Skin Irritation in Transdermal Drug Delivery Systems: A Strategy for its Reduction

Purpose Active pharmaceutical ingredients (API) in transdermal drug delivery systems (TDS) often causes skin irritation such as erythema and edema. We have studied a possible approach for the reduction of skin irritation by patch formulations that control the rates of skin permeation and elimination of API. Methods Loxoprofen (LX-base) was used to induce the skin irritation. The redness value (Δa) was evaluated as a measure of erythema by Chroma Meter. The in vitro skin permeation and release profiles were also investigated by using a side-by-side diffusion cell. Results The redness values were not correlated either with the cumulative amount of API permeated or the concentration of LX-base in the skin, but well correlated with the elimination rate of LX-base from the skin after the removal of the formulation. The formulation with gradual decrease of permeation rate during application accelerated the elimination rate after application, and resulted in the reduction of the skin irritation. Conclusions The skin pharmacokinetics of API, not only permeation during application but also release after the patch removal, was found to be a significant factor for skin irritation. To minimize the skin irritation, it’s also important to eliminate the residual API in the skin promptly after application.     

Transdermal Delivery of Fentanyl by Electroporation II. Mechanisms Involved in Drug Transport

Purpose. The aim of the present report was to systematically analyze the mechanisms involved in fentanyl transdermal transport by skin electroporation. Methods. The study was performed in vitro with full-thickness hairless rat skin, skin electroporation being carried out with five exponentially-decaying pulses of 100 V applied voltage and around 600 ms pulse duration. Results. Transport during and after pulsing are both important in transdermal delivery of fentanyl by skin electroporation. Rapid transport occurred during pulsing due to electrophoresis and diffusion through highly permeabilized skin. No electroosmosis was observed. The slow post-pulse passive transport was explained by lasting changes in skin permeability. Measurements of fentanyl quantities in the skin demonstrated that pulses rapidly loaded the viable part of the skin with fentanyl and hence rapidly overcame skin barrier. Conclusions. The different contributions of the transport mechanisms appear to depend on the physicochemical parameters of the transported molecule as well as the solution, suggesting that mechanistic analysis and careful consideration of formulation variables are essential for the development and optimization of drug delivery by skin electroporation.     

超声波技术在透皮药物传递系统中的应用

目的介绍超声波促进药物透皮吸收的物理方法的研究成果和进展。方法通过查阅国内外文献进行归纳和综述。结果与结论超声经皮给药促渗技术能够提供数倍于常规给药方法的持续稳定的渗透率,是一种极具潜力的给药方式,而且与其他方法联合应用的促渗效果更加显著。     

Evaluation of a Human Bio-Engineered Skin Equivalent for Drug Permeation Studies

Purpose. To test the barrier function of a bio-engineered human skin (BHS) using three model drugs (caffeine, hydrocortisone, and tamoxifen) in vitro. To investigate the lipid composition and microscopic structure of the BHS. Methods. The human skin substitute was composed of both epidermal and dermal layers, the latter having a bovine collagen matrix. The permeability of the BHS to three model drugs was compared to that obtained in other percutaneous testing models (human cadaver skin, hairless mouse skin, and EpiDerm). Lipid analysis of the BHS was performed by high performance thin layered chromatrography. Histological evalulation of the BHS was performed using routine H&E staining. Results. The BHS mimicked human skin in terms of lipid composition, gross ultrastructure, and the formation of a stratum corneum. However, the permeability of the BHS to caffeine, hydrocortisone, and tamoxifen was 3-4 fold higher than that of human cadaver skin. Conclusions. In summary, the results indicate that the BHS may be an acceptable in vitro model for drug permeability testing.     

Transdermal Delivery of Fentanyl by Electroporation I. Influence of Electrical Factors

Purpose. Electroporation, a method of reversibly permeabilizing lipid bilayers by the application of an electric pulse, has been shown to induce increased transdermal passage of molecules. The aim of the present report was to study in vitro with hairless rat skin the potential of electroporation for transdermal delivery of fentanyl. Results. The application of electric pulses can strongly promote transdermal delivery of fentanyl compared to passive diffusion through untreated skin. We also point out that the choice of the waveform of the electric pulses is important: at the same applied energy, a few exponentially-decaying (ED) pulses increased fentanyl permeation more than a few square-wave pulses and to the same extent as the repeated application of higher voltage-shorter duration ED pulses. A factorial design showed that the voltage, duration, and number of ED pulses allowed control of the quantity of drug transported through the skin. Conclusions. Skin electroporation could be a good way to improve the transdermal diffusion of fentanyl.     

