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Stem cells are recognized as an important target and tool in regenerative engineering. In this study, we explored the feasibility of engineering amniotic fluid-derived mesenchymal stem cell-secreted molecules (afMSC-SMs) as a versatile bioactive material for skin regenerative medicine applications in a time- and cost-efficient and straightforward manner. afMSC-SMs, obtained in powder form through ethanol precipitation, effectively contributed to preserving the self-renewal capacity and differentiation potential of primary human keratinocytes (pKCs) in a xeno -free environment, offering a potential alternative to traditional culture methods for their long-term in vitro expansion, and allowed them to reconstitute a fully stratified epithelium sheet on human dermal fibroblasts. Furthermore, we demonstrated the flexibility of afMSC-SMs in wound healing and hair regrowth through injectable hydrogel and nanogel-mediated transdermal delivery systems, respectively, expanding the pool of regenerative applications. This cell-free approach may offer several potential advantages, including streamlined manufacturing processes, scalability, controlled formulation, longer shelf lives, and mitigation of risks associated with living cell transplantation. Accordingly, afMSC-SMs could serve as a promising therapeutic toolbox for advancing cell-free regenerative medicine, simplifying their broad applicability in various clinical settings. [Display omitted] [ABSTRACT FROM AUTHOR]

Tracking drug disposition in the skin in a non-destructive and at least semi-quantitative fashion is a relevant objective for the assessment of local (cutaneous) bioavailability. Confocal Raman spectroscopy has been shown potentially useful in this regard and, importantly, recent advances have enabled the presence of applied chemicals in the viable epidermis below the stratum corneum (SC) to be determined without ambiguity and having addressed the challenges of (a) background signals from endogenous species and noise and (b) signal attenuation due to absorption and scattering. This study aimed to confirm these observations using a different vibrational spectroscopy approach - specifically, stimulated Raman scattering (SRS) microscopy – and the more conventional in vitro skin penetration test (IVPT). SRS is a nonlinear optical imaging technique which enables more precise location of the skin surface and enhanced skin depth resolution relative to confocal Raman microscopy. The method can also probe larger areas of the sample under investigation and identify the localization of the permeating chemical in specific structural components of the skin. Here, SRS was shown capable of tracking the uptake and distribution of 4-cyanophenol (CP), the same model compound used in the recent confocal Raman investigation, at depths beyond the SC following skin treatment with different vehicles and for different times. The SRS results correlated well with those from the confocal Raman experiments, and both were consistent with independent IVPT measurements. Acquired images clearly delineated CP preference for the intercellular lipid layers of the SC relative to the corneocytes. The stage is now set to apply these and other correlative techniques to examine commercial drug products. [Display omitted] [ABSTRACT FROM AUTHOR]

Microneedle drug delivery has recently emerged as a clinical method, and dissolving microneedles (DMNs) offer exclusive simplicity and efficiency, compared to the other kinds of microneedles. The tips of most currently available DMNs are cone/house-shaped to result in a lower penetration force. Penetration of the needle tips into the skin relies mainly on the back tape or external pressure, and their adhesion to the skin is relatively low. In addition, only the drug in the part of tips that are pierced into the dermis can be dissolved, resulting in drug waste. Inspired from the barbed structure of the honeybee stinger, we reported substrate-free DMNs with a barbed structure by a dual-molding process, which is suitable for mass production. Those DMNs showed 3-fold greater adhesion force between the needle tips and the skin, better dissolution and deeper penetration than house-shaped DMNs in vivo under the same conditions. For the in situ treatment of psoriasis in mice, the barbed DMNs required only the half dose of house-shaped DMNs to achieve similar efficacy. We reported substrate-free DMNs with barbed structure by dual-molding process, which showed 3-fold greater adhesion force between needle tips and skin, better dissolution and deeper penetration than house-shaped one. [Display omitted] [ABSTRACT FROM AUTHOR]

Topical treatments to modulate hair growth are generally limited by low drug bioavailability due to poor skin permeability. Here, we studied the use of STAR particles, which are millimeter-sized ceramic particles with protruding microneedles, to form micropores in the skin to increase skin permeability to hair growth-modulating drugs. STAR particle design and fabrication were optimized, and the resulting STAR particles were shown to reduce lag time and increase skin permeability to minoxidil and acyclovir by more than three-fold compared to no treatment in pig skin ex vivo. In rats, STAR particles also improved topical delivery of minoxidil and acyclovir, which resulted in an increase or a decrease in the number, length and/or thickness of hairs and/or the number of anagen-phase hair follicles after minoxidil or acyclovir treatment, respectively. Clinical exam and histological evaluation showed no evidence of skin irritation or other adverse effects of the treatments. We conclude that STAR particles can increase topical delivery of minoxidil and acyclovir to improve modulation of hair growth promotion and inhibition, respectively. Millimeter-sized STAR particles with three-arm microprojections formed micropores in the stratum corneum, increasing skin permeability to hair growth-modulating drugs. [Display omitted] • STAR particles are millimeter-sized ceramic particles with protruding microneedles. • STAR particles rubbed on skin formed micropores in stratum corneum. • STAR particle treatment increased skin permeability to hair growth-modulating drugs. • STAR particle treatment modulated hair growth in rats in vivo. [ABSTRACT FROM AUTHOR]

Microneedle-mediated transdermal delivery using nanocarriers can successfully overcome the barrier of the stratum corneum and protect drugs from elimination in skin tissues. However, the effectiveness of drug delivery to different layers of skin tissues and the circulatory system varies considerably, subject to the properties of the drug delivery system and delivery regime. How to maximise delivery outcomes remains unclear. In this study, mathematical modelling is employed to investigate this transdermal delivery under various conditions, using the skin model that is reconstructed based on the realistic skin anatomical structure. Treatment efficacy is evaluated in terms of drug exposure over time. The modelling results demonstrate the complex dependence of drug accumulation and distribution on the nanocarrier properties, microneedle properties and environment in different skin layers and blood. Specifically, delivery outcomes in the entire skin and blood can be improved by increasing the loading dose and reducing microneedle spacing. However, several parameters need to be optimised with respect to the specific location of the target site in the tissue for better treatment; these include the drug release rate, nanocarrier diffusivity in microneedle and skin tissue, nanocarrier transvascular permeability, nanocarrier partition coefficient between tissue and microneedle, microneedle length, wind speed and relative humidity. The delivery is less sensitive to the diffusivity and physical degradation rate of free drugs in microneedle, and their partition coefficient between tissue and microneedle. Results obtained from this study can be used to improve the design of the microneedle-nanocarrier combined drug delivery system and delivery regime. [Display omitted] • A mathematical model of microneedle-mediated transdermal delivery using nanocarriers. • Impacts of different microneedle properties, nanoparticle properties and environment. • Opportunities to improve the drug delivery system design for more effective treatment. [ABSTRACT FROM AUTHOR]

Emotional stress-induced sweating in glabrous skin of the palm and sole, which can be excessive in some individuals (hyperhidrosis), can negatively impact quality of life. Understanding the mechanisms underlying this response can lead to potential treatments. Transdermal iontophoresis is a method to administer ionized sudorific agents to sweat glands within the dermis. However, due to the reduced permeability of pharmacological agents in thicker skin such as the palms, this technique has been shown to be less effective when applied in thicker skin. Thus, we assessed the effectiveness of pre-treating palmar skin with microneedles to create micropores on the stratum corneum of the palm to enhance the iontophoretic delivery of pilocarpine to modulate sweat production. On three separate sessions, we applied microneedles (0.78 cm2, 190 needles with a length of 875 μm) to palm and forearm skin sites. Upon removal of the microneedles, we assessed the number of perforations colored by gentian violet in the forearm only (Protocol 1, n = 20), skin barrier function indexed by transepidermal water loss (TEWL) (Protocol 2, n = 21), and sweating induced by the iontophoretic application of 1% pilocarpine (Protocol 3, n = 43). Briefly, we measured 1) ∼172 dyed spots on forearm skin, 2) an increase of ∼300% and ∼ 900% in TEWL on palm and forearm skin, respectively; and 3) a 2-fold increase in sweating on the palm only following the application of the microneedles. Notably, the microneedle array failed to enhance pilocarpine delivery at either the palm or forearm skin sites. We showed the application of a microneedle array enhanced skin permeability and sweat production on the palm without a concomitant increase in pilocarpine delivery. Therefore, this methodology could be employed to advance our understanding of the causes and treatments of medical conditions such as hyperhidrosis. [Display omitted] • Application of microneedle arrays disrupted skin barrier function on palmar skin. • Microneedle pretreatment elevated iontophoretic pilocarpine-induced palmar sweating. • Microneedle pretreatment of forearm skin did not affect pilocarpine-induced sweating. • Increases in palmar sweating occurred without a concomitant increase in pilocarpine delivery. [ABSTRACT FROM AUTHOR]

