电穿孔技术促进萘普生经皮渗透的研究

目的：研究电穿孔技术对小分子离子型药物经皮渗透的影响。方法：应用双室扩散池方法研究电穿孔技术对萘普生在离体大鼠腹部皮肤经皮渗透的影响。并与被动扩散和离子导入进行比较。结果：外加电脉冲（指数衰减型脉冲,脉冲幅度为４００Ｖ,电容器电容为２．２ｕＦ,脉冲率为２０ｐｕｌｓｅｓ．ｍｉｎ＾－１,脉冲宽度τ≈６．０ｍｓ）或离子导入（１ｍＡ．ｃｍ＾－２,６ｈ）时,萘普生的渗透速率和累积渗透量均大于被动扩散。外加脉     

Transdermal delivery of nalbuphine and nalbuphine pivalate from hydrogels by passive diffusion and iontophoresis.

The objective of this study was to evaluate the in vitro transdermal permeation of nalbuphine hydrochloride (CAS 23277-43-2) (NA) and nalbuphine pivalate (NAP), a novel prodrug of NA, from different hydrogel formulations under passive diffusion as well as iontophoresis. Various concentrations of polymers, including polyvinylpyrrolidone (PVP) and hydroxypropyl cellulose (HPC) were used in the hydrogel formulations. The passive permeation rate of NA was affected by the polymer concentrations, which can be attributed to different viscosities of the hydrated formulations; whereas the passive permeation rate of NAP was not influenced by the various polymer concentrations. Iontophoresis significantly increased the permeation rates of NA and NAP from various hydrogel formulations through skin; the enhancement ratios were higher for NA in all the formulations studied. The iontophoretic permeation rates of NA were slightly decreased by the incorporation of polymers; however, the transdermal flux and membrane potential were independent of polymer concentrations for both NA and NAP, demonstrating that the polymer concentrations in the hydrogel formulations did not have significant effects on the iontophoretic permeation of NA and NAP.     

Transdermal drug delivery using electroporation. I. Factors influencing in vitro delivery of terazosin hydrochloride in hairless rats

The use of electroporation pulses as a physical means of enhancing the permeability of skin to deliver drugs is in the early stages of development. In this article, a systematic study examining the parameters influencing electroporative transdermal delivery of terazosin hydrochloride to hairless rat skin are reported. It was found that voltage, pulse length (tau), and number of pulses were the three most important parameters, in that order. For creating a significant enhancement in drug delivery to the skin, without causing any apparent change in its external appearance, it was necessary to deliver five or more exponentially decaying electroporation pulses, at 88 +/- 2.5 V (voltage across the skin), with a decay time constant of 20 ms. Electrodes with larger area could attain the same voltages across the skin with a much lower applied voltage and possessed other advantages with regard to performance of the drug delivery system.     

Transdermal drug delivery using electroporation. II. Factors influencing skin reversibility in electroporative delivery of terazosin hydrochloride in hairless rats

A previous study indicated that the parameters governing the performance of electroporative delivery to the skin, are voltage, pulse length, number of pulses and electrode area.1 This article describes a study in which the reversibility of the electroporation technique is evaluated with in vitro methods. The skin's reversal from an enhanced permeation mode as a result of electroporation to the base level was used as an index to understand the mechanism of drug delivery and also as a preliminary indicator of safety. Maximum delivery of the model drug, terazosin hydrochloride, occurred during the pulsing. Electroporative delivery with a wire electrode (small-area electrode, 0.56 cm(2)) using 20 pulses at U(skin,0) 88 V, and pulse length 20 ms, did not cause any damage to the skin. Increasing the pulse length to 60 ms, while keeping the rest of the parameters fixed, caused a visible change in the external appearance of the skin. However, with the use of a spiral electrode (large-area electrode, 2.74 cm(2)) at 60-ms pulse length, there was minimal damage to the skin. This may be attributed to the more uniform flow of current over the whole skin area. The large-area electrode required a smaller electrode voltage, U(electrode,0) for any given U(skin,0) and also delivered nearly double the instantaneous power density compared with the small-area electrode. These findings indicate that using shorter pulses and large-area electrodes is a safer technique than large pulses and small-area electrodes when electroporation is used to enhance skin's permeability for drug delivery.     

Transdermal delivery of insulin by ultrasonic vibration.

