药物透皮吸收及临床应用

药剂学是药学综合应用技术的科学。药剂学的发展历经了格林药剂时代、物理学药剂时代、生物药剂学时代、临床药剂学时代,目前进入药物传递系统DDS时代。透皮控制剂正是药剂学发展进程中的产物。透皮给药已成为当今临床重要的给药方式。本文就药物透皮吸收以及临床应用作简要的论述。     

天然透皮吸收促进剂的研究进展

自 20世纪 70年代中期美国首先提出透皮控释给药( TDDS)治疗方案并制成东莨菪碱贴片以来,透皮给药系统不断完善并得到了迅猛的发展.药物控释透皮制剂具有可避免药物在胃肠道的降解和肝脏首关效应、药物恒速释放和降低药物不良反应等独特优点.但透皮给药体系要求药物具有一定的透皮速率,而大部分药物的透皮速率都不能满足治疗要求,因此提高其透皮速率是开发透皮给药系统的关键.解决此问题常用方法有药剂学方法、化学方法和物理学方法等,而使用透皮吸收促进剂是应用最多的一种药剂学方法.     

促进药物透皮吸收的方法

目的：研究促进药物透皮吸收的方法,是为了提高药物的全身和局部作用,减少不良反应,以达到最佳治疗效果。方法：综述透皮给药系统研究新进展,介绍促进药物透皮吸收的药剂学方法、化学方法和物理方法。结果：促进药物透皮吸收的方法很多,发展也快。结论：并用两种或两种以上的方法,可能取得更好的治疗效果。     

乙醇脂质体透皮作用的研究与发展

目的：介绍乙醇脂质体透皮作用的研究与发展。方法：综合分析乙醇脂质体的组成及一般特性、制备及乙醇脂质体载药系统透皮给药的药剂学促透机制、最新的基础实验和研究进展。结果：作为各种药物的载体，乙醇脂质体具有其良好的药物包裹率和显著的促进药物透皮吸收特性。结论：乙醇脂质体新剂型透皮给药具有广阔的应用前景。     

透皮促进剂在透皮释放给药系统中的应用

本文介绍了透皮释放给药系统的特点,阐明了透皮促进剂的作用及其机理;介绍了国内外常用的透皮促进剂,综述其在透皮释放给药系统中合理知科学的应用。同时展示了透皮促进剂的新发展和药物增加透皮吸收的新研究。     

透皮促进剂在经皮给药系统中的应用近况

透皮促进剂是指所有能够增加药物透皮速度而对皮肤不造成严重刺激和损害的物质。近年来 ,经皮给药系统的基础实验取得了可喜进展 ,透皮制剂的组方及用现代方法对药物在体内或体外透皮吸收进行较系统的研究成绩显著。经皮给药的理论基础为给药后 ,药物能迅速穿透皮肤 ,被吸收进入血液循环而产生疗效。因此 ,研究经皮给药制剂时首先必须解决药物对皮肤的穿透性和透皮速率。目前的技术多采用添加月桂氮酮(Ａｚｏｎｅ)、亚油酸、丙二醇 (ＰＧ)等透皮促进剂来增加药物的穿透性和提高药物的透皮速率。在应用这些促进剂时 ,研究者又发现按一定比…     

浅谈透皮控释制剂

控释制剂能控制所含药物的释放速度,使其符合临床治疗的药物动力学要求,即使血药浓度较长时间保持恒定,避免峰谷现象,减少给药次数。它是以生物药剂学和药物动力学为基础,利用新工艺、新材料发展起来的新剂型。透皮控释制剂是通过皮肤表面给药,吸收转运而产生全身作用的新型制剂。它作为一种新的给药系统,其研究已扩展到心血管     

透皮吸收促进剂在巴布剂中的应用及研究

经皮给药系统不断完善并得到了发展，但许多药物透皮应用时并不能完全满足治疗要求，因此提高其透皮速率是开发透皮给药系统的关键。通过查阅近10年有关透皮吸收促进剂的文献资料，对透皮吸收促进剂及其在巴布剂中的应用情况进行分析、整理和归纳，为巴布剂的透皮吸收实验研究提供参考。     

