Noninvasive Transdermal Drug Delivery Research Articles

Palmitoylation enhances short polar peptide permeation across stratum corneum lipid bilayer: A molecular dynamics study

Designing chemical molecules that target the skin for non-invasive transdermal drug delivery is of significant interest for both wound healing and skincare applications. These skin-targeting molecules must permeate the outermost protective layer of the skin, the stratum corneum (SC), which consists of dead corneocytes embedded in a lipid matrix, to fulfill their biological functions. Adsorption onto and diffusion through the lipid matrix in the SC represent two key steps for the successful permeation of a skin-targeting molecule across the SC into the underlying skin layers. Here we compare the effects of cyclization and palmitoylation on the adsorption and diffusion of a short polar peptide across a model SC lipid bilayer using molecular dynamics simulations. The cyclized peptide showed slightly better binding to the SC lipid bilayer and similar interaction energies with SC lipids compared to the unmodified peptide. In contrast, the palmitoylated peptide exhibited much stronger interaction with SC lipids via insertion of its attached fatty acid tail into the SC lipid bilayer. The average diffusivity of the cyclized peptide across the SC lipid bilayer was approximately twice that of the unmodified peptide, whereas the palmitoylated peptide’s diffusivity was about 2.7 times higher. Thus, palmitoylation appears to be a promising strategy for enhancing the binding and permeability of short polar peptides across the SC lipid matrix.

Ultrasound Nanobubble Coupling Agent for Effective Noninvasive Deep-Layer Drug Delivery.

Conventional coupling agents (such as polyvinylpyrrolidone, methylcellulose, and polyurethane) are unable to efficiently transport drugs through the skin's dual barriers (the epidermal cuticle barrier and the basement membrane barrier between the epidermis and dermis) when exposed to ultrasound, hindering deep and noninvasive transdermal drug delivery. In this study, nanobubbles prepared by the double emulsification method and aminated hyaluronic acid are crosslinked with aldehyde-based hyaluronic acid by dynamic covalent bonding through the Schiff base reaction to produce an innovative ultrasound-nanobubble coupling agent. By amplifying the cavitation effect of ultrasound, drugs can be efficiently transferred through the double barrier of the skin and delivered to deep layers. In an in vitro model of isolated porcine skin, this agent achieves an effective penetration depth of 728µm with the parameters of ultrasound set at 2W, 650kHz, and 50% duty cycle for 20min. Consequently, drugs can be efficiently delivered to deeper layers noninvasively. In summary, this ultrasound nanobubble coupling agent efficiently achieves deep-layer drug delivery by amplifying the ultrasonic cavitation effect and penetrating the double barriers, heralding a new era for noninvasive drug delivery platforms and disease treatment.

MICRONEEDLES ASSISTED ENHANCEMENT OF TRANSDERMAL DELIVERY OF CURCUMIN THROUGH ORGANOGEL FORMULATION

Curcumin is a natural compound found in turmeric and has been shown to have anti-inflammatory and antioxidant properties. Topical delivery of curcumin through an organic emulsion-based gel can effectively target inflammation at specific sites on the body. The current study aims to formulate Pluronic based organogel of curcumin, whose absorption is further assisted by microneedles technology. Nine organogel formulations were prepared and optimized by 32 full factorization model to fix the ratio of lecithin[A] and Pluronic[B] concentration in order to get optimum drug release after 2 hours (Q2) and maximum release of drug after 8 hours (Q8). The in-vitro study through the Franz diffusion cell indicated a significant impact of Pluronic F-127 concentration on the release of drug. As increased concentration of Pluronic increased the viscosity of formulations which ultimately retarded the release of drug. Based on Design of Experiment (DoE) study, optimized batch containing 6.5% lecithin and 20.6% Pluronic was further studied for microneedle assisted ex-vivo skin permeation through rat skin. Permeation without microneedle poration was around 70.26% after 8 hours, which was significantly increased (around 25%) after microneedle treatment of the skin. The results indicated promising application microneedle assisted skin permeation as a non-invasive and controlled delivery of curcumin through the transdermal route. Further, in-vivo studies are recommended to further establish this promising concept, targeting a variety of inflammatory conditions, including arthritis, psoriasis, and eczema, etc., through non-invasive transdermal drug delivery systems.

Sustained Release Microneedles: Materials and Applications in Facial Rejuvenation.

