Structure-activity relationship of chemical penetration enhancers in transdermal drug delivery

Transdermal drug delivery (TDD) is the administration of therapeutic agents through intact skin for systemic effect. TDD offers several advantages over the conventional dosage forms such as tablets, capsules and injections. Currently there are about eight drugs marketed as transdermal patches. Examples of such products include nitroglycerin (angina pectoris), clonidine (hypertension), scopolamine (motion sickness), nicotine (smoking cessation), fentanil (pain) and estradiol (estrogen deficiency). Since skin is an excellent barrier for drug transport, only potent drugs with appropriate physicochemical properties (low molecular weight, adequate solubility in aqueous and non-aqueous solvents, etc) are suitable candidates for transdermal delivery. Penetration enhancement technology is a challenging development that would increase significantly the number of drugs available for transdermal administration. The permeation of drugs through skin can be enhanced by physical methods such as iontophoresis (application of low level electric current) and phonophoresis (use of ultra sound energy) and by chemical penetration enhancers (CPE). In this review, we have discussed about the CPE which have been investigated for TDD. CPE are compounds that enhance the permeation of drugs across the skin. The CPE increase skin permeability by reversibly altering the physicochemical nature of the stratum corneum, the outer most layer of skin, to reduce its diffusional resistance. These compounds increase skin permeability also by increasing the partition coefficient of the drug into the skin and by increasing the thermodynamic activity of the drug in the vehicle. This review compiles the various CPE used for the enhancement of TDD, the mechanism of action of different chemical enhancers and the structure-activity relationship of selected and extensively studied enhancers such as fatty acids, fatty alcohols and terpenes. Based on the chemical structure of penetration enhancers (such as chain length, polarity, level of unsaturation and presence of some special groups such as ketones), the interaction between the stratum corneum and penetration enhancers may vary which will result in significant differences in penetration enhancement. Our review also discusses the various factors to be considered in the selection of an appropriate penetration enhancer for the development of transdermal delivery systems.     

Biomaterials as novel penetration enhancers for transdermal and dermal drug delivery systems

Abstract

The highly organized structure of the stratum corneum provides an effective barrier to the drug delivery into or across the skin. To overcome this barrier function, penetration enhancers are always used in the transdermal and dermal drug delivery systems. However, the conventional chemical enhancers are often limited by their inability to delivery large and hydrophilic molecules, and few to date have been routinely incorporated into the transdermal formulations due to their incompatibility and local irritation issues. Therefore, there has been a search for the compounds that exhibit broad enhancing activity for more drugs without producing much irritation. More recently, the use of biomaterials has emerged as a novel method to increase the skin permeability. In this paper, we present an overview of the investigations on the feasibility and application of biomaterials as penetration enhancers for transdermal or dermal drug delivery systems.     

Percutaneous Permeation Enhancement by Terpenes: Mechanistic View

A popular approach for improving transdermal drug delivery involves the use of penetration enhancers (sorption promoters or accelerants) which penetrate into skin to reversibly reduce the barrier resistance. The potential mechanisms of action of penetration enhancers include disruption of intercellular lipid and/or keratin domains and tight junctions. This results in enhanced drug partitioning into tissue, altered thermodynamic activity/solubility of drug etc. Synthetic chemicals (solvents, azones, pyrrolidones, surfactants etc.) generally used for this purpose are rapidly losing their value in transdermal patches due to reports of their absorption into the systemic circulation and subsequent possible toxic effect upon long term application. Terpenes are included in the list of Generally Recognized As Safe (GRAS) substances and have low irritancy potential. Their mechanism of percutaneous permeation enhancement involves increasing the solubility of drugs in skin lipids, disruption of lipid/protein organization and/or extraction of skin micro constituents that are responsible for maintenance of barrier status. Hence, they appear to offer great promise for use in transdermal formulations. This article is aimed at reviewing the mechanisms responsible for percutaneous permeation enhancement activity of terpenes, which shall foster their rational use in transdermal formulations.     

The application of anethole,menthone, and eugenol in transdermal penetration of valsartan: Enhancement and mechanistic investigation

Context: The main barrier for transdermal delivery is the obstacle property of the stratum corneum. Many types of chemical penetration enhancers have been used to breach the skin barrier; among the penetration enhancers, terpenes are found as the most highly advanced, safe, and proven category.

Objective: In the present investigation, the terpenes anethole, menthone, and eugenol were used to enhance the permeation of valsartan through rat skin in vitro and their enhancement mechanism was investigated.