Overuse injuries or acute trauma in joints often lead to painful tendinopathy, and pharmacological treatment effects are limited. The site of the disease is hard to reach with drugs, both systemically and through the skin. Therapeutic gases may close this gap, as they permeate easier through tissues than conventional small molecules. We present a patch device releasing the anti-inflammatory gas carbon monoxide (CO) through the skin to the subcutaneous tendons and tissues. CO is chemically generated upon device activation and its design maximizes CO exposure to the underlying skin and protects the patient from all side and degradation products. The patch delivered CO successfully through the intact skin, granting lasting, subcutaneous CO exposure for up to 16 h. Furthermore, the released CO induced the proliferation of fibroblasts and the polarization of monocytes into anti-inflammatory M2 macrophages. In conclusion, the CO-releasing device might open an entirely new treatment option against tendinopathies in case of a positive outcome of future in vivo studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Hyaluronic acid (HA) has been widely used in cosmetics and topical preparations owing to its favorable moisturizing property and potential in enhancing drugs' skin permeability. Here, the influencing factors and underlying mechanism of HA on skin penetration were carefully investigated, and HA-modified Undecylenoyl-Phenylalanine (UP) liposomes (HA-UP-LPs) were designed as a proof of principle for efficacious transdermal drug delivery strategy to enhance the skin penetration and retention. An in vitro penetration test (IVPT) of HA with different molecular weights showed that low molecular weight HA (LMW-HA, 5 kDa and 8 kDa) could pass through the stratum corneum (SC) barrier and enter into the epidermis and dermis layers, whereas its high molecular counterparts (HMW-HA) were trapped on the SC surface. Mechanistic studies revealed that LMW-HA could interact with keratin and lipid in the SC meanwhile exerted a substantial skin hydration effect, which may partially contribute to the SC penetration benefit. In addition, the surface decoration of HA drove an energy-dependent caveolae/lipid raft-mediated endocytosis of the liposomes through direct binding to the CD44 receptors widely expressed on skin cell membranes. Notably, IVPT showed a 1.36-fold and 4.86-fold increase in skin retention of UP and a 1.62-fold and 5.41-fold increase in skin penetration of UP with HA-UP-LPs over UP-LPs and free UP at 24 h, respectively. As a result, the anionic HA-UP-LPs (−30.0 mV) showed enhanced drug skin penetration and retention compared with conventional cationic bared UP-LPs (+21.3 mV) on both in vitro mini-pig skin as well as in vivo mouse skin. Overall, the usage of LMW-HA might offer opportunities in developing novel topical preparations and skin care products with improved transdermal penetration and retention. [Display omitted] • HA (≤ 8 kDa) could penetrate the stratum corneum through strong skin hydration and interaction with keratin and lipids. • HA could enter HaCat cells via CD44 receptor-mediated endocytosis. • HA (> 10 kDa) was difficult to penetrate the stratum corneum and only stayed on the stratum corneum. • LMW-HA modified cationic liposomes was better in promoting drug skin penetration and retention than unmodified ones. • LMW-HA is a potential penetration enhancer for developing topical preparations and skin care products. [ABSTRACT FROM AUTHOR]

Glioblastoma Multiforme (GBM) is one of the challenging tumors to treat as it recurs, almost 100%, even after surgery, radiation, and chemotherapy. In many cases, recurrence happens within 2-3cm depth of the resected tumor margin, indicating the inefficacy of current anti-glioma drugs to penetrate deep into the brain tissue. Here, we report an injectable nanoparticle-gel system, capable of providing deep brain penetration of drug up to 4 cm, releasing in a sustained manner up to >15 days. The system consists of ∼222 nm sized PLGA nanoparticles (NP-222) loaded with an anti-glioma drug, Carmustine (BCNU), and coated with a thick layer of polyethylene glycol (PEG). Upon release of the drug from PLGA core, it will interact with the outer PEG-layer leading to the formation of PEG-BCNU nanocomplexes of size ∼33 nm (BCNU-NC-33), which could penetrate >4 cm deep into the brain tissue compared to the free drug (< 5 mm). In vitro drug release showed sustained release of drug for 15 days by BCNU-NP gel, and enhanced cytotoxicity by BCNU-NC-33 drug-nanocomplexes in glioma cell lines. Ex vivo goat-brain phantom studies showed drug diffusion up to 4 cm in tissue and in vivo brain-diffusion studies showed almost complete coverage within the rat brain (∼1.2 cm), with ∼55% drug retained in the tissue by day-15, compared to only ∼5% for free BCNU. Rat orthotopic glioma studies showed excellent anti-tumor efficacy by BCNU-NP gel compared to free drug, indicating the potential of the gel-system for anti-glioma therapy. In effect, we demonstrate a unique method of sustained release of drug in the brain using larger PLGA nanoparticles acting as a reservoir while deep-penetration of the released drug was achieved by in situ formation of drug-nanocomplexes of size <50 nm which is less than the native pore size of brain tissue (> 100 nm). This method will have a major impact on a challenging field of brain drug delivery. [Display omitted] • A unique PLGA nanoparticle system (222 nm), in situ releasing PEG-drug nanocomplexes (33nm), penetrating ∼4 cm in brain. • The larger nanoparticles act as drug reservoirs for sustained release of chemodrug for >15 days • The injectable gel is designed to perform dual functions of sustained drug release and enhanced diffusion for GBM therapy. [ABSTRACT FROM AUTHOR]

Alopecia is the most common and difficult-to-treat hair disorder. It usually brings a significant psychological burden to the patients. With the growing popularity of alopecia, the study of alopecia has gained more attention. Currently, only minoxidil and finasteride have been approved by the FDA for the treatment of alopecia, but the efficacy has always been unsatisfactory. As a new form of transdermal drug delivery, microneedles have been widely used in the treatment of alopecia and have proven to be effective. Microneedles delivery can improve the efficiency of local drug delivery and patients' compliance, which can achieve better therapeutic effects on hair-related diseases. Therefore, microneedles have gained much attention in the field of alopecia and hair regrowth promotion in recent years. This review summarizes the last decade of research on the microneedles delivery design for the treatment of alopecia or promotion of hair regrowth and provides a comprehensive evaluation of this field. Microneedles delivery strategy in stratified skin for promoting hair regrowth. Drugs can be combined with nanocarriers, exogenous stimulation, and the microneedles delivery system for targeted, controlled release delivery of drugs directly to the area of the hair follicle and the treatment of the disease. [Display omitted] • The types of alopecia and treatments are introduced. • Different types of microneedles in the field of alopecia are presented. • The clinical trials and current status of microneedles for alopecia are summarized. [ABSTRACT FROM AUTHOR]

The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability. [Display omitted] [ABSTRACT FROM AUTHOR]

