A Review on Natural Penetration Enhancer for Transdermal Drug Delivery System
Jadhav Sandhya, S. S. Siddheshwar
Pravara Rural College of Pharmacy, Pravaranagar A/P Loni – 413736, Tal - Rahata, Dist. – Ahmednagar.
*Corresponding Author E-mail: sandhyajadhav421@gmail.com
ABSTRACT:
The transdermal drug delivery route is gaining recognition as a promising method, given its advantages such as bypassing hepatic first-pass metabolism, reducing side effects and gastrointestinal issues, and enhancing patient compliance through pain-free self-administration. However, a significant challenge in this route lies in the difficulty of drug penetration through the skin, primarily due to the stratum corneum forming a protective barrier against the external environment. The efficacy of transdermally delivered drugs relies on their ability to cross this barrier and reach the systemic circulation. Penetration enhancers play a crucial role in facilitating this process by increasing skin permeability, thereby maintaining optimal drug levels in the bloodstream. These enhancers can be categorized as chemical, natural, or physical. This review focuses on exploring the potential of natural permeation enhancers for facilitating the transdermal permeation of drugs.
KEYWORDS: Transdermal drug delivery system, Permeation enhancer, Penetration barrier.
1. INTRODUCTION:
Offering a convenient alternative to intravenous, intramuscular, and oral administration routes, transdermal delivery stands out. By circumventing the first-pass effect in the liver, this method proves particularly suitable for drugs with low bioavailability when orally administered or those prone to adverse effects resulting from biotransformation.1 This approach offers the benefit of being painless, noninvasive, and easily applicable, with the added advantage of controlled release for prolonging the therapeutic effect.2
In the context of transdermal drug delivery systems, it is crucial to apply them to healthy skin. Consequently, there is a quest for methods that can transiently engage with the components of the epidermis, inducing a temporary alteration in its permeability to therapeutic substances.
Simultaneously, these methods should refrain from affecting the activity of the active substance, avoiding degradation, skin irritation, and permanent damage.3
Facilitating the permeation of the desired drug through the skin, penetration enhancers work by reducing the skin's impermeability. Desirable properties in these enhancers include pharmacological inertness, nonirritating, nontoxic, nonallergenic attributes, compatibility with drugs and excipients, odorlessness, tastelessness, colorlessness, and cost-effectiveness, coupled with excellent solvent properties.4
2. HUMAN SKIN: PENETRATION BARRIER:
Epidermis: The thickness of the exposed layer of the skin, approximately 10mm, is determined by the varying thickness of the multilayered epidermis, which is primarily influenced by the thickness of its cells and the number of layers.5
Dermis: Ranging from 3 to 5mm, this layer primarily comprises connective tissues essential for regulating body temperature, facilitating the supply of oxygen and nutrients to the skin, and eliminating toxic substances.6
Figure no. 1 (Different layers of the skin with three major routes of drug transport.)
Hypodermis: Serving as a supportive membrane for both the epidermal and dermal layers of the skin, it retains fat tissues and plays a crucial role in transdermal drug delivery. 7
3. Natural permeation enhancers:
Being a relatively new class of penetration enhancers in the pharmaceutical industry, natural permeation enhancers demand increased research attention due to their advantages, including cost-effectiveness and an improved safety profile. Further exploration in this field is necessary to develop stable transdermal formulations containing natural permeation enhancers (natural permeation enhancers), which can subsequently be scaled up for commercial transdermal drug products.8
a) Papain:
Studying the in vitro and in vivo permeation of low-molecular-weight heparin (LMWH), researchers explored the use of papain, a proteolytic enzyme. The combined administration of LMWH and papain emerged as a novel approach, demonstrating improvements in the absorption of orally administered heparin and, consequently, enhancing its bioavailability.9
b) Piperine:
In the investigation of piperine's impact on the in vitro permeation of aceclofenac across human cadaver skin, Fourier transform infrared technology was employed to examine the potential mechanism. The results revealed that piperine enhances the transdermal permeation of aceclofenac through a biphasic mechanism, involving the partial extraction of stratum corneum lipid and interaction with stratum corneum keratin.10
c) Capsaicin:
Belonging to the Solanaceae family, capsaicin is a prominent alkaloid within capsaicinoids and is exclusively produced in the capsicum fruits of the genus Capsicum.11 Examining the permeation-enhancing characteristics of capsaicin for naproxen, a comparison was made with azone, a standard enhancer. Prior to the experiment, varying amounts of the chosen enhancer were applied to the skin. Additionally, a formulation containing 3% capsaicin and a commercially available naproxen gel formulation underwent scrutiny, and subsequent results were compared.12
d) Myristica fragrans:
In the assessment of M. fragrans as a penetration enhancer in a transdermal gel formulation with diclofenac sodium as the target drug, various extracts of M. fragrans, including methanolic, chloroform, and n-hexane extracts, were employed for their penetration-enhancing properties.13
4. ESSENTIAL OIL:
