新型经皮渗透促进剂及作用机制的研究进展

角质层(stratumcorneum,SC)是皮肤给药的主要屏障,无论是局部经皮的皮内给药还是经皮吸收进入体循环发挥全身作用都必须克服SC的屏障作用。但绝大部分药物都难以有效地透过SC,在众多克服SC的方法中,化学渗透促进剂(chemical penetration enhancers,CPE)的应用最广泛。除传统的醇类、亚砜类、脂肪酸类、酯类、氮酮、多元醇类等,又发现或合成了许多新型高效的促进剂。文中对近年来国内外关于新型渗透促进剂的文献进行综述,以期为合成和发现更加安全、高效的渗透促进剂提供线索。     

经皮吸收促进剂的研究与应用进展

透皮给药系统作为最成功的非口服控释给药系统之一，可有效避免肝脏首过效应和胃肠道药物降解、调控释药速率及血药浓度、降低服药频率和不良反应、提高患者顺应性。经皮吸收促进剂在透皮给药系统研究中起着重要作用。现就其应用与联用、选择与评价、促透机制研究及其对水溶性和大分子药物的促透作用等方面，对近年来的研究进展进行综述。     

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 sonophoresis and chemical penetration enhancers on percutaneous transport of penbutolol sulfate

The effect of ultrasound and chemical penetration enhancers on transcutaneous flux of penbutolol sulfate across split-thickness porcine skin was investigated. Penbutolol sulfate is a potent, noncardioselective beta-blocker, which is used for the management of hypertension. The drug is one of the most lipid soluble of the β-adrenoceptor antagonists used clinically. It has an n-octanol/pH 7.4 buffer partition coefficient of 179 compared to a value of 22 for propranolol. The amount of penbutolol sulfate transported across the skin is low. In this project, we studied the effect of sonophoresis and chemical penetration enhancers on transdermal delivery of penbutolol sulfate. Low-frequency sonophoresis at a frequency of 20?kHz increased transcutaneous flux of penbutolol sulfate by 3.5-fold (27.37?±?μg?cm^?2?h^?1) compared to passive delivery (7.82?±?1.72?μg?cm^?2?h^?1). We also investigated the effect of 50% ethanol, 1% limonene and 2% isopropyl myristate (IPM) on transcutaneous permeation of penbutolol sulfate. IPM, ethanol and limonene at the concentration of 1%, 50% and 2%, respectively, increased the steady-state flux values of penbutolol sulfate 2.2- (17.07?±?3.24?μg?cm^?2?h^?1), 2.6?- (19.40?±?6.40?μg?cm^?2?h^?1) and 3.4-times (26.38?±?5.01?μg?cm^?2?h^?1) compared to passive delivery (7.76?±?2.9?μg?cm^?2?h^?1). The results demonstrate that although there were slight increases in flux values, ultrasound, ethanol, limonene and IPM did not significantly enhance the transdermal delivery of penbutolol sulfate. Future studies will examine ways of optimizing sonophoretic and chemical enhancer parameters to achieve flux enhancement.     

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.     

促进剂对酮洛芬巴布剂体外透皮性的影响探讨

目的:通过几种常用促进剂对酮洛芬巴布剂体外促渗作用研究,筛选出适合用于酮洛芬巴布剂的透皮促进剂。方法:分别制备单独含2%或4%的桉叶油、油酸、薄荷脑、聚乙二醇400、月桂氮芯卓酮、聚山梨醇酯-80的酮洛芬巴布剂贴片,以及4%的桉叶油分别与2%的油酸、薄荷脑、聚乙二醇400合用的酮洛芬巴布剂贴片,采用改良Franz透皮扩散池,以离体小鼠背部皮肤为透皮屏障,贴敷12h,以渗透速率及12h累积渗透量为指标,探讨促进剂对酮洛芬体外透皮性的影响。结果:与空白组对照,2%聚山梨醇酯-80、2%月桂氮卓芯酮单独使用不能明显提高酮洛芬的渗透速率(P>0.05),4%聚山梨醇酯-80、4%月桂氮卓芯酮和其他的促进剂都能明显的提高酮洛芬的经皮渗透(P<0.01),对酮洛芬透皮速率提高大小顺序为油酸≥桉叶油>薄荷脑>聚乙二醇400>月桂氮卓芯酮>聚山梨醇酯-80。结论:油酸、桉叶油、薄荷脑、聚乙二醇400均可作为酮洛芬巴布剂透皮促进剂。     