Upon exhaustive research, the transdermal drug delivery system (TDDS) has appeared as a potential, well-accepted, and popular approach to a novel drug delivery system. Ease of administration, easy handling, minimum systemic exposure, least discomfort, broad flexibility and tunability, controlled release, prolonged therapeutic effect, and many more perks make it a promising approach for effective drug delivery. Although, the primary challenge associated is poor skin permeability. Skin is an intact barrier that serves as a primary defense mechanism to preclude any foreign particle's entry into the body. Owing to the unique anatomical framework, i.e. , compact packing of stratum corneum with tight junction and fast anti-inflammatory responses, etc. , emerged as a critical physiological barrier for TDDS. Fusion with other novel approaches like nanocarriers, specially designed transdermal delivery devices, permeation enhancers, etc. , can overcome the limitations. Utilizing such strategies, some of the products are under clinical trials, and many are under investigation. This review explores all dimensions that overcome poor permeability and allows the drug to attain maximum potential. The article initially compiles fundamental features, components, and design of TDDS, followed by critical aspects and various methods, including in vitro , ex vivo , and in vivo methods of assessing skin permeability. The work primarily aimed to highlight the recent advancement in novel strategies for effective transdermal drug delivery utilizing active methods like iontophoresis, electroporation, sonophoresis, microneedle, needleless jet injection, etc. , and passive methods such as the use of liposomes, SLN, NLC, micro/nanoemulsions, dendrimers, transferosomes, and many more nanocarriers. In all, this compilation will provide a recent insight on the novel updates along with basic concepts, the current status of clinical development, and challenges for the clinical translation of TDDS. [Display omitted] [ABSTRACT FROM AUTHOR]

Microneedles are a rapidly developing method for the transdermal delivery of therapeutic compounds. All types of microneedles, whether solid, hollow, coated, or dissolving function by penetrating the stratum corneum layer of the skin producing a microchannel through which therapeutic agents may be delivered. To date, coated and hollow microneedles have been the most successful, despite suffering from issues such as poor drug loading capabilities and blocked pores. Dissolving microneedles, on the other hand, have superior drug loading as well as other positive attributes that make it an ideal delivery system, including simple methods of fabrication and disposal, and abundantly available materials. Indeed, dissolvable microneedles can even be fabricated entirely from the therapeutic agent itself thus eliminating the requirement for additional excipients. This focused review presents the recent developments and trends of dissolving microneedles as well as potential future directions. The advantages, and disadvantages of dissolving microneedles as well as fabrication materials and methods are discussed. The potential applications of dissolving microneedles as a drug delivery system in different therapeutic areas in both research literature and clinical trials is highlighted. Applications including the delivery of cosmetics, vaccine delivery, diagnosis and monitoring, cancer, pain and inflammation, diabetes, hair and scalp disorders and inflammatory skin diseases are presented. The current trends observed in the microneedle landscape with particular emphasis on contemporary clinical trials and commercial successes as well as barriers impeding microneedle development and commercialisation are also discussed. [Display omitted] • The recent developments/trends of dissolving microneedles and future directions. • The potential applications of dissolving microneedles in different therapeutic areas. • The microneedle contemporary clinical trials and commercial successes. • The possible regulatory pathways for microneedle commercialisation. • A patented novel method of fabricating dissolving microneedles entirely from drugs. [ABSTRACT FROM AUTHOR]

Muscle-targeted drug delivery is a major challenge in nanomedicine. The extravasation of nanomedicines (or nanoparticles) from the bloodstream into muscle tissues is hindered by the continuous endothelium, the so-called blood-muscle barrier. This study aimed to evaluate the optimal size of macromolecular drugs for extravasation (or passive targeting) into muscle tissues. We constructed a size-tunable polymeric delivery platform as a polymeric nanoruler by grafting poly(ethylene glycol)s (PEGs) onto the poly(aspartic acid) (PAsp) backbone. A series of PEG-grafted copolymers (gPEGs) with a narrow size distribution between 11 and 32 nm in hydrodynamic diameter (D H) were prepared by changing the molecular weight of the PEGs. Biodistribution analyses revealed that accumulation amounts of gPEGs in the muscle tissues of normal mice tended to decrease above their size of ~15 nm (or ~11 nm for the heart). The gPEGs accumulated in the skeletal muscles of Duchenne muscular dystrophy model mice (mdx mice) at a 2–3-fold higher level than in the skeletal muscles of normal mice. At the same time, there was a reduced accumulation of gPEGs in the spleen and liver. Intravital confocal laser scanning microscopy and immunohistochemical analysis showed extravasation and locally enhanced accumulation of gPEGs in the skeletal muscle of mdx mice. This study outlined the pivotal role of macromolecular drug size in muscle-targeted drug delivery and demonstrated the enhanced permeability of 11–32 nm-sized macromolecular drugs in mdx mice. [Display omitted] • Muscle-targeted drug delivery is a significant challenge in nanomedicine. • PEG-grafted copolymers (gPEGs) 11–32 nm in hydrodynamic diameter were synthesized. • gPEG accumulation in normal mouse muscle tissues tended to decrease above gPEG size of ~15 nm. • gPEGs 11–32 nm accumulated highly in the mdx skeletal muscle via EPR-like effect. [ABSTRACT FROM AUTHOR]

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e. , PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e. , Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e. , PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye. Penetrating-peptide-mediated non-invasive axitinib delivery to the posterior segment of the eye for anti-neovascularization. Good fundus-targeting provides a broad potential for the non-invasive treatment of fundus neovascular diseases. [Display omitted] • Due to unique eye physiology, drug delivery in eyes is difficult. • Transmembrane-peptide-mediated non-invasive drug delivery is suitable. • Penetrating-peptide-mediated non-invasive axitinib delivery was achieved. • Neovascularization was substantially reduced using this delivery system. [ABSTRACT FROM AUTHOR]

The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo. Level A (point-to-point) and Level C (single point) IVIVCs were evaluated by using PK-based mathematical equations and building IVIVC models between in vitro fraction of drug permeation and in vivo fraction of drug absorption. The study results showed that the three differently formulated fentanyl TDS have comparable (p > 0.05) heat effects both in vitro and in vivo. In addition, the predicted steady-state concentration (C ss) from in vitro flux data and the observed C ss in vivo showed no significant differences (p > 0.05). However, the effects of heat on enhancement of fentanyl bioavailability observed in vivo were found to be greater compared to those observed in vitro for all three drug products, resulting in a weak prediction of the impact of heat on bioavailability from the in vitro data. The results from the current work suggest that while IVPT can be a useful tool to evaluate the performance of fentanyl TDS in vivo with a relatively good predictability at a normal temperature condition and to compare the effect of heat on drug delivery from differently formulated TDS, additional testing measures would enhance the ability to predict the heat effects in vivo with a lower prediction error. [Display omitted] • IVPT can predict in vivo fentanyl absorption from TDS at normal temperature. • IVPT can evaluate the heat effects on drug delivery from differently formulated TDS. • A good IVIVC model for TDS can be developed using IVPT as an in vitro method. • Predicting heat effects in vivo from IVPT is more challenging for lipophilic drugs. [ABSTRACT FROM AUTHOR]

