Microporation-Mediated Transdermal Delivery of In Situ Gel Incorporating Etodolac-Loaded PLGA Nanoparticles for Management of Rheumatoid Arthritis.

Management of rheumatoid arthritis (RA) requires long-term administration of different medications since there has been no cure until now. Etodolac (ETD) is a nonsteroidal anti-inflammatory drug commonly used for RA management. However, its long-term administration resulted in severe side effects. This study aimed to develop a transdermal in situ gel incorporating ETD-loaded polymeric nanoparticles (NPs) to target the affected joints for long-term management of RA. Several PLGA NPs incorporating 1% ETD were prepared by nanoprecipitation and optimized according to the central composite design. The optimum NPs (F1) exhibited 96.19 ± 2.31% EE, 282.3 ± 0.62 nm PS, 0.383 ± 0.04 PDI, and -6.44 ± 1.69 ZP. A hyaluronate coating was applied to F1 (H-F1) to target activated macrophages at inflammation sites. H-F1 exhibited 287.4 ± 4.2 nm PS, 0.267 ± 0.02 PDI, and -23.7 ± 3.77 ZP. Pluronic F-127 in situ gel (H-F1G) showed complete gelation at 29 °C within 5 min. ETD permeation from H-F1G was sustained over 48 h when applied to microporated skin and exhibited significant enhancement of all permeation parameters. Topical application of H-F1G (equivalent to 8 mg ETD) to Wistarrat microporated skin every 48 h resulted in antirheumatic therapeutic efficacy comparable to commercial oral tablets (10 mg/kg/day).

New Formulation-Microporation Combination Approaches to Delivering Ciclopirox across Human Nails.

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients' adherence.

Immunolabeling for Detection of Endogenous and Overexpressed Peroxisomal Proteins in Mammalian Cells.

Peroxisomes are dynamic subcellular organelles in mammals, playing essential roles in cellular lipid metabolism and redox homeostasis. They perform a wide spectrum of functions in human health and disease, with new roles, mechanisms, and regulatory pathways still being discovered. Recently elucidated biological roles of peroxisomes include as antiviral defense hubs, intracellular signaling platforms, immunomodulators, and protective organelles in sensory cells. Furthermore, peroxisomes are part of a complex inter-organelle interaction network, which involves metabolic cooperation and cross talk via membrane contacts. The detection of endogenous and/or overexpressed proteins within a cell by immunolabelling informs us about the organellar and even sub-organellar localization of both known and putative peroxisomal proteins. In turn, this can be exploited to characterize the effects of experimental manipulations on the morphology, distribution, and/or number of peroxisomes in a cell, which are key properties controlling peroxisome function. Here, we present a protocol used successfully in our laboratory for the immunolabelling of peroxisomal proteins in cultured mammalian cells. We present immunofluorescence and transfection techniques as well as reagents to determine the localization of endogenous and overexpressed peroxisomal proteins.

Microneedle-mediated transdermal delivery of naloxone hydrochloride for treatment of opioid overdose.

Naloxone (NAL) is administered parenterally or intranasally for treating opioid overdose. The short duration of action of NAL calls for frequent re-dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of microneedles on improving the skin permeation of NAL hydrochloride. In vitro permeation of NAL across intact and microneedle-treated (Dr. Pen™ Ultima A6) porcine skin was evaluated. The effect of microneedle length and application duration, and donor concentration on NAL permeation were investigated. In-vitro in-vivo correlation of the permeation results was done to predict the plasma concentration kinetics of NAL in patients. In vitro passive permeation of NAL after 6 h was observed to be 8.25±1.06 µg/cm2. A 56- and 37-fold enhancement was observed with 500 and 250 µm needles applied for 1 min, respectively. Application of 500 µm MNs for 2 min significantly reduced the lag time to ~ 8 min and increasing the donor concentration for the same treatment group doubled the permeation (p < 0.05). Modeling simulations demonstrated the attainment of pharmacokinetic profile of NAL comparable to those obtained with the FDA-approved intramuscular and intranasal devices. Microneedle-mediated transdermal delivery holds potential for rapid and sustained NAL delivery for opioid overdose treatment.