促进药物透皮吸收方法的研究

透皮吸收制剂，特别是透皮给药系统是近年来药剂研究的重要课题之一。许多药物透皮给药后的渗透率达不到治疗要求，所以寻找促进药物透皮吸收的方法是开发透皮给药系统的关键之一。促进药物透皮吸收的方法有物理法和化学法。本文就近年来透皮吸收促进方法的研究概况作一综述。     

透皮吸收制剂的探讨

透皮吸收制剂量近年来药剂研究的主要课题之一。透皮制剂吸收的主要途径是药物穿透皮肤的汗孔或毛细血管进入血液循环而达到治疗目的。透皮制剂具有提高药物治疗效能。减少给药次数,降低副作用等特点,影响透皮吸收的因素很多,本文主要从皮肤渗透促进剂、软膏基质、以及皮肤因素三个方面进行了分析。现在透皮吸收制剂的研究正处方兴阶段不断新的理论和新的产品,透皮吸收制剂可望今后在防病、治疗方面发挥更大的作用。     

Epidemiological study on tobacco smoking and dependence in Hokkaido Prefecture]

A 1998 national survey of smoking and health problems reported that 18 million Japanese over 15-years-old, 53.9% of regular smokers in Japan, have tobacco dependence. The survey used the Tobacco Dependence Screening Questionnaire (TDS), the items in which do not strictly follow the criteria for ICD-10 dependence syndrome. In this study, to evaluate the validity of screening with the TDS for ICD-10 tobacco dependence, TDS and a questionnaire, consisting of items obtained from the ICD-10 dependence syndrome for tobacco use were administered to 1371 participants. The prevalence of tobacco dependence diagnosed according to the ICD-10 criteria was 20.9%. On the other hand, the ratio of tobacco dependence screened by the TDS was 60.1%. Furthermore, only 26.0% of participants screened as tobacco dependent by the TDS were diagnosed as being tobacco dependence according to ICD-10 criteria. These results indicate the possibility of overestimation of the rate of tobacco dependence using the TDS.     

Statistical considerations and impact of the FDA draft guidance for assessing adhesion with transdermal delivery systems and topical patches for ANDAs

ABSTRACT

Until 2016, a ratio of means (ROM) non-inferiority (NI) test was recommended in FDA product-specific guidances (PSGs) to evaluate adhesion performance for prospective generic transdermal delivery systems (TDS). However, the ROM NI test had low power for well-adhering TDS, which were becoming increasingly prevalent. Mathematical proof and simulation revealed that the low power wasn’t because the non-normality of adhesion data violated the normality assumption of parametric methods; it was because the ROM NI test was coupled with an adhesion scale where scores approached 0 as adhesion got better. In June 2016, FDA published a draft general guidance on TDS adhesion and recommended a new statistical approach, replacing the ROM NI test with a difference-of-means (DOM) NI test, using the same scale and primary endpoint (mean adhesion scores). An analysis of 40 TDS adhesion studies submitted in ANDAs after the publication of the 2016 draft guidance suggests that, consistent with simulation results, the new statistical approach markedly improves the low power, and thereby reduces the sample size required by the old approach for moderately to well-adhering TDS, while retaining comparable power for poorly adhering TDS. The new statistical approach thus enhances the potential approvability and patient access to well-adhering generic TDS.     

Development of a screening questionnaire for tobacco/nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV.

A 10-item questionnaire (the Tobacco Dependence Screener; TDS) for screening of tobacco/nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV was newly developed. The reliability and validity were assessed in three samples of smokers in Japan. A total of 58 male smokers completed the TDS and the Fagerstrom Tolerance Questionnaire (FTQ), and they were interviewed using the World Health Organization's Composite International Diagnostic Interview (Sample 1). A total of 118 male and 36 female smoking outpatients completed the TDS and the FTQ and provided a breath sample for carbon monoxide measurement (Sample 2). A total of 194 male smokers joined a health education program using a health risk appraisal (HRA) and reported their smoking status and completed the TDS 6 months after receiving the HRA results (Sample 3). The Cronbach's alpha coefficients for the TDS ranged from .74 to .81 among the samples, whereas those for the FTQ ranged from .41 to .64. Receiver operator characteristic analyses indicated that the TDS had a better screening performance for ICD-10, DSM-III-R, and DSM-IV diagnoses than did the FFQ. The TDS score significantly and positively correlated with the severity of the diagnoses, the carbon monoxide levels, number of cigarettes smoked per day, and years of smoking. The TDS score was significantly lower in those who quit smoking than in those who did not quit smoking after the HRA. It is suggested that the TDS is a reliable and useful screening questionnaire for tobacco/nicotine dependence according to ICD-10, DSM-III-R, and DSM-IV.     

