Pharmacokinetics of nitroglycerin and clonidine delivered by the transdermal route

This article describes in vitro and in vivo performance of two transdermal drug delivery systems. Transderm-Nitro delivers nitroglycerin for the treatment and prevention of angina for 24 hours following a single application. In a three-way crossover study comparing Transderm-Nitro with two other transdermal nitroglycerin products, mean plasma levels of drug were similar 0.5 and 6 hours after application; however, with Transderm-Nitro the area under the plasma concentration curve was highest and the coefficient of variation was least. A transdermal therapeutic system for delivering clonidine (Catapres-TTS) is used for the treatment of hypertension. In a two-way crossover study comparing Catapres-TTS and oral Catapres, plasma levels of clonidine with use of the transdermal system reached a steady-state value in 2 to 3 days and remained steady for the duration of the wearing period; plasma levels with oral Catapres, however, fluctuated markedly. The ratio of maximum ot minimum plasma levels during a dosing interval was 2 for oral Catapres and approximately 1 for Catapres-TTS. The potential use of intact skin as a route of entry for controlled delivery of drugs to the systemic circulation is promising.     

Pharmacokinetics of a new transdermal testosterone gel in gonadotrophin-suppressed normal men

OBJECTIVE: In a phase I single-centre, open, randomized study, the pharmacokinetics of two doses of a transdermal testosterone gel containing 2.5% testosterone were evaluated in 26 healthy male volunteers. DESIGN: To eliminate the influence of endogenous serum testosterone, gonadotrophins and endogenous testosterone secretion were suppressed by a single intramuscular injection of 400 mg norethisterone enanthate. Fourteen men applied 5.0 g and 12 men applied 2.5 g testosterone gel daily for 10 days. Half the men in each group washed the gel off 10 min after it had been applied. RESULTS: In all the men, a marked suppression of LH, FSH, testosterone, dihydrotestosterone (DHT) and oestradiol was observed after norethisterone treatment. Physiological serum concentrations of testosterone were restored during the 10-day treatment period in the group of men applying 5.0 g testosterone gel. Increasing serum concentrations of testosterone from day 1 to day 10 were observed. Oestradiol and DHT concentrations did not exceed normal values. Washing 10 min after gel application did not influence the resorption of testosterone. A dose of 2.5 g testosterone gel was insufficient to achieve physiological serum concentrations of testosterone. CONCLUSION: Testosterone replacement treatment with 5.0 g of this 2.5% testosterone gel is able to achieve constant physiological testosterone concentrations in gonadotrophin-suppressed men. Washing the skin after 10 min does not influence the pharmacokinetic profile and thus significantly reduces the risk of contamination of female partners or infants.     

Microneedles permit transdermal delivery of a skin-impermeant medication to humans

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. Here, we present a clinical study of MN-enhanced delivery of a medication to humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications.     

Design principles of chemical penetration enhancers for transdermal drug delivery

Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future.     

Pharmaceutical considerations of transdermal nitroglycerin delivery: The various approaches

When formulated as a sublingual or an oral sustained-release dosage form, nitroglycerin has certain shortcomings, i.e., decreased duration of antianginal action and extensive hepatic first-pass elimination, which limit its efficacy. The finding that administration of nitroglycerin in the form of topical ointment decreases the extent of hepatic first-pass elimination and increases the duration of therapeutic activity has pointed the way to the possibility of developing a more effective transdermal drug delivery device. Three such devices are the Nitrodisc, Nitro-Dur, and Transderm-Nitro systems. All three systems generate effective plasma drug levels within 30 minutes and maintain steady-state drug plasma levels as follows: the 16 cm² Nitrodisc at 280.6 ± 18.7 pg/ml for 32 hours; the 20 cm² Nitro-Dur at 201.4 ± 60.7 pg/ml for 24 hours; and the 20 cm² Transderm-Nitro system at 209.8 ± 22.8 pg/ml for 24 hours. In vitro studies show that the drug penetrates the skin with zero-order kinetics in all three systems, the rate for Nitrodisc being 20% greater than that of the other systems. When the daily nitroglycerin dose is calculated in terms of skin permeation rate and the device's surface area, the three transdermal systems become clinically interchangeable.     

