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.     

Effect of penetration enhancers on the transdermal delivery of bupranolol through rat skin

Bupranolol (BPL) is a suitable drug candidate for transdermal drug delivery system development based on its favorable physicochemical and pharmacokinetic properties. The effect of different penetration enhancers on the permeation of BPL across rat skin was studied using side-by-side diffusion cells. 2-Pyrrolidone (PY), 1-methyl-2-pyrrolidone (MPY), and propylene glycol (PG) at various concentrations were used as penetration enhancers along with 0.4% w/v aqueous suspension of BPL. Menthol at different concentrations in isopropanol-water (6:4) mixture also was used as an enhancer wherein BPL at 0.4% w/v was completely solubilized. Skin pretreatment studies were carried out with all the above enhancers to understand their role in the penetration enhancement effect. PY and MPY at 5% w/v concentrations increased the permeation of BPL by 3.8- and 2.4-fold, respectively, versus control (p < .01). PG at 10% and 30 w/v concentrations increased the flux of BPL by 2.5- and 5.0-fold, respectively, versus control (p < .001). Menthol at 2% w/v concentration increased the flux of BPL by 3.8-fold (p < .01) and further increase in menthol concentration significantly decreased the flux of BPL. Overall, pyrrolidones and menthol at low concentrations (5% w/v or less) and PG at 30% w/v concentration were effective as penetration enhancers for BPL.     

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.     

Effect of polyunsaturated fatty acids and some conventional penetration enhancers on transdermal delivery of atenolol

The aim of our present study was to evaluate the in vitro percutaneous absorption of atenolol, a well-known antihypertensive, from a series of formulations containing various penetration enhancers. Particularly the promoting effect of EPA and DHA, two polyunsaturated fatty acids (PUFAs), has been studied, and drug permeation data have been compared with those obtained with the other formulations containing "classic" penetration enhancers such as transcutol, d-limonene, and PG. Not all the penetration enhancers tested were effective in increasing atenolol percutaneous flux and the best permeation profile for atenolol was obtained with the formulation containing transcutol (B) and PUFA (E). To explain the enhancer mechanism, the atenolol diffusion and partitioning coefficients from the different formulations were calculated. The results indicated that PUFAs increased the apparent diffusion coefficient of the drugs but did not affect their apparent stratum corneum (SC)/vehicle partition coefficient (K(m)). At this same time transcutol exerted its enhancer effect increasing significantly the apparent SC/vehicle partition coefficient (K(m)) and in a minor amount the apparent diffusion coefficient of skin permeation process (D(m)). The potential application of formulations B and E in atenolol percutaneous absorption was determined from the calculation of the steady-state plasma concentrations (C(ss)). These values resulted within the drug therapeutic range and suggest that atenolol transdermal delivery could be feasible.     

不同渗透促进剂对复方盐酸多塞平乳膏体外经皮的促渗作用研究

目的研究不同浓度油酸和氮酮及其复合物对复方盐酸多塞平乳膏透皮吸收的影响,提高乳膏中两种主要有效成分盐酸多塞平和醋酸曲安奈德的渗透效果.方法选用1%氮酮(aonze,AZ)、2%AZ、1%油酸(oleic acid,OA)、2%OA、1%OA-AZ 5种渗透吸收促进剂,采用离体小鼠皮为皮肤模型,在Franz扩散池上进行促渗实验.结果 5种渗透吸收促进剂对复方盐酸多塞平乳膏中盐酸多塞平促渗能力为2%AZ＞1%OA-AZ＞2%OA＞1%AZ＞1%OA;对醋酸曲安奈德促渗能力为2%AZ＞1%OA-AZ＞1%AZ＞2%OA＞1%OA.结论在所选的5种渗透促进剂中,选用2%AZ渗透促进剂对复方盐酸多塞平乳膏体外经皮促渗作用最显著,油酸、氮酮联合应用有协同作用,比单用氮酮或油酸促渗能力强.     

