A Review on Chemical Permeation Enhancers used in the Formulation of Transdermal Drug Delivery System (original) (raw)
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Penetration enhancers for transdermal drug delivery system: A review
There is considerable interest in the skin as a site of drug application both for local and systemic effect. However, the skin, in particular the stratum corneum, poses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and increase the range of drugs for which topical and transdermal delivery is a viable option. This review describes enhancement techniques based on drug/vehicle optimisation such as Selection of correct drug or prodrug, Chemical potential adjustment, Ion pairs and complex Parameters Ideal limits Aqueous solubility >1mg/ml Lipophilicity 10<Ko/w<1000 Molecular weight <500 Daltons Melting point <200 0 C pH of aqueous saturated solution 5-9
2015
There is considerable interest in the skin as a site of drug application for both local and systemic effect. However, the skin, in particular the stratum corneum, possesses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and to increase the range of drugs for which topical and transdermal delivery is a viable option. Transdermal drug delivery system (TDDS) having objective to deliver the therapeutic moiety via the skin into the systemic circulation for its therapeutic effect. This route provides many advantages over other routes as avoiding first pass hepatic metabolism, decrease side effects, GI effects and increased bioavailability. The skin, in particular stratum corneum provides protective barrier that prevents the loss of physiologically essential substances and provide resistance to penetration and it is the rate limiting step in percutaneou...
Chemical penetration enhancers for transdermal drug delivery systems
Tropical Journal of Pharmaceutical Research, 2009
Skin as an important site of drug application for both local and systemic effects. However in skin, the stratum corneum is the main barrier for drug penetration. Penetration enhancement technology is a challenging development that would increase the number of drugs available for transdermal administration. The permeation of drug through skin can be enhanced by both chemical penetration enhancement and physical methods. In this review, we have discussed the chemical penetration enhancement technology for transdermal drug delivery as well as the probable mechanisms of action.
Design principles of chemical penetration enhancers for transdermal drug delivery
Proceedings of The National Academy of Sciences, 2005
Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future. stratum corneum ͉ spectroscopy ͉ skin irritation ͉ lipid
Chemical and Physical Enhancers for Transdermal Drug Delivery
a r e a o f 0. 1 %. I n t h i s w a y , d i f f u s i o n t h r o u g h t h e s k i n i s c o n t r o l l e d b y t h e p a r t i c u l a r characteristics of the stratum corneum. In order to obtain a sufficient drug flux and, in turn, the therapeutical objectives in question, an alternative is to use chemical percutaneous enhancers. These substances alter some of the properties of the stratum corneum. (López-Castellano & Merino, 2010) 2.2 Direct effects on the skin due to the use of transdermal penetration enhancers The lipid-protein-partititioning theory sets out the mechanisms by which enhancers alter skin lipids, proteins and/or partitioning behaviour (Barry, 1991): i) They act on the stratum corneum intracellular keratin by denaturing it or modifying its conformation, causing subsequent swelling and increased hydration; ii) They affect the desmosomes that maintain cohesion among corneocytes; iii) They modify the intercellular lipid domains to reduce the barrier-like resistance of the bilayer lipids. Disruption to the lipid bilayers can be homogeneous when the enhancer is distributed evenly within the complex bilayer lipids, but the accelerant is more likely to be heterogeneously concentrated within the domains of the bilayer lipids and iv) They alter the solvent nature of the stratum corneum, thus aiding the partitioning of the drug or a co-solvent into the tissue.(López-Castellano & Merino, 2010) 2.3 Indirect effects on the skin due to the use of transdermal penetration enhancers Chemical enhancers can produce: a) Modification of the thermodynamic activity of the vehicle. The permeation of a good solvent from the formulation, such as ethanol, can increase the thermodynamic activity of a drug; b) It has been suggested that, by permeating through the membrane, a solvent can 'drag' the permeant with it, though this concept is somewhat controversial and requires confirmation; c) Solubilising the permeant within the donor, especially when solubility is very low, as in the case of aqueous donor solutions, can reduce depletion effects and prolong drug permeation.(López-Castellano & Merino, 2010) 2.4 Classification of percutaneous chemical enhancers The classification of percutaneous enhancers is frequently based on the chemical class to which the compounds belong. Table 1 shows the principal classes of percutaneous enhancers. CHEMICAL CLASS COMPOUNDS Water Water Sulfoxides and similar chemicals Dimethyl sulfoxide, Dodecyl methyl sulfoxide Ureas Urea Alcohols Ethanol, Caprylic alcohol, Propylene glycol Pyrrolidones and derivatives N-methyl-2-pyrrolidone, 2-pyrrolidone Azone and derivatives Azone ® (1-dodecylazacycloheptan-2-one) Dioxolane derivatives SEPA ®
Role of Surfactants as Penetration Enhancer in Transdermal Drug Delivery System
Journal of Molecular Pharmaceutics & Organic Process Research, 2014
Human skin is a remarkably efficient barrier, designed to keep ''our insides in and the outsides out''. This barrier property causes difficulties for transdermal delivery of therapeutic agents. One long-standing approach to increase the range of drugs that can be effectively delivered via this route has been to use penetration enhancers, chemicals that interact with skin constituents to promote drug flux. To-date, a vast array of chemicals has been evaluated as penetration enhancers (or absorption promoters), yet their inclusion into topical or transdermal formulations is limited since the underlying mechanisms of action of these agents are seldom clearly defined. In this article we review some uses of the more widely investigated chemical penetration enhancers and discuss possible mechanisms of action. Hair Shaft Keratinocytes Sweat pore Epidermis Dermis Hypodermis Pacinian corpuscle Sweat gland Nerves Sebaceous gland Blood vessel Lymph vessel Hair follicle Arrectpr pili muscle Figure 1: Diagrammatic representation of skin.
