微乳在经皮给药系统中的应用

微乳经皮给药是目前国内外药学工作者研究的重点,也是目前药物制剂研发热点之一。本文主要从微乳的组成、促渗机制、微乳在经皮给药中的应用3个方面进行了综述。微乳经皮给药具有很好的应用前景。     

贴剂组分及月桂氮(艹卓)酮对吲哚美辛贴剂特性的影响

目的：观察聚异丁烯、液体石蜡、增粘剂和月桂氮艹卓酮同时作为压敏胶和药库层时,其组成对吲哚美辛贴剂特性的影响。方法：运用正交设计实验研究处方基质组成对药物透皮释放和胶层物理参数的影响,用改进的Ｆｒａｎｚ 体外释药装置研究离体鼠皮的透皮规律,建立高效液相色谱法测定了药物的透皮累积释放量和制剂含量。结果：实验发现基质组成中增粘剂和液体石蜡是决定药物渗透系数和剥离强度的主要因素,低相对分子质量聚异丁烯和增粘剂对初粘力影响最大,增粘剂对拉力强度有显著作用;在优选的处方基础上,找到月桂氮艹卓酮的理想浓度约为５ ％ ;各项指标均符合橡皮胶的国家标准;测定方法可靠。结论：组分中增粘剂对贴剂粘附性的影响最大,５ ％ 月桂氮艹卓酮对药物渗透系数的作用显著。     

Design of novel prodrugs for the enhancement of the transdermal penetration of indomethacin

A series of esters of indomethacin containing tertiary amine functional groups and designed for transdermal delivery were synthesized. The rates of chemical hydrolysis of all the esters in pH 7.4 phosphate buffer were determined. For N,N-diethylaminopropyl N-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indole acetate (ester 4), the rates of chemical hydrolysis in pH 5.5–11.25 buffers were investigated in detail. Ester 4 was chemically stable and had a higher n-octanol/water partition coefficient and a greater solubility in water at pH 7.4 than indomethacin. Furthermore, the rate of transdermal penetration of ester 4 through cadaver skin in Franz cells was found to be more than 10-times faster than that of indomethacin itself. Ester 4 was found to possess surface-active properties (CMC = 0.5 mg/ml). Assuming that micelles cannot penetrate biologic membranes, a corrected permeability coefficient was calculated for ester 4 using only the monomer concentration. This value, 3.6 × 10⁻² cm/h, was 100-times greater than that of indomethacin. These results suggest that prodrugs with structures similar to that of ester 4 may be useful for enhancing transdermal penetration of other carboxylic acid-containing anti-inflammatory agents.     

一种葛根素经皮给药系统体外透皮性能的初步考察

目的：制备葛根素经皮给药系统,并对其体外透皮性能进行考察。方法：以月桂氮酮为促透剂,卡波姆980为凝胶基质,制备葛根素经皮给药系统,用RP-HPLC法进行定量,采用改良Franz扩散池测定了32 h葛根素对离体大鼠皮肤累积渗透量。结果：葛根素累积渗透量拟合方程：Q=11.12t-45.18（r=0.9635）,32 h累积渗透量为（335.18±51.45）μg/cm2。结论：葛根素以零级动力学透过皮肤,所研制的葛根素经皮给药系统体外渗透性能良好,质量控制方法简便、快捷、准确。     

Advanced techniques for penetration enhancement in transdermal drug delivery system

Transdermal route has been recognized as a promising drug delivery system for systemic delivery of drugs and provides the advantage of avoidance of first-pass effect, ease of use, better patient compliance, maintaining constant blood level for longer period of time and decrease side effects. The major pitfalls of this route lie with difficulty in permeation of drugs through the skin. Several literatures have been published for enhancing the permeation of drugs by chemical approaches. However the present review highlighted about the advanced physical techniques used for enhancing delivery of drugs such as structure-based, electrically based, velocity based and several other miscellaneous physical techniques for enhancing the permeation of drugs. In addition to these, the present review also gives an exhaustive account on clinical data about these techniques and regulatory considerations for new drugs as well as generic product approval in transdermal drug delivery.     

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.     

