A Preformulation Strategy for the Selection of Penetration Enhancers for a Transungual Formulation

Onychomycosis is associated with the cutaneous fungal infection of the nail and the nail folds (skin surrounding the nail). It is therefore important to target drug delivery into the nail folds along with nail plate and the nail bed. Systematic and strategic selection of the penetration enhancers specific for the skin and the nail is discussed. Twelve penetration enhancers were screened for their ability to improve solubility, in vitro nail penetration, in vitro skin permeation, and in vitro skin penetration of the antifungal drug ciclopirox olamine. In contrast to transdermal drug delivery, the main selection criteria for skin penetration enhancer in topical drug delivery were increased drug accumulation in the epidermis and minimal permeation across the skin. Thiourea improved the solubility and nail penetration of ciclopirox olamine. It also showed enhancement in the transungual diffusion of the drug. Propylene glycol showed a 12-fold increase in solubility and 3-fold increase in epidermal accumulation of ciclopirox olamine, while minimizing the transdermal movement of the drug. Thiourea was the selected nail permeation enhancer and propylene glycol was the selected skin penetration enhancer of ciclopirox olamine. A combination of the selected enhancers was also explored for its effect on drug delivery to the nail and nail folds. The enhancer combination reduced the penetration of ciclopirox in the skin and also the permeation through the nail. The proposed preformulation strategy helps to select appropriate enhancers for optimum topical delivery and paves way towards an efficient topical formulation for passive transungual drug delivery.     

Development and Evaluation of α-Asarone Transdermal Patches Based on Hot-Melt Pressure-Sensitive Adhesives

A hot-melt, pressure-sensitive adhesive (HMPSA) based on styrene–isoprene–styrene was prepared, and its compatibility with various transdermal penetration enhancers was investigated. The effect of penetration enhancers on the adhesion properties of HMPSA was also studied. A drug-in-adhesive patch was formulated using α-asarone as a model drug, and penetration enhancers were screened by an in vitro transdermal study across excised pig skin. The pharmacokinetics in rabbits was also studied. The results show that HMPSA was miscible with most penetration enhancers (azone, menthol, isopropyl myristate, 1-methyl-pyrrolidinone, N,N-dimethylformamide, oleic acid), apart from propylene glycol. Penetration enhancers had a plasticizer-like effect that decreased the peel strength and shear strength of HMPSA. A combination of 1% oleic acid and 4% menthol had the highest in vitro penetration rate and was selected for patch preparation. The patch formulation was optimized by replacing some of the plasticizer by penetration enhancers to achieve good adhesion and effective transdermal flux. The final patch showed a high efficiency, with a relative bioavailability of 1,494%. This suggests that HMPSA may be a promising material for drug-delivery patches.     

<Emphasis Type="Italic">In vitro</Emphasis> Enhancement of Lactate Esters on the Percutaneous Penetration of Drugs with Different Lipophilicity

Lactate esters are widely used as food additives, perfume materials, medicine additives, and personal care products. The objective of this work was to investigate the effect of a series of lactate esters as penetration enhancers on the in vitro skin permeation of four drugs with different physicochemical properties, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. The saturated donor solutions of the evaluated drugs in propylene glycol were used in order to keep a constant driving force with maximum thermodynamic activity. The permeability coefficient (K _p), skin concentration of drugs (SC), and lag time (T), as well as the enhancement ratios for K _p and SC were recorded. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10–12 are more effective enhancers. Furthermore, the enhancement effect of lactate esters increases with a decrease of the drug lipophilicity, which suggests that they may be more efficient at enhancing the penetration of hydrophilic drugs than lipophilic drugs. The influence of the concentration of lactate esters was evaluated and the optimal concentration is in the range of 5∼10 wt.%. In sum, lactate esters as a penetration enhancer for some drugs are of interest for transdermal administration when the safety of penetration enhancers is a prime consideration.     

