Penetration Enhancers and the Percutaneous Absorption of Drugs: An Update

Abstract

Dermatological preparations may be formulated for optimal bioavailability by ensuring that the drug has maximum tendency to leave the vehicle and pass into the skin. Alternatively, compounds (penetration enhancers, accelerants, or sorption promoters) may be included in the formulation that themselves pass into the skin and in so doing reversibly decrease its resistance to drug passage. The literature on penetration enhancers to 1981 was comprehensively reviewed by Barry. This paper discusses work performed since that time, with special reference to glycols, sulfoxides, amides and amines, pyrrolidones, and Azone. These and other compounds continue to be investigated as penetration enhancers for both local and systemic delivery of drugs. An important future role lies in their incorporation into transdermal delivery systems.     

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.     

Design of fatty acid conjugates for dermal delivery and topical therapeutics

The development of topical and transdermal drug delivery systems has aimed at overcoming the remarkably efficient barrier property of human skin by nontoxic and nonirritant methods. Numerous chemical and physical approaches have been investigated to overcome the skin's formidable barrier function. This article reviews two types of drug delivery approaches currently under investigation, which aim to increase drug permeability into and through the skin, by using fatty acid conjugates. The first approach uses fatty-acid conjugates as chemical enhancers for topical drugs while avoiding irritation, which is usually caused by the conventional use of free fatty acids. The second approach uses a conjugation of fatty acids to hydrophilic drug molecules to create effective topical prodrugs. The polyunsaturated fatty acid (PUFA) ester prodrugs for dermal delivery may be particularly promising and more advantageous by playing a role of mutual prodrugs. This article presents an overview of the ongoing research on fatty acid conjugates for dermal application. The concepts, potential uses, limitations as well as their safety considerations are described.     

Site-specific drug delivery in the skin for the localized treatment of skin diseases

ABSTRACT

Introduction: Due to the well-organized structure and barrier function of the skin, it is generally difficult for drugs applied directly on the surface of skin to reach their expected site of action. Accordingly, site-specific drug delivery in the skin has been increasingly explored to facilitate the treatment of skin diseases and reduce the systemic toxicity.

Area covered: An overview of the generally used sites for drug delivery in the skin is herein presented. Different strategies including particle-based carriers, physical technologies, and chemical approaches are discussed with regards to their potential application in site-specific drug delivery in the skin.

Expert opinion: Particle-based carriers are of particular significance for the enhancement of drug delivery in the skin. Although no recommendation can be made regarding which type of carriers can provide better skin penetration, the lipid-based colloidal systems appear to be favored due to their compatibility. In addition, the physical technologies provide unique advantages in delivering hydrophilic macromolecules for the skin immunization. As a new class of permeation enhancers, skin penetrating peptides are gaining more attention in drug delivery to skin cells. For the design of robust site-specific drug delivery systems, the impacts of diseased state and drug properties should not be disregarded.     

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.     

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.     

Spray-on transdermal drug delivery systems

Introduction: Transdermal drug delivery possesses superior advantages over other routes of administration, particularly minimizing first-pass metabolism. Transdermal drug delivery is challenged by the barrier nature of skin. Numerous technologies have been developed to overcome the relatively low skin permeability, including spray-on transdermal systems.

Areas covered: A transdermal spray-on system (TSS) usually consists of a solution containing the drug, a volatile solvent and in many cases a chemical penetration enhancer. TSS promotes drug delivery via the complex interplay between solvent evaporation and drug–solvent drag into skin. The volatile solvent carries the drug into the upper layers of the stratum corneum, and as the volatile solvent evaporates, an increase in the thermodynamic activity of the drug occurs resulting in an increased drug loading in skin.

Expert opinion: TSS is easily applied, delivering flexible drug dosage and associated with lower incidence of skin irritation. TSS provides a fast-drying product where the volatile solvent enables uniform drug distribution with minimal vehicle deposition on skin. TSS ensures precise dose administration that is aesthetically appealing and eliminates concerns of residual drug associated with transdermal patches. Furthermore, it provides a better alternative to traditional transdermal products due to ease of product development and manufacturing.     

Status of terpenes as skin penetration enhancers

Since its introduction, transdermal drug delivery has promised much but, in some respects has still to deliver on that initial promise, due to inherent limitations imposed by the percutaneous route. The greatest obstacle for transdermal delivery is the barrier property of the stratum corneum. Many approaches have been employed to breach the skin barrier, of which, the most widely used one is that of chemical penetration enhancers. Of the penetration enhancers, terpenes are arguably the most highly advanced and proven category and are classified as generally regarded as safe (GRAS) by the Food and Drug Administration. This paper presents an overview of the investigations on the feasibility and application of terpenes as sorption promoters for improved delivery of drugs through skin.     

Dermal Penetration of Fentanyl: Inter‐ and Intraindividual Variations

Abstract: Fentanyl is a potent synthetic opioid that is increasingly being used in transdermal drug delivery systems. The target organ concentration of a drug administered dermally will depend on the rate of dermal absorption and the systemic elimination. We have studied the intra‐ and interindividual variation in dermal penetration of fentanyl in an in vitro model (static diffusion cells) with human skin, and compared the absorption of fentanyl from an aqueous solution with absorption from a commercial patch. The intraindividual variation in dermal penetration of fentanyl in aqueous solution was limited (18%) and no differences in penetration characteristics were observed between breast and abdominal skin. The interindividual variation in dermal penetration of fentanyl was extensive, with maximal fluxes ranging from 21–105 ng/cm²/hr following application of an infinite dose of fentanyl to the donor chamber. Use of transdermal drug delivery systems (patches) reduced the inter‐individual variation. The permeability coefficients after application of fentanyl in aqueous solution and through patches were identical (0.0011 cm/hr). One person had a higher than average penetration rate following patch application, which may indicate that the human skin and not the patch barrier was the rate‐determining factor for the other individuals included in this study.     