Ultrasonic vibration has been used to deliver insulin through the skin of hairless mice fasted overnight and partially immersed in an aqueous solution of insulin (20 units mL-1). The skin surface was exposed to ultrasonic vibration in two ultrasonic energy ranges (3000-5000 Pa and 5000-8000 Pa) at 48 kHz for 5 min. Blood glucose concentration was measured before and after exposure to insulin and ultrasonic vibration. In the group subjected to the lower energy vibrations, blood glucose fell rapidly to reach 34 +/- 11.9% of control values in 120 min, while when the animals were exposed to higher energy vibrations, the fall in blood glucose was 22.4 +/- 3.9% of control values at 120 min. The values remained low for the length of the experiment (240 min). Those exposed to insulin alone or ultrasonic vibration alone revealed no significant change in blood glucose concentration. It is postulated that ultrasonic vibration may alter skin permeability resulting in the absorption of insulin. That the blood glucose decrease was greater at the higher of the two energy ranges, suggests this factor could control insulin delivery.     

Drug delivery systems. 6. Transdermal drug delivery

Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side-effects with some of these formulations is indicative of absorption through the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by micro-organisms and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. Basically, four systems are available that allow for effective absorption of drugs across the skin. The microsealed system is a partition-controlled delivery system that contains a drug reservoir with a saturated suspension of drug in a water-miscible solvent homogeneously dispersed in a silicone elastomer matrix. A second system is the matrix-diffusion controlled system. The third and most widely used system for transdermal drug delivery is the membrane-permeation controlled system. A fourth system, recently made available, is the gradient-charged system. Additionally, advanced transdermal carriers include systems such as iontophoretic and sonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs have been formulated in transdermal systems, and others are being examined for the feasibility of their delivery in this manner (e.g., nicotine antihistamines, beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents). Research also continues on various chemical penetration enhancers that may allow delivery of therapeutic substances. For example, penetration enhancers such as Azone may allow delivery of larger-sized molecules such as proteins and polypeptides.     

Transdermal delivery of indomethacin by iontophoresis

The objective of this study was to construct a modified equation for the delivery of a drug by iontophoresis. Indomethacin was selected as a model since it has been widely used as a non-steroidal anti-inflammatory drug (NSAID) for external pharmaceutical preparations. The experiments were performed under a constant current in vivo using rat abdominal skin, and the plasma concentration was monitored by HPLC. Pharmacokinetic parameters were obtained from the plasma concentration profiles after intravenous injection. A theoretical value of the transdermal delivery of drug by iontophoresis was calculated from the plasma concentration and pharmacokinetic parameters. The experimental value was evidently higher than the theoretical one, suggesting the enhancement of passive diffusion with an increase of applied current. The modified equation was proposed for the delivery of a drug by iontophoresis incorporating enhanced passive diffusion.     

In vivo gene delivery by electroporation

The physical phenomenon of electroporation has been successfully exploited in vitro for the delivery of genes, drugs, and other molecules with increasing frequency over the past two decades. This type of electrically mediated delivery has been translated into an in vivo setting in more recent years with a focus on therapeutic molecules. One promising area is the delivery of genes as a therapy.Advances in molecular medicine have produced a very large amount of information about genes that translate to therapeutic molecules when expressed in living cells. Current standard methods for transferring genes utilize viruses to deliver DNA into cells. These viral methods have not yielded optimal results in most cases. Therefore, there is an increasing interest in nonviral methods for gene delivery. In vivo electrically mediated gene delivery is an attractive alternative because of the site specific nature of delivery as well as the universal applicability of electroporation. A review of the studies performed to investigate and develop this new gene delivery technology is presented.     

Antitumor drug delivery by tissue electroporation

Tissue electroporation has been explored to enhance the local delivery of chemotherapueutic agents to solid tumors. The technique, known as electrochemotherapy (ECT), uses high-voltage pulses to deliver drugs across cancerous tissues. ECT has been demonstrated to be an effective treatment for cutaneous malignancies. Recent studies also indicate that the applications of ECT can be extended from the treatment of cutaneous cancers to the treatment of tumors of vital organs such as brain, liver, lungs and others. This review also discusses electrogene antitumor therapy.     

Transdermal drug delivery by electroporation applied on the stratum corneum of rat using stamp-type electrode and frog-type electrode in vitro

Transdermal enhancement effects of electroporation applied only on the stratum corneum by two electrode types, the stamp-type electrode and the frog-type electrode, were investigated in vitro using excised rat skin. Carboxyfluorescein (CF) was selected as a model compound. The excised skin was set in a Franz type diffusion cell and a square wave electric pulse was applied to the stratum corneum under various electric pulse conditions. We determined the permeability of CF to the receptor compartment under these conditions. Voltage, electric pulse length, and number of electric pulses, were varied from 10 to 1000 V, 50 micros to 15 ms and 5 to 30 pulses, respectively. Flux rate was enhanced as the electric pulse condition strengthened. However, the maximum value was attained in the flux rate, above which no increase was observed despite strengthening of the electric pulse. Although at low electric pulses, the enhancement effect of the frog-type electrode was superior to that of the stamp-type electrode, the maximum flux rates were the same. These results indicate that electroporation on the stratum corneum using the stamp-type electrode or frog-type electrode, is useful for transdermal drug delivery.     

