Coated microneedles for transdermal delivery.

Coated microneedles have been shown to deliver proteins and DNA into the skin in a minimally invasive manner. However, detailed studies examining coating methods and their breadth of applicability are lacking. This study's goal was to develop a simple, versatile and controlled microneedle coating process to make uniform coatings on microneedles and establish the breadth of molecules and particles that can be coated onto microneedles. First, microneedles were fabricated from stainless steel sheets as single microneedles or arrays of microneedles. Next, a novel micron-scale dip-coating process and a GRAS coating formulation were designed to reliably produce uniform coatings on both individual and arrays of microneedles. This process was used to coat compounds including calcein, vitamin B, bovine serum albumin and plasmid DNA. Modified vaccinia virus and microparticles of 1 to 20 micro m diameter were also coated. Coatings could be localized just to the needle shafts and formulated to dissolve within 20 s in porcine cadaver skin. Histological examination validated that microneedle coatings were delivered into the skin and did not wipe off during insertion. In conclusion, this study presents a simple, versatile, and controllable method to coat microneedles with proteins, DNA, viruses and microparticles for rapid delivery into the skin.     

Surfactant-enhanced transdermal delivery by electroporation.

The objective of the experiment was to study the influence of sodium dodecyl sulfate (SDS) on transdermal transport of diffusants by electroporation. The resistance of porcine epidermis in contact with SDS solution (0.2% w/v) dropped by 40% within 24 h. SDS improved the efficiency of transdermal delivery of glucose, dextrans of molecular weight (MW) 4 kDa (FD4K) and 10 kDa (FD10K) by electroporation. However, the transport of dextran MW 35 kDa (FD35K) was not influenced significantly. Pretreatment of epidermis with SDS solution reduced its electroporation threshold from 80 to 60 V. It appears that presence of SDS during electroporation helps in achieving the desired transport with less electrical exposure dose. SDS enhanced the transdermal delivery of molecules by electroporation most likely by facilitating the barrier disruption during pulse application and also by prolonging the lifetime of electropores created by the pulse.     

Synergistic enhancement of testosterone transdermal delivery.

In this study, the effects of occlusion, octisalate (OS), and propylene glycol (PG) on the in vitro skin permeability of testosterone (TES) have been investigated. TES (either alone or with OS 5% w/v) was applied as a finite dose to full-thickness neonatal porcine skin mounted in flow-through diffusion cells and the amount of TES appearing in the receptor solution (20% v/v ethanol) was determined over 24 h. The skin was occluded with a microscope glass cover slip and to determine the effect of PG, 400 microl of PG/water mixtures (of varying PG concentration) was applied. In addition, the effect of Solugel (a proprietary hydrogel containing PG 25% w/w) and Tegaderm (a semipermeable film dressing) on the permeation of TES was assessed. Occlusion had no effect on the permeation of TES, however, OS increased the flux of TES 2.9-fold. The concentration of PG which produced optimal TES flux was 20% v/v, and this concentration resulted in a 1.9-fold increase in TES permeation. By combining OS, PG, and occlusion, TES permeation was increased 8.7-fold, which was a synergistic enhancement. In addition, Solugel and Tegaderm, when applied to the skin, produced a similar enhancement in TES permeation to that produced by PG 25% w/w and occlusion.     

A clinical snapshot of transdermal buprenorphine in pain management

New and effective analgesics for the treatment of pain are essential. Buprenorphine, a partial mu receptor agonist, offers unique physico-chemical and pharmacological qualities, making it an attractive first-choice opioid for the treatment of acute and chronic pain. Several delivery formulations are available including parental, sublingual tablet, sublingual solution and transdermal. The parental formulation has been administered intravenously, intramuscularly, epidurally and intrathecally. Transdermal patches allow the drug to be continuously absorbed through the skin and into the systemic circulation. This approach has been shown to have clinical benefit, along with high-level patient acceptability, compliance and improved quality of life. However, further randomised controlled trials are needed to focus on defining dose requirements in different pain states and the appropriateness and utilisation of adjuvant analgesics when required.     

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R=0.74; P<0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 microg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.     

Challenging the equipotency calculation for transdermal buprenorphine: four case studies

AIMS: Opioids produce analgesia via different pain pathways. The aim of these case studies was to address the issue of opioid rotation or switching, raising the important issue of conversion ratios between different compounds and routes of administration. RESULTS: We present two cases of neuropathic pain and two cases of nociceptive pain with a significant neuropathic component, which were successfully treated with transdermal buprenorphine after the failure of other opioids. CONCLUSION: In each case, effective pain relief was produced by a lower dose than the proposed equipotency ratio of 1:75 would indicate, suggesting that a ratio of 1:110 to 1:115 may be more appropriate.     

