Transdermal Delivery Rate Research Articles

Innovative freeze-drying technique in the fabrication of dissolving microneedle patch: Enhancing transdermal drug delivery efficiency.

Microneedle patch (MNP) has become a hot research topic in the field of transdermal drug delivery due to its ability to overcome the stratum corneum barrier. Among the various types of microneedles, dissolving microneedles represent one of the most promising transdermal delivery methods. However, the most used method for preparing dissolving microneedles, namely microfabrication, suffers from issues such as long drying time, susceptibility to humidity, and large batch-to-batch variability, which limit the development of dissolving microneedles. In this study, we report for the first time a method for preparing dissolving microneedles using freeze-drying technology. We screened substrates suitable for freeze-dried microneedle patch (FD-MNP) and used coating technology to enhance the mechanical strength of FD-MNP, allowing them to meet the requirements for skin penetration. We successfully prepared FD-MNP using hyaluronic acid as the substrate and insulin as the model drug. Scanning electron microscopy revealed that the microneedles had a porous structure. After coating, the mechanical strength of the microneedles was 0.61N/Needle, and skin penetration rate was 97%, with a penetration depth of 215μm. The tips of the FD-MNP dissolved completely within approximately 60s after skin penetration, which is much faster than conventional MNP (180s). In vitro transdermal experiments showed that the FD-MNP shortened the lag time for transdermal delivery of rhodamine 123 and insulin compared to conventional MNP, indicating a faster transdermal delivery rate. Pharmacological experiments showed that the FD-MNP lowered mouse blood glucose levels more effectively than conventional MNP, with a relative pharmacological availability of 96.59 ± 2.84%, higher than that of conventional MNP (84.34 ± 3.87%), P = 0.0095. After storage under 40℃ for two months, the insulin content within the FD-MNP remained high at 95.27 ± 4.46%, which was much higher than that of conventional MNP (58.73 ± 3.71%), P < 0.0001. In conclusion, freeze-drying technology is a highly valuable method for preparing dissolving microneedles with potential applications in transdermal drug delivery.

Electrospun Transdermal Patch for Contraceptive Hormone Delivery.

A transdermal patch for delivery of Levonorgestrel (LNG) can be used for long-acting contraception. In this study, we designed and characterized a patch made of nonwoven electrospun microfibers comprised of Polycaprolactone (PCL) encapsulating LNG for slow release in a mineral oil matrix. Scanning electron microscopy showed uniform, randomly oriented PCL fibers with large interconnected voids filled with mineral oil. Thermogravimetric analysis indicated that LNG loaded into PCL fibers had thermal stability up to ~200°C. Differential Scanning Calorimetry suggested that LNG was dispersed in the electrospun fibers without interaction between the LNG and PCL, and without formation of drug crystals. Fourier Transform Infrared spectroscopy and X-ray diffraction results further supported the conclusion that there was no chemical drug-polymer interaction in LNGloaded fibers. Effective in vitro flux (i) from patches into mineral oil was 1.9 µgcm-2h-1, (ii) from mineral oil across porcine skin was 4.6 µgcm-2h-1 and (iii) from patches across porcine skin was 1.7 μgcm- 2h-1, indicating that transdermal delivery rate was controlled by a combination of the patch and the skin. The LNG-loaded patches demonstrated steady delivery of LNG across skin for up to 5 days in vitro. With additional development, LNG-loaded electrospun PCL patches could be used for long-acting contraception.

The efficacy of anti-VEGF antibody-modified liposomes loaded with paeonol in the prevention and treatment of hypertrophic scars

The aim of this study was to investigate the efficacy of anti-VEGF antibody-modified Paeonol liposome gels (PAE-BEV-lip gels) in the prevention and treatment of hypertrophic scars (HS). Systematic optimization of the encapsulation process of anti-VEGF antibody-modified Paeonol liposomes (PAE-BEV-lips) was performed using Box–Behnken design with the optimized parameters as follows: SPC concentration of 7.36 mg mL−1; SPC-Chol-PAE:pNP-PEG3000-DOPE:BVE-PEG3000-DOPE ratio of 14:5:4:0.28:0.05, w/w; the hydration temperature of 41 °C; stripping using pH 7.5 sodium dihydrogen phosphate buffer; and ultrasound for 3 min (ultrasound time 2 s, interval 3 s, power 300 W). Using these conditions, the encapsulation efficiency of PAE reached the peak level, i.e. 73.61 ± 2.36%. The PAE-BEV-lips displayed unimodal size-distribution with a mean diameter of (235.7 ± 4.67) nm and a zeta potential of –(5.13 ± 0.25) mV. The investigation of the retention effect PAE-BEV-lip gels revealed a slower transdermal delivery rate, a remarkable dermal retention effect, and superior bioavailability compared to PAE gels and PAE conventional liposome gels (PAE-lip gels). Meanwhile, PAE-BEV-lip gels exhibited definite effects on the prevention and treatment of HS of the rabbit ears. The PAE-BEV-lip gels group showed a lower scar proliferation rate, fewer and looser collagenous fibers and fibromyocytes, more regular chondrocytes, less calcified tissue and fewer inflammatory cells compared to other groups. At the same time, PAE-BEV-lip gels significantly reduced scar hyperplasia index (1.34 ± 0.51) and levels of VEGF, TGF-β1 and TNF-α (30.90 ± 3.57, 733.2 ± 43.19 and 66.76 ± 2.98 ng·L−1, respectively), compared to the model group (p < .01).