Using Raman Spectroscopy in Studying the Effect of Propylene Glycol,Oleic Acid,and Their Combination on the Rat Skin

The permeability enhancement effect of oleic acid (OA) and propylene glycol (PG) as well as their (1:1 v/v) combined mixture was studied using rat skin. The percutaneous drug administration is a challenge and an opportunity for drug delivery. To date, there is limited research that illustrates the mechanism of penetration enhancers and their combinations on the skin. This project aims to explore the skin diffusion and penetration enhancement of PG, OA, and a combination of PG-OA (1:1 v/v) on rat skin and to identify the potential synergistic effect of the two enhancers utilizing Raman spectroscopy. Dissected dorsal skin was treated with either PG or OA or their combination for predetermined time intervals after which the Raman spectra of the treated skin were collected with the enhancer. A spectrum of the wiped and the washed skin were also collected. The skin integrity was tested before and after exposure to PG. The skin histology proved that the skin integrity has been maintained during experiments and the results indicated that OA disrupted rat skin lipid as evident by changes in the lipid peak. The results also showed that PG and OA improved the diffusion of each other and created faster, yet reversible changes of the skin peaks. In conclusion, Raman spectroscopy is a potential tool for ex vivo skin diffusion studies. We also concluded that PG and OA have potential synergistic reversible effect on the skin.     

Transbuccal Delivery of 5-Fluorouracil: Permeation Enhancement and Pharmacokinetic Study

The purpose of this study was to determine the effect of permeation enhancers on the transbuccal delivery of 5-fluorouracil (FU). The effect of permeation enhancers on in vitro buccal permeability was assessed using sodium deoxycholate (SDC), sodium dodecyl sulphate (SDS), sodium tauroglycocholate (STGC), and oleic acid and their concentrations for absorption enhancement were optimized. STGC appeared to be most effective for enhancing the buccal permeation of FU than the other enhancers. These enhancements by STGC were statistically significant (p < 0.05) compared to control. The order of permeation enhancement was STGC > SDS > SDC > oleic acid. Histological investigations were performed on buccal mucosa and indicated no major morphological changes. The enhancing effect of STGC on the buccal absorption of FU was evaluated from the mucoadhesive gels in rabbits. The absolute bioavailability of FU from mucoadhesive gels containing STGC increased 1.6-fold as compared to the gels containing no permeation enhancer. The mean residence time and mean absorption time considerably increased following administration of gel containing penetration enhancer compared with the gel without penetration enhancer.     

Transdermal delivery of zidovudine (AZT): The effects of vehicles,enhancers, and polymer membranes on permeation across cadaver pig skin

The purpose of this study was to investigate the effects of vehicles, enhancers, and polymer membranes on 3-azido-3-deoxythymidine (AZT) permeation across cadaver pig skin. Four binary vehicles (ethanol/water, isopropyl alcohol/water, polyethylene glycol 400/water, and ethanol/isopropyl myristate [IPM] were tested for AZT solubility and permeability across pig skin; ethanol/IPM (50/50, vol/vol) demonstrated the highest AZT flux (185.23 μ/cm²/h). Next, the addition of various concentrations of different enhancers (N-methyl-2-pyrrolidone [NMP], oleic acid, and lauric acid) to different volume ratios of ethanol/IPM was investigated for their effect on AZT solubility and permeability across pig skin. The use of 2 conbinations (ethanol/IPM [20/80] plus 10% NMP and ethanol/IPM [30/70] plus 10% NMP) resulted in increased AZT solubility (42.6 and 56.27 mg/mL, respectively) and also high AZT flux values (284.92 and 460.34 μg/cm²/h, respectively) without appreciable changes in lag times (6.25 and 7.49 hours, respectively) when compared with formulations using only ethanol/IPM at 20/80 and 30/70 volume ratios without addition of the enhancer NMP. Finally, AZT permeation across pig skin covered with a microporous polyethylene (PE) membrane was investigated. The addition of the PE membrane to the pig skin reduced AZT flux values to ∼50% of that seen with pig skin alone. However, the AZT flux value attained with ethanol/IPM (30/70) plus 10% NMP was 215.30 μg/cm²/h, which was greater than the target flux (208 μg/cm²/h) needed to maintain the steady-state plasma concentration in humans. The results obtained from this study will be helpful in the development of an AZT transdermal drug delivery system.     