非洛地平-美托洛尔复方贴剂的透皮吸收促进剂优化

目的：优化复合透皮吸收促进剂，制备非洛地平-美托洛尔复方贴剂，并对其外观、物理特性、体外药物释放和经皮渗透性能进行综合评价。方法：以药物体外释放速率和稳态透皮速率为指标，通过正交设计试验考察桉叶油醇、月桂氮[艹卓]酮和丙二醇体系对贴剂质量的影响，优选最佳复合透皮吸收促进剂构成。结果：优选的透皮吸收促进剂最佳含量分别为桉叶油醇5％、月桂氮[艹卓]酮3％和丙二醇12%，以该促透体系制备的贴剂药物体外释放速率和稳态透皮速率高，外观和理化特性较佳，物理黏性适宜，各指标均达到预期设计要求。结论：桉叶油醇-月桂氮[艹卓]酮-丙二醇（5：3：12）复合体系对非洛地平和关托洛尔的协同促透作用显著，且稳定可靠，是非洛地平关托洛尔复方贴剂的优良透皮吸收促进剂。     

促渗剂对氟比洛芬体外经皮渗透的影响

目的研究不同的促渗剂对氟比洛芬体外经皮渗透的促渗作用。方法采用TK-6A型透皮扩散仪,用人皮进行体外经皮渗透实验,考察不同的促渗剂[二甲基亚砜、月桂醇、丙二醇、月桂氮酮(氮酮)、尿素、油酸]及其组合对氟比洛芬体外透皮吸收的促渗作用,以HPLC法测定各时间点接受室中药物浓度,求算透皮吸收的有关参数,比较各促渗剂的促渗作用。结果15%二甲基亚砜、3%氮酮、1%尿素可使氟比洛芬经皮渗透速率分别提高1.8,1.5,1.1倍,促渗剂联用取得的促渗效果更佳,5%油酸 20%丙二醇 1%尿素可使该药物的经皮渗透速率提高6倍。结论单用促渗剂对氟比洛芬经皮渗透促渗效果有限,促渗剂联合使用可以显著提高氟比洛芬经皮渗透速率。     

不同促渗剂对硫酸沙丁胺醇颊粘膜吸收的影响

目的：筛选硫酸沙丁胺醇经颊粘膜吸收促渗剂。方法；采用单室扩散池研究硫酸沙丁胺醇通过金黄地鼠颊粘膜的药物渗透，考察不同促渗剂对药物经颊粘膜吸收的影响。结果；在１０ｈ内，２０ｍｇ／ｍｌ的药物生理盐水溶液渗透速率为３９．１５μｇ（ｃｍ＾２．ｈ）。当分别以相同药物浓度的饱和β－环糊精生理盐水，３％Ｔｗｅｅｎ８０与５％Ａｏｎｅ生理盐水，５％聚氧乙烯壬苯工醚生理盐水为溶媒，其渗透速率分别为７５．４６，１５２．     

