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Transdermal drug delivery systems (TDDSs) are designed to administer a consistent and effective dose of an active pharmaceutical ingredient (API) through the patient's skin. These pharmaceutical preparations are self-contained, discrete dosage forms designed to be placed topically on intact skin to release the active component at a controlled rate by penetrating the skin barriers. The API provides the continuous and prolonged administration of a substance at a consistent rate. TDDSs, or transdermal drug delivery systems, have gained significant attention as a non-invasive method of administering APIs to vulnerable patient populations, such as pediatric and geriatric patients. This approach is considered easy to administer and helps overcome the bioavailability issues associated with conventional drug delivery, which can be hindered by poor absorption and metabolism. A TDDS has various advantages compared to conventional methods of drug administration. It is less intrusive, more patient-friendly, and can circumvent first pass metabolism, as well as the corrosive acidic environment of the stomach, that happens when drugs are taken orally. Various approaches have been developed to enhance the transdermal permeability of different medicinal compounds. Recent improvements in TDDSs have enabled the accurate administration of APIs to their target sites by enhancing their penetration through the stratum corneum (SC), hence boosting the bioavailability of drugs throughout the body. Popular physical penetration augmentation methods covered in this review article include thermophoresis, iontophoresis, magnetophoresis, sonophoresis, needle-free injections, and microneedles. This review seeks to provide a concise overview of several methods employed in the production of TDDSs, as well as their evaluation, therapeutic uses, clinical considerations, and the current advancements intended to enhance the transdermal administration of drugs. These advancements have resulted in the development of intelligent, biodegradable, and highly efficient TDDSs. [ABSTRACT FROM AUTHOR]

Background: A carrying structure for targeted transdermal drug delivery is a transferosome. These unique liposomes are made of an edge activator and phosphatidylcholine. The most common antiviral drug is acyclovir, a synthetic nucleotide nucleoside analog derived from guanine. It works well to cure the varicella-zoster virus and the virus that causes herpes simplex (HSV), primarily HSV-1 and HSV-2. But its skin permeability is minimal. Therefore, this work aimed to use transferosomes to prepare acyclovir so that it could pass through the skin's barrier function. Objective: This study uses a 32-factorial factorial design to develop a transferosomal gel containing acyclovir through thin-film hydration method for painless acyclovir delivery services for skin disease treatment. Material and Methods: The independent variables are the amount of phospholipid (X1) and tween 80 (X2), while the dependent variables are particle size (Y1) and percentage entrapment efficiency (Y2). To create an ideal formulation, the produced transferosomes were assessed for particle size, in vitro drug release amount, and entrapment efficiency (EE%). A Carbopol 934 gel basis was prepared using the optimized acyclovir transferosome formulation, and its drug concentration, pH, spreadability, viscosity, and stability were assessed. Results: With small particles ranging from 176.6 to 324.4 nm, the produced acyclovir transferosomes had a high EE% range from 66.34 to 76.42 %. According to the in vitro release study, there is a negative correlation between in vitro release and EE%. The formulation TF5, including 1%w/w of carbopol 940, provides a superior profile of drug absorption in vitro. Consequently, acyclovir can enter the skin as transferosomes and cross the stratum corneum barrier. Conclusion: Acyclovir can be transformed into a transfersomal gel, which will improve antiviral efficacy, get over the skin's protective layer, prevent adverse oral reactions, and eventually improve patient adherence. [ABSTRACT FROM AUTHOR]

The delivery of therapeutical molecules through the skin, particularly to its deeper layers, is impaired due to the stratum corneum layer, which acts as a barrier to foreign substances. Thus, for the past years, scientists have focused on the development of more efficient methods to deliver molecules to skin distinct layers. Microneedles, as a new class of biomedical devices, consist of an array of microscale needles. This particular biomedical device has been drawing attention due to its ability to breach the stratum corneum, forming micro-conduits to facilitate the passage of therapeutical molecules. The microneedle device has several advantages over conventional methods, such as better medication adherence, easiness, and painless self-administration. Moreover, it is possible to deliver the molecules swiftly or over time. Microneedles can vary in shape, size, and composition. The design process of a microneedle device must take into account several factors, like the location delivery, the material, and the manufacturing process. Microneedles have been used in a large number of fields from drug and vaccine application to cosmetics, therapy, diagnoses, tissue engineering, sample extraction, cancer research, and wound healing, among others. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs; as novel solvents for improving the solubility of drugs in carriers; as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs; and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structureactivity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs. [ABSTRACT FROM AUTHOR]

This research presents novel ibuprofen derivatives in the form of alkyl ester salts of L-amino acids with potential analgesic, anti-inflammatory, and antipyretic properties for potential use in transdermal therapeutic systems. New derivatives of (RS)-2-[4-(2-methylpropyl)phenyl]propionic acid were synthesized using hydrochlorides of alkyl esters (ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and pentyl) of L-glutamine. These were further transformed into alkyl esters of L-amino acid ibuprofenates through neutralization and protonation reactions. Characterization involved spectroscopic methods, including nuclear magnetic resonance and Fourier-transform infrared spectroscopy. Various physicochemical properties were investigated, such as UV–Vis spectroscopy, polarimetric analysis, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, water solubility, octanol/water partition coefficient, and permeability through pig skin using Franz diffusion cells. The research confirmed the ionic structure of the obtained hydrochlorides of alkyl esters of L-amino acids and ibuprofenates of alkyl esters of L-glutamic acid. It revealed significant correlations between ester chain length and thermal stability, crystallinity, phase transition temperatures, lipophilicity, water solubility, skin permeability, and skin accumulation of these compounds. Compared to the parent ibuprofen, the synthesized derivatives exhibited higher water solubility, lower lipophilicity, and enhanced skin permeability. This study introduces promising ibuprofen derivatives with improved physicochemical properties, highlighting their potential for transdermal therapeutic applications. The findings shed light on the structure–activity relationships of these derivatives, offering insights into their enhanced solubility and skin permeation, which could lead to more effective topical treatments for pain and inflammation. [ABSTRACT FROM AUTHOR]