Smart Patch Systems: Iontophoretic Microheater Assemblies for Controlled Transdermal Delivery

The majority of currently approved transdermal drug delivery systems utilise low doses of low molecular weight lipophilic drugs, falling within the category of first generation approaches. Systems incorporating improvements such as chemical enhancers, heat, iontophoresis and non-cavitational ultrasound to reversibly disrupt the structure of the stratum corneum, fall under second generation approaches. Although heat is a somewhat uncommon and perhaps understudied enhancement technique, there is considerable evidence to suggest that it can significantly increase epidermal penetration. Given the tolerable nature of these temperatures, there is a clear opportunity for heat assisted absorption to be incorporated into future transdermal drug delivery systems. The use of heat has been shown to increase the rate of transdermal drug delivery in a number of applications, such as administration of fentanyl and lidocaine. The aim of the present project has been to investigate the development of a hybrid smart patch system, which involves the integration of transdermal heat transfer with iontophoresis. This would enable enhanced drug delivery to be achieved in a controlled manner without significant disruption to the skin’s structure. Iontophoresis provides a mechanism through which delivery rate may be controlled to a high degree of specificity. It is therefore possible to regulate or inhibit delivery rate over a period of time, due to the direct relationship between the applied current and transdermal flux. Rate control may be the responsibility of the patient, or more commonly, controlled by incorporation of a microprocessor, enabling complex and bespoke delivery profiles to be enacted. The addition of the transdermal heater, in this instance, brings a new dimension to the delivery process, but there remains a considerable challenge to the design and implementation of the proposed smart patch. The basic approach is outlined in Figure 1. In order to address the issue of controlled release and subsequent flux, the design incorporates a temperature sensitive hydrogel as a drug entrapment matrix or reservoir. Hydrogels have traditionally been employed as a barrier mechanism or encapsulation medium in a number of drug delivery studies, where their manipulation and/or degradation may be controlled by environmental influences, hydrolysis and enzyme interaction. In this prototype, thermal control (typically 45oC) facilities the release of drug from the gel, and its subsequent transfer across the stratum corneum is induced through the combination of heat and iontophoresis. The design of the microheater / iontophoretic electrode assembly is described and its operation characterised. The drug delivery profiles from prototype smart patches employing a range of model drugs are critically assessed. The extent to which precise control and augmentation of both the release and transdermal delivery rate, for a range of drug species and therapeutic agents has been assessed. Figure 1

Fabrication of a novel partially dissolving polymer microneedle patch for transdermal drug delivery.

Polymer microneedles (MNs) have gained increasing attention as a minimally invasive method for efficiently delivering drugs and vaccines in a patient-friendly manner. Herein, an easy and mild process with O2 plasma treatment was used to fabricate polyvinylpyrrolidone (PVP)-polyvinyl alcohol (PVA) MN patches, and efficient, sustained transdermal delivery was achieved. The diffusion rate of the entrained molecules could be controlled by adjusting the ratio of PVP-PVA. Optical coherence tomography was used to monitor the in vitro penetration in real time and to measure the penetration depth. Rhodamine 6G and fluorescein isothiocyanate-labeled bovine serum albumin (BSA-FITC) were used to explore the potential for using partially dissolving MNs as a transdermal delivery device. Confocal microscopy images revealed that the model drug can gradually diffuse from the puncture sites to a deeper depth. The drug-release profile also demonstrated that the PVP-PVA MNs can provide a successful and sustained release and that the transdermal delivery rate was regulated by the PVP-PVA ratio. Furthermore, the two-stage processing strategy developed in this study provides a simple and easy method for localizing the drug in the needle. The partially dissolving MNs developed in this study may serve as a promising device for controlled drug release and for biological storage applications.