Pharmacokinetics of formulated tenoxicam transdermal delivery systems

To investigate the feasibility of developing a new tenoxicam transdermal delivery system (TDS), the pharmacokinetics of tenoxicam from various formulated TDS were evaluated and compared with values following oral administration of tenoxicam and with application of a piroxicam plaster (Trast) marketed in Korea. Based on previous in-vitro study results, a mixture of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) (40:60) was used as a vehicle, and caprylic acid, capric acid, lauric acid, oleic acid or linoleic acid (each at 3%) was added as an enhancer. Triethanolamine (5%) was used as a solubilizer, and Duro-Tak 87-2510 as a pressure-sensitive adhesive. Among these fatty acids used for the formulation of tenoxicam TDS, caprylic acid showed the greatest enhancing effect; the area under the plasma concentration-time profile (AUC) decreased in the order of caprylic acid>linoleic acid>or=oleic acid>lauric acid>capric acid. Compared with oral administration, maximum plasma concentration (Cmax) was significantly lower, and time to reach Cmax (Tmax) delayed with all formulated tenoxicam TDS. All formulated TDS resulted in a lower AUC than with the oral formulation, except for TDS containing caprylic acid, although the difference was statistically significant only with capric acid. The AUC for all the formulated tenoxicam TDS was significantly higher than that of the piroxicam plaster; TDS with caprylic acid increased AUC 8.53-fold compared with the piroxicam plaster. Even though the Tmax of tenoxicam TDS was not significantly different from that of the piroxicam plaster, Cmax was higher; formulations containing caprylic acid and linoleic acid increased Cmax by 7.39- and 8.76-fold, respectively. In conclusion, a formulation containing 1.5 mL DGME-PGML (40:60) with 3% caprylic acid and 5% triethanolamine mixed with 6 g Duro-Tak 87-2510 could be a good candidate for developing a new tenoxicam TDS to maintain a comparable extent of absorption to oral delivery while attaining a prolonged effect with fewer toxic events.     

TDS exposure project: Application of the analytic hierarchy process for the prioritization of substances to be analyzed in a total diet study

The objective of this article is to develop a general method based on the analytic hierarchy process (AHP) methodology to rank the substances to be studied in a Total Diet Studies (TDS). This method was tested for different substances and groups of substances (N = 113), for which the TDS approach has been considered relevant. This work was performed by a group of 7 experts from different European countries representing their institutes, which are involved in the TDS EXPOSURE project. The AHP methodology is based on a score system taking into account experts' judgments quantified assigning comparative scores to the different identified issues. Hence, the 10 substances of highest interest in the framework of a TDS are trace elements (methylmercury, cadmium, inorganic arsenic, lead, aluminum, inorganic mercury), dioxins, furans and polychlorinated biphenyls (PCBs), and some additives (sulfites and nitrites). The priority list depends on both the national situation (geographical variations, consumer concern, etc.) and the availability of data. Thus, the list depends on the objectives of the TDS and on reachable analytical performances. Moreover, such a list is highly variable with time and new data (e.g. social context, vulnerable population groups, emerging substances, new toxicological data or health-based guidance values).     

Transdermal delivery of nicotine in normal human volunteers: a single dose and multiple dose study

The absorption of nicotine delivered by a transdermal delivery system (TDS) was investigated in two separate studies, (A) a dose proportionality study and (B) a multiple dose study. In the dose range of 15-60 mg nicotine, the AUC and Cmax values were proportional to the dose. The levels achieved were in the same range as reported in smokers, following absorption from nicotine chewing gum. The TDS used in the present study produced sustained levels of nicotine for 24 h. No significant accumulation of nicotine was evident as a result of multiple dose administration using a 30-mg nicotine patch. Absorption of nicotine from the TDS was 80-90% and the rate of delivery was similar during both studies.     