Clinical assessment of the use of topical liquid diclofenac following laser microporation of cutaneous neurofibromas in individuals with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with a prevalence of 1:3000 births and a wide variety of clinical manifestations. Cutaneous neurofibromas (cNF) are among the most common visible manifestations of NF1 and present a major clinical burden for patients. NF1 patients with cNF often report decreased quality of life, emotional well-being and physical comfort. Developing effective medical therapies for cNF has been identified as a priority for the majority of adults with NF1. METHODS: The study was an open, controlled and prospective proof-of-concept clinical trial. The topical treatment consisted of two steps: cNF microporation using a laser device followed by topical application of one drop of diclofenac 25 mg/mL on the surface of the cNF (T neurofibroma = treatment) or physiological saline (C neurofibroma = control) and reapplied twice daily for 3 days. Neurofibroma assessments included visual and dermatoscopy observations noting color and presence of necrosis, presence of flaccidity, measurements in two dimensions, photographs, and histopathology after excision. The primary efficacy variable was the presence of tissue necrosis. The primary safety variable was the occurrence of treatment-related adverse events. RESULTS: Six patients were included in the study. The treatment resulted in transitory topical changes (healing of the microporation grid with formation of scintillating tissue layer, hyperemia and desquamation), with no statistically significant variation in the dimensions of the T and C neurofibromas in relation to pretreatment measurements. There was no necrosis in the T or C neurofibromas. In the histopathological analysis, there was no significant difference in the distribution of chronic (lymphocytic) inflammatory infiltrate in the papillary reticular dermis (subepithelial), type of infiltrate (diffuse, perivascular, or both), presence of fibrosis, and presence of atrophy among the T and C neurofibromas. No adverse events attributable to the use of diclofenac were reported during the treatment period. CONCLUSIONS: Treatment did not result in significant alterations in terms of presence of tissue necrosis, size, or histopathological features in the T neurofibromas or in comparison to the C neurofibromas. Topical diclofenac with laser microporation was well-tolerated, with no adverse events attributable to diclofenac reported. Whether these observations are due to minimal systemic and neurofibroma exposure remain to be explored in dosage studies with larger patient groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03090971) retrospectively registered March 27, 2017.

Investigation of the Dual-Stage Method of Active Er:YLF Laser Drug Delivery Through the Nail and Laser-Induced Transformations of the Drug Extinction Spectrum.

BACKGROUND AND OBJECTIVE: A novel dual-stage method for active laser drug delivery (DSLADD) in the treatment of nail diseases is being presented. This method includes sequentially performed microporation of the nail with submillisecond pulses of Er:YLF laser radiation through a layer of an aqueous solution of drug deposited on the nail surface (Stage 1) and exposure this layer to the same laser radiation to deliver drug under the nail plate (Stage 2). The delivery of methylene blue (MB) as one of the possible drugs in the treatment of nail diseases is investigated. The influence of the thickness of the MB layer, as well as the energy and number of applied laser pulses, on the rate of active laser delivery is discussed. To illustrate the possible effect of delivery on the drug delivered, special attention is paid to the deformation of the extinction spectrum of MB solution after laser irradiation. STUDY DESIGN/MATERIALS AND METHODS: Diode-pumped Er:YLF laser was used for DSLADD. The process of DSLADD under the nail plate was investigated using digital video microscopy. For different values of the thickness of MB solution layer applied to the nail plate and the energy of laser pulses, the number of laser pulses required to create a single through a microchannel in the nail plate and the number of laser pulses required to deliver the solution to the ventral side of the nail plate after its microporation were registered. The mass and the dose of MB solution penetrated under the nail plate, and the rate of MB solution delivery through a single microchannel was determined. Investigation of the influence of Er:YLF laser radiation parameters on the extinction spectrum of the drug was performed using a fiber spectrometer. The extinction spectra of the 0.001% aqueous solution of MB were recorded before and after exposure to a different number of Er:YLF laser pulses with the energy of 1-4 mJ. RESULTS: It was found that the minimum number of laser pulses required for active Er:YLF laser drug delivery under the nail corresponds to the MB layer thickness of 100 µm and the laser pulse energy of 4 mJ. It is shown that in this case, the rate of active laser delivery of MB solution reaches 0.26 ± 0.03 mg/pulse. The radiation of the Er:YLF laser affects the shape of the extinction spectrum of the aqueous solution of MВ, which is associated with the transition of the dye from the monomeric to dimeric state. Depending on the laser pulse energy, the fraction of a certain conformational state in the aqueous MB solution can decrease or increase, stimulating a possible change in its photodynamic and antiseptic activity. CONCLUSION: For the first time, a novel DSLADD through the nail has been described and investigated in vitro. It was demonstrated that at Er:YLF laser pulse repetition rate of f = 30 Hz, microporation of the nail plate and drug delivery through a single microchannel will be about 1.5 s. Lasers Surg. Med. © 2021 Wiley Periodicals LLC.