不同促渗剂对盐酸芦氟沙星体外经皮渗透的影响

目的　研究几种常用促渗剂对盐酸芦氟沙星体外经皮渗透的影响。方法　用紫外分光光度法检测浓度 ,采用改进Franz扩散池 ,比较几种常用促渗剂对盐酸芦氟沙星渗透系数的影响。结果　1%氮酮和 1%氮酮 10 %丙二醇可显著增大盐酸芦氟沙星的渗透系数 (P <0 .0 1)。结论　 1%氮酮和1%氮酮 10 %丙二醇可作为促渗剂用于盐酸芦氟沙星的透皮吸收制剂     

盐酸丁卡因凝胶剂经皮渗透作用

目的：制备盐酸丁卡因凝胶剂，并考察不同透皮促进剂对其透皮吸收的影响。方法：配制含不同透皮促进剂的盐酸丁卡因凝胶剂，采用简单扩散小室和紫外分光光度法测定药物透皮吸收量。结果：加1%月桂氮Zhuo酮，加1%，3%，5%薄荷脑或加两者混合透皮促进剂，将药物碱化均可显著增加盐酸丁卡因凝胶剂的透皮吸收量，其累积释药量与时间呈线性关系。结论：单独使用1%月桂氮Zhuo酮对盐酸丁卡因凝胶透皮吸收作用不明显，3%，5%薄荷脑或加1%月桂氮Zhuo酮两者混合透皮保进剂对盐酸丁卡因凝胶透皮吸收作用明显，1%月桂氮Zhuo酮 3%薄荷脑对盐酸丁卡因凝胶透皮吸收作用最明显。     

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.     

Virtual design of chemical penetration enhancers for transdermal drug delivery

Traditional drug design is a laborious and expensive process that often challenges the pharmaceutical industries. As a result, researchers have turned to computational methods for computer-assisted molecular design. Recently, genetic and evolutionary algorithms have emerged as efficient methods in solving combinatorial problems associated with computer-aided molecular design. Further, combining genetic algorithms with quantitative structure-property relationship analyses has proved effective in drug design. In this work, we have integrated a new genetic algorithm and nonlinear quantitative structure-property relationship models to develop a reliable virtual screening algorithm for the generation of potential chemical penetration enhancers. The genetic algorithms-quantitative structure-property relationship algorithm has been implemented successfully to identify potential chemical penetration enhancers for transdermal drug delivery of insulin. Validation of the newly identified chemical penetration enhancer molecular structures was conducted through carefully designed experiments, which elucidated the cytotoxicity and permeability of the chemical penetration enhancers.     

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.     

Modification of buccal drug delivery following pretreatment with skin penetration enhancers

The effect of the lipophilic skin penetration enhancers octisalate (OS), padimate O (PO), and Azone (AZ) on in vitro buccal permeability was assessed using caffeine (CAF), estradiol (E2), and triamcinolone acetonide (TAC) as model permeants. Buccal permeability was assessed in modified Ussing chambers, through both untreated porcine buccal mucosa and mucosa pretreated with an enhancer (5% w/v in 95% v/v ethanol) or ethanol alone. To ensure sink conditions were present, E2 permeability experiments were also performed with bovine serum albumin (BSA) 4% in the receptor solution. Mucosa-buffer partition studies were performed to determine the effect of enhancer pretreatment on the log mucosa-buffer partition coefficient (logK) of E2 and TAC. CAF permeability was only increased following pretreatment with ethanol 95%. E2 buccal transport was not altered following OS pretreatment, but was reduced by 26.3% with PO pretreatment and 67.6% with AZ pretreatment. Similar results were obtained with BSA 4% in the receptor solution. The logK of E2 was increased 1.4-fold and 2.2-fold in PO- and AZ-pretreated tissues, respectively, suggesting that the reduction in flux caused by PO and AZ may have been due to enhanced E2 tissue retention. The effect of OS and PO on TAC permeability was no different to that of ethanol. However, AZ enhanced TAC permeability 4.1-fold and this was accompanied by a 2.4-fold increase in the logK of TAC.     