Programmable transdermal drug delivery of nicotine using carbon nanotube membranes

Carbon nanotube (CNT) membranes were employed as the active element of a switchable transdermal drug delivery device that can facilitate more effective treatments of drug abuse and addiction. Due to the dramatically fast flow through CNT cores, high charge density, and small pore dimensions, highly efficient electrophoretic pumping through functionalized CNT membrane was achieved. These membranes were integrated with a nicotine formulation to obtain switchable transdermal nicotine delivery rates on human skin (in vitro) and are consistent with a Fickian diffusion in series model. The transdermal nicotine delivery device was able to successfully switch between high (1.3 ± 0.65 μmol/hr-cm²) and low (0.33 ± 0.22 μmol/hr-cm²) fluxes that coincide with therapeutic demand levels for nicotine cessation treatment. These highly energy efficient programmable devices with minimal skin irritation and no skin barrier disruption would open an avenue for single application long-wear patches for therapies that require variable or programmable delivery rates.     

茵陈蒿汤经透皮给药治疗胆绞痛的研究

目的：为探索治疗胆绞痛新途径，采用中药经透皮给药系统（ＴＤＳ），并结合现代测试方法试图阐明机制。方法：茵陈蒿汤为主的１２味中药制成乳膏剂贴敷患者胆囊区；分成三组：（Ａ）胆绞痛急诊就医者３０例、（Ｂ）胆石症准备手术且有右上腹疼痛者２８例、（Ｃ）对照组２０例；除观察止痛疗效外，还采用薄层层析一分光光度法，检测尿液、胆汁、胆囊和膏药中的药用成份一对羟苯乙酮。结果：（１）疼痛症状明显缓解率７６％（４４／５８例），其中Ａ组８０％（２４／３０例），Ｂ组７１％（２０／２８例），二组差异无显著性（Ｐ＞０．０５）；（２）Ｂ组尿液、胆汁、胆囊和乳膏剂中的对羟苯乙酮含量分别为３９．０４±６．９９，７９．３４±２１．６９（ｍｍｏｌ．Ｌ－１）；０．４６±０．１０，１．８３７±０．２１（ｍｏｌ．ｋｇ－１），４种标本中的含量进行比较，差异均有非常显著性（Ｐ＜０．００１）。结论：茵陈等中药透过皮肤局部给药不仅能治疗胆绞痛，而且具有药物进入靶器官浓度明显高于全身的优越性，从而发挥较好的疗效。     

吡喹酮透皮给药治疗小鼠日本血吸虫病效果

目的 观察吡喹酮透皮剂对不同发育阶段日本血吸虫感染和再感染早期的治疗效果。方法 各试验组昆明小鼠均感染日本血吸虫尾蚴40±2条, 对一次感染和再感染早期的昆明小鼠进行透皮治疗。各试验均设对照组, 感染后42 d 解剖冲虫, 计算减虫率、 减肝卵率和减毛蚴孵化率, 评价透皮剂的治疗效果。ELISA检测初次感染和再感染不同时期IgG 抗体水平的动态变化。结果 首次感染后1、 7、 14、 21、 28 d减虫率分别为48.9%、 0、 28.8%、 84.3%、 70.2%; 再感染后1 d和 14 d减虫率分别为85.6%和90.8%。首次感染后随感染时间延长, 小鼠体内特异性IgG抗体水平逐渐上升; 再感染后小鼠体内针对小鼠抗虫卵可溶性抗原特异性IgG 阳性和阴性比值明显上升。结论 吡喹酮透皮剂对不同发育阶段的日本血吸虫均有不同程度的杀灭作用, 对再感染早期童虫的减虫效果更好。     

Clinical experience with rate-controlled delivery of antihypertensive therapy by a transdermal system

The efficacy of transdermal clonidine, alone and in combination with diuretics, has been demonstrated in several studies involving patients with mild to moderate essential hypertension. In one 3-month open study, 64% of patients (wearing one to three 3.5 cm2 transdermal patches) achieved sustained blood pressure reductions throughout the treatment period. In this large study, side effects requiring discontinuation of drug were not observed. Transdermal clonidine reduced plasma renin activity and urinary aldosterone excretion to the same extent as that reported for oral clonidine. Renal function or serum electrolytes were not affected during therapy with transdermal clonidine. Another study showed that patients receiving oral clonidine and hydrochlorothiazide experienced comparable blood pressure reductions when switched to transdermal patches. Plasma drug concentrations measured during treatment with the transdermal patches were similar to the trough levels observed during treatment with oral clonidine. The equipotency of oral and transdermal therapy in combination with hydrochlorothiazide was also demonstrated in two remaining studies. In one of these studies it was suggested that daily variations in blood pressure induced by the peak and trough drug levels of the oral form were minimized by the stable drug levels characteristics of the transdermal device.     