Effects of Dimethylformamide and L-Menthol Permeation Enhancers on Transdermal Delivery of Quercetin

In this work a feasibility study of transdermal delivery system for quercertin (Q) in carbopol gel through abdominal hairless pig skin in vitro was performed. Dimethylformamide (DMF) and L-menthol (M) were selected as enhancers. Permeation experiences were carried out by using Franz-type diffusion cells. Phosphate saline buffer (pH 7.4) was used in the receptor compartments. All the system was maintained at 32 ± 0.5°C with a circulating water jacket and magnetic stirring (180 rpm). Samples were analysed by UV-VIS spectrophotometer at 255 nm. Flux (J_m) values, permeation (P) and diffusion (D) coefficients were obtained. Results of Q in CG permeation experiences with different percentages of DMF and M showed that 16.7% DMF and 1.95% L-menthol enhancers were the best quantities for the system tested. Enhancer effect can be attributed to direct action on membrane structure by promoting its distension. Therefore, enhancer substitutes for water in pores, improving active principal permeation through pig skin. M significantly increases Q permeation about 17 times higher than control. The results of permeation experiments with M and DMF using the same enhancer concentration (1.42%) conclude that M action is 9 times higher than DMF, approximately, indicating that M is an effective enhancer for a transdermal therapeutic system of Q in CG as vehicle.     

Transdermal Delivery of Metoprolol by Electroporation

Electroporation, i.e., the creation of transient pores in lipid membranes leading to increased permeability, could be used to promote transdermal drug delivery. We have evaluated metoprolol permeation through full thickness hairless rat skin in vitro following electroporation with an exponentially decaying pulse. Application of electric pulses increased metoprolol permeation as compared to diffusion through untreated skin. Raising the number of twin pulses (300 V, 3 ms; followed after 1 s by 100 V, 620 ms) from 1 to 20 increased drug transport. Single pulse (100 V, 620 ms) was as effective as twin pulse application (2200 V, 1100 V or 300 V, 3 ms; followed after 1 s by 100 V, 620 ms). In order to investigate the effect of pulse voltage on metoprolol permeation, 5 single pulses (each separated by 1 min) were applied at varying voltages from 24 to 450 V (pulse time 620 ms). A linear correlation between pulse voltage and cumulative metoprolol transported after 4 h suggested that voltage controls the quantity of drug delivered. Then, the effect of pulse time on metoprolol permeation was studied by varying pulse duration of 5 single 100 V pulses from 80 to 710 ms (each pulse also separated by 1 min). Cumulative metoprolol transported after 4 h increased linearly with the pulse time. Therefore, pulse time was also a control factor of the quantity of drug delivered but to a lesser extent than the voltage at least at 100 V. The mechanisms behind improved transdermal drug delivery by electroporation involved reversible increased skin permeability, electrophoretic movement of drug into the skin during pulse application, and drug release from the skin reservoir formed by electroporation. Thus, electroporation did occur as shown by the increased transdermal permeation, on indicator of structural skin changes and their reversibility. Electroporation has potential for enhancing transdermal drug delivery.     

性激素类药物经皮给药制剂研究进展

介绍了近年来国内外性激素类药物经皮给药制剂的研究进展,包括化学促渗技术以及新剂型技术在此方面的应用情况,旨在为性激素类药物经皮给药制剂的深度开发提供参考。经皮给药制剂可避免肝脏首过效应,显著延长药物作用时间,为需长期用药尤其是性激素类药物的使用者提供了一个新的治疗选择。     

Utility of Three-Dimensional Skin From Human-Induced Pluripotent Stem Cells as a Tool to Evaluate Transdermal Drug Permeation

Transdermal drug delivery is an attractive route for administration of drugs, and it offers several advantages such as painless administration. To accurately predict the rate of human skin permeation for new transdermal drug formulations, we developed a novel assessment system using induced pluripotent stem cells (iPSCs). Skin was generated from iPSC-derived keratinocytes and fibroblasts. In the histological and immunohistochemical examination, cellular markers (keratin 14 and keratin 10) for the epidermal basal and suprabasal layers were clearly detected within the multilayer structures produced in the human iPSC-based three-dimensional skin model. The results from our permeation study indicate that an initial lag time exists during permeation of 5(6)-carboxyfluorescein and fluorescein isothiocyanate dextran 4000. Furthermore, the permeation for these model drugs in human iPSC-based skin was inversely proportional to the molecular weight of the drugs. These results of the present iPSC-based skin are useful basic information as a first step for developing a new assessment system to predict the efficacy of drug permeation in human skin by using iPSC-based skin.     