Development and evaluation of a heparin gel for transdermal delivery via laser-generated micropores.

Aim: Our study investigated the feasibility of transdermal delivery of heparin, an anticoagulant used against venous thromboembolism, as an alternative to intravenous administration. Materials & methods: Skin was pretreated using ablative laser (Precise Laser Epidermal System [P.L.E.A.S.E.®] technology) for enhanced delivery of heparin. In vitro permeation studies using static Franz diffusion cells provided a comparison between delivery from 0.3% w/v heparin-loaded poloxamer gel and solution across untreated and laser-treated dermatomed porcine ear skin. Results: No passive delivery of heparin was observed. Laser-assisted delivery from solution (26.07 ± 1.82 µg/cm2) was higher (p < 0.05) than delivery from heparin gel (11.28 ± 5.32 µg/cm2). However, gel is likely to sustain the delivery over prolonged periods like a maintenance dose via continuous intravenous infusion. Conclusion: Thus, ablative laser pretreatment successfully delivered heparin, establishing the feasibility of delivering hydrophilic macromolecules using the transdermal route.

Laser irradiation of ocular tissues to enhance drug delivery.

Scleral and corneal membranes represent substantial barriers against drug delivery to the eye. Conventional hypodermic needles-based intraocular injections are clinically employed to overcome these barriers. This study, for the first time, investigated a non-invasive alternative to intraocular injections by laser irradiation of ocular tissues. The P.L.E.A.S.E.® laser device was applied on excised porcine scleral and corneal tissues, which showed linear relationships between depths of laser-created micropores and laser fluences at range 8.9-444.4 J/cm2. Deeper and wider micropores were observed in scleral relative to corneal tissues. The permeation of rhodamine B and fluorescein isothiocyanate (FITC)-dextran were investigated through ocular tissues at different laser parameters (laser fluences 0-44.4 J/cm2 and micropore densities 7.5 and 15%). Both molecules showed enhanced permeation through ocular tissues on laser irradiation. Maximum transscleral permeation of the molecules was attained at laser fluence 8.9 J/cm2 and micropore density 15%. Transcorneal permeation of rhodamine B increased with increasing either laser fluence or micropore density, while that of FITC-dextran was not affected by either parameter. The transscleral water loss increased significantly after laser irradiation then returned to the baseline values within 24 h, indicating healing of the laser-created micropores. Laser irradiation is a promising technique to enhance intraocular delivery of both small and large molecule drugs.

Transdermal delivery of FITC-Dextrans with different molecular weights using radiofrequency microporation.

BACKGROUND: Transdermal delivery is of great importance for the effective delivery of bioactive or therapeutic agents into a body. The microporation device based on radiofrequency can be used to enhance delivery efficiency by removing the epidermis layer. METHODS: The micropores were developed on pig skin and human cadaver skin with dermal and epidermal layers by the microporation device. The regeneration of micropores in the human cadaver skin caused by microporation was confirmed using an optical microscope and haematoxylin/eosin (H&E) staining. The permeability of fluorescein isothiocyanate-dextrans (FITC-dextrans) with different molecular weights through the pig and human cadaver skins were measured using Franz diffusion cell. RESULTS: The optical image and histological analysis confirmed that the micropores on the skin were recovered over time. The enhanced permeability through micropores was confirmed by Franz diffusion cell. The lower molecular weight of FITC-dextran permeated more on both human and pig skin. In addition, the permeation rate was higher in pig skin than in human skin. CONCLUSIONS: We believe that the microporation device can be used as a potential technique for effective transdermal drug delivery.