Penetratin-induced transdermal delivery from HII mesophases of sodium diclofenac

Penetratin, a cell penetrating peptide is embedded within a reversed hexagonal (HII) mesophase for improved transdermal delivery of sodium diclofenac (Na-DFC). The HII mesophase serves as the solubilization reservoir and gel matrix whereas penetratin is the transdermal penetration enhancer for the drug. The systems were characterized and the interactions between the components were determined by SAXS, ATR-FTIR and SD-NMR. High affinity of Na-DFC to glycerol monooleate (GMO) was revealed, associated with increasing the order within the water channels. This affinity is enhanced upon heating and seems to be associated with GMO dehydration. Penetratin (PEN) is entrapped at the hydrophilic region of the HII mesophase, between the GMO headgroups, reducing the order of the system and decreasing the size of the hexagonal domains.The transdermal delivery rate of Na-DFC through porcine skin, from the HII mesophases, was enhanced by PEN and so also the cumulative transport crossing the skin. PEN induced accelerated drug diffusion through the stratum corneum, towards the different skin layers.The transdermal delivery enhancement is explained from the results of the ATR-FTIR analysis. It seems that PEN accelerates the structural transition of skin lipids from hexagonal to liquid. The disordering results in enhanced diffusion of Na-DFC through the stratum corneum, followed by enhanced overall penetration of the drug.

Radio Frequency-Microchannels for Transdermal Delivery: Characterization of Skin Recovery and Delivery Window

Transdermal delivery through Radio-Frequency-MicroChannels (RF-MCs) was proven to be a promising delivery method for hydrophilic drugs and macromolecules that must be injected. An important issue in assessing this technology is the life span of the microchannels (MCs). The time window in which the MCs remain open affects the delivery rate and determine the effective delivery duration. The present work focused on the characterization of the ViaDor-MCs recovery and closure process by measurements of transepidermal water loss (TEWL) before and after the formation of MCs, evaluation of the delivery window, and assessment of skin histology. Testosterone-cyclodextrin complex was used as the model drug for evaluation of the transdermal delivery. In-vitro permeation system and in-vivo guinea pig animal model were used in the delivery studies. Our findings demonstrate the recovery process of MCs created by the RF ablation technology. The observed gradual skin recovery affected the transdermal delivery rate. A significant transdermal delivery was shown up to 24 hrs post device application suggesting that an extended delivery of water soluble drugs, including macromolecules, is possible. The histology assessments demonstrated repair and healing of the induced MCs indicating that the RF micro-channeling technology is minimally invasive, transient in nature with no resulting skin trauma.

In vitro and in vivo transdermal iontophoretic delivery of naloxone, an opioid antagonist

The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated. To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24h. The in vitro steady-state skin permeation flux of naloxone current-proportionally (0-360 μA/cm(2)) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4h to 24h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 μA/cm(2) were 136 and 305 μg/h/cm(2), respectively. These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients.

A TRANSDERMAL DRUG DELIVERY SYSTEM CONTAINING DEFERIOXAMINE MESYLATE FOR THE TREATMENT OF BETA-THALASSAEMIA MAJOR

Patients with beta-thalassaemia major need blood transfusion frequently during their whole life. However, frequent transfusions will eventually lead to the accumulation of trivalent iron, resulting in iron overload. To reduce iron overload, patients are administered regularly with intravenous or subcutaneous infusion of deferioxamine mesylate (DFO). Nevertheless, high costs of medication, poor patient compliance, and side effects limit its use and patient's acceptance. To overcome such drawbacks, we developed a novel transdermal delivery system to administer the DFO instead of traditional injections. We assayed the feasibility of fabricating a transdermal DFO patch using the single-layer drug-in-adhesive drug delivery system. We used the pressure-sensitive adhesives and hydrogels as the drug reservoirs and studied the release profile of DFO from the transdermal patches in vitro. In order to enhance the transdermal delivery rate, chemical enhancers, polysorbate 80 and oleic acid, and physical enhancer, ultrasound, were incorporated into the monolith DFO patches. Experimental results showed that the combination of polysorbate 80 and oleic acid in the pressure-sensitive adhesives enhanced the penetration efficiency through nude mice skin. The pretreatment of nude mice skin with ultrasound temporally changed the diffusional resistance and facilitated DFO penetration through the skin. We expect that the new delivery system can enable the drug to penetrate through skin at a stable rate and reach the circulation system successfully, thus allowing the concentration of drug to achieve the therapeutic effect.