微针经皮给药系统应用于皮肤肿瘤治疗的研究进展

经皮给药系统（TDDS）作为一种经表皮给药途径递药,近年来受到广泛关注。然而,皮肤的主要屏障角质层极大地限制了大部分药物的药效。微针（MNs）可穿透角质层,为药物经皮渗透创造瞬时微通道,从而递送药物至真皮层或皮下。同时MNs给药微创、操作简单、无痛且药物可控释放,因此在皮肤局部或全身给药具有广阔的应用前景。综述MNs的制备、分类及其应用于皮肤肿瘤治疗的最新研究进展,探讨MNs在生物医药研究领域的发展前景,为MNs经皮给药系统应用于临床提供参考。     

Prodrugs of Gestodene for Matrix-Type Transdermal Drug Delivery Systems

Purpose. The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. Methods. Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. Results. One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. Conclusions. Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.     

Transdermal Delivery of Macromolecules Using Skin Electroporation

Purposes. (1) To evaluate the feasibility of transdermal delivery ofmacromolecules by skin electroporation. (2) To assess the influenceof the molecular weight of the permeant on transport and examinewhether there exists a cut-off value of molecular weight. (3) Tolocalize the transport pathways of the macromolecules in the skin. Methods. FITC-dextran (FD) of increasing molecular weight (4.4, 12and 38 kDa) were used as model macromolecules to study the extentof transport across hairless rats skin in vitro and to localize theirdistribution in the skin by confocal scanning laser microscopy. Results. Electroporation enhanced the transport of the macromoleculesas compared to passive diffusion. The transdermal delivery by skinelectroporation of FITC and FD 4.4 was equivalent whereas transportof higher molecular weight FD was lower but significant. FITC and FD38 were observed in the epidermis both around and in the keratinocytes. Conclusions. Transdermal and topical delivery of macromolecules ofat least 40 kDa can be achieved by skin electroporation.     

电致孔技术在透皮给药中的应用

电致孔可显著提高药物的经皮吸收,有望用于多肽和蛋白质类生物大分子药物的透皮给药.本文对电致孔法的透皮促渗机制、影响因素以及安全性进行了讨论,并介绍了有关实验装置及其在透皮给药中的应用.     

酮洛芬不同透皮制剂的体外透皮性和释放性

分别制备含1%、3%、5%酮洛芬的混合型巴布剂、交联型巴布剂、透皮贴剂,以同浓度的酮洛芬凝胶剂作为对照组,采用改良Franz透皮扩散池,以离体小鼠皮肤为透皮屏障,考察酮洛芬在不同制剂中的体外透皮和释放性能.结果表明,同浓度酮洛芬在不同受试制剂的透皮速率依序为交联型巴布剂＞混合型巴布剂＞凝胶剂＞透皮贴剂;3%酮洛芬在不同贴膏剂中的释放速率依序为混合型巴布剂＞交联型巴布剂＞透皮贴剂.     

Porcine Ear Skin as a Model for the Assessment of Transdermal Drug Delivery to Premature Neonates

PURPOSE: The purpose of this study was (i) to validate differentially tape-stripped, porcine skin as an in vitro model for the evaluation of transdermal drug delivery (TDD) to premature neonates, (ii) to determine whether the model could estimate neonatal skin permeability as a function of postconceptional age (PCA), and (iii) to demonstrate that iontophoretic delivery permits precise control of drug input independent of skin barrier function. METHODS: Passive permeation of caffeine, phenobarbital, and lidocaine across tape-stripped porcine skin barriers was measured. Iontophoretic delivery of lidocaine across skins with different barrier competencies was also evaluated. RESULTS: For all drugs, passive permeation correlated with skin barrier function; that is, with transepidermal water loss (TEWL): Jss = A x exp[B x TEWL]. Combining this result with a previously derived dependence of TEWL upon the PCA of premature neonates in vivo allowed a relative value of Jss to be predicted for a given PCA. Comparison of these predictions showed excellent agreement with experimental data reported for diamorphine. Iontophoretic lidocaine delivery was precisely controllable independent of barrier competency. CONCLUSIONS: Porcine skin, in vitro, differentially tape-stripped to specific barrier competencies, is a useful model to explore TDD in premature neonates. The potential for iontophoresis to provide improved dose control and adjustment, irrespective of skin barrier maturity, is established.     