Equipotent doses to switch from high doses of opioids to transdermal buprenorphine

Introduction  The aim of this study was to evaluate the equianalgesic ratio of transdermal buprenorphine (TD BUP) with oral morphine and TD fentanyl in a sample of consecutive cancer patients receiving stable doses of 120–240 mg of oral morphine or 50–100 μg of TD fentanyl, reporting adequate pain and symptom control. Materials, methods, and results  Patients receiving daily stable doses of opioids for more than 6 days, with no more than two doses of oral morphine (20 and 40 mg, respectively) as needed, were switched to TD BUP using a fentanyl–BUP ratio of 0.6:0.8 and an oral morphine–BUP ratio of 70:1. Opioid doses, pain and symptom intensity, global satisfaction, and number of breakthrough medication were recorded before switching (T0), 3 days after (T3), and 6 days after (T6). Eleven patients were recruited in a period of 1 year, and data were complete for ten patients. The mean age was 61.6 (SD 9.5), and five patients were males. No significant changes in pain and symptom intensity were found, except improvement in reported constipation (p = 0.014), as well as in global satisfaction with the analgesic treatment. No significant changes in breakthrough pain medication were observed. Conclusion  The results of this study suggest that stable patients receiving relatively high doses of oral morphine or TD fentanyl could be safely switched to TD BUP, by using a ratio of 70:1 and 0.6:0.8, respectively, maintaining the same level of analgesia.     

A study of microemulsion systems for transdermal delivery of triptolide.

Triptolide possesses immunosuppressive, anti-fertility and anti-cancer activities. Due to its severe toxicity, microemulsions with controlled, sustained and prolonged delivery of triptolide via a transdermal route are expected to reduce its adverse side effects. The purpose of the present study was to investigate the microemulsions for transdermal delivery of triptolide. The pseudo-ternary phase diagrams were developed and various microemulsion formulations were prepared using oleic acid as an oil, Tween 80 as a surfactant and propylene glycol as a cosurfactant. The droplet size of microemulsions was characterized by photocorrelation spectroscopy. The transdermal ability of triptolide from microemulsions was evaluated in vitro using Franz diffusion cells fitted with mouse skins and triptolide was analyzed by high-performance liquid chromatography. The effect of menthol as a permeation enhancer, and the loading dose of triptolide in microemulsions on the permeation rate were also evaluated. The triptolide-loaded microemulsions showed an enhanced in vitro permeation through mouse skins compared to an aqueous solution of 20% propylene glycol containing 0.025% triptolide. The permeation of microemulsions accorded with the Fick's first diffusion law. No obvious skin irritation was observed for the studied microemulsion ME6, but the aqueous solution of 20% propylene glycol containing 0.025% triptolide revealed the significant skin irritation. The results indicate that the studied microemulsion systems, especially ME6, may be promising vehicles for the transdermal delivery of triptolide.     

Clinical update on the pharmacology,efficacy and safety of transdermal buprenorphine

Buprenorphine was not used widely in clinical practice over many years, mainly due to analgesic potency and clinical safety concerns based on misinterpreted animal data. Contrary to previous concerns, however, no analgesic ceiling effect and no antagonism of combined pure μ‐opioid receptor agonists is seen within the therapeutic dose range. In recent studies, buprenorphine could be effectively and safely combined with full μ‐agonists, and switching between buprenorphine and another opioid provided comparable pain relief based on equianalgesic doses. Moreover, buprenorphine exerts an antihyperalgesic effect, which is due—at least in part—to antagonistic activity at κ‐opioid receptors. Buprenorphine pharmacokinetics are not altered by advanced age or renal dysfunction. In addition, the risk of respiratory depression is lower than with other opioids including morphine, hydromorphone, methadone and fentanyl. Unlike morphine and fentanyl, there is no immunosuppressive activity with buprenorphine at therapeutic analgesic doses. Transdermal buprenorphine has significantly improved the clinical use of the drug, providing continuous buprenorphine release for up to 96h. In clinical trials, patients receiving transdermal buprenorphine experienced significantly greater pain relief, better sleep, and a reduced need for rescue therapy, compared to placebo. Large‐scale post‐marketing studies have confirmed the effectiveness of transdermal buprenorphine in treating moderate‐to‐severe cancer and non‐cancer pain including neuropathic syndromes. Finally, the comparably low incidence of CNS adverse events and constipation, and the possibility of use in severe renal dysfunction without a need for dose adjustment make buprenorphine well suited for chronic pain management in at‐risk patients, such as diabetics, elderly or renally impaired individuals including those requiring haemodialysis.     