Development and Evaluation of Ethyl Cellulose-Based Transdermal Films of Furosemide for Improved In Vitro Skin Permeation

Transdermal films of the furosemide were developed employing ethyl cellulose and hydroxypropyl methylcellulose as film formers. The effect of binary mixture of polymers and penetration enhancers on physicochemical parameters including thickness, moisture content, moisture uptake, drug content, drug–polymer interaction, and in vitro permeation was evaluated. In vitro permeation study was conducted using human cadaver skin as penetration barrier in modified Keshary–Chein diffusion cell. In vitro skin permeation study showed that binary mixture, ethyl cellulose (EC)/hydroxypropyl methylcellulose (HPMC), at 8.5:1.5 ratio provided highest flux and also penetration enhancers further enhanced the permeation of drug, while propylene glycol showing higher enhancing effect compared to dimethyl sulfoxide and isopropyl myristate. Different kinetic models, used to interpret the release kinetics and mechanism, indicated that release from all formulations followed apparent zero-order kinetics and non-Fickian diffusion transport except formulation without HPMC which followed Fickian diffusion transport. Stability studies conducted as per International Conference on Harmonization guidelines did not show any degradation of drug. Based on the above observations, it can be reasonably concluded that blend of EC–HPMC polymers and propylene glycol are better suited for the development of transdermal delivery system of furosemide.     

渗透促进剂对紫草素透过大鼠腹部皮肤的作用

研究不同浓度的丙二醇、氮酮和油酸对紫草素透过大鼠腹部皮肤的影响．实验结果表明,不同浓度的丙二醇对紫草素经皮渗透均有促进渗透作用,丙二醇浓度为10％时促渗效果最佳,油酸也具有促进紫草素的经皮渗透作用,但是在本实验中氮酮抑制紫草素的经皮渗透。     

Microemulsion for topical delivery of fenoprofen calcium: in vitro and in vivo evaluation

The aim of this study was to investigate microemulsion (ME) based topical delivery system for fenoprofen calcium (FPCa) to eliminate its oral gastrointestinal adverse effects. ME was prepared by the water titration method using oleic acid as oil phase, tween 80 as a surfactant and propylene glycol as a cosurfactant. Oleic acid was selected as oil phase due to its good solubilizing capacity. ME existence region was determined using pseudo-ternary phase diagrams for preparing different formulations. Six different formulations were selected with various values of oil (25–68%), water (2–3%), and the mixture of surfactant and cosurfactant (1:1) (24–67%). The selected ME formulae were characterized for optical birefringence, transmission electron microscopy (TEM), pH, % transmittance, electronic conductivity, drug content, droplet size, rheological properties and stability evaluation. In vitro release study of FPCa from ME s through the synthetic membrane and hairless rat skin were evaluated. The optimized formula ME5 consisting of 5% w/w FPCa, 60% w/w oleic acid as oil phase, 3% w/w aqueous phase, and 32% w/w of surfactant phase containing Tween 80 and propylene glycol (1:?1) showed the highest transdermal flux and highest skin permeation rate. Finally, the % inhibition of carrageenan-induced rat paw edema of the optimized formula ME5 was highly significant (p?0.001) as compared to plain gel of FPCa. In conclusion, ME is a promising technique for topical delivery of FPCa.     

Microemulsions Containing Medium-Chain Glycerides as Transdermal Delivery Systems for Hydrophilic and Hydrophobic Drugs