Effect of penetration modifiers on the dermal and transdermal delivery of drugs and cosmetic active ingredients

In this study the effect of 2 penetration modifiers, dimethyl isosorbide (DMI) and diethylene glycol monoethyl ether (DGME) on the skin delivery of hydroquinone (HQ), salicylic acid (SA) and octadecenedioic acid (DIOIC) was investigated. Ten percent DMI and DGME were separately formulated into oil-in-water emulsions containing 1.8% HQ, SA and DIOIC, respectively. Skin delivery and the flux across split-thickness human skin of the active ingredients were determined using Franz diffusion cells. An emulsion with 10% water incorporated instead of the water-soluble penetration modifiers served as a control. The study showed that neither 10% DMI nor 10% DGME significantly enhanced the skin permeation of the various lipophilic active ingredients or the uptake into the skin. It was hypothesized that the addition of the penetration modifiers to the emulsions not only enhanced the solubility of the various active ingredients in the skin but also in the formulation, resulting in a reduced thermodynamic activity and hence a weaker driving force for penetration. Therefore, the effect of DMI and DGME on the solubility of the active ingredients in the skin was counteracted by a simultaneous reduction in the thermodynamic activity in the formulation.     

Effect of penetration enhancers on in vitro percutaneous penetration of nimesulide through rat skin

The influence of several penetration enhancers alone and/or in various combinations on the percutaneous penetration of nimesulide (NM) from Carbopol 934 based gel formulations was investigated. Skin permeation studies were performed using Franz-type diffusion cells and full-thickness abdominal rat skin. Various types of compounds such as ethanol, isopropyl alcohol, propylene glycol, Transcutol, Tween 80 and oleic acid were employed as penetration enhancers. The steady-state flux, the lag time and permeability coefficients of NM for each formulation were calculated. The results showed that the skin permeability of NM from gels tested was significantly increased (P < 0.05) by isopropyl alcohol (40%) and the combination of oleic acid (3%) with Transcutol (30%) when compared with the control formulation. In conclusion, these substances could be considered as penetration enhancers for NM topical formulations.     

透皮吸收促进剂在经皮给药系统中的质控和评价方法

透皮吸收制剂是国际上第三代药物制剂的研究重点领域。透皮吸收促进剂在处方中的合理应用和质量控制及其评价方法日益重要。通过对透皮促进机理、协同作用等的探讨,介绍透皮吸收促进剂的选用原则,并对透皮给药制剂和局部用药局部起效的皮肤外用制剂处方中使用的要求加以讨论,介绍了现有的评价方法和基本的技术要求。     

Influence of nanosized delivery systems with benzyl nicotinate and penetration enhancers on skin oxygenation

Many novel nanosized delivery systems have been designed for topical application of drugs since they can overcome the skin barrier and improve drug bioavailability. The increased absorption is often a consequence of a reversibly disrupted barrier function of the skin by the vehicle itself or by specific ingredients that act as penetration enhancers. This paper reports the effects of two nanosized systems (microemulsion and liposomes), in the presence and absence of penetration enhancers (PE), on the topical delivery of a lipophilic drug in vivo and compares that to classical hydrogel formulation. A vasodilator benzyl nicotinate (BN), which increases the blood flow of the skin, was incorporated into the formulations, and skin oxygenation was followed by electron paramagnetic resonance oximetry. It was found that microemulsions and liposomes (with or without PE) accelerate the rate of BN action when compared to hydrogel. However, incorporation of PE in microemulsion also improves the effectiveness of BN action. To understand why PE enhances the action of BN, its effect on the structure of the stratum corneum was investigated in vitro. The increased fluidity of the stratum corneum lipids provides an explanation for the greater penetration of BN into the skin when the drug and PE are together incorporated into the appropriate formulation.     

Role of complexes formation between drugs and penetration enhancers in transdermal delivery

The use of chemical penetration enhancers (CPE) is growing due to their ability to improve drug delivery through the skin. A possible mechanism of penetration enhancement could involve the complex formation between drug and components in the pharmaceutical formulation, thus altering the physicochemical properties of the active substance. Here, modelling studies indicate that hydrocarbon and oxygen-containing terpenes (penetration enhancers) could form complexes with drugs. Satisfactory correlations have been obtained between the predicted molecular properties of enhancers and their enhancement effects.     