Derived from aromatic plants, essential oils are natural products containing a blend of various volatile compounds with aromatic scents. These compounds primarily include terpenes, terpenoids, and phenylpropanoids.14 Essential oils, serving as penetration enhancers, facilitate the delivery of drug compounds into the skin through interactions with intercellular lipids. This interaction involves various physical processes, including increased disorder, phase separation, and fluidization. Due to their easy permeation through the skin, these oils are also readily eliminated from the body through urine and feces.15
Essential oil as skin permeation enhancer:
To diminish barrier properties, penetration enhancers engage with tissue components by partitioning into the stratum corneum SC without inducing harm to the underlying skin cells.16
a) Cardamom oil:
Belonging to the Zingiberaceae family, cardamom Elettaria cardamomum is a widely used spice in India.17 In in vitro permeation studies conducted on rabbit abdominal skin, cardamom oil demonstrated an enhanced penetration of the drugs indomethacin, diclofenac, and piroxicam.18
b) Rosemary oil:
Derived from Rosmarinus officinalis, rosemary oil exhibited enhanced skin permeation activity when investigated for its effects on diclofenac sodium topical gel. This enhancement in skin absorption was observed at concentrations of 0.5% and 1%, respectively.19
c) Turpentine oil:
In the exploration of permeation-enhancing activity for diclofenac dimethylamine matrix patches across artificial skin in the Franz diffusion cell, turpentine oil's effectiveness was scrutinized. The findings revealed a correlation between increasing concentration of turpentine and enhanced permeation.20
d) Eucalyptus oil:
Conducting permeation studies on full-thickness human skin, it was discovered that when combined with 70% (w/v) isopropyl alcohol, eucalyptus oil enhanced the permeation of chlorhexidine (2% [w/v]) into the dermis and the lower layer of the epidermis. This effect was observed in comparison to the solution of chlorhexidine/ isopropyl alcohol alone.21
e) Niaouli oil:
Conducting in vitro studies on hairless mouse skin, the permeation-enhancing effect of niaouli oil was investigated at a concentration of 10% (w/w) in propylene glycol, using estradiol as the model drug. The results indicated that niaouli oil exhibited greater effectiveness in the transdermal permeation of estradiol compared to essential oils such as cajput, myrtle, orange, and cardamom.22
f) Fennel oil:
Fennel oil, extracted from the seeds of Foeniculum vulgare within the Umbelliferae family, demonstrated superior percutaneous penetration enhancement for trazodone hydrochloride compared to eucalyptus oil, citronella oil, and mentha oil in permeation studies. The observed variations in permeation enhancement activity among the oils may be attributed to the diverse physicochemical properties and molecular weights of phytochemicals present in each essential oil.23
g) Almond oil:
The study involved the formulation and evaluation of topically applied ketoprofen gels and patches, with a focus on assessing almond oil as a penetration enhancer through artificial membrane/ rabbit skin. The results indicated that almond oil, when employed in various concentrations, effectively enhanced the penetration of drugs from transdermal gels and patches across synthetic membrane/rabbit skin, with particular prominence observed at a 3% concentration.24
5. TERPENES:
Terpenes, a diverse class of compounds selected prominently in transdermal drug delivery research, encompass a wide spectrum of members exhibiting heterogeneity. The impact of a specific terpene on the skin, notably its lipophilicity, is influenced by its unique physicochemical properties.25
a)Farnesol:
Found in essential oils like citronella, neroli, cyclamen, lemongrass, tuberose, balsam, and tolu, farnesol is a sesquiterpene alcohol. In comparative studies, it was noted that at a concentration of 0.25%, farnesol exhibited a higher enhancement in the permeation of diclofenac sodium when compared to other terpenes.26
b) Menthol:
Derived from the flowering tops of Mentha piperita, menthol stands out as a potent penetration enhancer. Combining menthol and limonene offers a prototype of terpenes suitable for use as permeation enhancers.27
c) Eucalyptol:
Due to its spicy aroma and taste, eucalyptol finds applications in the cosmetic, fragrance, and flavoring industries. Additionally, 1,8-cineole has been employed for enhancing the percutaneous absorption of various lipophilic drugs through hairless mouse skin.28
d) Eugenol:
The permeation-enhancing effect of eugenol was assessed for lornoxicam, a nonsteroidal anti-inflammatory drug belonging to the oxicam class. Formulation of transdermal patches containing lornoxicam was followed by in vitro studies conducted in a Franz diffusion cell, utilizing rat skin.29
CONCLUSION:
Due to its advantages, the field of transdermal drug delivery has been experiencing rapid development, prompting extensive research efforts to incorporate an increasing number of drugs through this route. However, the skin poses a limitation to drug permeation, leading to the use of permeation enhancers to augment the permeability of poorly absorbed drugs and maintain their bioavailability. This review article provides a comprehensive summary of various natural permeation enhancers (NPEs) that can be employed to expedite drug permeation across the skin for the development of transdermal delivery systems. The article also outlines the parameters essential for conducting permeation studies. The discussion in this article encompasses diverse NPEs that hold potential for accelerating drug permeation across the skin in the development of transdermal drug delivery systems (TDDS).
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Received on 15.01.2024 Modified on 12.02.2024
Accepted on 04.03.2024 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2024; 14(2):155-158.
DOI: 10.52711/2231-5659.2024.00024