Transdermal delivery has proven to be one of the most favorable methods among novel drug delivery systems. Since drugs administered by transdermal delivery systems avoid the gastrointestinal tract, and thus avoid conversion by the liver, the likelihood of liver dysfunction and gastrointestinal tract irritation as side effects is low. Drug delivery through the skin has other advantages, such as maintaining an effective rate of drug delivery over time, a steady rate of circulation, and the benefits of a passive delivery system and diffusion. Transdermal drug delivery is achieved using patches which consist of different and specific layers. In the last few decades, many types of patches have been approved worldwide, such as medical plasters, which have been generally applied to the skin for localized diseases. Such patches can be traced back to ancient China (around 2000 BCE) and are the early precursors of today's transdermal patches. With the help of effective design, materials, manufacturing, and evaluation, a large number of drugs can now be administered using this valuable advanced technology. This study reviews different types of polymer patches, their advantages and disadvantages, and different studies related to transdermal drug delivery methods, and the advantages and disadvantages of each method. Different mechanisms of transdermal drug delivery system with patches are also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Various perivascular drug delivery techniques have been demonstrated for localized post-treatment of intimal hyperplasia: a vascular inflammatory response caused by endothelial damages. Although most perivascular devices have focused on controlling the delivery duration of anti-proliferation drug, the confined and unidirectional delivery of the drug to the target tissue has become increasingly important. In addition, careful attention should also be paid to the luminal stability and the adequate exchange of vascular protein or cell between the blood vessel and extravascular tissue to avoid any side effect from the long-term application of any perivascular device. Here, a highly flexible and porous silk fibroin microneedle wrap (Silk MN wrap) is proposed to directly inject antiproliferative drug to the anastomosis sites while ensuring sufficient vascular exchanges. Drug-embedded silk MNs were transfer-molded on a highly flexible and porous silk wrap. The enhanced cell compatibility, molecular permeability, and flexibility of silk MN wrap guaranteed the structural integrity of blood vessels. Silk wrap successfully supported the silk MNs and induced multiple MN penetration to the target tissue. Over 28 days, silk MN wrap significantly inhibited intimal hyperplasia with a 62.1% reduction in neointimal formation. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite many ongoing and innovative approaches, there are still formidable challenges in the clinical translation of oral peptide drugs into marketable products due to their low absorption and poor bioavailability. Herein, a novel nanocarrier platform was developed that employs a hydrophobic ion-pairing (HIP) of model peptide (insulin) and the anionic bile salt (sodium glycodeoxycholate, SGDC), and markedly improves intestinal absorption via the bile acid pathway. The developed HIP-nanocomplexes (C1 and C2) were optimized, characterized, and in vitro and in vivo evaluation were performed to assess oral efficacy of these system. The optimal molar ratios of C1 and C2-nanocomplexes were 30:1 and 6:1 (SGDC:insulin), respectively. Compared to the insulin solution, the C1 and C2 nanocomplexes significantly enhanced the permeation of insulin across the Caco-2 cell monolayers, with 6.36- and 4.05-fold increases in apparent permeability, respectively. Uptake mechanism studies were conducted using different endocytosis inhibitors and apical sodium-dependent bile acid transporter (ASBT)-transfected MDCK cells, which demonstrated the involvement of the energy-dependent ASBT-mediated active transport. Furthermore, the intrajejunal administration of C1 and C2 resulted in their pharmacological availabilities (PA) being 6.44% and 0.10%, respectively, indicating increased potential for C1, when compared to C2. Similarly, the PA and the relative bioavailability with intrajejunal administration of the C1 were 17.89-fold and 16.82-fold greater than those with intracolonic administration, respectively, confirming better jejunal absorption of C1. Overall, these findings indicate that the HIP-nanocomplexes could be a prominent platform for the effective delivery of peptides with improved intestinal absorption. [Display omitted] [ABSTRACT FROM AUTHOR]

Delivery of therapeutic peptides upon oral administration is highly desired and investigations report that the cell-penetrating peptide (CPP) penetratin and its analogues shuffle and penetramax show potential as carriers to enhance insulin delivery. Exploring this, the specific aim of the present study was to understand the impact that their complexation with a lipidated or non-lipidated therapeutic cargo would have on the delivery, to evaluate the effect of differences in membrane interactions in vitro and in vivo , as well as to deduce the mode of action leading to enhanced delivery. Fundamental biophysical aspects were studied by a range of orthogonal methods. Transepithelial permeation of therapeutic peptide was evaluated using the Caco-2 cell culture model supplemented with epithelial integrity measurements, real-time assessment of the carrier peptide effects on cell viability and on mode of action. Pharmacokinetic and pharmacodynamic (PK/PD) parameters were evaluated following intestinal administration to rats and tissue effects were investigated by histology. The biophysical studies revealed complexation of insulin with shuffle and penetramax, but not with penetratin. This corresponded to enhanced transepithelial permeation of insulin, but not of lipidated insulin, when in physical mixture with shuffle or penetramax. The addition of shuffle and penetramax was associated with a lowering of Caco-2 cell monolayer integrity and viability, where the lowering of cell viability was immediate, but reversible. Insulin delivery in rats was enhanced by shuffle and penetramax and accompanied by a 10–20-fold decrease in blood glucose with immediate effect on the intestinal mucosa. In conclusion, shuffle and penetramax, but not penetratin, demonstrated to be potential candidates as carriers for transmucosal delivery of insulin upon oral administration, and their effect depended on association with both cargo and cell membrane. Interestingly, the present study provides novel mechanistic insight that peptide carrier-induced cargo permeation points towards enhancement via the paracellular route in the tight epithelium. This is different from the anticipated belief being that it is the cell-penetrating capability that facilitate transepithelial cargo permeation via a transcellular route. [Display omitted] [ABSTRACT FROM AUTHOR]

The transdermal drug delivery system is an exceptionally safe and well-tolerable therapeutic approach that has immense potential for delivering active components against bone-related pathologies. However, its use is limited in the current clinical practices due to the low skin permeability of most active drugs in the formulation. Thus, innovations in the methodologies of skin permeation enhancement techniques are suggested to overcome this limitation. Although various transdermal drug delivery systems are studied to date, there are insufficient studies comparing the therapeutic efficacy of transdermal delivery systems to oral delivery systems. Thus, creating a decision-making dilemma between oral or transdermal therapies. Therefore, a timely review is inevitable to develop a platform for future researchers to develop next-generation transdermal drug delivery strategies against skeletal diseases that must be convenient and cost-effective for the patients with improved therapeutic efficacy. Here, we will outline the most recent strategies that can overcome the choice limitation of the drug and enhance the transdermal adsorption of various types of drugs to treat bone disorders. For the first time, in this review paper, we will highlight the preclinical and clinical studies on the different transdermal delivery methods. Thus, providing insight into the current therapeutic approaches and suggesting new directions for the advancements in transdermal drug delivery systems against bone disorders. [Display omitted] [ABSTRACT FROM AUTHOR]

Tacrolimus has shown efficacy in eye inflammatory diseases. However, due to the drug lability, its formulation into a stable ophthalmic product remains a challenge. Tacrolimus-loaded nanocapsules (NCs) were designed for ocular instillation. Further, the stability and effects of the formulation were analyzed under different experimental conditions. Physicochemical characterization of the NCs revealed suitable homogeneous size and high encapsulation efficiency. Moreover, the lyophilized formulation was stable at ICH long term and accelerated storage conditions, for at least 18 and 3 months, respectively. The tacrolimus NCs did not elicit any eye irritation in rabbits after single- and multiple-dose applications. Additionally, ex vivo penetration assays on isolated porcine cornea and pharmacokinetics analyses in various rabbit eye compartments demonstrated the superiority of the NCs in retention and permeation into the anterior chamber of the eye compared to the free drug dissolved in oil. Moreover, multiple dose ocular instillation of the NCs in rats allowed high tacrolimus levels in the eye with very low plasma concentrations. Finally, the developed delivery system achieved a significant decrease in four typical inflammatory markers in a murine model of keratitis, an anterior chamber inflammation. Furthermore, these NCs, applied as eye drops, displayed clinical and histological efficacy in the mainly posterior chamber inflammation model of murine, experimental auto-immune uveitis. [Display omitted] [ABSTRACT FROM AUTHOR]

Estimation of joint residence time of a drug is a key requirement for rational development of intraarticular therapeutics. There is a great need for a predictive model to reduce the high number of animal experiments in early stage development. Here, a Franz-cell based porcine ex-vivo permeation model is proposed, and transsynovial permeation of fluorescently-labeled dextrans in the range of potential drug candidates (10–150 kDa), as well as a small molecule (fluorescein sodium) and charged dextran derivates, have been determined. In addition, a lipopolysaccharide (LPS) -induced synovitis model was assessed for inflammatory biomarker levels and its effect on permeation of the solutes. Size-dependent permeability was observed for the analytes, which distinctly differed from findings with an artificial polycarbonate membrane, which is a widely used model. LPS was found to successfully stimulate an inflammatory response and led to a reduced size selectivity of the synovial membrane. 150 kDa dextran flux was accelerated approximately 2.5-fold in the inflamed state, whereas the permeation of smaller molecules was little affected. Moreover, by varying the LPS concentrations, the ex-vivo model was shown to produce varying degrees of synovitis-like inflammation. A simple and highly relevant ex-vivo tool for investigation of transsynovial permeation was developed, offering the further advantage of mimicking synovitis-induced permeability changes. Thus, this model provides a promising method for formulation screening, while reducing the need for animal experiments. [Display omitted] • ex-vivo synovial explant model allows quantification of drug leakage from the joint. • LPS induced synovitis partially mimics inflammatory permeability changes in-vivo. • porcine ex-vivo model shows superiority in IVIVC over usual artificial membranes. • assessment of the substance-dependent permeability in terms of size or charge. [ABSTRACT FROM AUTHOR]