Materials and methods: Skin permeation studies of valsartan across rat skin in the absence and the presence of terpenes at 1% w/v, 3% w/v, and 5% w/v in vehicle were carried out using the transdermal diffusion cell sampling system across rat skin and samples were withdrawn from the receptor compartment at 1, 2, 3, 4, 6, 8, 10, 12, and 24?h and analysed for drug content by the HPLC method. The mechanism of skin permeation enhancement of valsartan by terpenes treatment was evaluated by Fourier transform infrared spectroscopy (FTIR) analysis and differential scanning calorimetry (DSC).

Results: All the investigated terpenes provided a significant (p?<?0.01) enhancement in the valsartan flux at a concentration of 1%, and less so at 3% and 5%. The effectiveness of terpenes at 1% concentration was in the following order: anethole?>?menthone?>?eugenol with 4.4-, 4.0-, and 3.0-fold enhancement ratio over control, respectively. DSC study showed that the treatment of stratum corneum with anethole shifted endotherm down to lower melting point while FTIR studies revealed that anethole produced maximum decrease in peak height and area than other two terpenes.

Conclusion: The investigated terpenes can be successfully used as potential enhancers for the enhancement of skin permeation of lipophilic drug.     

Chemical penetration enhancers: a patent review

Background: Ever since transdermal drug delivery came into existence, it has offered great promises, although most of them are yet to be fulfilled owing to some intrinsic restrictions of the transdermal route. On the positive side, transdermal drug delivery systems present advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. The greatest hindrance in the percutaneous delivery is the obstruction property of the stratum corneum, the outermost layer of the skin, in addition to usual problems such as skin binding, skin metabolism, cutaneous toxicity and prolonged lag times. Objective: This paper reviews investigations on the feasibility and application of penetration enhancers as described in recent patents, which help in the selection of a suitable sorption promoter(s) for enhanced delivery of medicaments through the skin. Method: The patents granted under various categories of penetration enhancers have been discussed including fatty acids, terpenes, fatty alcohol, pyrrolidone, sulfoxides, laurocapram, surface active agents, amides, amines, lecithin, polyols, quaternary ammonium compounds, silicones, alkanoates and so on. Conclusion: Scores of promising chemicals have been harnessed for their skin permeation promoting capacity as mentioned earlier. In future, many more chemicals and putative enhancers are likely be documented and patented.     

Penetration enhancers

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.     

Penetration enhancers

One long-standing approach for improving transdermal drug delivery uses penetration enhancers (also called sorption promoters or accelerants) which penetrate into skin to reversibly decrease the barrier resistance. Numerous compounds have been evaluated for penetration enhancing activity, including sulphoxides (such as dimethylsulphoxide, DMSO), Azones (e.g. laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (for example propylene glycol, PG, a common excipient in topically applied dosage forms), surfactants (also common in dosage forms) and terpenes. Many potential sites and modes of action have been identified for skin penetration enhancers; the intercellular lipid matrix in which the accelerants may disrupt the packing motif, the intracellular keratin domains or through increasing drug partitioning into the tissue by acting as a solvent for the permeant within the membrane. Further potential mechanisms of action, for example with the enhancers acting on desmosomal connections between corneocytes or altering metabolic activity within the skin, or exerting an influence on the thermodynamic activity/solubility of the drug in its vehicle are also feasible, and are also considered in this review.     

Chemical enhancers for transdermal drug transport.

In its first part, this review paper discusses skin morphology and barrier function of the stratum corneum for drug permeation after its transdermal administration or topical application. Further, the paper presents the main methods for overcoming the skin permeation barrier, which plays an important role for transdermal drug administration. Focus is on the method of chemical permeation enhancement. The chemical enhancers are categorised by their chemical structure. Examples of the most effective enhancers are given for the chemical groups of alcohols, amines and amides, polyalcohols, terpenes, fatty acids and their esters, macro cyclic compounds, sulfoxides, tensides, and others, as e.g. soft enhancers.     

Enhanced transdermal delivery of atenolol from the ethylene-vinyl acetate matrix

To enhance transdermal delivery of atenolol, ethylene-vinyl acetate (EVA) matrix of drug containing penetration enhancer was fabricated. Effect of penetration enhancer on the permeation of atenolol through the excised rat skin was studied. Penetrating enhancers showed the increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene 2-oleyl ether showed the best enhancement. For the controlling transdermal delivery of atenolol, the application of EVA matrix containing permeation enhancer could be useful in the development of transdermal drug delivery system.     