lontophoretic Delivery of a Series of Tripeptides Across the Skin in Vitro

The iontophoresis of eight tripeptides, of the general structure alanine–X–alanine, has been measured across hairless mouse skin in vitro. The peptides were blocked (a) at the carboxyl terminus using the mixed anhydride reaction with t-butylamine and (b) at the amino terminus by acetylation with ¹⁴C-acetic anhydride. The nature of the central residue (X) was varied by selecting one of five neutral amino acids, two negatively chargeable moieties (aspartic and glutamic acids), and a positively chargeable species (histidine). Constant current iontophoresis at 0.36 mA/cm², using Ag/AgCl electrodes, was performed for 24 hr in diffusion cells, which allowed both anode and cathode to be situated on the same (epidermal) side of a single piece of skin. Due to a combination of osmotic and electroosmotic forces, the anodal iontophoretic flux of neutral peptides was significantly greater than passive transport. Steady-state fluxes were not achieved, however, suggesting that time-dependent changes in the properties of the skin barrier may be occurring. Limited, further experiments confirmed that, on a 24-hr time scale, these changes were not fully reversible. The cathodal delivery of anionic permeants was well controlled at a steady and highly enhanced rate by the current flow. This behavior closely paralleled earlier work using simple negatively charged amino acids and N-acetylated amino acid derivatives. It appears that the normalized iontophoretic flux of these anionic species is independent of lipophilicity but may be inversely related to molecular weight. The positively charged peptide, Ac–Ala–His–Ala–NH(Bu^t), showed greater anodal iontophoretic enhancement when delivered from a donor solution at pH 4.0 than from a solution at pH 7.4. This was consistent with (a) the corresponding behavior of histidine alone and (b) the existence of a pK _a for these compounds at 6. Steady-state delivery was not achieved, although the levels of enhancement, especially at pH 4, were the largest observed. A preliminary investigation of tripeptide stability to either (i) electrolysis in the donor compartment or (ii) cutaneous metabolism revealed very little degradation under the conditions of the experiment. Overall, this research supports the principle of enhanced peptide delivery across the skin by iontophoresis and indicates a number of areas (e.g., mechanism and extent of current-induced changes in skin barrier function, molecular size dependence, pathways of current flow) on which further work should be focused.     

Insights into the percutaneous penetration of antidiabetic agents

It has been suggested that destruction of β cells through apoptosis leads to type 1 diabetes (T1DM) while type 2 diabetes (T2DM) is caused mainly by increased insulin resistance. Several therapeutic agents are available for the management of diabetes. While researchers continue to investigate disease-modifying compounds, it is also important to develop alternative drug delivery systems for existing medications with the goal of modulating bioavailability and/or pharmacokinetic half-life. Transdermal drug delivery offers a number of advantages including improved compliance, lack of gastric irritation and the possibility of altering bioavailability and and/or half-life. In this review, the percutaneous penetration of antidiabetic agents is discussed. This is particularly significant given the fact that several compounds with hypoglycemic properties are being developed by academic research laboratories and the biotechnological industry. Microneedles, sonophoresis, chemical penetration enhancers and iontophoresis are some of the approaches used for the transdermal delivery of antidiabetic agents. It is anticipated that with more research, some of these transdermal drug delivery systems will be incorporated into clinical practice.     

透皮促进剂对白花前胡甲素体外经皮渗透的影响

目的:考察透皮促进剂对白花前胡甲素(dl-praeruptorin A,Pd-Ia)体外经皮渗透的影响。方法:采用改进的Franz扩散池,以大鼠离体皮肤为渗透屏障,用高效液相色谱法对Pd-Ia进行含量测定,考察月桂氮酮(Azone)及1%Azone与不同浓度丙二醇(PG)混合物对Pd-Ia透皮吸收的影响。结果:使用Azone对Pd-Ia有促透作用,1%Azone效果较好,平均渗透速率达到4.064μg.cm-2.h-1;1%Azone与15%PG合用促透效果最好,平均渗透速率达到4.889μg.cm-2.h-1,且与单用1%Azone有显著性差异(P<0.05)。结论:1%Azone与15%PG合用时,含0.5%Pd-Ia溶液体外渗透具有最大促透效果,体现出协同作用。     

Percutaneous Absorption Enhancement of an Ionic Molecule by Ethanol–Water Systems in Human Skin

Ethanol–water systems enhance permeation of ionic solutes through human stratum corneum. Optimum enhancement of salicylate ion permeation has been observed with ethanol volume fractions near 0.63. The mechanism of action of ethanol–water systems enhancing skin permeation was investigated by in vitro skin permeation studies combined with Fourier transform infrared spectroscopy experiments. The increased skin permeation of the ionic permeant by the ethanol–water systems may be associated with alterations involving the polar pathway. Polar pathway alterations may occur in either or both the lipid polar head and proteinaceous regions of the stratum corneum. Ion-pair formation may also contribute to increased permeation. However, the decreased permeation of salicylate ion observed at higher volume fractions of ethanol may be attributed to decreased uptake of permeant into the stratum corneum.     

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.     