Transcutaneous immunization (TCI) has the advantages of avoiding the liver first-pass effect, good compliance and convenient use compared with the traditional oral or injection vaccination. However, the stratum corneum (SC) of the skin is the main obstacle that limits the entry of antigen molecules into the epidermis for activating dendritic cells (DCs). In the present study, the hyaluronic acid (HA) and galactosylated chitosan (GC) modified ethosome (Eth-HA-GC) was prepared through layer-by-layer self-assembly method. Eth-HA-GC has good stability and can be effectively phagocytosed by the bone-marrow-derived DCs (BMDCs) in vitro. The ovalbumin (OVA) loaded Eth-HA-GC (OVA@Eth-HA-GC) can promote BMDCs' expression of CD80, CD86 (DCs maturation-associated marker molecules), TNF-α, IL-2 and IL-6. Subsequently, a novel OVA@Eth-HA-GC-loaded silk fibroin (OVA@Eth-HA-GC/SF) nanofibrous mats were fabricated through green electrospinning. The OVA@Eth-HA-GC/SF mats exhibit good transdermal performance in vitro. Transdermal administration with OVA@Eth-HA-GC/SF mats induced the serum anti-OVA-specific IgG and increased the expression of IFN-γ, IL-2 and IL-6 by spleen cells in vivo. Furthermore, the use of OVA@Eth-HA-GC/SF mats evidently inhibited the growth of EG7 tumor in the murine model. These results demonstrate the OVA@Eth-HA-GC/SF mats can effectively stimulate the immune response to OVA through transdermal administration. In conclusion, the antigens@Eth-HA-GC/SF mats is a promising TCI system. Unlabelled Image • A novel hyaluronic acid (HA) and galactosylated chitosan (GC) modified ethosome (Eth-HA-GC) was prepared through layer-by-layer self-assembly. • Eth-HA-GC showed a good performance on targeting and inducing the maturation of dendritic cells (DCs). • The green electrospun silk fibroin (SF) nanofibrous mats loaded with Eth-HA-GC (Eth-HA-GC/SF) can effectively deliver ovalbumin (OVA) through the skin. • OVA@Eth-HA-GC/SF effectively elicited both cellular and humoral immune responses to OVA through transdermal administration in the mouse model. • OVA@Eth-HA-GC/SF evidently inhibited the growth of EG7 tumor in the mouse model through transdermal administration. [ABSTRACT FROM AUTHOR]

Biological macromolecular drugs, such as antibodies and fusion protein drugs, have been widely employed for the treatment of various diseases. Administration routes are typically via invasive intravenous or subcutaneous injection with needles; the latter is challenging for applications involving inflamed skin (e.g., psoriasis) due to concerns of expansion of inflammation. As a method of non-invasive transdermal drug delivery, we previously demonstrated that iontophoresis (IP) using weak electric current (0.3–0.5 mA/cm2) enables transdermal permeation of hydrophilic macromolecules, such as small interfering RNA and nanoparticles into the skin, and subsequent exertion of their functions. The underlying mechanism was revealed to be via intercellular junction cleavage by cellular signaling activation initiated by Ca2+ influx. Based on these findings, in the present study, we hypothesized that non-invasive intradermal delivery of biological macromolecular drugs could be efficiently achieved via IP. Fluorescence of FITC-labeled IgG antibody was broadly observed in the skin after IP administration (0.4 mA/cm2 for 1 h) and extended from the epidermis to the dermis layer of hairless rats; passive antibody diffusion was not observed. In imiquimod-induced psoriasis model rats, antibodies were also delivered via IP into inflamed skin tissue. Additionally, upregulation of interleukin-6 mRNA levels, which is related to pathological progression of psoriasis, was significantly inhibited by IP of the anti-tumor necrosis factor-α drug etanercept, but not by its subcutaneous injection. Importantly, IP administration of etanercept significantly ameliorated epidermis hyperplasia, a symptom of psoriasis. Taken together, the present study is the first to demonstrate that IP can be applied as a non-invasive and efficient intradermal drug delivery technology for biological macromolecular drugs. Unlabelled Image [ABSTRACT FROM AUTHOR]

Skin diseases such as lupus, cancer, psoriasis, and hyperhidrosis can potentially be treated effectively by suppressing allele-specific genes using small interfering RNA (siRNA). Injections of siRNA into skin, though effective, are painful and cover small surface areas and thus are not suitable as a long-term treatment option. Topical delivery of siRNA is an attractive alternative option to mediate RNA interference (RNAi). However, the barrier function of the epidermis impedes effective permeation of siRNA into the skin. Herein, we describe topical delivery of siRNA using ionic liquids (ILs) capable of complexing with siRNA non-covalently and delivering it effectively. Using complementary and synergistic strategies of ionic liquids, we report delivery of effective doses of siRNA into skin. The first strategy involved the use of hydrophobic cations to robe the siRNA and the second strategy involved the use of choline-geranic acid ionic liquid (CAGE) to enhance its dermal penetration. In vitro studies in porcine skin confirmed the synergistic effect of these strategies in enhancing epidermal and dermal penetration. In vivo application of siRNA formulation to SKH-1E hairless mice significantly suppressed GAPDH expression with no clinical evidence of toxicity. This is a simple, personalized, and scalable platform for effective topical delivery of siRNA for treating genetic skin diseases. Unlabelled Image [ABSTRACT FROM AUTHOR]

Topical treatment of mild-to-moderate psoriasis with corticosteroids suffers from challenges that include reduced drug bioavailability at the desired site of action. The retention of therapeutics within the epidermis can safely treat skin inflammation, scaling, and erythema associated with psoriasis while avoiding possible side effects associated with systemic treatments. We successfully synthesized and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-fluocinolone acetonide (FLUO) conjugate that allows the controlled release of the FLUO to reduce skin inflammation. Additionally, the application of a hyaluronic acid (HA)-poly-L-glutamate cross polymer (HA-CP) vehicle boosted skin permeation. During in vitro and ex vivo analyses, we discovered that PGA-FLUO inhibited pro-inflammatory cytokine release, suggesting that polypeptidic conjugation fails to affect the anti-inflammatory activity of FLUO. Additionally, ex vivo human skin permeation studies using confocal microscopy revealed the presence of PGA-FLUO within the epidermis, but a minimal presence in the dermis, thereby reducing the likelihood of FLUO entering the systemic circulation. Finally, we demonstrated that PGA-FLUO applied within HA-CP effectively reduced psoriasis-associated phenotypes in an in vivo mouse model of human psoriasis while also lowering levels of pro-inflammatory cytokines in tissue and serum. Overall, our experimental results demonstrate that PGA-FLUO within an HA-CP penetration enhancer represents an effective topical treatment for psoriasis. Unlabelled Image • Rationally designed polypeptide-based conjugates for topical delivery. • Increased anti-inflammatory activity after corticosteroid conjugation using bioresponsive polymer-drug linkers. • Improved skin penetration using a hyaluronic acid-polyglutamic acid cross-polymer as vehicle. • Synergistic combination of drug conjugation and penetration enhancer provides an elevated reduction in inflammation in vivo. • This strategy represents a possible palliative treatment for inflammatory skin diseases such as psoriasis. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia is a common form of scalp hair loss that affects men in their mid-twenties and increases with age. Finasteride (FNS) has been approved and used orally to treat androgenetic alopecia; however, systemic effects on other androgen-dependent tissues cause severe side-effects. To overcome these systemic effects and target hair follicles in the scalp only, numerous topical formulations of FNS have been developed and further combined with the solid microneedle (SMN) technique to create micro-channels in the skin, thus overcoming the skin barrier properties. However, low delivery efficiency and concerns over patient safety of SMNs remain major limitations of the treatment. In the present study, we developed a novel FNS delivery system comprising powder-carrying microneedles (PCMs), which is a patch-less and self-administered powder delivery technique that simultaneously overcomes the safety issues. This system could directly implant FNS inside the skin by encapsulating the FNS powder in the center of the PCMs. In addition, we introduced the concept of a diffusion enhancer for this system, which facilitated the dissolution and release of the implanted FNS powder to achieve its successful intradermal delivery. Using implanted FNS powder as a reservoir inside the skin, this novel system permitted sustained release of the implanted FNS powder for 3 days with only one application of FNS-PCMs. In addition, compared with the topical FNS-gel, the developed system showed a higher efficacy in promoting hair growth and increased the amount and density of hair while addressing the safety concerns. This approach has the potential to advance the field of transdermal drug delivery for any type of powdered drug in a wide variety of biomedical applications. [ABSTRACT FROM AUTHOR]