Pharmacokinetics of new testosterone transdermal therapeutic systems in gonadotropin-releasing hormone antagonist-suppressed normal men.

In a phase I single-center, open, randomized pilot study with a three-way cross-over design the pharmacokinetics of three testosterone-containing transdermal therapeutic systems were evaluated in healthy male volunteers. Testosterone TTS HEXAL type 1 and 2 are nonscrotal membrane patches differing in the kind of adhesive used. 6 subjects were treated with low dose Testosterone TTS type 1, high dose Testosterone TTS type 1 and low dose Testosterone TTS type 2. To eliminate the influence of endogenous serum testosterone, the endogenous testosterone secretion was suppressed by the GnRH antagonist cetrorelix. In all subjects under GnRH antagonist treatment a marked suppression of LH, FSH, testosterone, DHT and estradiol was observed. Physiologic testosterone levels were achieved during the 24-hour-application period. Maximal serum levels were reached after 4 hours with both TTS systems. Both systems appear suited for further testing because both enable a physiological circadian profile to be achieved. GnRH-antagonist pretreatment is a useful model to evaluate the effect of exogenous testosterone in clinical studies, when, due to fluctuations in endogenous hormone levels, an estimation of the proportion of exogenous steroid is not possible.     

Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery.

Mammalian skin owes its remarkable barrier function to its outermost and dead layer, the stratum corneum. Transdermal transport through this region occurs predominantly through intercellular lipids, organized largely in bilayers. Electroporation is the creation of aqueous pores in lipid bilayers by the application of a short (microseconds to milliseconds) electric pulse. Our measurements suggest that electroporation occurs in the intercellular lipid bilayers of the stratum corneum by a mechanism involving transient structural changes. Flux increases up to 4 orders of magnitude were observed with human skin in vitro for three polar molecules having charges between -1 and -4 and molecular weights up to slightly more than 1000. Similar flux increases were observed in vivo with animal skin. These results may have significance for drug delivery and other medical applications.     

Ionic liquids as a class of materials for transdermal delivery and pathogen neutralization