We evaluated the ability of microemulsions containing medium-chain glycerides as penetration enhancers to increase the transdermal delivery of lipophilic (progesterone) and hydrophilic (adenosine) model drugs as well as the effects of an increase in surfactant blend concentration on drug transdermal delivery. Microemulsions composed of polysorbate 80, medium-chain glycerides, and propylene glycol (1:1:1, w/w/w) as surfactant blend, myvacet oil as the oily phase, and water were developed. Two microemulsions containing different concentrations of surfactant blend but similar water/oil ratios were chosen; ME-lo contained a smaller concentration of surfactant than ME-hi (47:20:33 and 63:14:23 surfactant/oil/water, w/w/w). Although in vitro progesterone and adenosine release from ME-lo and ME-hi was similar, their transdermal delivery was differently affected. ME-lo significantly increased the flux of progesterone and adenosine delivered across porcine ear skin (4-fold or higher, p < 0.05) compared to progesterone solution in oil (0.05 ± 0.01 μg/cm²/h) or adenosine in water (no drug was detected in the receptor phase). The transdermal flux of adenosine, but not of progesterone, was further increased (2-fold) by ME-hi, suggesting that increases in surfactant concentration represent an interesting strategy to enhance transdermal delivery of hydrophilic, but not of lipophilic, compounds. The relative safety of the microemulsions was assessed in cultured fibroblasts. The cytotoxicity of ME-lo and ME-hi was significantly smaller than sodium lauryl sulfate (considered moderate-to-severe irritant) at same concentrations (up to 50 μg/mL), but similar to propylene glycol (regarded as safe), suggesting the safety of these formulations.     

Molecular organization of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy

ATR-FTIR spectroscopy is useful in investigating the lateral organization of Stratum corneum (SC) lipids in full-thickness skin. Based on studies of the thermotropic phase transitions in n-tricosane and in excised human skin, the temperature dependence of the CH₂ scissoring bandwidth emerged as a measure of the extent of orthorhombic and hexagonal phases. This dependence provides a simpler measure of the lateral order in lipid assemblies than the common spectroscopic approaches based on difference spectra, curve fitting of the CH₂ scissoring region, and the position of the CH₂ stretching vibrations. It has the advantages of ease of determination, relatively low variability, and high discriminative power for the type of lateral intermolecular chain packing. A comparison of the lateral organization of the lipids at the SC surface of mammalian skin using the scissoring bandwidth revealed considerable differences between human abdominal skin (containing mostly orthorhombic phases), porcine ear skin (containing mostly hexagonal phases), and reconstructed human epidermis (containing mostly disordered phases). This parameter also correctly described the different effects of propylene glycol (minimally disturbing) and oleic acid (formation of a highly disordered phase) on the SC lipids in excised human skin. The procedure described here is applicable to in vivo studies in the areas of dermatology, transdermal drug delivery, and skin biophysics.     

Enhancement in the Transdermal and Localized Delivery of Honokiol Through Breast Tissue

Honokiol is a natural phenolic anti-cancer compound isolated from an extract of seed cones from Magnolia grandiflora. This study investigated the transdermal delivery of honokiol using various enhancement methods and to explore the potential of honokiol to treat breast cancer directly via delivery through mammary papilla. Poration of dermatomed human skin with microneedles significantly increased the delivery of honokiol by nearly 3-fold (97.81?±?18.96 μg/cm²) compared with passive delivery (32.56?±?5.67 μg/cm²). Oleic acid was found to be the best chemical penetration enhancer, increasing the delivery almost 27-fold (868.06?±?100.91 μg/cm²). Addition of oleic acid also resulted in better retention of drug in the porcine mammary papilla (965.41?±?80.26 μg/cm²) compared with breast skin (294.16?±?8.49 μg/cm²). Anti-cancer effect of honokiol was demonstrated with the decrease in the release of cytokine IL-6 and further suppression of Ki-67 proliferative protein. In addition, the topical honokiol formulation investigated was found to be safe and non-irritant. In summary, both microneedles and chemical enhancers can improve the absorption of honokiol through skin. Directly applying honokiol on mammary papilla is a potential administration route which can increase localized delivery into breast tissue.     