NMR characterisation and transdermal drug delivery potential of microemulsion systems.

The purpose of this study was to investigate the influence of structure and composition of microemulsions (Labrasol/Plurol Isostearique/isostearylic isostearate/water) on their transdermal delivery potential of a lipophilic (lidocaine) and a hydrophilic model drug (prilocaine hydrochloride), and to compare the drug delivery potential of microemulsions to conventional vehicles. Self-diffusion coefficients determined by pulsed-gradient spin-echo NMR spectroscopy and T(1) relaxation times were used to characterise the microemulsions. Transdermal flux of lidocaine and prilocaine hydrochloride through rat skin was determined in vitro using Franz-type diffusion cells. The formulation constituents enabled a broad variety of microemulsion compositions, which ranged from water-continuous to oil-continuous aggregates over possible bicontinuous structures, with excellent solubility properties for both lipophilic and hydrophilic compounds. The microemulsions increased transdermal flux of lidocaine up to four times compared to a conventional oil-in-water emulsion, and that of prilocaine hydrochloride almost 10 times compared to a hydrogel. A correlation between self-diffusion of the drugs in the vehicles and transdermal flux was indicated. The increased transdermal drug delivery from microemulsion formulations was found to be due mainly to the increased solubility of drugs and appeared to be dependent on the drug mobility in the individual vehicle. The microemulsions did not perturb the skin barrier, indicating a low skin irritancy.     

Liquid crystalline pharmacogel based enhanced transdermal delivery of propranolol hydrochloride.

A novel pharmacogel was developed for the enhanced transdermal delivery of propranolol hydrochloride (PH). The synthesized prodrugs, propranolol palmitate hydrochloride (PPH) and propranolol stearate hydrochloride (PSH) self-assembled to form gel simply upon mixing alcoholic solution of prodrug with an aqueous solution in a specified ratio. By varying the ratio of prodrug, alcohol and water, three-component phase diagram was constructed which revealed isotropic-gel-vesicular dispersion regions, respectively concomitant to increasing the ratio of water. The gel phase is termed 'Pharmacogel' and exhibits birefringence under plane-polarized light corroborating the presence of lamellar liquid crystals. The pharmacogel by virtue of high chemical potential gradient and improved physicochemical properties showed the enhanced in-vitro skin permeation flux of 51.5+/-3.7 and 42.5+/-3.1 microg/cm(2)/h from PPH and PSH gel, respectively, as compared to 1.9+/-0.1 microg/cm(2)/h for control; and decrease in lag time (1.8 and 2.8 h for PPH and PSH gel, respectively) compared to control (7.6 h) was observed. The admixing of egg lecithin (EL) in increasing ratio concomitantly decreased the flux values to 31.7+/-2.1 microg/cm(2)/h (at a mole ratio of 50:50 PPH:EL) and increased the lag time. In the gel containing 50% EL, the addition of span 40 and cholesterol slightly reduced the permeation while sodium deoxycholate and Tween-80 improved it. The plasma drug levels following transdermal application of control were low (C(max)=23 ng/ml) while in PPH gel, it increased with time reaching C(max) of 94 ng/ml at 8 h post-application of PPH gel (C(max) of 75 ng/ml at 12 h post application of PL5 gel) and maintained for longer times. The AUC(0-32 h) for PPH gel was much higher (1968 ng h/ml) than control (AUC(0-18 h) was 239 ng h/ml), while EL mixed gel also showed better absorption (AUC(0-32 h) was 1707 ng h/ml). The gel formulations also caused less irritation than control, while mixed gel showed least irritation. This novel self-assembled pharmacogel providing high transdermal permeation with many variables to regulate the delivery is therefore having a great potential in percutaneous delivery.     

Topical and transdermal delivery of antisense oligonucleotides

Antisense oligonucleotides have great potential as therapeutic agents. As a result, a variety of chemistries have been developed to improve the efficacy of these molecules without compromising their specificity. Because the skin is such a large organ with extensive accessibility, it is a natural target for drug delivery. It is, however, an effective barrier, so physical and chemical methods to improve drug penetration have been developed. These enhancement techniques can be combined with modified oligonucleotide chemistries to provide sufficient levels of antisense activity either within the skin or systemically. This review will describe in vitro and in vivo experiments that demonstrate the potential of antisense oligonucleotides to treat both dermal and systemic disorders.     