Transdermal and dermal delivery of adefovir: Effects of pH and permeation enhancers

The objective of this work was to investigate feasibility of transdermal and dermal delivery of adefovir (9-(2-phosphonomethoxyethyl)adenine), a broad-spectrum antiviral from the class of acyclic nucleoside phosphonates. Transport of 2% adefovir through and into porcine skin and effects of various solvents, pH, and permeation enhancers were studied in vitro using Franz diffusion cell. From aqueous donor samples, adefovir flux through the skin was 0.2-5.4 microg/cm2/h with greatest permeation rate at pH 7.8. The corresponding adefovir skin concentrations reached values of 120-350 microg/g of tissue. Increased solvent lipophilicity resulted in higher skin concentration but had only minor effect on adefovir flux. A significant influence of counter ions on both transdermal and dermal transport of adefovir zwitterion was observed at pH 3.4. Permeation enhancer dodecanol was ineffective, 1-dodecylazepan-2-one (Azone) and dodecyl 2-(dimethylamino)propionate (DDAIP) showed moderate activity. The highest adefovir flux (11.3+/-3.6 microg/cm2/h) and skin concentration (1549+/-416 microg/g) were achieved with 1% Transkarbam 12 (5-(dodecyloxycarbonyl)pentylammonium 5-(dodecyloxycarbonyl)pentylcarbamate) at pH 4. This study suggests that, despite its hydrophilic and ionizable nature, adefovir can be successfully delivered through the skin.     

Retinyl acetate-loaded nanoparticles: dermal penetration and release of the retinyl acetate

Retinyl acetate (RA) loaded polymeric nanoparticle (NP) carriers were prepared using two different single polymers, ethyl cellulose (EC) and poly (ethylene glycol)-4-methoxycinnamoylphthaloylchitosan (PCPLC). The stability of RA to aqueous solution and UVA light was significantly improved when encapsulated with PCPLC, whilst EC encapsulation gave some improved stability in water but showed no improved photostability. Ex vivo application of free RA and the RA-loaded PCPLC NPs onto the surface of the freshly excised skin from a baby mouse indicated a significantly slower skin absorption rate for the encapsulated RA. However, 100% retention of the encapsulated RA in the skin tissue was observed after 24h. Confocal fluorescent analysis of the skin pieces applied with the RA-loaded PCPLC NPs indicated likely entry and accumulation of the PCPLC NPs and RA at the hair follicles. Release of RA from the PCPLC NP carriers was confirmed through the detection of an increasingly higher RA/PCPLC fluorescent signal ratio deeper into the dermis and away from the hair follicles.     

Transdermal delivery of indomethacin and levonorgestrel using clofibric acid amides as penetration enhancers

The enhancing properties of clofibric acid amides on the transdermal delivery of indomethacin and levonorgestrel were studied in vitro using full-thickness hairless mouse skin. The enhancers possessed alkyl side chains varying from 2 (1) to 16 (7) carbons. Indomethacin was applied in propylene glycol and levonorgestrel in 1-butanol, and all enhancers were applied at 0.4 M in propylene glycol 1 h prior to drug treatment. 1-Butanol was chosen as the vehicle for levonorgestrel since it was found to deliver more drug transdermally than propylene glycol. Since this was a volatile solvent, all experiments with levonorgestrel were performed under occlusion. The greatest increases in permeability coefficients and skin retention of model drugs were observed with compounds 4, 5, and 6. The permeability coefficient enhancement ratio (ER) for indomethacin and 4 was 3.1, for 5 was 10.9, and for 6 was 14.6. Skin content ER values were 4.6, 5.3, and 1.8, respectively. Levonorgestrel permeability coefficient ER values were lower, 1.6 for 4, 2.6 for 5, and 1.9 for 6. Skin content ER values for this model drug were 1.7, 4.3, and 2.3, respectively. Azone, however, was less effective than 5 and 6 for both model drugs with respect to permeability coefficients and 24-h receptor concentrations. For skin contents and indomethacin, 2-7 were more effective than Azone, and for levonorgestrel, 5, 6, and 7. Indomethacin enhancement was dependent on concentration of enhancer 6 (0.1, 0.2, 0.4, 0.6, 0.8 M), the maximum being observed for 0.4, 0.6, and 0.8 M. Permeation enhancement of both drugs was dependent on the length of the alkyl side chain of the enhancer. It is proposed that these compounds may be useful for transdermal drug delivery, although further testing needs to be performed.