A Novel Transdermal Delivery System for the Anti-Inflammatory Lumiracoxib: Influence of Oleic Acid on <Emphasis Type="Italic">In Vitro</Emphasis> Percutaneous Absorption and <Emphasis Type="Italic">In Vivo</Emphasis> Potential Cutaneous Irritation

Transdermal delivery of non-steroidal anti-inflammatory drugs may be an interesting strategy for delivering these drugs to the diseased site, but it would be ineffective due to low skin permeability. We investigated whether oleic acid (OA), a lipid penetration enhancer in poloxamer gels named poloxamer-based delivery systems (PBDS), can improve lumiracoxib (LM) delivery to/through the skin. The LM partition coefficient (K) studies were carried out in order to evaluate the drug lipophilicity grade (K _{octanol/buffer}), showing values >1 which demonstrated its high lipophilicity. Both in vitro percutaneous absorption and skin retention studies of LM were measured in the presence or absence of OA (in different concentrations) in PBDS using porcine ear skin. The flux of in vitro percutaneous absorption and in vitro retention of LM in viable epidermis increased in the presence of 10.0% (w/w) OA in 25.0% (w/w) poloxamer gel. In vivo cutaneous irritation potential was carried out in rabbits showing that this formulation did not provide primary or cumulative cutaneous irritability in animal model. The results showed that 25.0% poloxamer gel containing 10.0% OA is potential transdermal delivery system for LM.     

Development of Novel Microemulsion-Based Topical Formulations of Acyclovir for the Treatment of Cutaneous Herpetic Infections

The present investigation aims at developing microemulsion-based formulations for topical delivery of acyclovir. Various microemulsions were developed using isopropyl myristate/Captex 355/Labrafac as an oil phase, Tween 20 as surfactant, Span 20 as cosurfactant, and water/dimethylsulfoxide (1:3) as an aqueous phase. Transcutol, eucalyptus oil, and peppermint oil were used as permeation enhancers. In vitro permeation studies through laca mice skin were performed using Franz diffusion cells. The optimum formulation containing 2.5% Transcutol as the penetration enhancer showed 1.7-fold enhancement in flux and permeation coefficient as compared to marketed cream and ointment formulation. In vivo antiviral studies were performed in female Balb/c mice against induced herpes simplex virus I infection. A single application of microemulsion formulation containing 2.5% Transcutol given 24 h post-injection resulted in complete suppression of development of herpetic skin lesions.     

Simple Amides of Oleanolic Acid as Effective Penetration Enhancers

Transdermal transport is now becoming one of the most convenient and safe pathways for drug delivery. In some cases it is necessary to use skin penetration enhancers in order to allow for the transdermal transport of drugs that are otherwise insufficiently skin-permeable. A series of oleanolic acid amides as potential transdermal penetration enhancers was formed by multistep synthesis and the synthesis of all newly prepared compounds is presented. The synthetized amides of oleanolic acid were tested for their in vitro penetration promoter activity. The above activity was evaluated by means of using the Fürst method. The relationships between the chemical structure of the studied compounds and penetration activity are presented.     

Synthesis,physico-chemical properties and penetration activity of alkyl-6-(2,5-dioxopyrrolidin-1-yl)-2-(2-oxopyrrolidin-1-yl)hexanoates as potential transdermal penetration enhancers

Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. The series of seven esters of substituted 6-aminohexanoic acid as potential transdermal penetration enhancers was formed by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by ¹H NMR, ¹³C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC method for the lipophilicity measurement and their lipophilicity (log k) was determined. Hydrophobicities (log P/C log P) of the studied compounds were also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio/DFT calculations of geometry. All the synthesized esters were tested for their in vitro transdermal penetration enhancer activity. The relationships between the lipophilicity and the chemical structure (SLR) of the studied compounds as well as the relationships between their chemical structure and transdermal penetration activity are mentioned.     

Percutaneous Penetration Modifiers and Formulation Effects: Thermal and Spectral Analyses