Use of nanocarriers for transdermal vaccine delivery

Transdermal delivery is a safe, noninvasive method of administering vaccines directly onto bare skin, offering several potential advantages over traditional needle delivery. This technology is limited by the relative inefficiency of transport of large-molecular-weight vaccine antigens across intact skin. Recent evidence has shown that this barrier can be overcome by properly structured nanosized particles (nanocarriers). The specialized assembly of each type of nanocarrier gives each unique properties and different interactions within the stratum corneum. The use of nanocarriers for vaccine delivery is a platform technology, applicable to delivery of a variety of existing and potential vaccines.     

低频超声经皮给药治疗进展

<正>超声促渗最早报道于1954年[1],是以超声作为物理促渗手段增加皮肤的通透性,使药物可以通过皮肤而吸收入体。但由于皮肤通透性很低,早期超声渗透仅能适用于一些低相对分子质量药物。Mitragotri在1995年于Science上报道了低频超声(20~100 k Hz)可明显提高皮肤对药物的通透性,使得诸如胰岛素的一些大分子蛋白可以经皮给药,效果良好。低频超声经皮给药相比静脉给药是一种无创、     

Treatment of cancer-related pain with transdermal buprenorphine: a report of three cases

Three patients suffering from pain arising from renal and metastasing prostate and breast cancer were successfully treated with transdermal buprenorphine. The three cases demonstrate that transdermal buprenorphine is an easy-to-use and effective therapeutic option for the treatment of advanced cancer pain, that it can also be used in opioid rotation as an alternative after formerly applied steps II or III opioids have failed and that long-term treatment without dose escalation or compromise in tolerability is possible.     

Safety of buprenorphine transdermal system in the management of pain in older adults

Objectives: To evaluate whether buprenorphine transdermal system (BTDS; Butrans®) is an option for the treatment of chronic pain in older adults.

Methods: This retrospective analysis of 16 placebo- and active-controlled and uncontrolled studies (N = 6566) evaluated the safety and tolerability profile in patients exposed to BTDS and compared the safety profiles associated with BTDS treatment in older patients ≥ 65 years of age (65 to 98 years) and younger patients < 65 years of age (18 to 64 years). Safety analyses included adverse events (AEs), laboratory values, and electrocardiograms.

Results: Overall, the incidence of AEs was similar in the ≥ 65 year patient cohort (N = 1715) and the < 65 year patient cohort (N = 4843) (63.8% and 61.0%, respectively). The older patient cohort experienced more constipation, peripheral edema, and urinary tract infection, but fewer application-site AEs (eg, erythema, irritation, pruritus, rash) and headaches. A statistically significant treatment-by-age interaction was observed for fall, arthralgia, and localized and non-application site-related rash, suggesting a differential increase in the risk of these events among older patients treated with BTDS that cannot be explained by age or treatment alone. A similar trend was observed for accidents and injuries, and for falls, in patients treated with both BTDS and active controls (oxycodone/acetaminophen [OXY/APAP] and hydrocodone/acetaminophen [HCD/APAP]), suggesting an opioid class effect. However, due to small sample sizes of the active control groups, a statistical test of treatment-by-age interaction could not be conducted for the active controls. The incidences of serious AEs and of clinically significant increases in liver enzymes, such as AST, ALT and bilirubin were small, regardless of age.

Conclusion: BTDS appears to be a viable option for the management of pain in older adults, but the benefits need to be tempered by potential risks among older adults.     

Evaluation of constant current alternating current iontophoresis for transdermal drug delivery.

Previous studies in our laboratory have demonstrated that alternating current (AC) iontophoresis can significantly decrease skin electric resistance and enhance the transport of charged permeants across skin. Flux variability of neutral permeants during AC iontophoresis was also found to be less than that of conventional direct current (DC) iontophoresis. The objectives of the present study were to evaluate flux enhancement of constant current AC transdermal iontophoresis and compare the AC flux with that of constant current DC iontophoresis. Iontophoresis studies of AC amplitude of 1, 2, and 5 mA were conducted in side-by-side diffusion cells with donor solution of 0.015, 0.15, and 1.0 M tetraethylammonium (TEA) chloride and receiver solution of phosphate buffered saline (PBS) using human epidermal membrane (HEM). Conventional constant current DC iontophoresis of 0.2 mA was also performed under similar conditions. TEA and mannitol were the model permeants. The following are the major findings in the present study. The flux of TEA increased proportionally with the AC current for all three TEA chloride concentrations and at the AC frequency used in the present study. When the permeant and its counter ion were the only ionic species in the donor chamber, the fluxes during DC iontophoresis were weakly dependent of its donor concentration. The fluxes of TEA during constant current AC iontophoresis were moderately related to the donor concentration with the highest TEA flux observed under the 1.0 M TEA chloride condition although the relationship between flux and donor concentration was not linear. A trend of decreasing electroosmotic transport with increasing donor TEA chloride concentration was observed with significant sample-to-sample variability during DC iontophoresis. Mannitol permeability was also observed to decrease with increasing TEA chloride concentration in the donor under the AC conditions, but data variability under AC was significantly smaller than that under DC. The results in the present study indicate that constant current AC iontophoresis under conditions tolerable to human (2 and 5 mA) can provide predictable fluxes that were lower than but of comparable magnitude as those of conventional constant current DC iontophoresis (0.2 mA).     