Transdermal and transmucosal powdered drug delivery.

High-velocity powder injection is a promising new drug-delivery technique that provides needle- and pain-free delivery of traditional drugs, drugs from biotechnology such as proteins, peptides, and oligonucleotides as well as traditional and genetic vaccines. The energy of a transient helium gas jet accelerates fine drug particles of 20 microns-100 microns diameter to high velocities and delivers them into skin or mucosal sites. This review describes the configuration and operating principles of devices that accelerate the particles, the required properties of the particles, the characteristics of the target tissues, and features of the developmental test methods. Preclinical and clinical results that best characterize the technology and introduce its potential as a drug-delivery platform are presented.     

Enhanced transdermal delivery of tetracaine by electroporation

The effect of electroporation on the transport of tetracaine through skin in vitro was studied using side-by-side compartment diffusion cells method. After achieving steady state by passive diffusion, fluxes of tetracaine achieved with passive diffusion, electroporative pulse and iontophoresis were compared. Electroporation (square-wave pulse, voltage 130 V, pulse time 0.4 s, pulse frequency 40 pulses min(-1)) or iontophoresis (0.2.mA cm(-2), lasting for 4 h) increased the transport of tetracaine through skin. The flux of tetracaine at 0.25 h after electroporation (pulse number 400) was 54.6+/-6.0 microg.cm(-2).h(-1), that after iontophoresis was 17.4+/-5.8 microg.cm(-2).h(-1) and that after passive diffusion was 8.2+/-0.5 microg.cm(-2).h(-1). In addition, the fluxes of tetracaine increased with the increasing of pulse number. From these results, it is clear that electroporation is effective in enhancing transdermal delivery of tetracaine and its function is better than iontophoresis.     

Transdermal delivery of contraceptives

Contraceptive agents are administered to the body through a variety of routes. Research has recently been directed at examining the transdermal route for systemic delivery of contraceptive agents, including estrogens and progestins. The transdermal route has several potential advantages over the other routes of administration: (1) improved compliance, (2) once-weekly administration, (3) delivery is easily terminated, and (4) some side effects can be alleviated based on more constant delivery rates. This article reviews the permeability of skin toward contraceptive steroids and how skin permeability is evaluated. The metabolism of contraceptive steroids is also considered. Transdermal delivery systems used to deliver contraceptives are presented, followed by a detailed discussion of several delivery systems for specific contraceptive agents such as levonorgestrel and estradiol. The potential problem of skin irritation is presented as it relates to transdermal contraceptive delivery systems, all of which will be worn chronically.     

Transdermal delivery of beta-blockers

Beta-adrenoceptor blocking drugs (beta-blockers) are one of the most frequently used class of cardiovascular drugs that are mainly used in conventional dosage forms., which have their own limitations including hepatic first-pass metabolism, high incidence of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Essentially, attempts have been made to develop novel drug delivery systems for beta-blockers, including transdermal delivery systems, to circumvent the drawbacks of conventional drug delivery. However, so far none of the beta-blocker drugs have been marketed as transdermal delivery systems. Nevertheless, there have been noteworthy research endeavours worldwide at the laboratory level to investigate the skin permeation and to develop transdermal formulations of beta-blockers including: propranolol, metoprolol, atenolol, timolol, levobunolol, bupranolol, bopindolol, mepindolol, sotalol, labetolol, pindolol, acebutolol and oxprenolol. Innovative research exploiting penetration-enhancing strategies, such as iontophoresis, electroporation, microneedles and sonophoresis, holds promise for the successful use of these drugs as consumer-friendly transdermal dosage forms in clinical practice. This paper presents an overview of the transdermal research on this important class of drugs.     