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.     

Nanoemulsions as potential vehicles for transdermal and dermal delivery of hydrophobic compounds: an overview

Introduction: In recent years, nanoemulsions have been investigated as potential drug delivery vehicles for transdermal and dermal delivery of many compounds especially hydrophobic compounds in order to avoid clinical adverse effects associated with oral delivery of the same compounds. Droplet size and surface properties of nanoemulsions play an important role in the biological behavior of the formulation.

Areas covered: In this review, current literature of transdermal and dermal delivery of hydrophobic compounds both in vitro as well as in vivo has been summarized and analyzed.

Expert opinion: Nanoemulsions have been formulated using a variety of pharmaceutically acceptable excipients. In many cases of dermal and transdermal nanoemulsions, the skin irritation or skin toxicity issues on human beings have not been considered which needs to be evaluated properly. In the last decade, much attention has been made in exploring new types of nanoemulsion-based drug delivery system for dermal and transdermal delivery of many hydrophobic compounds. This area of research would be very advantageous for formulation scientists in order to develop some nanoemulsion-based formulations for their commercial exploitation and clinical applications.     

Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil: in vitro evaluation of drug permeation by infrared spectroscopy

Recently, we carried out a research on new liposomal systems prepared by using in their composition a few penetration enhancers which differ for chemical structure and physicochemical properties. The penetration enhancer-containing vesicles (PEVs) were prepared by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy) ethanol (Transcutol^®), capryl-caproyl macrogol 8-glyceride (Labrasol^®), and cineole.To study the influence of the PEVs on (trans)dermal delivery of minoxidil, in vitro diffusion experiments were performed through new born pig skin and the results were compared with that obtained applying the vesicular system without enhancer (control) after pretreatment of the skin with the various enhancers. In this study, Fourier transform infrared spectroscopy (FTIR), attenuated total reflectance FTIR (ATR-FTIR) and FTIR imaging were used to evaluate the effective penetration of minoxidil in the skin layers and to discover the influence of the enhancer on the drug topical delivery. These analytical studies allowed us to characterize the drug formulations and to evaluate the vesicle distribution into the skin. Recorded spectra confirmed that the vesicle formulations with penetration enhancers promoted drug deposition into the skin.     

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.     

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.     

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.     

Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil

The aim of this work was to evaluate the ability of a few different penetration enhancers to produce elastic vesicles with soy lecithin and the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called Penetration Enhancer-containing Vesicles (PEVs) were prepared as dehydrated–rehydrated vesicles by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy)ethanol (Transcutol^®), capryl-caproyl macrogol 8-glyceride (Labrasol^®), and cineole. Soy lecithin liposomes, without penetration enhancers, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, and vesicle deformability.The influence of PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through newborn pig skin in comparison with traditional liposomes and ethanolic solutions of the drug also containing each penetration enhancer. A skin pre-treatment study using empty PEVs and conventional liposomes was also carried out.Results showed that all the used penetration enhancers were able to give more deformable vesicles than conventional liposomes with a good drug entrapment efficiency and stability. In vitro skin penetration data showed that PEVs were able to give a statistically significant improvement of minoxidil deposition in the skin in comparison with classic liposomes and penetration enhancer-containing drug ethanolic solutions without any transdermal delivery. Moreover, the most deformable PEVs, prepared with Labrasol^® and cineole, were also able to deliver to the skin a higher total amount of minoxidil than the PE alcoholic solutions thus suggesting that minoxidil delivery to the skin was strictly correlated to vesicle deformability, and therefore to vesicle composition.     

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.     

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。     

Penetration enhancers in proniosomes as a new strategy for enhanced transdermal drug delivery

The aim of this work is to investigate penetration enhancers in proniosomes as a transdermal delivery system for nisoldipine. This was performed with the goal of optimising the composition of proniosomes as transdermal drug delivery systems. Plain proniosomes comprising sorbitan monostearate, cholesterol, ethanol and a small quantity of water were initially prepared. Subsequently, proniosomes containing lecithin or skin penetration enhancers were prepared and evaluated for transdermal delivery of nisoldipine. The plain proniosomes significantly enhanced the transdermal flux of nisoldipine to reach 12.18 μg cm⁻² h⁻¹ compared with a saturated aqueous drug solution which delivered the drug at a rate of 0.46 μg cm⁻² h⁻¹. Incorporation of lecithin into such proniosomes increased the drug flux to reach a value of 28.51 μg cm⁻² h⁻¹. This increase can be attributed to the penetration enhancing effect of lecithin fatty acid components. Replacing lecithin oleic acid (OA) produced proniosomes of comparable efficacy to the lecithin containing system. The transdermal drug flux increased further after incorporation of propylene glycol into the OA based proniosomes. Similarly, incorporation of isopropyl myristate into plain proniosomes increased drug flux. The study introduced enhanced proniosomes as a promising transdermal delivery carrier and highlighted the role of penetration enhancing mechanisms in enhanced proniosomal skin delivery. The study opened the way for another line of optimisation of niosome proconcentrates.     

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.