Novel chemical permeation enhancers for transdermal drug delivery
Transdermal drug delivery has been accepted as a potential non-invasive route of drug administration, with advantages of prolonged therapeutic action, decreased side effect, easy use and better patient compliance. However, development of transdermal products is primarily hindered by the low permeability of the skin. To overcome this barrier effect, numerous new chemicals have been synthesized as potential permeation enhancers for transdermal drug delivery. In this review, we presented an overview of the investigations in this field, and further implications on selection or design of suitable permeation enhancers for transdermal drug delivery were also discussed.
New Approaches in Topical Delivery Through Using Various Permeation Barrier Enhancers
Topical delivery of drug is an appealing ways of conservative way in administrating for systematic therapeutics. Human skin is refractive to most molecules, particularly hydrophilic ones, in spite of the existence of trans-barrier route. Overcoming the logical obstacle of skin transportation has become one of issue to design delivery systems of transdermal drug. The crucial of preserving this protective barrier after breaching nanosized (5 nm-10 µm) skin surface is for purposes of transdermal drug delivery. Alternatively, sufficient deformable and stable nano-sized carriers can help in achieving controlled and reliable drug delivery across skin barrier. Their ability to act as drug carriers on, in and ideally below skin barrier(s) must be preserved. A proper design of self-regulating, ultra-adaptable and stable hetero-aggregates can overt spontaneously and deliver drugs through primary skin barrier and minimizing the cutaneous drug clearance; this grants deep/targeted deposition and prolonged action of the carrier-transported drugs. Therapeutic products based on ultraadaptable self-regulating, nano-sized (~100nm) carriers are under development. In meantime, there is tremendous potential to overcome the skin barrier in enhancing transport of drug molecules offered by chemicals. However, single chemicals are limited in their efficiency to interfere low concentration's skin barrier and will cause skin irritation at most for high concentration's skin barriers. However, chemical mixtures made up by many components resulted in supplying lofty potency to permeate the skin in contrast with single chemicals that not necessary cause irritation. This write-up is an overview on systems of chemical mixtures' employed synergistic offering a better process of enhancing permeation of skin.
A Concise Outline on Innovative Permeation Enhancers in Transdermal Drug Delivery Approach
INDIAN DRUGS
The transdermal drug administration system represents a potent substitute for administering medications orally and is also designed to offer a substitute for hypodermic injections. Presently, three generations of penetration enhancer to permeate through skin are available 1st Generation embraces chemical approaches and pertain to augment the efficacy of the drug transferred across the integral skin, 2nd generation encompasses physical permeation technologies and 3rd generation consists of microneedle and needleless penetration enhancers. There is renewed interest in transdermal drug delivery. This review focuses on some existing novel approaches and the additive upshot of techniques for increasing the permeation of drugs via skin penetration. By using the right methods, drug carriers, or certain chemical agents, it is important to cause the stratum corneum to change physically or biomolecularly.
Review on Transdermal Drug Delivery Systems
Journal of Pharmaceutics and Drug Development, 2014
During the past decades, intensive studies have focused on the technologies in drug delivery, and with the rapid developments and explorations in technologies, traditional drug delivery means are being replaced by the more effective and advanced ones. The creation of transdermal drug delivery system (TDDS) has been one of the most sophisticated and innovative approaches of drug deliveries. The transdermal drug delivery system has attracted considerale attention because of its many potential advantages, including better patient compliance, avoidance of gastrointestinal disturbances, hepatic first-pass metabolism and sustained delivery of drugs to provide steady plasma profiles, particularly for drugs with short half-lives, reduction in systemic side effects and enhanced therapeutic efficacy [1-6]. Recently, transdermal drug delivery system (TDDS) has become a more and more important approach to administering drugs. Based on its advantages, which are not achievable by other modes of administration, many researchers are dedicated to the study of it, and have made great progress. Although the skin offers a painless interface for systemic drug delivery, it also presents limitations which are mainly caused by the stratum corneum. In this work, we state the increasingly impact of TDDS, discuss the limitations of it, and last but not least, we highlight the methods for overcoming these limitations by using permeation enhancers, microneedles, iontophoresis. Despite these advantages, most of the transdermal candidates have low permeability. The drugs administered across skin should have the three constraining characteristics: appropriate partition coefficient, low molecular mass (<500Da), and small required dose (upto milligrams) [3]. The limitations of transdermal drug delivery are caused by skin which protects against and is impermeable to foreign molecules. The human skin is consisted of two main layers: the layer of epidermis and the layer of dermis. Stratum corneum is the epidermis's outermost layer that composed of stratified keratinocytes, multiple lipid bilayers of ceramidas, fatty acids, cholesterol and cholesterol esters. Stratum corneum provides an extremely effective physical barrier for the control of drug penetration [2,7-10]. Therefore, attempts to overcome this skin barrier is presently an important area of pharmaceutical and toxicological research. The techniques that weaken the barrier have included permeation enhancers [11-43], microneedles [44-68] and iontophoresis [69-84]. Chemical permeation enhancers In the last 50 years, a large number of chemical permeation enhancers (CPEs) which are defined as substances that interact with the major constituents of skin barrier, stratum corneum, to promote penetration of drugs into skin. The ideal enhancer should have the following conditions: 1. Non-pharmacological activities. 2. Nontoxic, non-allergenic, and non-irritating. 3. Rapid-acting with predictable and reproducible activity. 4. When removed from the skin surface, the penetrability of the skin should recover immediately. 5. Cosmetically acceptable with suitable skin feel [11]. The part of penetration enhancer in topical formulations has been becoming significantly and undoubtedly, and they would permit the delivery of broader classes of drugs through the stratum corneum in the future.