CHARACTERIZATION OF A 7 DAY 17β-ESTRADIOL TRANSDERMAL DELIVERY SYSTEM: PHARMACOKINETICS IN HEALTHY POSTMENOPAUSAL WOMEN

To assess the delivery characteristics of a new 7 day 17β-estradiol transdermal delivery system (TDS), estradiol and estrone pharmacokinetics were evaluated following a single 7 d application of one TDS or two TDSs in 24 healthy, postmenopausal women in a nonblind, randomized, two-period crossover study. Serial blood samples and total urine output were collected before (baseline measurement of endogenous hormone) and during TDS application, and for 24 h (urine) or 72 h (blood) following TDS removal. Serum was assayed for estradiol and estrone by a validated radioimmunoassay (RIA) method. The combined amounts of estradiol and its conjugates, and estrone and its conjugates in urine were determined by validated RIA methods. Overall, one or two estradiol TDSs were well tolerated by healthy, postmenopausal female volunteers. Estradiol absorption from the TDS was characterized by a zero-order process and was dose proportional, resulting in average steady-state serum estradiol concentrations of 16 and 33 pg mL⁻¹ above baseline during the 7 d application of one and two TDSs, respectively. Parallel but smaller increases in serum estrone concentrations were observed, resulting in an increase in the serum estradiol/estrone concentration ratio from approximately 0·2 at baseline to median values of 0·64 and 0·88 during application of one and two TDSs, respectively. The 7 day 17β-estradiol TDS delivered a nominal estradiol dose of 0·02 mg/24 h during the intended wear period.     

In vitro comparative studies of two marketed transdermal nicotine delivery systems: Nicopatch and Nicorette

The aim of this work was to compare in vitro the performances at delivering nicotine of two transdermal delivery system (TDS): Nicorette (8.3 mg/10 cm(2) nicotine content) and Nicopatch (17.5 mg/10 cm(2)). Release profiles were obtained using the FDA paddle method, and skin permeation profiles using Franz-type diffusion cells. Using the first method, nicotine release followed the polymer matrix diffusion-controlled process, as suggested by the linear Q versus t(1/2) relationship. Cumulative amounts released from Nicopatch were twice the amounts released from Nicorette, but the released fractions were almost equal for both TDS ( approximately 50%). Using diffusion cells, skin permeation rates were constant over the time: they were not significantly different between both TDS and close to in vivo claimed releases: Nicorette should be considered as more efficient at delivering nicotine through skin than Nicopatch. However, cumulative permeated amounts were overestimated, indicating that the actual diffusion surface area exceeded the effective diffusion surface area of the cells. Reducing the trimmed TDS surface area led not only to a reduction of the cumulative permeated amounts, but also to a reduction of the permeation rates. Therefore, the usefulness of the method to evaluate skin permeation parameters of TDS is questioned.     

Testicular dysgenesis syndrome and Leydig cell function

Fertility among human beings appear to be on the decline in many Western countries, and part of the explanation may be decreasing male fecundity. A hypothesis has been put forward that decreasing semen quality may be associated with a testicular dysgenesis syndrome (TDS), a spectrum of disorders originating in early foetal life. TDS comprises various aspects of impaired gonadal development and function, including testicular cancer. A growing body of evidence, including animal models and research in human beings, points to lifestyle factors and endocrine disrupters as risk factors for TDS. We present our view of the emerging role of Leydig cell dysfunction with subsequent decreased testosterone levels in the pathogenesis of TDS.     

Exposure assessment within a Total Diet Study: A comparison of the use of the pan-European classification system FoodEx-1 with national food classification systems

A Total Diet Study (TDS) consists of selecting, collecting and preparing commonly consumed foods purchased at retail level and analysing them for harmful and/or beneficial chemical substances. A food classification system is needed to link food consumption data with the contaminant concentration data obtained in the TDS for the exposure assessment. In this study a comparison was made between the use of a national food classification systems and the use of FoodEx-1, developed and recommended by the European Food Safety Authority (EFSA). The work was performed using data of six European countries: Belgium, Czech Republic, France, The Netherlands, Spain and the UK. For each population, exposure to contaminant A (organic compounds) and/or contaminant B (inorganic compound) was assessed by the Monte Carlo Risk Assessment (MCRA) software using the national classification system and FoodEx-1 for food consumption data and for TDS laboratory results. Minimal differences between both approaches were observed. This observation applied for both contaminant A and contaminant B. In general risk assessment will be similar for both approaches; however, this is not guaranteed. FoodEx-1 proved to be a valuable hierarchic classification system in order to harmonise exposure assessment based on existing TDS results throughout Europe.