Fundamental investigation of a novel drug delivery system,a transdermal delivery system with jet injection

A new drug delivery system simultaneously using jet injection and a transdermal delivery system was proposed. After pretreatment of hairless rat skin by a jet injector containing physiological saline without any drug to make a pore in the skin, aqueous solution containing gentamycin sulfate, nicardipine hydrochloride or theophylline was applied on the pore. Absorption clearance (volume flow rate) through the skin (the product of permeability coefficient and application area) was almost the same (0.4 μl/h) with any type of drug and regardless of properties and concentrations. Plasma concentration of gentamycin when the distance between the injector and skin surface was 5 mm was twice that when there was no space between the two. It was found by morphological observation that injection from 5 mm away made a larger pore in the stratum corneum (about 0.3 mm²) and a clear saline reservoir in the viable epidermis and dermis. Mathematical analysis showed that this larger pore greatly increased the skin delivery (absorption) rate, whereas the saline reservoir increased it little. This high delivery rate continued for over 1 week with theophylline.     

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.     

可固化mPEG-PDLLA胶束作为载体的新型吲哚美辛口服给药系统的体外研究(英文)

本研究旨在制备吲哚美辛固化聚合物胶束(IND-SPM),并研究其体外释放特性。IND-SPM以交联聚维酮XL-10作为载体,并以聚乙二醇单甲醚?聚乳酸嵌段共聚物(mPEG-PDLLA)作为药物载体,通过溶液吸收法,用旋转蒸发仪蒸发溶剂后制得吲哚美辛固化聚合物胶束(IND-SPM)。取IND 20 mg,以PBS 250 mL为溶出介质进行体外溶出度实验。结果表明,30 min内吲哚美辛的释放量高于90%(w/w)。DSC,1H NMR和SEM结果证明IND被包裹在mPEG-PDLLA中。随着聚合物的用量的增加,吲哚美辛的溶解度可提高4.6倍。IND-SPM适用于开发成片剂或胶囊剂。     

Oleodendrimers: A novel class of multicephalous heterolipids as chemical penetration enhancers for transdermal drug delivery

This paper reports synthesis and evaluation of Janus type generation G-1 and G-2 dendrimers. The dendrimers have been constructed by linking two building blocks, dendrons and oleic acid, through ester and amide bonds and were well characterized by Fourier-transform infrared (FT-IR), ¹H NMR, ¹³C NMR and electrospray ionization mass spectrometry (ESI-MS). The dendrimers have been evaluated for in vitro cytotoxicity using sulforhodamine B assay (SRB assay) and in vivo skin irritation potential. The ester linked dendrimers did not exhibit any cytotoxicity even up to 80 μg/ml while G-1 and G-2 generations dendrimers with amide linkage exhibited toxicity above 70 μg/ml and 21 μg/ml, respectively, none of the dendrimers showed any skin irritation. All the dendrimers, tested for their skin permeation enhancement potential using diclofenac sodium (DS) as a model drug at a concentration of 1% in gels, showed significant increase in steady-state flux (ER_flux) of the drug as compared to control (without enhancer), and oleic acid. Amongst the dendrimers, the ester linked G-1 and G-2 dendrimers showed highest ER_flux, 3.33 ± 0.31 and 3.39 ± 0.21, respectively.     

Enhancement of transdermal delivery of progesterone using medium-chain mono and diglycerides as skin penetration enhancers

We evaluated whether medium-chain mono and diglycerides (MCG) can be utilized to optimize the transdermal delivery of progesterone (PGT). MCG was studied at 10–70% (w/w) in propylene glycol (a polar solvent) or Myvacet oil (nonpolar solvent); PGT was used at 1% (w/w). The topical (to the skin) and transdermal (across the skin) delivery of PGT were evaluated in vitro using porcine ear skin. When incorporated in propylene glycol, MCG at 10% enhanced the topical and transdermal delivery of PGT by 2.5- and 7-fold, respectively. At 20–50%, topical delivery was further enhanced while transdermal delivery gradually returned towards baseline. At 70%, MCG enhanced neither the delivery to viable skin nor the transdermal delivery of PGT. Similar concentration-dependent effects were observed when MCG was incorporated in Myvacet oil, but their magnitudes were 2- to 3-fold smaller. The relative safety of MCG was assessed in cultured fibroblasts and compared to propylene glycol (regarded as safe) and sodium lauryl sulfate (moderate-to-severe irritant). Both MCG and propylene glycol were substantially less cytotoxic than sodium lauryl sulfate. We conclude that formulations containing 10% MCG in propylene glycol may be a simple and safe method to improve the transdermal delivery of progesterone and promote its use in hormone replacement therapy.     