Biofilm-protected microbial infections in skin are a serious health risk that remains to be adequately addressed. The lack of progress in developing effective treatment strategies is largely due to the transport barriers posed by the stratum corneum of the skin and the biofilm. In this work, we report on the use of Ionic Liquids (ILs) for biofilm disruption and enhanced antibiotic delivery across skin layers. We outline the syntheses of ILs, analysis of relevant physicochemical properties, and subsequent neutralization effects on two biofilm-forming pathogens: Pseudomonas aeruginosa and Salmonella enterica. Further, the ILs were also examined for cytotoxicity, skin irritation, delivery of antibiotics through the skin, and treatment of biofilms in a wound model. Of the materials examined, choline-geranate emerged as a multipurpose IL with excellent antimicrobial activity, minimal toxicity to epithelial cells as well as skin, and effective permeation enhancement for drug delivery. Specifically, choline-geranate was comparable with, or more effective than, bleach treatment against established biofilms of S. enterica and P. aeruginosa, respectively. In addition, choline-geranate increased delivery of cefadroxil, an antibiotic, by >16-fold into the deep tissue layers of the skin without inducing skin irritation. The in vivo efficacy of choline-geranate was validated using a biofilm-infected wound model (>95% bacterial death after 2-h treatment). This work establishes the use of ILs for simultaneous enhancement of topical drug delivery and antibiotic activity.Microorganisms that are protected in a biofilm pose a significant health risk due to their antibiotic resistance and recalcitrance to treatment. Biofilm-protected bacteria account for ∼80% of total bacterial infections in humans and are 50–1,000 times more resistant to antibiotics than their planktonic counterparts (1). The antibiotic resistance of many biofilms originates in a layer of extracellular polymeric substances (EPSs) comprising polysaccharides, humic acids, nucleic acids, and peptides (2) that serve as a transport barrier. Further, biofilms are able to grow and persist on living as well as nonliving surfaces and are routinely found in hospital settings where patients are at high risk (3, 4). For example, the opportunistic Gram-negative pathogen, Pseudomonas aeruginosa, is commonly associated with high rates of morbidity and mortality, including urinary tract infections, septicemia, and endocarditis (5).Biofilms are especially problematic when they establish on human skin because their presence serves to escalate the severity of pathology and slow wound healing (6). In addition, the sustained presence of dermal biofilms, which increases the severity and duration of bacterial infections, elevates the risk of contact transfer in home and hospital settings. Several common dermatological diseases, including atopic dermatitis, bullous impetigo, diabetic ulcers, and acne, routinely manifest biofilms of Staphylococcus aureus and other bacteria (7, 8).Effective treatment of skin-based bacterial biofilms has been identified as a serious and unmet medical need (1, 9). However, biofilms established on skin are inherently difficult to treat, largely due to the outermost layer of the skin, the stratum corneum (SC), being a natural barrier for drug delivery. The SC is an effective transport barrier and severely limits diffusion of drugs (10). Although the SC may sometimes be compromised at the site of the skin biofilm due to the presence of a wound, an effective treatment must deliver antibiotics to all areas of infection. Biofilms often persist in the periphery of the actual wound, beneath an intact, healthy skin barrier because they exhibit local deep-tissue invasion (11, 12). To address this pathological concern, several formulation- and device-based methods were developed to increase drug delivery into skin (10) and biofilms (13, 14); however, their utility is limited. Specifically, device-based methods are difficult to use on large skin areas. Further, the presence of wounds at the site of biofilms poses a challenge in the use of devices. Formulation-based approaches make use of penetration enhancers such as fatty acids and alcohols, which often disrupt the skin lipid bilayer, thus enhancing transport (15). This approach often suffers from the inability to simultaneously enhance transport across both the SC and the biofilm. In addition, biofilm formation often leads to skin inflammation, leading to keratinocyte apoptosis and inhibition of reepithelialization (16). Formulations that are designed to enhance transdermal transport often contain strong penetration enhancers that can further inflame the wound site and adversely affect wound healing (17).Here, we report the use of both ionic liquids (ILs) and deep eutectic solvents (DESs) as a dual-purpose strategy for both disruption and neutralization of biofilm-forming pathogens, as well as drug delivery into and across the skin. Briefly, ILs are organic salts comprised of an organic cation and an organic or inorganic anion that, when mixed in 1:1 molar ratio (true ionic liquid), give rise to a room-temperature ionic liquid (RTIL) (18). Conversely, DESs are broadly defined as a mixture of charged and neutral species, either in equimolar or imbalanced ratios, that, when combined, have a much lower melting point than the individual component. Taken together, both ILs and DESs have gained acceptance for their beneficial antimicrobial and antifungal properties as demonstrated in several reports over the last decade (19–22). More recently, both ILs and DESs were found to increase drug solubility and serve as a carrier for topical drug delivery (23–26). Our comprehensive approach is unique in that we examine a panel of in-house synthesized ILs and DESs (henceforth referred to as ILs for simplicity) for all of the following applications: (i) antimicrobial properties on two biofilm forming Gram-negative pathogenic bacteria, Pseudomonas aeruginosa ATCC15692 and Salmonella enterica serovar Typhimurium LT2; (ii) cytotoxicity effects on mammalian cell lines; (iii) skin irritation potential; (iv) transdermal drug delivery properties; and (v) treatment of biofilm on a skin-wound model. This comprehensive screening strategy enabled the discovery of one IL, choline-geranate (11), which emerged as a multipurpose formulation with excellent antimicrobial activity, minimal toxicity to epithelial cells as well as skin, and effective permeation enhancement for drug delivery.     