Veterinary drug delivery: potential for skin penetration enhancement

A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.     

Physicochemical effects of terpenes on organogel for transdermal drug delivery

It is accepted that terpenes are effective penetration enhancers to promote the passage of drugs or chemicals through the human skin barrier. However the physical and chemical changes of a pharmaceutical vehicle induced by the incorporation of terpenes have not been explored. Thus, this study examines the effects of three terpenes (linalool, cineole, limonene) on the rheology and chemical stability of an organogel composed of dibutyllauroylglutamide (GP1) and propylene glycol (PG). At a given GP1 concentration, oxygen-containing linalool and cineole decreased gel moduli (elastic and viscous) and brittleness, and the reverse was obtained for hydrocarbon limonene. Probably, linalool and cineole interfered with hydrogen bonding between GP1 molecules while limonene could have initiated a phase separation-mediated gelation, changing the gel morphology. Microcalorimetry detected minute heat endotherms for gels (with and without terpenes) subjected to accelerated heat testing. These heat changes could arise from a small degree of structural disruption of the gel network. Heat endotherms normalized with respect to GP1 content were used to assess gel chemical stability. Although the terpenes altered rheology, they did not significantly affect the chemical stability of the gels. This is the first in the literature that reports the effect of penetration enhancers, such as terpenes, on the physical, rheological and chemical characteristics of a model pharmaceutical formulation for topical and transdermal drug delivery.     

不同基质和透皮促进剂对秋水仙碱凝胶剂体外透皮特性的影响

目的优选秋水仙碱凝胶剂基质和相应的透皮促进剂,为制备秋水仙碱透皮给药新制剂提供参考资料。方法采用改良的Franz扩散池法,并通过RP-HPLC法测定接收液中秋水仙碱的含量。结果3种基质的秋水仙碱凝胶体外透皮比率为Carbopol基质凝胶>HPMC基质凝胶>CMC-Na基质凝胶。以Carbopol为基质,加入几种透皮促进剂后,秋水仙碱凝胶的体外透皮速率为丙二醇>冰片>氮酮>薄荷油。结论凝胶剂作为秋水仙碱透皮吸收新剂型可行。     

渗透促进剂对莫达芬尼透皮作用的影响

目的：研究10种渗透促进剂对莫达芬尼透皮吸收的影响。方法：采用改良的Franz扩散池，以40％PEG-400生理盐水溶液为接受介质，以大鼠离体腹部皮肤为透皮屏障，计算不同单元渗透促进剂作用下莫达芬尼累积渗透量Q、稳态流量Js及相关参数。结果：不同促渗剂对莫达芬尼有不同程度的促渗作用，氮酮、丁香油、月桂酸、薄荷醇对莫达芬尼促透作用比较显著，其增渗倍数分别是空白对照组的17．3850，16．3303，9．3297，8．7037倍。结论：此研究为莫达芬尼透皮吸收制剂处方的设计提供依据。     

不同促渗剂对蛇床子软膏透皮吸收特性的影响

目的考察不同促渗剂对蛇床子软膏透皮吸收的影响。方法采用改良Franz扩散池,以离体裸鼠皮肤为屏障,考察氮酮、油酸和高良姜油等不同种类的促渗剂对蛇床子软膏的累积渗透量、渗透吸收速率、增渗倍数等参数的影响。结果几种促渗剂对蛇床子软膏的透皮吸收均有较好的促进作用,其中以3%高良姜油效果最佳。结论高良姜油对蛇床子素经皮吸收具有显著的促进作用,为蛇床子经皮给药制剂处方设计和新药开发提供了依据。     

Drug delivery systems. 6. Transdermal drug delivery

Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side-effects with some of these formulations is indicative of absorption through the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by micro-organisms and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. Basically, four systems are available that allow for effective absorption of drugs across the skin. The microsealed system is a partition-controlled delivery system that contains a drug reservoir with a saturated suspension of drug in a water-miscible solvent homogeneously dispersed in a silicone elastomer matrix. A second system is the matrix-diffusion controlled system. The third and most widely used system for transdermal drug delivery is the membrane-permeation controlled system. A fourth system, recently made available, is the gradient-charged system. Additionally, advanced transdermal carriers include systems such as iontophoretic and sonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs have been formulated in transdermal systems, and others are being examined for the feasibility of their delivery in this manner (e.g., nicotine antihistamines, beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents). Research also continues on various chemical penetration enhancers that may allow delivery of therapeutic substances. For example, penetration enhancers such as Azone may allow delivery of larger-sized molecules such as proteins and polypeptides.     