Wrinkled and loose skin resulting from collagen degradation along with fibers decreasing reflects the youth diminishing. Microneedles (MNs) have opened up new avenues for the development of painless and noninvasive transdermal drug delivery systems for facial rejuvenation. Encapsulated drugs or molecules are transmitted to targeted tissues via percutaneous microchannels, which eliminate potential gastric stimulation or first-pass metabolic effects, as well as boost patient compliance. Although MNs are considered effective and feasible therapeutic alternatives to metals, silicon, and polymers, traditional procedures with reduction processes continue to encounter methodological limitations. In recent years, promising additive manufacturing processes such as three-dimensional printing and two-photon polymerization manufacturing have been developed with the aim of overcoming the limitations by traditional processes to facilitate an efficient and economic production mode. This review summarizes the design, material selection, and manufacturing method for recently advanced MN systems. Furthermore, we also highlight specific polymeric or natural microneedle products, like hyaluronan, plant derivates, and vitamins, for esthetic applications in this review. Impact Statement In this review, the materials and manufactural routes of microneedles (MNs) are detailed. Moreover, similar to the diagnostic or therapeutic MNs, the feature of dispensation with training and ready-to-use is perfect for beautification and anti-aging, which necessitate repeated and long-term usage. Furthermore, the specific polymeric or natural products for esthetic applications of MNs are highlighted in this review.

Increasing Skeletal Muscle Mass in Mice by Non-Invasive Intramuscular Delivery of Myostatin Inhibitory Peptide by Iontophoresis

Sarcopenia is a major public health issue that affects older adults. Myostatin inhibitory-D-peptide-35 (MID-35) can increase skeletal muscle and is a candidate therapeutic agent, but a non-invasive and accessible technology for the intramuscular delivery of MID-35 is required. Recently, we succeeded in the intradermal delivery of various macromolecules, such as siRNA and antibodies, by iontophoresis (ItP), a non-invasive transdermal drug delivery technology that uses weak electricity. Thus, we expected that ItP could deliver MID-35 non-invasively from the skin surface to skeletal muscle. In the present study, ItP was performed with a fluorescently labeled peptide on mouse hind leg skin. Fluorescent signal was observed in both skin and skeletal muscle. This result suggested that the peptide was effectively delivered to skeletal muscle from skin surface by ItP. Then, the effect of MID-35/ItP on skeletal muscle mass was evaluated. The skeletal muscle mass increased 1.25 times with ItP of MID-35. In addition, the percentage of new and mature muscle fibers tended to increase, and ItP delivery of MID-35 showed a tendency to induce alterations in the levels of mRNA of genes downstream of myostatin. In conclusion, ItP of myostatin inhibitory peptide is a potentially useful strategy for treating sarcopenia.

Plasma polymer barrier layers to control the release kinetics from dissolvable microneedle patches

AbstractDissolving microneedles are a noninvasive transdermal drug delivery platform that offers painless needle‐free patient treatment. Current strategies to control the kinetics of drug release from the polymeric microneedle patches consist of adjusting the bulk polymer formulations and/or encapsulating the cargo in controlled delivery vehicles. Instead, in this study, the drug release rates were altered by modifying the surface properties of the microneedles using plasma polymer coatings with tailored properties. The main advantage of this one‐step, solvent‐free, and scalable method is that it can be applied to any type of microneedles regardless of their drug cargo or bulk material. Octadiene plasma polymer films were found to suppress the burst release effect of otherwise rapidly dissolving microneedles and to reduce the dissolution rate by a factor of four compared to uncoated control patches. The approach presented in this study offers an alternative, highly tunable, and customizable strategy for controlling drug release rate from microneedle patches.

Transdermal Delivery of Macromolecules Using Two-in-One Nanocomposite Device for Skin Electroporation.

Delivery of hydrophilic molecules through the skin using electroporation is a promising alternative approach to intradermal injection. Recently, we developed a two-in-one electrode/reservoir material composed of carbon nanotubes and agarose hydrogel. In this work, we evaluated the potential of the device to achieve non-invasive transdermal drug delivery using skin electroporation. As it involved an electrode configuration different from the literature, critical questions were raised. First, we demonstrated the efficiency of the device to permeabilize the skin of hairless mice, as observed by propidium iodide (PI) uptake in the nuclei of the epidermis cells through macro fluorescence imaging and histology. Application of Lucifer yellow (LY) at different times after unipolar electroporation treatment demonstrated the partial reversibility of the skin permeabilization after 30 min, and as such, that barrier function properties tended to be restored. We uncovered, for the first time to our knowledge, an intrinsic asymmetry of permeation pathways generated in the stratum corneum during treatment. Electrophoresis was here the main driving force for macromolecule delivery, but it competed with passive diffusion through the generated aqueous pathways for smaller molecules. Finally, we validated 4 kDa dextran labelled with fluorescein isothiocyanate (FD4) as a model molecule to optimize the electrical parameters, needed to improve macromolecule delivery.