New clinical applications of transdermal testosterone delivery in men and women.

This paper reviews recent progress in the development and clinical application of testosterone transdermal delivery systems designed for physiological replacement therapy in men and women. The biopharmaceutic goal of physiologic replacement therapy is to produce serum levels and circadian patterns of testosterone and its active metabolites that mimic the normal physiology of testosterone in the particular target population. For the treatment of adult hypogonadal men, the nightly 24 h application of the Androderm testosterone transdermal system (5 mg per day) achieves this goal - as demonstrated in a series of clinical pharmacokinetic studies. For the treatment of adolescent males, physiologic replacement can be approximated by modifying the dose and duration of Androderm application so as to mimic the patterns of nocturnal testosterone secretion observed during puberty. With the objective of providing physiological replacement for women with diminished testosterone production, an experimental testosterone matrix transdermal system (TMTDS) has been developed and is currently undergoing clinical evaluation. In parallel with the development of testosterone transdermal systems, physicians have been investigating a number of conditions, in both males and females, where testosterone production is diminished and replacement therapy may be beneficial. Three of these new clinical applications will be illustrated - the use of Androderm for the treatment of adolescent males with beta-thalassemia, the use of Androderm for the treatment of HIV+ men, and the use of the TMTDS for the treatment of HIV+ women. From the biopharmaceutic and clinical perspectives, the development of testosterone transdermal systems represents an important achievement in controlled drug delivery.     

A duplex "Gemini" prodrug of naltrexone for transdermal delivery.

Transdermal naltrexone delivery is desirable in the treatment of narcotic dependence and alcoholism. The purpose of this study was to increase the delivery rate of naltrexone (NTX) across human skin by using a novel prodrug. A duplex "gemini" prodrug of naltrexone was synthesized and evaluated. In vitro human skin permeation rates of naltrexone and prodrug were measured using a flow-through diffusion cell system. Drug concentrations in the skin were quantitated at the end of the diffusion experiment. The prodrug was hydrolyzed on passing through the skin and appeared mainly as naltrexone in the receiver compartment. The prodrug provided a significantly higher naltrexone equivalent flux across human skin in vitro than naltrexone base. The naltrexone equivalent solubilities of naltrexone and the prodrug in the donor solution were not significantly different. No significant increase in drug concentration in the skin after prodrug treatment, as compared to naltrexone, was observed. The naltrexone equivalent permeability from the prodrug exceeded the permeability of naltrexone base by two-fold. Due to the design of this prodrug, toxicities associated with this compound should be nonexistent, because only naltrexone and carbon dioxide (carbonic acid) are released when the prodrug is cleaved.     

Identification of penetration enhancers for testosterone transdermal delivery from spray formulations.

The goal of this study was to identify a suitable penetration enhancer-containing formulation for the transdermal delivery of testosterone from a spray. The first step involved in vitro measurement of drug flux from a 1:1 ethanol/water saturated solution across hairless rat skin, which had been pre-treated with a series of penetration enhancers. Isopropyl myristate (IPM) was found to be the most efficient excipient, increasing testosterone transport by more than a factor of 5. The enhancing ability of IPM was also apparent when the drug was formulated in 3:1 ethanol/propylene glycol, a more compatible vehicle for use in a spray. IPM was then incorporated into this formulation directly (as opposed to being used to pre-treat the skin) over a range of concentrations from 10-25% v/v, and testosterone transport was evaluated when delivered from either a solution, or from a mechanical spray, or from an aerosol (which also contained 50% v/v propellant). At the highest level of enhancer, the flux was improved 2.5-fold from both the spray and the aerosol, relative to a control. However, these formulations were far from optimally conceived, in that the amount of drug which eventually contacted the skin represented only approximately 10% of the pulverized quantity from the spray, and approximately 40% of that from the aerosol. Repeated application, especially from the aerosol, improved matters somewhat, but further work is clearly required before the concept can be developed for practical application.