Laser-assisted skin delivery of immunocontraceptive rabies nanoparticulate vaccine in poloxamer gel.

A painless skin delivery of vaccine for disease prevention is of great advantage in improving compliance in patients. To test this idea as a proof of concept, we utilized a pDNA vaccine construct, pDNAg333-2GnRH that has a dual function of controlling rabies and inducing immunocontraception in animals. The pDNA was administered to mice in a nanoparticulate form delivered through the skin using the P.L.E.A.S.E.® (Precise Laser Epidermal System) microporation laser device. Laser application was well tolerated, and mild skin reaction was healed completely in 8 days. We demonstrated that adjuvanted nanoparticulate pDNA vaccine significantly upregulated the expression of co-stimulatory molecules in dendritic cells. After topical administration of the adjuvanted nano-vaccine in mice, the high avidity serum for GnRH antibodies were induced and maintained up to 9 weeks. The induced immune response was of a mixed Th1/Th2 profile as measured by IgG subclasses (IgG2a and IgG1) and cytokine levels (IFN-γ and IL-4). Using flow cytometry, we revealed an increase of CD8+ T-cells and CD45R B cells upon the administration of the adjuvanted vaccine. Our previous study used the same pDNA nanoparticulate vaccine through an IM route, and a comparable immune response was induced using P.L.E.A.S.E. However, the vaccine dose in the current study was four-fold less than what was applied through the IM route.We concluded that laser-assisted skin vaccination has a potential of becoming a safe and reliable vaccination tool for rabies vaccination in animals or even in humans for pre- or post-exposure prophylaxis.

Delivering Molecular Beacons via an Electroporation-Based Approach Enables Live-Cell Imaging of Single RNA Transcripts and Genomic Loci.

Molecular beacons (MBs) are synthetic oligonucleotide probes that are designed to fluoresce upon hybridization to complementary nucleic acid targets. In contrast to genetically encoded probes that can be readily introduced into cells via standard transfection procedures, using MBs to obtain reliable intracellular measurements entails a reliable delivery method that maximizes MB entry while minimizing cell damage. One promising approach is microporation, a microliter volume electroporation-based method that exhibits reduced harmful events as compared with traditional electroporation methods. In this chapter, we describe in detail microporation steps for MB delivery that we have utilized over the past several years, followed by examples demonstrating successful MB-based imaging of specific RNA transcripts and genomic loci at the single-molecule level.

Fundamentals of fractional laser-assisted drug delivery: An in-depth guide to experimental methodology and data interpretation.

In the decade since their advent, ablative fractional lasers have emerged as powerful tools to enhance drug delivery to and through the skin. Effective and highly customizable, laser-assisted drug delivery (LADD) has led to improved therapeutic outcomes for several medical indications. However, for LADD to reach maturity as a standard treatment technique, a greater appreciation of its underlying science is needed. This work aims to provide an in-depth guide to the technology's fundamental principles, experimental methodology and unique aspects of LADD data interpretation. We show that drug's physicochemical properties including solubility, molecular weight and tissue binding behavior, are crucial determinants of how laser channel morphology influences topical delivery. Furthermore, we identify strengths and limitations of experimental models and drug detection techniques, interrogating the usefulness of in vitro data in predicting LADD in vivo. By compiling insights from over 75 studies, we ultimately devise an approach for intelligent application of LADD, supporting its implementation in the clinical setting.

Evaluation of microneedles-assisted in situ depot forming poloxamer gels for sustained transdermal drug delivery.