Drug Delivery to Various Body Organs via Non-blood Circulatory Pathway

Delivery of nucleic acid therapeutics to target body organs requires injection of nanocarriers into the bloodstream. However, as such nanocarriers would also be delivered to non-target organs, low delivery efficiency to target organs and risk of unexpected effects are clear limitations of this technology. We recently applied iontophoresis (IP) for direct delivery of nucleic acid therapeutics to various organs. IP relies on a weak electric current for noninvasive transdermal drug delivery. We found that IP can deliver hydrophilic macromolecules and nanoparticles into the skin. We previously succeeded in transdermal delivery of siRNA, and subsequent knockdown (70%) of target mRNA levels in the skin via IP of siRNA (Int. J. Pharm., 383, 2010, Kigasawa et al.). Moreover, we found that cell signal activation and cleavage of intercellular junctions are induced by IP (J. Biol. Chem., 289, 2014, Hama et al.). We hypothesized that this phenomenon should be observed in not only skin but also other organs, and subsequently carried out IP of nucleic acid therapeutics to various body organs including liver, pancreas and kidney. This technique resulted in delivery of nucleic acid therapeutics into the various target body organs, and subsequent knockdown of target genes. These results suggest that direct delivery to target body organs via non-blood circulatory pathway is possible. This technology may offer a solution to the various limitations associated with current drug delivery systems (DDS).

Non-invasive delivery of biological macromolecular drugs into the skin by iontophoresis and its application to psoriasis treatment

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.

Noninvasive transdermal delivery of liposomes by weak electric current.

Noninvasive transdermal drug delivery (NTDD) offers an exciting new method of administration relative to conventional routes, but is associated with some challenges. Liposomes are capable of encapsulating transdermally-unfavorable drugs. However, the horny layer of skin is a significant barrier that limits efficient transdermal delivery of liposomes. Iontophoresis using weak electric current (WEC) represents a NTDD technology. WEC treatment of liposomes applied to the skin surface improves transdermal penetration of encapsulated drugs by cooperative effects. In this review, we provide an overview of the application of WEC/liposomes for transdermal delivery of macromolecules and low molecular weight drugs. We compare the transdermal delivery and therapeutic efficiency of the combined system with conventional routes of administration and their individual use. We discuss a novel perspective on the mechanism of WEC-mediated transdermal delivery of liposomes, which suggests that WEC activates the intracellular signaling pathway for transdermal permeation and induces unique endocytosis in skin cells.

Mechanistic study of transdermal delivery of macromolecules assisted by ionic liquids

Transdermal delivery of large hydrophilic molecules is a long-standing challenge owing to the strong diffusive barrier properties of the skin. Using choline and geranic acid (CAGE) based ionic liquid (IL) as a delivery technology, we report a significant improvement of transdermal transport of dextrans of various molecular weights up to 150 kDa. In addition, it is the first time that we show CAGE decreased the size-dependence of transport and thus can be applied to a broad range of solutes. At the molecular scale, we conducted Fourier Transform Infrared (FTIR) spectroscopy studies which showed lipid extraction in the skin due to CAGE. Based on these experimental observations, we built a novel theoretical model that elucidates how CAGE-induced skin structural changes result in faster macromolecular diffusion for enhanced permeability. The fundamental understanding gained from this study demonstrates the potential of ionic liquids as an effective and noninvasive transdermal drug delivery method.

PHONOPHORESIS VERSUS ULTRASOUD THERAPY IN MYOFASCIAL PAIN DYSFUNCTION SYNDROME

Purpose: Myofascial pain dysfunction syndrome (MPDs) coupled by trigger points (TPs) has been conversed medically and dentally for over a century. Phonophoresis (PH) is a non-invasive transdermal drug delivery system that use ultrasound (US) to enhance the distribution of topically applied drugs which provide less chance of an overdose and permit both local and systemic treatment effects. The aim: of this study was to assess the outcome of phonophoresis with Extrauma and ultrasound therapies in the treatment of myofascial pain dysfunction syndrome. Patients and method: twenty cases with MPDs of TPs in the masseter muscle were selected and divided into two groups; study group (PH): comprised ten female patients that were treated with phonophoresis (PH) using Extrauma gel for 10 sessions over three weeks. Control group (US): comprised ten female patients that were treated with ultrasound (US) for 10 sessions over three weeks. Postoperative clinical assessment including visual analogue scale (VAS) and maximum mouth opening (MMO) were assessed. Results: Comparison of VAS between the two groups at immediate post-operative period showed that PH group recorded decrease and significant values and at six months post-operative period the two groups showed non-significant decrease in VAS. MMO showed non-significant increase values in both groups along the follow up periods. Conclusion: Extrauma phonophoresis in the masseter muscle trigger points considered an effective treatment option for myofascial pain dysfunction syndrome.