Veterinary drug delivery: potential for skin penetration enhancement

A range of topical products are used in veterinary medicine. The efficacy of many of these products has been enhanced by the addition of penetration enhancers. Evolution has led to not only a highly specialized skin in animals and humans, but also one whose anatomical structure and skin permeability differ between the various species. The skin provides an excellent barrier against the ingress of environmental contaminants, toxins, and microorganisms while performing a homeostatic role to permit terrestrial life. Over the past few years, major advances have been made in the field of transdermal drug delivery. An increasing number of drugs are being added to the list of therapeutic agents that can be delivered via the skin to the systemic circulation where clinically effective concentrations are reached. The therapeutic benefits of topically applied veterinary products is achieved in spite of the inherent protective functions of the stratum corneum (SC), one of which is to exclude foreign substances from entering the body. Much of the recent success in this field is attributable to the rapidly expanding knowledge of the SC barrier structure and function. The bilayer domains of the intercellular lipid matrices within the SC form an excellent penetration barrier, which must be breached if poorly penetrating drugs are to be administered at an appropriate rate. One generalized approach to overcoming the barrier properties of the skin for drugs and biomolecules is the incorporation of suitable vehicles or other chemical compounds into a transdermal delivery system. Indeed, the incorporation of such compounds has become more prevalent and is a growing trend in transdermal drug delivery. Substances that help promote drug diffusion through the SC and epidermis are referred to as penetration enhancers, accelerants, adjuvants, or sorption promoters. It is interesting to note that many pour-on and spot-on formulations used in veterinary medicine contain inert ingredients (e.g., alcohols, amides, ethers, glycols, and hydrocarbon oils) that will act as penetration enhancers. These substances have the potential to reduce the capacity for drug binding and interact with some components of the skin, thereby improving drug transport. However, their inclusion in veterinary products with a high-absorbed dose may result in adverse dermatological reactions (e.g., toxicological irritations) and concerns about tissue residues. These are important considerations when formulating a veterinary transdermal product when such compounds are added, either intentionally or otherwise, for their penetration enhancement ability.     

马钱子巴布剂体外透皮实验及促透剂的筛选

目的:考察不同促透剂对马钱子巴布剂中马钱子碱、士的宁的体外透皮吸收的影响,筛选合适的促透剂。方法:采用改良Franz扩散池对离体大鼠皮肤进行体外透皮实验,RP-HPLC法测定含不同促透剂的马钱子巴布剂中活性成分的累积渗透量(Q_n)和透过率(T)。结果:马钱子巴布剂体外透皮吸收符合零级动力学方程,不同的促透剂对透皮吸收影响的顺序为:DMF>月桂氮芯卓酮(氮酮)>丙二醇>薄荷醇。在给定的范围内(≤5%),氮酮和薄荷醇的促透性能均是随着浓度增大而先升后降,二甲基甲酰胺和丙二醇的促透效果都是随着浓度增大而增强。结论:不同浓度的促透剂均能一定程度促进马钱子巴布剂活性成分的透皮吸收,其中以5%DMF的促渗效果最好。     

罂粟碱凝胶的研制及不同透皮促进剂对其透皮作用的影响

目的：探讨透皮吸收促进剂对罂粟碱凝胶透皮吸收的影响。方法：采用简单扩散小室，用紫外分光光度测定了5种处方罂粟碱凝胶离体鼠皮透皮吸收药量。结果：罂粟碱透皮累积释药量与时间呈线性关系，与不含吸收促进剂的凝胶比较，吸收促进剂对罂粟碱透皮吸收的影响为油酸＞油酸＋月桂氨卓酮＞二甲亚砜＞月桂氮卓酮。结论：油酸能明显促进罂粟碱的透皮吸收，而水溶性的透皮吸收促进剂对罂粟碱的透皮吸收作用不明显。     

美洛昔康凝胶剂的研制

目的：寻找合适的透皮促进剂,使美洛昔康凝胶剂起效时间缩短。方法：配制不同处方的凝胶剂,采用Franz扩散小池,HPLC检测药物浓度进行离体皮肤渗透实验,然后用志愿者进行在体药效测定。结果：月桂氮酮使美洛昔康透皮速率提高,但滞后时间延长,在体消炎镇痛效果不佳;单用乙醇不延长滞后时间,在体起效时间缩短。结论：含乙醇的凝胶剂消炎镇痛效果最好。