In this study, for the first time, we have reported a sustained transdermal drug delivery from thermoresponsive poloxamer depots formed within the skin micropores following microneedle (MN) application. Firstly, we have investigated the sol-gel phase transition characteristics of poloxamers (PF®127, P108, and P87) at physiological conditions. Rheological measurements were evaluated to confirm the critical gelation temperature (CGT) of the poloxamer formulations with or without fluorescein sodium (FS), as a model drug, at various concentrations. Optimized poloxamer formulations were subjected to in vitro release studies using a vial method. Secondly, polymeric MNs were fabricated using laser-engineered silicone micromolds from various biocompatible polymeric blends of Gantrez S-97, PEG 10000, PEG200, PVP K32, and PVP K90. The MN arrays were characterized for mechanical strength, insertion force determination, in situ dissolution kinetics, moisture content, and penetration depth. The optimized MN arrays with good mechanical strength and non-soluble nature were used to create micropores in the neonatal porcine skin. Microporation in neonatal porcine skin was confirmed by dye-binding study, skin integrity assessment, and histology study. Finally, the in vitro delivery of FS from optimized poloxamer formulations was conducted across non-porated vs microporated skin samples using vertical Franz diffusion cells. Results concluded that permeation of FS was sustained for 96 h across the MN-treated skin samples containing in situ forming depot poloxamer formulations compared to non-microporated skin which sustained the FS delivery for 72 h. Confocal microscopic images confirmed the distribution of higher florescence intensity of FS in skin tissues after permeation study in case of MN-treated skin samples vs intact skin samples.

Numerical Investigation of Analytical Models of Drug Flux Through Microporated Skin.

In this study, drug flux through microporated skin was modeled using detailed numerical solution of the diffusion equation. The results of the modeling were compared to previously published simplified and easy to use analytical equations. Limitations and accuracy of these equations were investigated. Appropriate modifications of the equations were identified to expand them to wider practical applications when pore shape is not circular. Numerical simulations have shown a good accuracy of the new simple equations when these are used within their limits of application.

Using a simple equation to predict the microporation-enhanced transdermal drug flux.

The mathematical model describing drug flux through microporated skin was previously developed. Based on this model, two mathematical equations can be used to predict the microporatio-enhanced transdermal drug flux: the complex primal equation containing a variety of experimentally-determined variables, and the simplified straightforward equation. In this study, experimental transdermal fluxes of three corticosteroids through split-thickness human skin treated with a microneedle roller were measured, and the values of fluxes compared with those predicted using both the more complex and simplified equations. According to the results of the study, both equations demonstrated high accuracy in the prediction of the fluxes of corticosteroids. The simplified equation was validated and confirmed as robust using regression analysis of literature data. Further, its capability and ease of use was exemplified by predicting the flux of methotrexate through the skin microporated with laser and comparing with published experimental data.

Synergistic effects of dendritic cell targeting and laser-microporation on enhancing epicutaneous skin vaccination efficacy.

Due to its unique immunological properties, the skin is an attractive target tissue for allergen-specific immunotherapy. In our current work, we combined a dendritic cell targeting approach with epicutaneous immunization using an ablative fractional laser to generate defined micropores in the upper layers of the skin. By coupling the major birch pollen allergen Bet v 1 to mannan from S. cerevisiae via mild periodate oxidation we generated hypoallergenic Bet-mannan neoglycoconjugates, which efficiently targeted CD14+ dendritic cells and Langerhans cells in human skin explants. Mannan conjugation resulted in sustained release from the skin and retention in secondary lymphoid organs, whereas unconjugated antigen showed fast renal clearance. In a mouse model, Bet-mannan neoglycoconjugates applied via laser-microporated skin synergistically elicited potent humoral and cellular immune responses, superior to intradermal injection. The induced antibody responses displayed IgE-blocking capacity, highlighting the therapeutic potential of the approach. Moreover, application via micropores, but not by intradermal injection, resulted in a mixed TH1/TH17-biased immune response. Our data clearly show that applying mannan-neoglycoconjugates to an organ rich in dendritic cells using laser-microporation is superior to intradermal injection. Due to their low IgE binding capacity and biodegradability, mannan neoglycoconjugates therefore represent an attractive formulation for allergen-specific epicutaneous immunotherapy.

Pre-Microporation Improves Outcome of Pancreatic Islet Labelling for Optical and 19F MR Imaging.