Trials and tribulations of skin iontophoresis in therapeutics

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.

Temperature mapping near the surface of ultrasound transducers using susceptibility- compensated magnetic resonance imaging

Magnetic resonance imaging (MRI)-based temperature mapping very close to the surface of an ultrasound transducer is not possible due to the large magnetic susceptibility- induced image artifacts that arise from the materials used in transducer construction. Here, it is shown in phantoms that "susceptibility-compensated" MRI sequences can be used to measure thermal increases approximately 1 mm from the surface of a 4-element cymbal array transducer, which has been used widely for noninvasive transdermal drug delivery. The estimated temperatures agree well with those measured using thermocouples.

Investigation of In Vitro Iontophoresis Facilitated Transdermal Delivery of Glycine

The research presented in this paper discusses the potential of iontophoresis facilitated transdermal delivery of glycine. Iontophoresis has been widely investigated as a noninvasive transdermal drug delivery system. Iontophoresis is the use of a low electric current to carry ionized as well as unionized drug molecules across tissues (like skin) in a noninvasive technique. In the present paper, a custom made low cost, battery powered, portable transdermal iontophoretic system has been investigated for the various parameters of transdermal iontophoretic drug delivery namely drug density in donor formulation, current density, current profile, presence of competitive ions and type of electrode material. In vitro release studies of glycine, as a drug, were done using a modified Franz type glass diffusion cell through excised mouse skin. Factors affecting the delivery of glycine (a non-essential amino acid used to treat schizophrenia, anxiety, insomnia, hypoglycemia etc.) by iontophoresis include concentration of glycine in donor solution, ionic strength of donor solution, density of applied current & its aspect ratio. The change in frequency and electrode type (Ag/AgCl & stainless steel) did not have any significant effect on glycine delivery. In conclusion it could be stated that it is possible to achieve appreciable control over the transdermal delivery of glycine by the low-cost portable iontophoretic drug delivery system developed.

Permeabilisation and solubilisation of soybean phosphatidylcholine bilayer vesicles, as membrane models, by polysorbate, Tween 80

To understand better the wide-spread pharmaceutical use of non-ionic surfactant Tween 80 (TW), the colloidal properties of the surfactant alone and in combinations with the common phospholipid, phosphatidylcholine (PC), were studied. Static and dynamic light scattering revealed that TW solubilises PC at TW/PC ∼2.75/1 mol/mol and that TW micelle disintegration occurs on time-scale of 2.5 min, independent of amphipath concentration. This is up to nearly 300-times faster than the TW caused dissolution of PC containing unilamellar vesicles. The apparent dissolution time of TW/PC mixed aggregates, in contrast, decelerates from >700 min to <5 min upon increasing starting total amphipath concentration, with thermal activation energy ≥24 (≤80) kJ mol −1. The aggregate dissolution rate in highly concentrated TW/PC suspensions reflects the dissolved polysorbate-aggregate exchange rate (∼6.7 × 10 −3 s −1) rather than TW flip-flop rate across a bilayer (>0.2 min −1). PC solubilisation proceeds linearly with the square-root of time, and is kinetically governed by the speed of surfactant diffusion through the bulk ( D ∼ 2.8 × 10 −11 m 2 s −1). Creation of small Tween-phosphatidylcholine mixed micelles is typically preceded by pre-solubilisation structures, first in the form of deformable, strongly fluctuating, bilayer vesicles and then of elongated, presumably thread-like, mixed micelles. TW/PC mixed micelles become smaller with growing surfactant/lipid molar ratio, whereas TW/PC mixed vesicles become more and more leaky with increasing surfactant concentration. Our results highlight the molecular and kinetic aspects of polysorbate-membrane interactions and provide a rationale for the popularity of Tween surfactants in pharmaceutical products: such surfactants can solubilise fatty molecules and bilayer membranes but need quite a long time for this, which is available in pharmaceutical preparations but normally not in vivo; this makes Tweens relatively efficient and safe. Furthermore, our data could help design better ultra-deformable mixed lipid-surfactant vesicles for the non-invasive transdermal drug delivery across the skin.