Transdermal drug delivery: penetration enhancement techniques

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 drug selection, prodrugs and ion-pairs, supersaturated drug solutions, eutectic systems, complexation, liposomes, vesicles and particles. Enhancement via modification of the stratum corneum by hydration, chemical enhancers acting on the structure of the stratum corneum lipids and keratin, partitioning and solubility effects are also discussed. The mechanism of action of penetration enhancers and retarders and their potential for clinical application is described.     

Enhanced transdermal delivery of triprolidine from the ethylene-vinyl acetate matrix.

Triprolidine-containing matrix was fabricated with ethylene-vinyl acetate (EVA) copolymer to control the release of the drug. The permeation rate of triprolidine in the stripped skin was greatly larger than that in the whole skin. Thus it showed that the stratum corneum acts as a barrier of skin permeation. The effect of penetration enhancer and stripping of skin on the permeation of triprolidine through the excised mouse skin was studied. Penetrating enhancers showed increased flux probably due to the enhancing effect on the skin barrier, the stratum corneum. Among enhancers used such as glycols, fatty acids and non-ionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The permeability of triprolidine was markedly increased with stripping of the mouse skin to remove the stratum corneum that acts as a barrier of skin permeation. For the controlling transdermal delivery of triprolidine, the application of EVA membrane containing permeation enhancer could be useful in the development of transdermal drug delivery system.     

Branched-chain alkanols as skin permeation enhancers: quantitative structure-activity relationships

One long-standing approach for improving transdermal drug delivery is using penetration enhancers which reversibly decrease the skin barrier resistance. Though the skin permeation enhancement effect of chemical penetration enhancers has been studied extensively, their quantitative structure-activity relationships have not been adequately investigated. In this paper, we established the correlation equations between enhancement potencies and the physico-chemical parameters relevant to lipophilicity and position of hydroxyl group for 16 alkanols using the stepwise multiple linear regression analysis. These equations reveal that the enhancement potencies of alkanols are excellently correlated with their lipophilicity and position of the hydroxyl group. The enhancement potency of an alkanol will increase when it has greater lipophilicity but will decrease as the hydroxyl group moves from the end of the alkyl chain towards the center.     

Enhanced transdermal delivery of loratadine from the EVA matrix

Various enhancers, such as fatty acids (saturated, unsaturated), glycerides, propylene glycols, and non-ionic surfactants, have been incorporated in the loratadine-EVA matrix to increase the rate of skin permeation of loratadine from an EVA matrix. The enhancing effects of these enhancers on the skin permeation of loratadine were evaluated using a modified Keshary-Chien cell fitted with intact excised rat skin. The penetration enhancers showed a higher flux, probably due to the enhancing effect on the skin barrier, the stratum corneum. Among the enhancers used, such as the fatty acids, glycols, propylene glycols, and non-ionic surfactants, linoleic acid showed the best enhancement. For the enhanced transdermal delivery of loratadine, application of an EVA matrix containing a permeation enhancer might be useful in the development of a transdermal drug delivery system.     

Strategies for overcoming the stratum corneum

Transdermal drug delivery has many advantages over the oral administration of drugs. This is the reason why many researchers have extensively investigated the transdermal absorption of drugs. However, a much smaller number of drugs are marketed using this route of delivery, compared to oral dosage forms, because drug absorption across the skin is very low due to the stratum corneum (the main barrier for drug absorption across the skin). Overcoming the penetration barrier would significantly improve the development of an efficient transdermal drug delivery system. Several techniques have been developed, or are under development, to bypass the stratum corneum. Approaches that have been made to overcome the stratum corneum fit into five different categories: (i) device and formulation; (ii) modification of stratum corneum by chemical enhancers; (iii) ablation; (iv) bypassing the stratum corneum via appendages; and (v) electrically assisted methods such as iontophoresis and electroporation. Furthermore, possible combinatorial uses of several approaches have been studied. Although the safety issues of these synergistic approaches still require clarification, several combinations could be promising. Finally, there is a necessity to regulate the intradermal disposition of drugs to develop a more efficient transdermal drug delivery system after overcoming the skin barrier.