Transdermal Drug Delivery by Electroporation: The Effects of Surfactants on Pathway Lifetime and Drug Transport

Electroporation creates aqueous pathways by short high-voltage pulses resulting in a transient perme-abilization of stratum corneum and an increase in the transdermal delivery rate. However the aqueous pathways will reseal after pulsing, which leads to the rapid drop of transdermal flux. In the present study, the surfactants were added to the donor solution to hinder the shrinkage and resealing of the electropore, and to prolong the lifetime of the aqueous pathways with the consideration that the surfactants could reduce the surface energy of the electropore. These effects of surfactants were demonstrated by the dynamic electrical resistance of the skin and the fluorescent imaging of the local transport regions. Piroxicam (PIX) was transported percutaneously in the presence of surfactants in vitro. Owing to the longer lifetime of aqueous pathways, together with the promotion of PIX availability at the barrier exterior and the improvement in the partition of PIX into the aqueous pathways, the presence of surfactants led to a remarkable increase in the transdermal delivery rate during electroporation and a significant growth of the accumulative transdermal amount of PIX.

Transdermal Delivery of Piroxicam by Surfactant Mediated Electroporation

A lipophilic, nonsteroidal antiinflammation drug, piroxicam, was administered by skin electroporation using short, high-voltage pulses. The transdermal delivery of piroxicam during the electroporation was buffered due to the higher partition in skin lipids than in aqueous environments, which is called entrapment. Entrapment is the main resistance to transdermal delivery of lipophilic drugs. Two types of surfactants were used to enhance the skin electroporation. Tween 80 (0.2 g/L) and sodium dodecyl sulphate (SDS, 3 mg/mL) improve the solubility and diffusion rate of the drug in the hydrophobic local transport regions and reduce the entrapment of piroxicam in the skin. The transdermal delivery rate of piroxicam is increased 30- to 50-fold. However, the entrapment of piroxicam in the skin still occurred when Tween 80 was added. The SDS provides higher and more stable transdermal delivery rates of piroxicam than Tween 80, and also reduces the entrapment of piroxicam in the skin.

Response surface method: a novel strategy to optimize iontophoretic transdermal delivery of thyrotropin-releasing hormone.

To maximize the iontophoretic transdermal delivery rate of thyrotropin-releasing hormone (TRH) facilitated by periodically monophase-pulsed current across excised skin. The pH of the buffer, the ionic strength in the solution, the frequency of the periodically monophase-pulsed current and the current on/off ratio were chosen as the key variables. A response surface method was applied to optimize the transdermal delivery rate of TRH under different operational conditions. The optimum operating conditions were achieved via experimentation based on the response surface method by systematically adjusting the pH of the buffer, the ionic strength in the solution, the current amplitude, frequency and the active temporal ratio of the pulsed current. The rate of permeation of TRH crossing the skin during iontophoresis varied from two to ten-fold, depending on operating conditions. Only a few steps, two in this work, were needed to reach the optimal. The response surface near the region of the maximal point was thoroughly described with a quadratic function. A maximal transdermal rate of permeation of TRH, 103.2 micrograms h-1 cm-2, was obtained when the donor solution was at pH = 7.0, ionic strength = 0.037, and with a periodically monophase-pulsed current iontophoresis with duty cycle = 75%. The effect of pulse frequency was not statistically significant.

Absorption of Transdermally Delivered Ketorolac Acid in Humans

Transdermal delivery of ketorolac acid, a potent analgesic, through human skin in vitro and in vivo was evaluated. The following three transdermal solutions were selected to study the in vitro skin permeation rate of ketorolac acid: formulation A, isopropyl alcohol:water:isopropyl myristate (IPA/water/IPM; 11:7:1); formulation B, ethanol: propylene glycol:isopropyl myristate (ET/PG/IPM; 11:7:2); and formulation C, IPM/capmul (glyceryl mono‐ and dicaprylate; Monoctanoin). The permeation of ketorolac acid through cadaver skin from a saturated drug solution was evaluated at 32°C with a modified Franz diffusion cell. The in vitro skin fluxes were 180, 177, and 14 μg/cm2/h for fomulations A, B, and C, respectively. The systemic bioavailability of ketorolac acid from three transdermal formulations was evaluated in nine healthy subjects in a randomized three‐way crossover fashion. Hill Top chambers were used as prototype dermal delivery devices to load the drug solution. This procedure was followed by the immediate application of devices to human subjects for 24h. Blood samples were collected at various time intervals up to 48 h, and the samples were assayed by HPLC. The basic pharmacokinetic parameters were derived from the drug plasma concentration versus time plot. The maximum drug plasma concentrations were 1.265, 0.696, and 0.092 μg/mL for formulations A, B, and C, respectively. Formulation A provided the highest in vitro and in vivo transdermal delivery rate among the three formulations studied. An excellent correlation between the in vitro steady‐state skin flux and the area under the curve of in vivo plasma drug concentration versus time was observed for all the three formulations.