Effects of Enantiomer and Isomer Permeation Enhancers on Transdermal Delivery of Ligustrazine Hydrochloride

Enantiomers and isomers, such as D-limonene, L-limonene, and α-terpinene, were selected as enhancers. The effects and mechanisms of penetration enhancers on in vitro transdermal delivery of ligustrazine hydrochloride (LH) across hairless porcine dorsal skin were investigated. Transdermal fluxes of LH through porcine skin were determined in vitro by Franz-type diffusion cells. D-limonene, L-limonene, and α-terpinene could significantly promote the transdermal fluxes of LH, but no statistical difference (p > 0.05) between them was found. The lag time of L-limonene and α-terpinene were 2.55 and 2.20 times compared with that of D-limonene. Fourier transform-infrared (FTIR) was carried out to analyze the effects of enhancers on the biophysical natures of the stratum corneum (SC) and the permeation enhancement mechanism. FTIR spectra revealed that the changes of peak shift and peak area due to C-H stretching vibrations in the SC lipids were associated with the selected enhancers. All of them could perturb and extract the SC lipids to different extent and L-limonene showed obvious changes. Morphological changes of the skin treated with enhancers were monitored by a scanning electron microscope (SEM). The extraction of the SC lipids by the enhancers led to the disruption of SC and the desquamated SC flake. Apparent density (AD) was newly proposed to estimate the desquamated extent of SC flake. The results showed that the enantiomers and isomers enhanced the permeation of LH by pleiotropic mechanisms.     

Transdermal Delivery of Insulin Using Microneedles in Vivo

PURPOSE: The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. METHODS: Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. RESULTS: Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. CONCLUSIONS: Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.     

Rapid Temporal Control of Transdermal Drug Delivery by Electroporation

Pharmaceutical Research -     

Inpatient Prescribing and Monitoring of Fentanyl Transdermal Systems: Adherence to Safety Regulations

Background:

National safety guidelines were developed to minimize the occurrence of serious adverse drug events (ADEs) associated with the use of the fentanyl transdermal system (FTS), however, reports of use in opioid-naïve patients for treatment of acute pain and associated ADEs continue to occur.

Objective:

To evaluate the prescribing patterns of the FTS for adherence to recent US regulatory recommendations and identify the impact of health information technology (HIT) on adherence rates.

Methods:

A retrospective pre- and postintervention analysis was performed in hospitalized adult patients receiving FTS. Electronic medication order instructions and text questions were incorporated into FTS electronic medication orders. The primary outcome measure was adherence of FTS medication orders to regulatory guidelines defined as (a) a new order in an opioid-tolerant patient for use in moderate to severe chronic pain or (b) continuation of the documented home dose in use for at least 7 days. Safety measures included respiratory rate and documented ADEs.

Results:

Adherence rates were significantly increased in the postintervention cohort as compared to the preintervention cohort (48.7% vs 85.0%; P < .0001). Incidence of ADEs was significantly lower post intervention (34.7% vs 23.3%; P = .043), including a lower incidence of respiratory depression (16.7% vs 8.3%; P = .043). Documentation was increased in the postintervention cohort (76% vs 100%). However, supporting documentation confirmed responses in only 59.2% of records reviewed.

Conclusions:

Incorporation of HIT via electronic order text questions increased overall adherence rates to regulatory recommendations, increased documentation, and decreased the rate of associated ADEs.     

Synthesis of Conjugated Chitosan and its Effect on Drug Permeation from Transdermal Patches

The aim of this study was to synthesis the conjugated chitosan by covalent attachment of thiol moieties to the cationic polymer, mediated by a carbodiimide to improve permeation properties of chitosan. Thioglycolic acid was covalently attached to chitosan by the formation of amide bonds between the primary amino groups of the polymer and the carboxylic acid groups of thioglycolic acid. Hence, these polymers are called as thiomers or thiolated polymers. Conjugation of chitosan was confirmed by Fourier transform-infrared and differential scanning calorimetric analysis. Matrix type transdermal patches of carvedilol were prepared using the different proportions of chitosan and chitosan-thioglycolic acid conjugates (2:0, 1.7:0.3, 1.4:0.6, 1:1, 0.6:1.4 and 0.3:1.7) by solvent casting technique. Prepared matrix type patches were evaluated for their physicochemical characterization followed by in vitro evaluation. Selected formulations were subjected for their ex vivo studies on Wistar albino rat skin and human cadaver skin using the modified Franz diffusion cell. As the proportion of conjugated chitosan increased, the transdermal patches showed increased drug permeation. The mechanism of drug release was found to be nonFickian profiles. The present study concludes that the transdermal patches of carvedilol using conjugated chitosan with different proportions of chitosan were successfully developed to provide improved drug permeation. The transdermal patches can be a good approach to improve drug bioavailability by bypassing the extensive hepatic first-pass metabolism of the drug.