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases. [ABSTRACT FROM AUTHOR]

Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch®). Pores induced by the microprojections were found to close by ~25% in diameter within the first 30 min, and almost completely close by ~6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of ~1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between ~518–583 ps. The ratio of free-bound NAD(P)H (α1/α2) in unaffected areas of the viable epidermis was ~2.5–3.0, whereas the ratio at puncture holes was almost double at ~4.2–4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch® treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch®, are transient, with the skin recovering rapidly within 1–2 days in the epidermis after application. Unlabelled Image [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a major adverse effect of paclitaxel. Several liposome-based products have been approved and demonstrated superior efficacy and safety profiles for other drugs. The first objective of this work was to evaluate the effect of liposome formulation of paclitaxel (L-PTX) on neurotoxicity in-vitro and in-vivo in comparison to the standard Taxol® formulation. The second aim was to investigate the effect of formulation on paclitaxel biodistribution following intravenous administration in an animal model. Free paclitaxel was toxic to cell of neuronal origin (IC50 = 18.4 μg/mL) at a lower concentration than to lung cancer cells (IC50 = 59.1 μg/mL), and L-PTX demonstrated a comparable toxicity in both cell lines (IC50 = 31.8 and 33.7 μg/mL). Administration of L-PTX at 2 mg/kg per dose for a total of 4 doses on day 0, 2, 4, and 6 to rats did not result in increased sensitivity in response to mechanical or thermal stimulation of hind paws, in comparison to Taxol® administration at the same dose level that resulted in neuropathy. Paclitaxel biodisposition was evaluated for two formulations in plasma, liver, lung, brain, spinal cord, skin and muscle of rats after single intravenous dose at 6 mg/kg. The exposure to paclitaxel in brain, spinal cord, muscle, and skin was lower in the L-PTX group compared to Taxol® group. PEGylated liposomes containing paclitaxel were successfully developed and demonstrated reduced neurotoxicity in-vitro in neuronal cells and prevented development of peripheral neuropathy in-vivo. This proof of concept study showed that formulation in nanoparticles is a promising approach for reducing (or preventing) neurotoxicity caused by cancer drugs. Unlabelled Image • Liposomal paclitaxel did not lead to neuropathy that was observed for Taxol® group. • Biodisposition data qualified previously developed physiologically-based model. • Liposomal paclitaxel reduced exposure in skin, muscle, brain, spinal cord. • Similar exposure to paclitaxel was observed in skin and muscle tissues. [ABSTRACT FROM AUTHOR]

Mucoadhesive drug formulations have been studied and used as alternatives to conventional formulations in order to achieve prolonged retention at the intended site. In addition to providing a controlled drug release, several drugs and disease conditions might benefit from mucoadhesive formulations, contributing to better therapeutic outcomes. Here, we describe the development and the in vitro/in vivo characterization of a mucoadhesive in situ gellifying formulation using PF127, a thermo reversible polymer, entrapping budesonide (BUD), a potent corticosteroid used for the treatment of a wide range of inflammatory diseases, including those affecting mucosas, such as in the GI tract. PF127 formulations (15–17%) were successfully prepared by a cold method as a thermo reversible in situ gelling dispersion for mucosal drug delivery, as confirmed by DSC. Sol-gel temperatures of PF127 formulations (25–39 °C) were observed by dynamic gelation and determined by microrheology and oscillatory rheometry. X-ray diffractograms and TEM images showed that BUD was completely solubilized within the polymeric micelles. In vitro , the gels showed 5–14 g force of mucoadhesion, and the ex vivo studies confirmed that the formulation efficiently adhered to the mucosa. Histopathological analysis combined with fluorescence images and ex vivo intestinal permeation confirmed that the formulation remained on the TGI mucosa for at least 4 h after administration. In vivo studies conducted in a murine model of intestinal mucositis demonstrated that the 16% PF127 BUD formulation was able to resolve the inflammatory injury in the intestinal mucosa. Results demonstrate that fine-tuning of PF127 formulations along with adequate selection of the drug agent, thorough characterization of the dispersions and their interactions with biological interfaces leads to the development of effective controlled drug delivery systems targeted to GI inflammatory diseases. Unlabelled Image [ABSTRACT FROM AUTHOR]

Antioxidants (AOs) play a crucial role in the protection and maintenance of health and are also integral ingredients in beauty products. Unfortunately, most of them are sensitive due to their instability and insolubility. The use of liposomes to protect AOs and expand their applicability to cosmeceuticals, thereby, is one of the most effective solutions. Notwithstanding their offered advantages for the delivery of AOs, liposomes, in their production and application, present many challenges. Here, we provide a critical review of the major problems complicating the development of liposomes for AO delivery. Along with issues related to preparation techniques and encapsulation efficiency, the loss of protective function and inefficiency of skin permeability are the main disadvantages of liposomes. Corresponding development strategies for resolving these problems, with their respective advantages and drawbacks, are introduced, discussed in some depth, and summarized in these pages as well. Advanced liposomes have a vital role to play in the development and delivery of AOs in practical cosmeceutical product applications. Unlabelled Image • Classification of antioxidants and their action mechanism in scavenging ROS. • Benefits of liposome for antioxidant delivery in cosmeceutical applications. • Challenges to expansion of liposomal applications in cosmeceuticals. • Development strategies of novel techniques and advanced liposome-based carriers. • New generations of liposome for delivery of antioxidants in cosmeceuticals. [ABSTRACT FROM AUTHOR]

Abstract In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 μg DXM/cm2 skin encapsulated in CMS-NC (12 nm diameter, 5.8% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25% CD1a+ cells were found within the epidermal CMS-NC+ population compared to approximately 3% CD1a+/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Abstract Hollow microneedles can help overcome the skin permeation barrier imposed by the stratum corneum and facilitate transcutaneous delivery of nanoparticle delivery systems. In the present study, we investigated the use of the hollow microneedle array for intradermal delivery of polymeric nanoparticles (NPs) in rats. Compared to intravenous and subcutaneous routes of administration, intradermal delivery of polymeric NPs via a hollow microneedle array resulted in a unique pharmacokinetic profile, characterized by an early burst transit through the draining lymph nodes and a relatively limited overall systemic exposure. Based on high local lymphatic concentrations achieved, we investigated the use of this modality for vaccine delivery. A model antigen ovalbumin (OVA) and TLR agonists imiquimod and monophosphoryl Lipid A encapsulated in poly(d , l -lactide- co -glycolide) (PLGA) NPs were used as the vaccine formulation. Compared to soluble OVA-based vaccine, OVA loaded NPs demonstrated faster antibody affinity maturation kinetics. Moreover, antigen loaded NPs delivered via a hollow microneedle array elicited a significantly higher IgG2a antibody response and higher number of interferon (IFN)-γ secreting lymphocytes, both markers of Th1 response, in comparison to antigen loaded NPs delivered by intramuscular injection and soluble antigen delivered through hollow microneedle array. Overall, our results show that hollow microneedle mediated intradermal delivery of polymeric NPs is a promising approach to improve the effectiveness of vaccine formulations. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin ( in vitro ) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro – in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1 h of transient heat (42 ± 2 °C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences ( p ≥ 0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations. [ABSTRACT FROM AUTHOR]

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500 μm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700 μm) due to their small size and capacity to ‘self-propel’. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (p < 0.05) higher delivery doses without visible skin damage compared to the use of a chemical penetration enhancer. Transdermal OVA doses of up to 1 μg were achieved in a single 90-second treatment, which was sufficient to trigger an antigen-specific immune response. Furthermore, ultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home. [ABSTRACT FROM AUTHOR]