Transdermal Delivery of Buprenorphine through Cadaver Skin

The skin permeation of buprenorphine base and HCl salt through cadaver skin was investigated. The octanol-water partition coefficient and solubilities of both buprenorphine free base and HCl salt were determined at 32 degrees C. As expected, buprenorphine free base was more lipophilic than its HCl salt and was practically insoluble in aqueous buffer at pH 8.7. The drug solubility decreased exponentially as the pH of the solution increased, whereas the permeability coefficient increased as the donor solution pH decreased. The skin flux of buprenorphine.HCl was significantly higher than that of the free base from propylene glycol/lauric acid vehicle mixtures. Buprenorphine base permeation through tape-stripped epidermis suggested that in addition to stratum corneum, viable epidermis presented a significant diffusion barrier because of the very low aqueous solubility of the free base observed. The mean steady-state skin fluxes of buprenorphine.HCl were 20.3 and 29.7 micrograms/cm2/h from propylene glycol:lauryl alcohol: ethanol (80:15:5) and propylene glycol: propylene glycol monolaurate: water (80:15:5) vehicle mixtures, respectively. The skin flux of buprenorphine.HCl from various monolithic matrix patches was also evaluated. When capric acid, lauric acid, and lauryl alcohol were separately incorporated into an adhesive matrix, the skin flux of buprenorphine.HCl was enhanced by a factor of 2 to 3.5. Finally, based on the total body clearance and minimum effective concentration of buprenorphine, a transdermal delivery rate of 2.5 micrograms/cm2/h from a 20-cm2 patch was estimated. The in vitro skin permeation data clearly suggest that transdermal delivery of buprenorphine is feasible to achieve a desired systemic analgesic effect.

Transdermal iontophoretic delivery of arginine-vasopressin (I): Physicochemical considerations

The enhancement in the transdermal delivery of arginine-vasopressin (AVP), a nonapeptide antidiuretic hormone (ADH), was studied using the Transdermal Periodic lontotherapeutic System (TPIS). The TPIS is capable of generating a pulse current at a specific combination of waveform, frequency and ON/OFF ratio. The in vitro permeation studies of AVP across the hairless rat skin was conducted under TPIS application and the results were compared with that by passive diffusion. Vasopressin was found to be relatively stable during the course of the experiment. The effect of pH and ionic strength of the donor solution and drug concentration on the AVP flux was evaluated. Under the application of TPIS, the transdermal delivery rate of AVP could be enhanced as much as 1000-fold and the degree of enhancement was noted to be dependent upon the physicochemical conditions used during the iontophoresis treatment. The flux of AVP at pH 5.0 and 7.4 was similar at constant ionic strength, but increased substantially as the ionic strength decreased. A linear relationship was established between AVP flux and AVP concentration in the donor compartment. The skin permeability enhanced by TPIS treatment is reversible and upon termination of iontophoretic application, the AVP flux was observed to return to that by passive diffusion alone.

Thermodynamic study on enhancement of percutaneous penetration of drugs by Azone.

The mechanism whereby Azone (AZ, 1-dodecylazacycloheptan-2-one) enhances drug penetration through the hairless rat abdominal skin was investigated thermodynamically. Three kinds of drugs, indomethacin, ibuprofen and sulfanilamide which have similar solubilities in a mixed organic solvent (ethanol-diethylcarbitol, 40:60 v/v), were selected to evaluate the drug penetration with or without 5% AZ. Transdermal delivery rates were determined at 27 and 37 degrees C by using an in vitro diffusion cell procedure and the abdominal full-thickness skin of hairless rat. The solubility of each of the three drugs in the solvent with AZ was similar to that without AZ. Ethanol in the vehicle penetrated through the skin prior to the drugs. Activation energies for the skin penetration of the three drugs in the presence of AZ were decreased compared to those in its absence. For all drugs the partition coefficients between the skin and vehicle with AZ were 2-80 times higher than those without it. The activity coefficients of drugs in the presence of AZ in the skin were 2-90 times lower than those without the enhancer. These results suggested that the enhancing effect of AZ was not due to changing the solubility of the drugs in solvents but to increasing the thermodynamic activities and the affinities of the drugs to skin.