dryness. The resultant residue was then reconstituted with 10 ml of water and analyzed for drug contents spectrophotometrically [9].

Parameters
Using the linear regression analysis method  be expressed in the form of enhancement ratio (ER) [11] in the following way: (2) ER = The apparent partition coefficients (PC) of the drugs are expressed by the following equation [12].
(3) PC = The partitioning of the drugs into the skin is illustrated by the partition ratio (PR) [13] as follows:

Effect of DIMDOL on in vitro penetration of 5-FU
The permeation parameter values: Mean fluxes (J), permeability coefficients (Kp) and enhancement ratios (ER) of 5-FU before and after treatment of skin with DIMDOL, THG and Azone are shown in Table 1.
The permeation profiles of the mean quantity permeated for 5-FU accumulated against time in presence and absence of enhancers are shown in Figure 1. From Table 2 it can be seen that all the three enhancers has decreased the resistance to the diffusion of 5-FU as the mean untreated apparent diffusion coefficient value is 0.135±0.02 X 10 -3 /hr only.    : 10.14302/issn.2572-5424.jgm-16-1170 Vol-1 Issue 1 Pg. no.-50 exercised rat skin, while THG and Azone increased the drug permeation to 110 and 93-fold, respectively. The partitioning results with these enhancers are shown in Table 4.

Tramadol HCI
Form Table 4 it can be seen that all the three enhancers has decreased the resistance to the diffusion of tramadol HCI as the mean untreated diffusion coefficient value of the drug is 0.11± 0.02 X10 -3 cm 2 /hr only, while with DIMDOL this value was observed to be 2.64 ± 0.13 X 10 -3 cm 2 /hr.

Discussion
Penetration enhancers are generally reported as substances which could temporarily reduce the barrier action of the stratum corneum (SC) [14]. Stratum corneum is the major barrier to transdermal transport of drugs and the mechanism of drug transport through this barrier is considered to be through the process of partitioning and diffusion that may be directly influenced by the molecular properties of the penetrants including the solubility, size and shape [15]. Transdermal drug absorption involves the processes of drug partitioning from the vehicle into the stratum corneum, diffusion of drug through the stratum corneum, drug partitioning from stratum corneum to aqueous viable tissue, and drug diffusion through the viable tissue to the dermal microcirculation. If a penetration enhancer acts on any one or more of the first three processes described above, it is likely to be effective [16].
In the present work, we report the synthesis

Disclouse of Confilct of Interest
The authors of the research article do not have any type of financial and/or non-financial competing interests with other people or organization.

Authors Contributions
AK, GMK and MHR conceived of, designed and performed experimental work the study. GMK, MHR and AK, jointly worked on statistical analysis, preparation of the graphs and final version of the manuscript. All authors read and approved the final manuscript.