Hyaluronan-modified transfersomes based hydrogel for enhanced transdermal delivery of indomethacin

Hyaluronic acid (HA), as a hygroscopic and biocompatible molecule, has displayed unique permeation enhancement in transdermal delivery systems. Hence, indomethacin (IND) was encapsulated in HA-modified transfersomes (IND-HTs) to enhance transdermal IND delivery to reduce adverse effects in this study. The physiochemical properties of IND-HTs were characterized. Results showed that the prepared IND-HTs were spherical and revealed good entrapment efficiency (87.88 ± 2.03%), with a nanometric particle size (221.8 ± 93.34 nm). Then, IND-HTs were further incorporated into a carbopol 940 hydrogel (IND-HTs/Gel) to prolong retention capacity on the skin. The in vitro release and skin permeation experiments of IND-HTs/Gel were carried out with the Franz diffusion cells. It was found that IND-HTs/Gel exhibited sustained drug release, as well as superior drug permeation and flux across the skin. Confocal laser scanning microscopy showed improved penetration of HTs/Gel with a wider distribution and higher fluorescence intensity. The hematoxylin–eosin stained showed that HA improved the transdermal effect by changing the microstructure of skin layers and decreasing skin barrier function. In addition, IND-HTs/Gel showed significant analgesic activity in hot plate test and no potentially hazardous skin irritation. This study indicated that the developed IND-HTs/Gel could be a promising alternative to conventional oral delivery of IND by topical administration.     

Nano-transfersomes as a novel carrier for transdermal delivery

The aim of this study was to design and optimize a nano-transfersomes of Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3³ factorial design (Box–Behnken) was used to derive a polynomial equation (second order) to construct 2-D (contour) and 3-D (Response Surface) plots for prediction of responses. The ratio of lipid to surfactant (X₁), weight of lipid to surfactant (X₂) and sonication time (X₃) (independent variables) and dependent variables [entrapment efficiency of DDEA (Y₁), entrapment efficiency of CRM (Y₂), effect on particle size (Y₃), flux of DDEA (Y₄), and flux of CRM (Y₅)] were studied. The 2-D and 3-D plots were drawn and a statistical validity of the polynomials was established to find the compositions of optimized formulation. The design established the role of the derived polynomial equation, 2-D and 3-D plots in predicting the values of dependent variables for the preparation and optimization of nano-transfersomes for transdermal drug release.     

Drug delivery to the eye with a transdermal therapeutic system

A matrix-type transdermal therapeutic system was developed for treating diseases of the eye where it is difficult for drug molecules to reach with conventional topical instillation. Prednisolone was employed as a model drug. An in vivo study using rats showed that the daily application of the patch maintained a constant plasma concentration of the drug, which was equivalent the therapeutic plasma level following three times daily oral administration (30 mg), for approximately 24 h. Transdermal delivery provided equivalent to or higher bioavailability (drug distribution) to the eyeball of topical administration. Moreover, pharmacokinetic analysis indicated that the present transdermal therapeutic system may be clinically effective as a new treatment for ocular diseases.     

Interaction of indomethacin with a new penetration enhancer,dodecyl 2-(NN-dimethylamino)propionate (DDAIP): its effect on transdermal delivery

The new biodegradable penetration enhancer DDAIP (dodecyl 2-(N,N-dimethylamino)propionate) shows a striking enhancement of the acidic drug indomethacin through shed snake skin. This enhancement appears to be due partially to some interaction between the drug and the enhancer. This interaction was examined using UV, IR, ¹H- and ¹³C-NMR spectrometry and differential scanning calorimetry (DSC). The existence of preferential hydrogen bonding between the carboxylic acid group of indomethacin and the tertiary amine group of the enhancer and a dipole-dipole interaction was demonstrated.     

Iontophoresis: a potential emergence of a transdermal drug delivery system

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application.     

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.     

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.