The effect of vehicle mixtures on transdermal permeation has been studied using transient flux profiles from porcine skin flow through diffusion cells. Such data characteristically exhibit a large amount of variability between treatments (vehicle and penetrant combinations) as well as noise within treatments. A novel mathematical model has been used that describes longitudinal variation as a time varying diffusivity. Between treatment variability was described by a mixed effects model. A quantitative structure property relationship (QSPR) was developed to describe the effects of the penetrant and vehicle mixture properties on the mean diffusivity and partition coefficient in the membrane. The relationship included terms for the logP and molecular weight of the penetrant and the refractive index of the vehicle mixture with R 2 > 0.95 for K and > 0.9 for partition coefficient (as K ⋅ D ). This analysis improved on previous work, finding a more parsimonious model with higher predictability, while still identifying the mixture refractive index as a key descriptor in predicting vehicle effects. The concordance with established and expected relationships lends confidence to this new methodology for evaluating transient, finite dose, transdermal flux data collected using traditional experimental methods. [ABSTRACT FROM AUTHOR]

Immunization with radiation-attenuated sporozoites (RAS) via mosquito bites has been shown to induce sterile immunity against malaria in humans, but this route of vaccination is neither practical nor ethical. The importance of delivering RAS to the liver through circulation in eliciting immunity against this parasite has been recently verified by human studies showing that high-level protection was achieved only by intravenous (IV) administration of RAS, not by intradermal (ID) or subcutaneous (SC) vaccination. Here, we report in a murine model that ID inoculation of RAS into laser-illuminated skin confers immune protection against malarial infection almost as effectively as IV immunization. Brief illumination of the inoculation site with a low power 532 nm Nd:YAG laser enhanced the permeability of the capillary beneath the skin, owing to hemoglobin-specific absorbance of the light. The increased blood vessel permeability appeared to facilitate an association of RAS with blood vessel walls by an as-yet-unknown mechanism, ultimately promoting a 7-fold increase in RAS entering circulation and reaching the liver over ID administration. Accordingly, ID immunization of RAS at a laser-treated site stimulated much stronger sporozoite-specific antibody and CD8 + IFN-γ + T cell responses than ID vaccination and provided nearly full protection against malarial infection, whereas ID immunization alone was ineffective. This novel, safe, and convenient strategy to augment efficacy of ID sporozoite-based vaccines warrants further investigation in large animals and in humans. [ABSTRACT FROM AUTHOR]

Oral administration of ciclosporin A (CsA) is indicated in the treatment of severe recalcitrant plaque psoriasis. However, CsA is both nephro- and hepatotoxic and its systemic administration also exposes the patient to other severe side effects. Although topical delivery of CsA, targeted directly to psoriatic skin, would offer significant advantages, there are no topical formulations approved for dermatological use. The aim of this work was to formulate CsA loaded polymeric micelles using the biodegradable and biocompatible MPEG-dihexPLA diblock copolymer and to evaluate their potential for delivering the drug selectively into the skin without concomitant transdermal permeation. Micelle formulations were characterised with respect to drug content, size and morphology. Micelle and drug penetration pathways were subsequently visualised with confocal laser scanning microscopy (CLSM) using fluorescein labelled CsA (Fluo-CsA) and Nile-Red (NR) labelled copolymer. Visualisation studies typically use fluorescent dyes as “model drugs”; however, these may have different physicochemical properties to the drug molecule under investigation. Therefore, in this study it was decided to chemically modify CsA and to use this structurally similar fluorescent analogue to visualise molecular distribution and transport pathways. Molecular modelling techniques and experimental determination of log D served as molecular scale and macroscopic methods to compare the lipophilicity of CsA and Fluo-CsA. The spherical, homogeneous and nanometre-scale micelles (with Z av from 25 to 52 nm) increased the aqueous solubility of CsA by 518-fold. Supra-therapeutic amounts of CsA were delivered to human skin (1.4 ± 0.6 μg/cm 2 , cf. a statistically equivalent 1.1 ± 0.5 μg/cm 2 for porcine skin) after application of the formulation with the lowest CsA and copolymer content (1.67 ± 0.03 mg/ml of CsA and 5 mg/ml of copolymer) for only 1 h without concomitant transdermal permeation. Fluo-CsA was successfully synthesised, characterised and incorporated into fluorescent NR-MPEG-dihexPLA micelles; its conformation was not modified by the addition of fluorescein and its log D, measured from pH 4 to 8, was equivalent to that of CsA. Fluo-CsA and NR-MPEG-dihexPLA copolymer were subsequently visualised in skin by CLSM. The images indicated that micelles were preferentially deposited between corneocytes and in the inter-cluster regions (i.e. between the clusters of corneocytes). Fluo-CsA skin penetration was deeper in these structures, suggesting that inter-cluster penetration is probably the preferred transport pathway responsible for the increased cutaneous delivery of CsA. [ABSTRACT FROM AUTHOR]

Enhanced skin permeability is known to be achieved during sonophoresis due to ultrasound-induced cavitation. However, the mechanistic role of cavitation during sonophoresis has been extensively investigated only for low-frequency (LFS, < 100 kHz) applications. Here, mechanisms of permeability-enhancing stable and inertial cavitation were investigated by passively monitoring subharmonic and broadband emissions arising from cavitation isolated within or external to porcine skin in vitro during intermediate- (IFS, 100–700 kHz) and high-frequency sonophoresis (HFS, > 1 MHz). The electrical resistance of skin, a surrogate measure of the permeability of skin to a variety of compounds, was measured to quantify the reduction and subsequent recovery of the skin barrier during and after exposure to pulsed (1 second pulse, 20% duty cycle) 0.41 and 2.0 MHz ultrasound over a range of acoustic powers (0–21.7 W) for 30 min. During IFS, significant skin resistance reductions and acoustic emissions from cavitation were measured exclusively when cavitation was isolated outside of the skin. Time-dependent skin resistance reductions measured during IFS correlated significantly with subharmonic and broadband emission levels. During HFS, significant skin resistance reductions were accompanied by significant acoustic emissions from cavitation measured during trials that isolated cavitation activity either outside of skin or within skin. Time-dependent skin resistance reductions measured during HFS correlated significantly greater with subharmonic than with broadband emission levels. The reduction of the skin barrier due to sonophoresis was reversible in all trials; however, effects incurred during IFS recovered more slowly and persisted over a longer period of time than HFS. These results quantitatively demonstrate the significance of cavitation during sonophoresis and suggest that the mechanisms and post-treatment longevity of permeability enhancement due to IFS and HFS treatments are different. [ABSTRACT FROM AUTHOR]

Abstract: Transdermal permeation enhancers are compounds that temporarily decrease skin barrier properties to promote drug flux. In this study, we investigated enhancers with amino acids (proline, sarcosine, alanine, β-alanine, and glycine) attached to hydrophobic chain(s) via a biodegradable ester link. The double-chain lipid-like substances displayed no enhancing effect, whereas single-chain substances significantly increased skin permeability. The proline derivative l-Pro2 reached enhancement ratios of up to 40 at 1% concentration, which is higher than that of the well-established and standard enhancers Azone, DDAIP, DDAK, and Transkarbam 12. No stereoselectivity was observed. l-Pro2 acted synergistically with propylene glycol. Infrared studies revealed that l-Pro2 forms a separate liquid ordered phase in the stratum corneum lipids and has no significant effect on proteins. l-Pro2 action was at least partially reversible as measured by skin electrical impedance. Toxicity in keratinocyte (HaCaT) and fibroblast (3T3) cell lines showed IC50 values ranging from tens to hundreds of μM, which is comparable with standard enhancers. Furthermore, l-Pro2 was rapidly decomposed in plasma. In vivo transdermal absorption studies in rats confirmed the enhancing activity of l-Pro2 and suggested its negligible skin toxicity and minimal effect on transepidermal water loss. These properties make l-Pro2 a promising candidate for potential clinical use. [Copyright &y& Elsevier]