BACKGROUND: In vitro labelling of cells and small cell structures is a necessary step before in vivo monitoring of grafts. We modified and optimised a procedure for pancreatic islet labelling using bimodal positively charged poly(lactic-co-glycolic acid) nanoparticles with encapsulated perfluoro crown ethers and indocyanine green dye via microporation and compared the method with passive endocytosis. RESULTS: Pancreatic islets were microporated using two pulses at various voltages. We tested a standard procedure (poration in the presence of nanoparticles) and a modified protocol (pre-microporation in a buffer only, and subsequent islet incubation with nanoparticles on ice for 10 min). We compared islet labelling by microporation with labelling by endocytosis, i.e. pancreatic islets were incubated for 24 h in a medium with suspended nanoparticles. In order to verify the efficiency of the labelling procedures, we used 19F magnetic resonance imaging, optical fluorescence imaging and confocal microscopy. The experiment confirmed that microporation, albeit fast and effective, is invasive and may cause substantial harm to islets. To achieve sufficient poration and to minimise the reduction of viability, the electric field should be set at 20 kV/m (two pulses, 20 ms each). Poration in the presence of nanoparticles was found to be unsuitable for the nanoparticles used. The water suspension of nanoparticles (which served as a surfactant) was slightly foamy and microbubbles in the suspension were responsible for sparks causing the destruction of islets during poration. However, pre-microporation (poration of islets in a buffer only) followed by 10-min incubation with nanoparticles was safer. CONCLUSIONS: For labelling of pancreatic islets using poly(lactic-co-glycolic acid) nanoparticles, the modified microporation procedure with low voltage was found to be safer than the standard microporation procedure. The modified procedure was fast, however, efficiency was lower compared to endocytosis.

siRNA-mediated Silencing of Peroxisomal Genes in Mammalian Cells.

RNAi technologies are a valuable tool in the identification and investigation of proteins that are involved in peroxisome biogenesis and function. Small interfering RNA (siRNA) has developed into the most commonly used RNAi tool for the induction of transient, short-term silencing of protein coding genes. Although siRNA can induce gene knockdown in a variety of mammalian cell lines, their utility is limited by efficient uptake of synthetic oligonucleotides into the cells. Here, we describe different transfection methods that have been successfully used by us to silence peroxisomal genes in a variety of cell lines, including primary human skin fibroblasts, which are usually difficult to transfect.

Sustained epidermal powder drug delivery via skin microchannels.

Transdermal delivery of hydrophilic drugs is challenging. This study presents a novel sustained epidermal powder delivery technology (sEPD) for safe, efficient, and sustained delivery of hydrophilic drugs across the skin. sEPD is based on coating powder drugs into high-aspect-ratio, micro-coating channels (MCCs) followed by topical application of powder drug-coated array patches onto ablative fractional laser-generated skin MCs to deliver drugs into the skin. We found sEPD could efficiently deliver chemical drugs without excipients and biologics drugs in the presence of sugar excipients into the skin with a duration of ~12h. Interestingly the sEPD significantly improved zidovudine bioavailability by ~100% as compared to oral gavage delivery. sEPD of insulin was found to maintain blood glucose levels in normal range for at least 6h in chemical-induced diabetes mice, while subcutaneous injection failed to maintain blood glucose levels in normal range. sEPD of anti-programmed death-1 antibody showed more potent anti-tumor efficacy than intraperitoneal injection in B16F10 melanoma models. Tiny skin MCs and 'bulk' drug powder inside relatively deep MCCs are crucial to induce the sustained drug release. The improved bioavailability and functionality warrants further development of the novel sEPD for clinical use.

Modelling drug flux through microporated skin.

A simple mathematical equation has been developed to predict drug flux through microporated skin. The theoretical model is based on an approach applied previously to water evaporation through leaf stomata. Pore density, pore radius and drug molecular weight are key model parameters. The predictions of the model were compared with results derived from a simple, intuitive method using porated area alone to estimate the flux enhancement. It is shown that the new approach predicts significantly higher fluxes than the intuitive analysis, with transport being proportional to the total pore perimeter rather than area as intuitively anticipated. Predicted fluxes were in good general agreement with experimental data on drug delivery from the literature, and were quantitatively closer to the measured values than those derived from the intuitive, area-based approach.