The study investigated the formulation effects of laurocapram and iminosulfurane derived penetration modifiers on human stratum corneum using thermal and spectral analyses. Firstly, formulations of penetration modifiers were assessed as enhancers/retardants using the model permeant, diethyl-m-toluamide followed by investigation of their mechanisms of action using differential scanning calorimetry (DSC) and attenuated total reflectance Fourier-transform infra-red spectroscopy. The penetration modifiers investigated were laurocapram, 3-dodecanoyloxazolidin-2-one (N-0915), S,S-dimethyl-N-(4-bromobenzoyl) iminosulfurane (DMBIS), S,S-dimethyl-N-(2-methoxycarbonylbenzenesulfonyl) iminosulfurane (DMMCBI) and tert-butyl 1-dodecyl-2-oxoazepan-3-yl-carbamate (TBDOC) that were formulated in either water, propylene glycol (PG), ethanol or polyethylene glycol 400 (PEG 400). The results explain the mechanism for the first time why an enhancer can become a retardant or vice versa depending upon the vehicle in which it is applied to the skin. DSC indicated that penetration modifier formulations enhanced permeation of active mainly by disruption and fluidization of the stratum corneum lipid bilayers while IR data indicated characteristic blue shifts with decreases in peak intensity. On the other hand, DSC of penetration modifier formulations showing retardation depicted elevated T _m2 with a strengthening of lipid–protein complex while IR results indicated formation of multiple peaks around 1,738 cm⁻¹ transition in stratum corneum spectra suggesting retardation may be caused by organization of SC lipids by increased H-bonding.     

Liposomal hydrogel formulation for transdermal delivery of pirfenidone

Context: Pirfenidone (PFD) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The current oral administration of PFD has several limitations including first pass metabolism and gastrointestinal irritation.

Objective: The aim of this study is to investigate the feasibility of transdermal delivery of PFD using liposomal carrier system.

Materials and methods: PFD-loaded liposomes were prepared using soy phosphatidylcholine (SPC) and sodium cholate (SC). Encapsulation efficiency (EE) of PFD in liposomes was optimized using different preparation techniques including thin film hydration (TFH) method, direct injection method (DIM) and drug encapsulation using freeze–thaw cycles. In vitro drug release study was performed using dialysis membrane method. The skin permeation studies were performed using excised porcine ear skin model in a Franz diffusion cell apparatus.

Results and discussion: The average particle size and zeta-potential of liposomes were 191?±?4.1?nm and ?40.4?±?4.5?mV, respectively. The liposomes prepared by TFH followed by 10 freeze–thaw cycles showed the greatest EE of 22.7?±?0.63%. The optimized liposome formulation was incorporated in hydroxypropyl methyl cellulose (HPMC) hydrogel containing different permeation enhancers including oleic acid (OA), isopropyl myristate (IPM) and propylene glycol (PG). PFD-loaded liposomes incorporated in hydrogel containing OA and IPM showed the greatest flux of 10.9?±?1.04?μg/cm²/h across skin, which was 5-fold greater compared with free PFD. The cumulative amount of PFD permeated was 344?±?28.8?μg/cm² with a lag time of 2.3?±?1.3?h.

Conclusion: The hydrogel formulation containing PFD-loaded liposomes can be developed as a potential transdermal delivery system.     

几种辛香中药对辣椒碱巴布剂促透皮吸收作用的研究

通过对辛香中药的研究筛选辣椒碱巴布剂的透皮吸收促进剂,提高辣椒碱的透皮扩散速率。采用分别在辣椒碱巴布剂中添加薄荷醇、冰片、桉叶油3种辛香类中药的方法,以月桂氮酮为对照,进行透皮渗透试验。结果表明3种辛香类中药和月桂氮酮对药物的迁移都有一定的促进作用,其中以桉叶油最为突出,其次为冰片、薄荷、氮酮。     

The Experimental Evaluation and Molecular Dynamics Simulation of a Heat-Enhanced Transdermal Delivery System

Transdermal delivery systems are useful in cases where preferred routes such as the oral route are not available. However, low overall extent of delivery is seen due to the permeation barrier posed by the skin. Chemical penetration enhancers and invasive methods that disturb the structural barrier function of the skin can be used to improve transdermal drug delivery. However, for suitable drugs, a fast-releasing transdermal delivery system can be produced by incorporating a heating source into a transdermal patch. In this study, a molecular dynamics simulation showed that heat increased the diffusivity of the drug molecules, resulting in faster release from gels containing ketoprofen, diclofenac sodium, and lidocaine HCl. Simulations were confirmed by in vitro drug release studies through lipophilic membranes. These correlations could expand the application of heated transdermal delivery systems for use as fast-release-dosage forms.