Abstract: Transdermal drug delivery system (TDDS) utilizes the skin as executable route for drug administration but the foremost barrier against drug permeability is the stratum corneum and therefore, it limits therapeutic bioavailability of the bioactive. This review focuses on the recent advancements in the TDDS which include iontophoresis, sonophoresis, electroporation, microneedles, magnetophoresis, photomechanical waves and electron beam irradiation. These advancements are exhaustively discussed with techniques involved with their beneficial claims for different categories of bioactive. However, a lot of research has been carried out in TDDS, still the system has many pros and cons such as inconsistent drug release, prevention of burst release formulation and problems related to toxicity. In addition to that, to exploit the TDDS more efficiently scientists have worked on some combinational approaches for manufacturing TDDS viz., chemical–iontophoresis, chemical–electroporation, chemical–ultrasound, iontophoresis–ultrasound, electroporation–iontophoresis electroporation–ultrasound and pressure waves–chemicals and reported the synergistic effect of the same for safe, effective and practical use of TDDS. The present article covers all the above-mentioned aspects in detail and hence the article will assuredly serve as an enlightening tool for the visionaries working in the concerned area. [Copyright &y& Elsevier]

Abstract: Low-frequency ultrasound has been studied extensively due to its ability to enhance skin permeability. In spite of this effort, improvements in enhancing the efficacy of transdermal ultrasound treatments have been limited. Currently, when greater skin permeability is desired at a given frequency, one is limited to increasing the intensity or the duration of the ultrasound treatment, which carries the risk of thermal side effects. Therefore, the ability to increase skin permeability without increasing ultrasound intensity or treatment time would represent a significant and desirable outcome. Here, we hypothesize that the simultaneous application of two distinct ultrasound frequencies, in the range of 20kHz to 3MHz, can enhance the efficacy of ultrasound exposure. Aluminum foil pitting experiments showed a significant increase in cavitational activity when two frequencies were applied instead of just one low frequency. Additionally, in vitro tests with porcine skin indicated that the permeability and resulting formation of localized transport regions are greatly enhanced when two frequencies (low and high) are used simultaneously. These results were corroborated with glucose (180Da) and inulin (5000Da) transdermal flux experiments, which showed greater permeant delivery both into and through the dual-frequency pre-treated skin. [Copyright &y& Elsevier]

Abstract: The objective of the present study was to investigate the effect of polyarginine chain length on topical delivery of surface modified NLCs. Design of experiments (DOE) was used to optimize number of arginines required to deliver active drug into deeper skin layers. The NLCs were prepared by hot-melt technique and the surface of NLCs was modified with six-histidine tagged cell penetrating peptides (CPPs) or YKA. In vivo confocal microscopy and Raman confocal spectroscopy studies were performed using fluorescent dye encapsulated NLCs and NLC-CPPs. Spantide II (SP) and ketoprofen (KP) were used as model drugs for combined delivery. In vitro skin permeation and drug release studies were performed using Franz diffusion cells. Inflammatory response corresponding to higher skin permeation was investigated in allergic contact dermatitis (ACD) mouse model. NLCs had a particle size of 140±20nm with higher encapsulation efficiencies. The negative charge of NLC was reduced from −17.54 to −8.47mV after surface modification with CPPs. In vivo confocal microscopy and Raman confocal spectroscopy studies suggested that a peptide containing 11 arginines (R11) had significant permeation enhancing ability than other polyarginines and TAT peptides. The amount of SP and KP retained in dermis after topical application of NLC-R11 was significantly higher than solution and NLC after 24h of skin permeation. SP was not found in receiver compartment. However, KP was found in receiver compartment and the amount of KP present in receiver compartment was increased approximately 7.9 and 2.6 times compared to the control solution and NLCs, respectively. In an ACD mouse model, SP+KP-NLC-R11 showed significant reduction (p <0.05) in ear thickness compared to SP+KP solution and SP+KP-NLC. Our results strongly suggest that the surface modification of NLC with R11 improved transport of SP and KP across the deeper skin layers and thus results in reduction of inflammation associated with ACD. [Copyright &y& Elsevier]

Abstract: The objective of the present study was to evaluate the effect of oleic acid modified polymeric bilayered nanoparticles (NPS) on combined delivery of two anti-inflammatory drugs, spantide II (SP) and ketoprofen (KP) on the skin permeation. NPS were prepared using poly(lactic-co-glycolic acid) (PLGA) and chitosan. SP and KP were encapsulated in different layers alone or/and in combination (KP-NPS, SP-NPS and SP+KP-NPS). The surface of NPS was modified with oleic acid (OA) (‘Nanoease’ technology) using an established procedure in the laboratory (KP-NPS-OA, SP-NPS-OA and SP+KP-NPS-OA). Fluorescent dyes (DiO and DID) containing surface modified (DiO-NPS-OA and DID-NPS-OA) and unmodified NPS (DiO-NPS and DID-NPS) were visualized in lateral rat skin sections using confocal microscopy and Raman confocal spectroscopy after skin permeation. In vitro skin permeation was performed in dermatomed human skin and HPLC was used to analyze the drug levels in different skin layers. Further, allergic contact dermatitis (ACD) model was used to evaluate the response of KP-NPS, SP-NPS, SP+KP-NPS, KP-NPS-OA, SP-NPS-OA and SP+KP-NPS-OA treatment in C57BL/6 mice. The fluorescence from OA modified NPS was observed up to a depth of 240μm and was significantly higher as compared to non-modified NPS. The amount of SP and KP retained in skin layers from OA modified NPS increased by several folds compared to unmodified NPS and control solution. In addition, the combination index value calculated from ACD response for solution suggested an additive effect and moderate synergism for NPS-OA. Our results strongly suggest that surface modification of bilayered nanoparticles with oleic acid improved drug delivery to the deeper skin layers. [Copyright &y& Elsevier]

Abstract: Over the past decade, microneedles have been shown to dramatically increase skin permeability to a broad range of compounds by creating reversible microchannels in the skin. However, in order to achieve sustained transdermal drug delivery, the extent and duration of skin''s increased permeability needs to be determined. In this study, we used electrical impedance spectroscopy to perform the first experiments in human subjects to analyze the resealing of skin''s barrier properties after insertion of microneedles. Microneedles having a range of geometries were studied in conjunction with the effect of occlusion to test the hypothesis that increasing microneedle length, number, and cross-sectional area together with occlusion leads to an increase in skin resealing time that can exceed one day. Results indicated that in the absence of occlusion, all microneedle treated sites recovered barrier properties within 2h, while occluded sites resealed more slowly, with resealing windows ranging from 3 to 40h depending on microneedle geometry. Upon subsequent removal of occlusion, the skin barrier resealed rapidly. Longer microneedles, increased number of needles, and larger cross-sectional area demonstrated slower resealing kinetics indicating that microneedle geometry played a significant role in the barrier resealing process. Overall, this study showed that pre-treatment of skin with microneedles before applying an occlusive transdermal patch can increase skin permeability for more than one day, but nonetheless allow skin to reseal rapidly after patch removal. [Copyright &y& Elsevier]

Abstract: Thermal ablation is a promising mechanism to increase permeability of the skin''s outer barrier layer of stratum corneum while sparing deeper living tissues. In this study, finite element modeling predicted that the skin surface should only be heated on the microsecond timescale in order to avoid significant temperature rises in living cells and nerve endings in deeper tissue. To achieve such short thermal pulses, we developed a microdevice that rapidly heats a few microliters of water by an electrical discharge and ejects the resulting superheated steam at the skin surface on a timescale on the order of 100μs. According to its design, we showed that this microdevice selectively removed stratum corneum of cadaver skin without significantly removing deeper tissue. This one-dimensional depth control was supplemented through the use of a masking film containing 100μm-diameter holes placed on the skin surface during ablation to define the ablated skin area and thereby provide three-dimensional control over tissue removal. Using this approach, thermal ablation increased skin permeability to sulforhodamine B and bovine serum albumin by at least 1000-fold in vitro. We conclude that microsecond thermal ablation of skin can selectively remove stratum corneum and thereby dramatically increase skin permeability for transdermal drug delivery. [Copyright &y& Elsevier]