川芎嗪靶向透皮辅助治疗结核性胸膜炎的临床疗效观察

目的评价川芎嗪经超声电导靶向透皮治疗结核性胸膜炎的疗效。方法 90例初治结核性渗出性胸膜炎患者随机分为对照组、静脉组、超声电导组各30例。对照组采用胸腔引流及全身抗结核治疗;静脉组在对照组基础上联合川芎嗪静脉滴注2周;超声电导组在对照组基础上联合川芎嗪靶向透皮治疗2周。观察治疗后热退时间、胸水消失时间、胸膜肥厚情况。计量资料用±s表示,3组间比较采用方差分析,组间两两比较采用q检验。以P0.05为差异具有统计学意义。结果对照组、静脉组、超声电导组的退热时间分别为3.9±2.5d、3.3±1.8d、3.2±1.7d,3组间无显著差异;胸水消退时间及胸膜厚度分别为7.9±2.6d、6.6±2.4d、6.3±2.4d和2.85±0.99mm、1.74±0.57mm、1.68±0.45mm,静脉组及超声电导组间无统计学差异,但较对照组均有统计学差异。结论川芎嗪经超声电导透皮辅助治疗结核性胸膜炎,具有安全、有效、无创、简便的优点。     

Pharmacokinetics and safety of paclitaxel delivery into porcine airway walls by a new endobronchial drug delivery catheter

Background and objective

Intratumoral administration of chemotherapeutic agents is a treatment modality that has proven efficacious in reducing the recurrence of tumours and increases specificity of treatment while minimizing systemic side effects. Direct intratumoral injection of malignant airway obstruction has potential therapeutic benefits but tissue drug concentrations and side‐effect profiles are poorly understood.

Methods

Bronchial wall injection of generic paclitaxel (PTX) (102 injections of 0.05, 0.5, 1.5 or 2.5 mg/mL in 10 healthy pigs), saline (14 injections in 2 healthy pigs) or Abraxane (ABX) (24 injections of 0.5 mg/mL in 4 healthy pigs) was performed with a microneedle infusion catheter. Local histopathology, plasma and tissue PTX concentrations were evaluated at 7, 20 or 28 days post‐injection.

Results

Injection of generic PTX directly into the bronchial wall at doses up to 1.5 mg/mL only caused minimal tissue injury. Dose‐limiting tissue reaction was observed at 2.5 mg/mL. Plasma PTX was detectable for up to 5 days but not at 28 days, with area under the curve (AUC)_(0‐5d) 20‐ to 50‐fold lower than the AUC_(0‐∞) of 6300 ng h/mL for the approved intravenous dose. At 7 and 28 days post‐injection, bronchial PTX tissue concentrations were above a 10‐nmol/L cancer therapeutic level. PTX was not found in peripheral tissues. Similar results were observed between ABX and generic PTX.

Conclusion

Results of these studies confirm the administration of PTX directly into the bronchial wall is safe and feasible. PTX was detectable in plasma for <7 days but tissue concentrations remained therapeutic throughout the follow‐up period.

     

Iontophoretically enhanced transdermal delivery of an ACE inhibitor in induced hypertensive rabbits: Preliminary report

Summary Both conventional direct current (DC) and pulsedmode DC constant-current iontophoresis were used to investigate enhanced transdermal delivery of the angiotensin-converting enzyme (ACE) inhibitor captopril to rabbits with acutely induced hypertension. Passive transdermal captopril administration and pulsed DC constant-current iontophoresis of the vehicle were studied as control experimentation. Mean arterial pressure (MAP) was not significantly (p>0.05) altered following passive transdermal delivery of captopril (n=4) or after iontophoretic delivery of the vehicle alone (n=4). Pressure reduction was evident within 10 minutes of iontophoretic enhancement of transdermal captopril delivery. DC mode constant-current (n=4) iontophoretic transdermal captopril administration caused MAP to fall by 21% from a mean hypertensive level of 66±5 mmHg to a mean post-treatment level of 52±6 mmHg (p<0.05) within 60 minutes. Pulsed DC mode constant-current (n=4) iontophoresis of captopril caused mean MAP to fall on average by 27% from 62±6 to 45±5 mmHg (p<0.05), also within 60 minutes. This paper provides the first report on the enhanced efficiency during iontophoretic delivery of an ACE inhibitor. We have concluded that both modes of constant-current iontophoresis of captopril offer a safe and effective means of pressure reduction in rabbits with induced hypertension and that there is no significant difference in efficacy between the two forms of enhanced delivery. These results have potential applications for enhanced transdermal delivery of ACE inhibitors in humans.     

Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 microm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats.