Transdermal Drug Delivery Applications Research Articles

Evaluation of design and insertion analysis of a conical shaped polymeric based microneedle for transdermal drug delivery applications

Transportation of drug through parental routes are conventionally followed through hypodermic injection methods, where hypodermic injections are administered into the human skin for drug release. However, there are some issues observed when these hypodermic needles are being used, there are instances where the needle is being inserted leaves some needle fractures in the skin. To cater to the issue scientific researchers are voraciously working on designing and developing polymeric type of microneedle structures for various medical diagnostic applications for glucose monitoring, drug delivery, and other applications. This article presents the structural design of a conicalshaped polymeric microneedle and the insertion force while being pierced into the skin. Simulations at different insertion angles on microneedle are analyzed by arriving with total needle displacements in the process of insertion. The von mises stress is also analyzed with applied force at different insertion angles resulted in incremental change in stress exerted by the microneedle. The resultant stress is below the yield stress which makes the microneedle pierce into the skin without breakage.

Synthesis of nanohybrid reinforced electrospun methylcellulose/ polyvinyl alcohol /polyethylene glycol nanofiber: study of material properties for possible biomedical applications

Over the past few epochs, emerging transdermal drug delivery systems (TDDSs) have gotten major devotion through incessant level of interest. The effort of this work is to understand the influence of nano-reinforcing agent on the morphology, property and its drug carrying capacity of the nanohybrid reinforced ketorolac tromethamine (KT) drug loaded electrospun nanofibrous web. In this study, cellulose nanocrystals (CNCs) extracted successfully from jute fibres (JF) and nanocollagen (NCG) was isolated from waste fish scales for the assembling of CNC-NCG reinforced MC/PVA/PEG electrospun nanofibrous bio-nanocomposites (BNCs) mat for transdermal drug delivery applications. The isolated nanoparticles (CNC & NCG) and the synthesized electrospun bio-nanocomposite were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), Scanning electron microscopy (SEM), optical microscopy, Field emission scanning electron microscopy (FESEM).

Cell-Penetrating Peptides as Passive Permeation Enhancers for Transdermal Drug Delivery.

Cell-penetrating peptides have been widely used as a tool to gain access to cytosol for numerous applications. The review highlights the advances made in preclinical and clinical research using cell-penetrating peptides since their discovery in 1980s. Further, the emphasis is on summarizing the role of cell-penetrating peptides as permeation enhancers for transdermal and topical drug delivery applications. A summary table of preclinical studies utilizing various peptides in combination with different active ingredients and drug delivery systems is included. Lastly, we capture the challenges associated with the cell-penetrating peptides to translate the preclinical work to clinical applications.

Nanoclay Reinforced Ternary Blends Based on Biodegradable Polymers for Drug Delivery Application.

In this study, ternary blends based on chitosan, polyvinyl alcohol, and polyethylene glycol reinforced with organically modified montmorillonite (nanoclay) clay were synthesized. These ternary blends were evaluated as transdermal drug delivery patches using tramadol as a model drug. The FTIR study showed interaction among important functional groups and compatibility among the mixing components. Among drug-loaded formulations, composite MA12 shows maximum thermal stability with 27.9% weight residue at 540°C. The prepared formulations exhibited crystalline nature as observed by XRD analysis. SEM studies revealed that there are no gaps and cracks in prepared films and nanoclay was found dispersed in the formulations. The swelling ratio was higher in pH 1.2 as compared to pH 4.5 and pH 6.8 buffers, and there was an increase in swelling with an increase in PVA concentration. Moreover, the drug release test performed in phosphate buffer pH 6.8 showed that tramadol release from nanocomposite films increases with an increase in PEG concentration. Permeation studies indicated that the rate of permeation increased with a decrease in PVA concentration. The permeation rate was found to be higher for samples without nanoclay. The overall results suggest nanocomposite films as excellent candidates for transdermal drug delivery application.

Towards Micropump- and Microneedle-based Drug Delivery using Micro Transdermal Interface Platforms (MicroTIPs).

Micro Transdermal Interface Platforms (MicroTIPs) will combine minimally invasive microneedle arrays with highly miniaturized sensors, actuators, control electronics, wireless communications and artificial intelligence. These patch-like devices will be capable of autonomous physiological monitoring and transdermal drug delivery, resulting in increased patient adherence and devolved healthcare. In this paper, we experimentally demonstrate the feasibility of controlled transdermal drug delivery using a combination of 500 μm tall silicon microneedles, a commercial micropump, pressure and flow sensors, and bespoke electronics. Using ex-vivo human skin samples and a customized application/retraction system, leak-free delivery of volumes ranging from 0.7-1.1 mL has been achieved in under one hour. Clinical Relevance - This work experimentally confirms the feasibility of combining micropumps with microneedle arrays for applications in transdermal drug delivery.

Nanogel Development and its Application in Transdermal Drug Delivery System

Background: Nanogels are hydrophilic polymer networks that range in size from 20 to 200 nanometers. Polymer is used to make nanogels, which can be obtained from natural or manu-factured sources. Nanogels can deliver peptides, antigens, carbohydrates, oligonucleotides, proteins, and genes, among other things. These nanogels also provide inorganic materials, such as silver na-noparticles and quantum dots. Both solid and liquid nanogels have the same properties. These nanogels penetrate the stratum corneum more effectively than conventional gels. Dermatology and cosmetology have both experimented with nanoscale technology. Objective: The medication can penetrate the stratum corneum through a variety of routes. One of the ways lipids can infiltrate the skin membrane is through the transcellular route. Cream, gel, oint-ment, lotion, thin-film, and foams are among the topical preparations used. Nanogels are catego-rised into two types: those that respond to stimuli and those that cross-link. For the manufacture of nanogels, numerous polymers of synthetic, natural, or semisynthetic origin are commonly em-ployed. Nanoprecipitation, emulsion polymerization, and dispersion polymerization are all ways to make these nanogels. These nanogels are rarely released by diffusion mechanism employing the Fick’s law. Conclusions: The nano gel is a new advanced technology that allows to improve drug molecule pen-etration in the stratum corneum. If poorly soluble and permeable medications are administered through this nanogel technology, their solubility and permeability will be improved.

Nanostructured lipid carrier system: A compendium of their formulation development approaches, optimization strategies by quality by design, and recent applications in drug delivery

AbstractThe lipid-based colloidal carriers, such as nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), nanocapsules, liposomes, and microemulsion, are the latest and significant entrants in the development of drug delivery systems owing to their myriad advantages. The NLCs are second-generation SLNs having unstructured matrix, have high drug loading, and provide long-term drug stability in comparison to SLNs and other colloidal systems, which show lower drug loading and experience burst release/drug expulsion during storage. This review is aimed to summarize the formulation development and optimization strategies for NLCs as reported in the literature collected from authentic databases. Various types of NLCs, formulation components, methods of preparation, characterization parameters, optimization (statistical designs) strategies, toxicity, regulatory aspects, and their applications in oral, parenteral, ocular, pulmonary, nose-to-brain, tumor targeting, and transdermal drug delivery have been dealt in detail. Patents granted on the NLCs have also been enlisted.

Converting Tretinoin into Ionic Liquids for Improving Aqueous Solubility and Permeability across Skin.

The aim of this study is to convert tretinoin (Tr), an active pharmaceutical ingredient (API), into ionic liquid for improving aqueous solubility and permeability of Tr in transdermal drug delivery applications. Three ionic liquids of Tr (TrILs) were synthesized through neutralization reactions, which were characterized to confirm the compositions and ionic interactions. The in vitro drug release studies and skin penetration tests were carried out to assess the performance of formulations containing TrILs. The TrIL formed by choline and Tr at the molar ratio of 2:1 (2[Ch][Tr]), was found to have prominent solubility, stability as well as permeability. In contrast with the insoluble Tr, 2[Ch][Tr] presented as clear and transparent aqueous solution even after diluted to 14%. The aqueous solution of 2[Ch][Tr] demonstrated better permeation effect, of which the solution with 20% of 2[Ch][Tr] showed the optimal delivery efficiency in both epidermis (2.09 ± 0.18‰) and dermis (3.31 ± 0.48‰), realizing the improvement on the permeability of API. Meanwhile, TrILs can be easily fabricated as o/w emulsions as transdermal formulation. The emulsions are also able to improve the skin permeability of Tr, though the enhanced effect is inferior to TrILs solutions. Ionic liquid technology can be used to improve solubility and permeability of Tr, providing a high potential strategy for the development of topical formulations and the desired transdermal application of drugs.

Molecularly Imprinted Polymers as State-of-the-Art Drug Carriers in Hydrogel Transdermal Drug Delivery Applications.

Molecularly Imprinted Polymers (MIPs) are polymeric networks capable of recognizing determined analytes. Among other methods, non-covalent imprinting has become the most popular synthesis strategy for Molecular Imprinting Technology (MIT). While MIPs are widely used in various scientific fields, one of their most challenging applications lies within pharmaceutical chemistry, namely in therapeutics or various medical therapies. Many studies focus on using hydrogel MIPs in transdermal drug delivery, as the most valuable feature of hydrogels in their application in drug delivery systems that allow controlled diffusion and amplification of the microscopic events. Hydrogels have many advantages over other imprinting materials, such as milder synthesis conditions at lower temperatures or the increase in the availability of biological templates like DNA, protein, and nucleic acid. Moreover, one of the most desirable controlled drug delivery applications is the development of stimuli-responsive hydrogels that can modulate the release in response to changes in pH, temperature, ionic strength, or others. The most important feature of these systems is that they can be designed to operate within a particular human body area due to the possibility of adapting to well-known environmental conditions. Therefore, molecularly imprinted hydrogels play an important role in the development of modern drug delivery systems.

Applications of polysaccharides in topical and transdermal drug delivery: A recent update of literature

The main aim of transdermal drug delivery (TDD) is to deliver a specific dose of drug across the skin and to reach systemic circulation at a controlled rate. On the other hand skin is the target for topical drug delivery. Mentioned drug delivery systems (DDS) have numerous advantages compared to oral and parenteral routes. Avoidance of first-pass metabolism, prevent drug degradation due to harsh environment of the stomach, allow controlled drug delivery, provide patient compliance, and pain-free administration are a few of them. To achieve all of them, a DDS with suitable polymer is the primary requisite. Based on the recent trends, natural polymers have been more popular in comparison to synthetic polymers because the former possesses favourable properties including nontoxic, biodegradable, biocompatible, low cost, sustainable and renewable resources. In this context polysaccharides, composed of chains of monosaccharides bound together by glycosidic bonds, have been successfully employed to augment drug delivery into and across the skin with various formulations such as gel, membrane, patches, nanoparticles, nanofibres, nanocomposite, and microneedles. In this chapter, various polysaccharides such as cellulose, chitosan, and their semisynthetic derivatives, alginate, pectin, carrageenan etc, were discussed with their diverse topical and TDD applications. In addition, various formulations based on polysaccharides and limitations of polysaccharides were also briefly discussed.

Pressure sensitive adhesives in transdermal drug delivery system

Transdermal drug delivery systems (TDDS) are used to transfer medicines into the systemic circulation through the skin. (Trans)dermal patches are well-known pharmacological formulations that are applied to the skin’s surface for a variety of reasons, ranging from treating cutaneous diseases to achieving a systemic impact. Transdermal drug delivery (TDD) devices rely heavily on adhesives. In addition to the normal functional adhesive qualities, adhesives for TDD applications must be biocompatible with the skin, chemically compatible with the medication, and enable consistent, efficient drug administration. One of the most important components of a TDDS is the pressure-sensitive adhesive (PSA). PSA’s primary role is to aid patch adherence to the skin, but it also serves as a matrix for the medication and other excipients. As a result, PSA impacts other important quality aspects of the TDDS, such as drug distribution, flux through skin, and physical and chemical stability of the completed product, in addition to patch adherence. This article addresses transdermal drug delivery systems, their benefits and drawbacks, and their uses in pharmaceuticals, as well as providing detailed information on pressure sensitive adhesives.

The effects of molecular weight of hyaluronic acid on transdermal delivery efficiencies of dissolving microneedles

Hyaluronic acid (HA) is widely adopted to fabricate dissolving microneedles for transdermal drug delivery applications, yet the structure-activity relationship between molecular weight of HA and transdermal delivery efficiency of microneedles (HA-MNs) has not been fully explored, particularly in the transdermal delivery of small molecule drugs. Herein, we report the fabrication of three types of HA-MNs of various molecular weights (10k, 74k and 290k Da), which incorporate rhodamine B as the model drug. We assess the influence of molecular weight of HA on the mechanical properties of HA-MNs and transdermal delivery of rhodamine B in vitro and in vivo. The mechanical strength of all types of HA-MNs exceeds the minimal force requirement for skin penetration, with the highest values of compression force found in 10k-HA-MN. Interestingly, 74k-HA-MN that owns a medium mechanical strength, exhibits the highest efficiency in transdermal delivery of rhodamine B in a porcine skin and a Franz cell transdermal model. Further in vivo fluorescence imaging of HA-MN-treated mice reveals a tunable transdermal delivery of rhodamine B, which is controllable according to the molecular weight of HA. Importantly, 74k-HA-MN treatment demonstrates the highest initial delivering amount and longest retention time of rhodamine B in mice. In addition, histological examinations of puncture sites of the skin tissues confirm the complete recovery of skin and excellent biocompatibility of HA-MNs.

Targeted Delivery of Anesthetic Agents to Bone Tissues using Conductive Microneedles Enhanced Iontophoresis for Painless Dental Anesthesia

AbstractPain management during dental procedures is a cornerstone for successful daily practice. In current practice, the traditional needle and syringe injection is used to administer local anesthesia. However, the appearance of long needles and the pain associated with it often leads to dental anxiety deterring timely interventions. Microneedles (MNs) have emerged as a minimally invasive alternative to hypodermic needles and shown to be effective in transdermal drug delivery applications. In this article, the potential use of MNs for local anesthesia delivery in dentistry is explored. The development of a novel conductive MN array that can be used in combination with iontophoresis technique to achieve drug penetration through the oral mucosa and the underlying bone tissue is presented. The conductive MN array plays a dual‐role, creating micro‐conduits and lowering the resistance of the oral mucosa. The reduced tissue resistance further enhances the application of a low‐voltage current that is able to direct and accelerate the drug molecules to target the sensory nerves supplying teeth. The successful delivery of lidocaine using this new strategy in a clinically relevant rabbit incisor model is shown to be as effective as the current gold standard.

Swellable microneedles based transdermal drug delivery: Mathematical model development and numerical experiments

Recently, swellable microneedles (SMNs) have gained significant interest due to their potential applications in transdermal drug delivery (TDD). SMNs swell by absorbing interstitial fluid in the skin, and they facilitate drug transport into the skin without polymer dissolution. To establish the SMNs for practical usages, one requires an accurate understanding of the drug transport mechanisms from these MNs that would allow both controlled TDD as well as optimisation of the MN geometries. In addressing this issue, a mathematical model is formulated which incorporates the key parameters defining the skin properties and physicochemical properties of the MNs, such as the polymer swelling capacity, mechanical deformation, amount of drug loading, and penetration depth in the skin. Numerical simulations are performed using well-defined MN parameters which represent the MN constituent and drug, namely, polyvinyl alcohol and insulin, in this study. The proposed mathematical model predicts that insulin diffuses into the blood to reach a maximum concentration of 11.72 ng/ml in 1.5 h, and ~95% insulin is eliminated from the blood within 11 h. The rate of insulin diffusion to blood increases with an increase in MN swelling. However, not much difference is observed in the insulin profiles when MNs swell more than two times their mass as the skin tends to displace the MN out of the skin, as it increases the length of the diffusion pathway for the drug in the skin layers. The depth of MN penetration affects the overall insulin delivery, with insulin getting eliminated from the body in 8 h when MN is fully inserted into the skin. The rate of change of blood concentration of insulin is found to increase and decrease non-linearly with time for the cases studied in this paper. The developed model provides a platform for optimization of SMNs for the controlled delivery of different drug molecules.

Preparation and Physicochemical Characterization of a Diclofenac Sodium-Dual Layer Polyvinyl Alcohol Patch.

The aim of this study is to prepare a dual layer polyvinyl (PVA) patch using a combination of electrospinning techniques and cryogelation (freeze-thaw process) then subsequently to investigate the effect of freeze-thaw cycles, nanofiber thickness, and diclofenac sodium (DS) loading on the physicochemical and mechanical properties and formulation of dual layer PVA patches composed of electrospun PVA nanofibers and PVA cryogel. After the successful preparation of the dual layer PVA patch, the prepared patch was subjected to investigation to assess the effect of freeze-thaw cycles, nanofiber thickness and percentages of DS loading on the morphology, physiochemical and mechanical properties. Various spectroscopic techniques such as scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR), water contact angle, and tensile tests were used to evaluate the physicochemical and mechanical properties of prepared dual layer PVA patches. The morphological structures of the dual layer PVA patch demonstrated the effectiveness of both techniques. The effect of freeze-thaw cycles, nanofiber thickness, and DS percentage loading on the crystallinity of a dual layer PVA patch was investigated using XRD analysis. The presence of a distinct DS peak in the FTIR spectrum indicates the compatibility of DS in a dual layer PVA patch through in-situ loading. All prepared patches were considered highly hydrophilic because the data obtained was less than 90°. The increasing saturation of DS within the PVA matrix increases the tensile strength of prepared patches, however decreased its elasticity. Evidently, the increasing of electrospun PVA nanofibers thickness, freeze-thaw cycles, and the DS saturation has improved the physicochemical and mechanical properties of the DS medicated dual layer PVA patches, making them a promising biomaterial for transdermal drug delivery applications.

Drug‐Eluting Medical Textiles: From Fiber Production and Textile Fabrication to Drug Loading and Delivery

Back Cover: Drug-eluting medical textiles have been extensively used in various biomedical applications recently due to their cost-effectiveness and unique physical and chemical properties. Different fiber production, textile fabrication, and drug loading technologies are used to process the biomaterials to three-dimensional medical textiles that can be used for wound care, tissue engineering, and transdermal drug delivery applications. This is reported by Samaneh Ghazanfari and co-workers in article number 2100021.

Fabrication of epirubicin loaded core/shell electrospun fibers with effective transdermal sustained-release properties

Epirubicin-loaded polyacrylonitrile nanofibers were fabricated by the low energy water-in-oil emulsion electrospinning technique using the drug solution as the aqueous phase and the N, N- dimethylformamide solution of polyacrylonitrile as the oil phase. Tween 80 as a surfactant was applied to contribute to the formation of the core/shell structure of fibers. The in vitro drug release of these drug-loaded nanofibers obeyed the Korsmeyer-Peppas equation, by exhibiting a good sustained-release performance. In addition, in vitro permeation studies across artificial human skin showed that the prepared nanofibers had effective transdermal sustained-release behavior and the optimum drug cumulative amounts reached 61% in 24 h. The nanofiber membrances exhibited good flexibility and high tensile strength (7.93 MPa), which favors their potential application in transdermal drug delivery.

Controlled release of enrofloxacin by vanillin-crosslinked chitosan-polyvinyl alcohol blends

In transdermal drug delivery applications uniform drug distribution and sustained release are of great importance to decrease the side effects. In this direction in the present research, vanillin crosslinked chitosan (CS) and polyvinyl alcohol (PVA) blend based matrix-type transdermal system was prepared by casting and drying of aqueous solutions for local delivery of enrofloxacin (ENR) drug. Subsequently, the properties including the morphology, chemical structure, thermal behavior, tensile strength, crosslinking degree, weight uniformity, thickness, swelling and drug release of the CS-PVA blend films before and after crosslinking were characterized. In vitro drug release profiles showed the sustained release of ENR by the incorporation of vanillin as a crosslinker into the CS-PVA polymer matrix. Furthermore, the release kinetic profiles revealed that the followed mechanism for all samples was Higuchi and the increase of vanillin concentration in the blend films resulted in the change of diffusion mechanism from anomalous transport to Fickian diffusion. Overall, the obtained results suggest that the investigated vanillin crosslinked CS-PVA matrix-type films are potential candidates for transdermal drug delivery system.

Design and optimization of a microneedle with skin insertion analysis for transdermal drug delivery applications

Effectively delivering the drugs through the human skin with less pain and reducing the chance of tissue damage are the main attributes of a microneedle. This paper presents an out-of-plane single silicon carbide (SiC) microneedle having six lumens for drug passing. The total length of the proposed microneedle is about 350 μm with the inner diameter of 30 μm and the outer diameter of 52 μm. COMSOL multiphysics software is used to analyze the performances of the proposed microneedle. The simulated durability of the microneedle is investigated by applying the axial load which generates less stress and deformation. Then, an optimized microneedle tip is designed which reduce pain during insertion. The flow analyses of various viscosity based fluids inside the microneedle are also investigated. Among the selected fluids, the flow of the ibuprofen shows a lowest velocity distribution because of its high dynamic viscosity. The maximum flow rates of ibuprofen are found as 0.01 μL/min and 0.9 μL/min while the inlet pressure are 10 kPa and 100 kPa respectively. On the contrary, a low viscosity fluid such as water provides flow rates of 45.24 μL/min and 433.49 μL/min at same inlet pressures. To verify the performances of our proposed microneedle, a skin model consisting three layers of stratum corneum, epidermis and dermis is designed. Simulation results confirm that the proposed microneedle successfully penetrated the skin model and remains unbroken.

The molecular mechanism behind the stabilization of insulin by choline and geranate (CAGE) ionic liquids - computational insights into oral insulin drug formulation.

Insulin is a principal hormone that is involved in the regulation of glucose levels in the blood. Oral insulin formulation is a recent development in drug delivery systems. Biocompatible choline-based ionic liquids (ILs) show promising antibacterial activity and are useful for oral and transdermal drug delivery applications. Choline and geranate (CAGE) ILs enhance the stability and oral efficacy of insulin delivery. The molecular mechanism behind insulin formulation in the oral form is at issue. In the present work, the molecular-level understanding of CAGE ILs in insulin is scrutinized by employing atomistic molecular dynamics (MD) simulations. To identify the stability of insulin in an IL medium, we have studied a series of concentration (mole fraction 0.05-1.00) of CAGE ILs with an insulin dimer. It can be well evidenced from the experimental reports that in an aqueous medium, there is a refashioning of CAGE nanostructures at 0.50 mole fraction. It is found from our calculations that the first solvation shell of insulin is readily occupied by choline and geranate ions in the presence of water. Moreover, the geranate ions strongly interacted with the water molecules and thereby, eliminating the intermolecular hydrogen bonding (H-bonding) interactions towards the insulin at 0.30-0.50 mole fraction of CAGE ILs. The most desirable 0.30-0.50 mole fraction of CAGE invigorates water-mediated H-bonding interactions with geranate ions, which also enhances the electrostatic behavior around the vicinity of the insulin dimer. These important findings can help in the development of oral insulin drug delivery and related applications.