Transdermal delivery of levosimendan

The aim of this study was to determine if transdermal penetration of levosimendan, a novel positive inotropic drug, could be enhanced and controlled by formulation modifications. Penetration of levosimendan across human epidermis in vitro was determined using abdominal excised skin and diffusion cells. Predicted steady-state plasma concentrations of levosimendan were estimated using permeabilities and pharmacokinetic parameters of levosimendan. For penetration enhancement we used different pH values, co-solvents, cyclodextrins, surfactants, penetration enhancers, liposomes, and iontophoresis. Sodium lauryl sulfate, ethanol, oleic acid, and soya phosphatidylcholine or their combinations clearly increased levosimendan permeation across the skin in vitro. Iontophoresis was also an efficient method to increase transdermal permeation of levosimendan. A hydrophilic co-solvent/penetration enhancer is needed to achieve better permeability of levosimendan across the skin. In conclusion, transdermal delivery of levosimendan can be significantly increased by formulation modification. Based on kinetic calculations, therapeutic plasma concentrations may be achievable transdermally.     

Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs

The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection.     

Transdermal testosterone delivery: comparison between scrotal and nonscrotal delivery systems.

The purpose of this investigation was to study the bioequivalence of two testosterone transdermal delivery systems (T-TDSs). Testoderm, designed to deliver testosterone through scrotal skin, and Androderm, designed for nonscrotal permeation. In vitro permeation and release kinetics as well as in vivo pharmacokinetics in the castrated Yucatan miniature swine (minipigs) model of both T-TDSs were studied side by side under the same experimental conditions. In vitro skin permeation kinetics studies demonstrated that testosterone permeates through minipig dorsal skin at zero-order kinetics from both T-TDSs. The nonscrotal T-TDS, however, has a permeation rate which is approximately 13 times higher than that for the scrotal T-TDS. The release of testosterone from the nonscrotal T-TDS showed a biphasic release profile between cumulative amount released and time, whereas a monophasic release profile between cumulative amount released and square root of time was observed for the scrotal T-TDS. Pharmacokinetic analysis of plasma testosterone profiles in minipigs indicated a significant difference (p < 0.001) in daily dose of testosterone delivered (1.20 versus 4.83 mg/day), maximum concentration (Cmax) (54.2 versus 218.0 ng/dl), and area under concentration-time curve (AUC0-28)[665 versus 3208 (ng/dl) x hr] between these T-TDSs. However, there is no difference in time to reach Cmax mean residence time, and daily-delivered-dose-normalized Cmax and AUC0-28. The difference in pharmacokinetic profiles resulted from the difference in daily doses delivered, which could be attributed remarkably to the difference in permeation rate (approximately 13-fold) between the nonscrotal and scrotal T-TDSs.     

Lipid and electroosmosis enhanced transdermal delivery of insulin by electroporation

Transdermal transport of insulin and extraction of interstitial glucose under anodal iontophoresis (electroosmosis) following electroporation in the presence of 1,2-dimyristoylphophatidylserine (DMPS) was studied. An earlier study showed that DMPS increased the transport of insulin across porcine epidermis under electroporation by approximately fourfold. It was suggested that DMPS increased the lifetime of electropores in the epidermis resulting in an enhanced transport of permeants. When electroosmosis was applied across the epidermis following electroporation with DMPS, the enhancement of insulin transport was approximately 18-fold over electroporation alone. When the same strategy was applied to extract interstitial glucose, the enhancement was approximately 23-fold over electroporation alone. Real-time transdermal insulin transport kinetics was measured using FITC-labeled insulin and a custom-made vertical diffusion apparatus that had a fluorescence cuvette as the receiver compartment. Insulin transport by electroporation alone showed a nonlinear kinetics that is most likely due to the resealing of the electropores with time. The transport kinetics when electroporation was carried out in the presence of DMPS was more linear, confirming earlier studies that suggested the DMPS stabilizes transport paths formed by electroporation. The data suggests that in vivo, noninvasive insulin delivery to therapeutic levels and glucose extraction may be achieved by combining electroporation with anionic lipids and electroosmosis.     

Dermal and transdermal delivery: prodrugs

Attempts to deliver drugs into and through the skin (dermal and transdermal delivery) have not been very successful because the physicochemical properties of drugs are often not optimal. Prodrugs can be used to optimize those physicochemical properties of drugs and optimize their delivery by transiently masking their polar functional groups. For a drug to cross the rate-limiting barrier to delivery (the stratum corneum) it must dissolve in and cross multiple lipid and aqueous phases within the stratum corneum. Prodrugs can be designed to exhibit increased lipid and aqueous solubilities resulting in increased delivery. In order to identify the optimal prodrugs, they must be evaluated as saturated solutions where their thermodynamic activities are maximal in the solution and in the skin. If prodrugs are evaluated at concentrations less than at saturation, inaccurate conclusions about the optimal physicochemical properties may result. Prodrugs must be designed to optimize both their lipid and aqueous solubilities to optimize their delivery into and through the skin.