Due to its reduced invasiveness, low rejection rate, and remarkable ease of administration, transdermal drug delivery (TDD) has recently become a viable alternative to oral and injectable administration. The transdermal medication delivery method is a treatment strategy that is extraordinarily safe and well-tolerated and has enormous potential for delivering active ingredients against a variety of illnesses. However, because to the low skin permeability of the majority of active medicines in the formulation, its application is currently restricted in clinical settings. To get over this restriction, new strategies for skin permeation improvement techniques are offered. The drug delivery industry has undergone a revolution due to recent advances at the nano and microscale. A growing trend in drug delivery applications is the use of several kinds of microneedles (MNs), in particular because they are safe, compliant with patient preferences, and practical. Microneedles are a distinct, cutting-edge, and successful method created to administer medicinal chemicals and immunological components in a number of disorders. With appropriate examples and recent developments, various MN types--solid, hollow, coated, dissolving, and hydrogel forming--are described. We summarize recent developments in microneedles for therapeutic uses in this review. [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]

Background: Skin being the largest organ of the human body plays a very important role in the permeation and penetration of the drug. In addition, the transdermal drug delivery system (TDDS) plays a major role in managing dermal infections and attaining sustained plasma drug concentration. Thus, evaluation of percutaneous penetration of the drug through the skin is important in developing TDDS for human use. Material and methods: Various techniques are used for getting the desired drug penetration, permeation, and absorption through the skin in managing these dermal disorders. The development of novel pharmaceutical dosage forms for dermal use is much explored in the current era. However, it is very important to evaluate these methods to determine the bioequivalence and risk of these topically applied drugs, which ultimately penetrate and are absorbed through the skin. Results: Currently, numerous skin permeation models are being developed and persuasively used in studying dermatopharmacokinetic (DPK) profile and various models have been developed, to evaluate the TDD which include ex vivo human skin, ex vivo animal skin, and artificial or reconstructed skin models. Conclusion: This review discusses the general physiology of the skin, the physiochemical characteristics affecting particle penetration, understand the models used for human skin permeation studies and understanding their advantages, and disadvantages. [ABSTRACT FROM AUTHOR]

[Display omitted] • A strategy to realize zero-order skin delivery of CLO and GRA. • The PSA consist of polydimethylaminoethyl acrylate and hydroxyphenyl adhesive. • The competing doubly ionic H-bond interaction determined the process. Transdermal drug delivery system (TDDS) was an effective way to realize controlled drug delivery. However, realizing zero-order controlled drug skin delivery was still challenging in the drug-in-adhesive patch. This study provided a strategy to accomplish this delivery form by stabilizing the drug concentration in adhesive through concentration-dependent competitive interaction. Clonidine (CLO) and Granisetron (GRA) were chosen as the model drugs which were of high skin permeability, and polydimethylaminoethyl acrylate (EA) as an excipient to interact with hydroxyphenyl adhesive (HP). Drug release, permeation and pharmacokinetic study were conducted to evaluate the controlled effect of HP-EA. The molecular interaction was characterized by FT-IR, 1H NMR and XPS. Dynamic simulation and molecular docking further clarified the competitive interaction involved in the release process. Both the drug skin permeation study of CLO and GRA patch based on the HP-EA adhesive showed good zero-order fitting with r of 0.994 and 0.998, compared with non-functional adhesive (0-PSA). Furthermore, the pharmacokinetic study of the CLO patch showed a plateau phase for around 52 h without influencing the area under concentration–time curve (AUC), indicating that the HP-EA could realize zero-order drug skin delivery. The mechanism study revealed that EA serving as a 'buffer component' promoted the conversion of the ionic CLO to the neutrals the as the neutrals released, which stabilized '1% neutrals CLO concentration'. In conclusion, the drug delivery system based on the concentration-dependent competitive interaction broadened our understanding of the molecular mechanisms involved in zero-order controlled release in transdermal patches which would promote the development of zero-order drug delivery in TDDS. [ABSTRACT FROM AUTHOR]

Recently, transdermal treatment of rheumatoid arthritis (RA) has received increasing attention due to the advantages of improving patient compliance and avoiding gastrointestinal side effects. However, the stratum corneum (SC) barrier limits the transdermal delivery of most substances. Therefore, we constructed tetramethylpyrazine-loaded dissolving microneedle patches (TMP-DMNPs) and investigated its anti-rheumatoid arthritis effect. The cone-shaped dissolving microneedle patch had complete, neatly arranged needles and great mechanical strength. It could effectively penetrate the stratum corneum when applied to the skin. In vitro transdermal experiment showed that DMNPs could significantly promote the transdermal penetration of TMP compared with TMP-cream. The needles were completely dissolved within 18 min and the applied skin recovered completely within 3 h. The excipients and blank DMNP had good safety and biocompatibility to human rheumatoid arthritis fibroblast synovial cells. To compare the therapeutic effects, the animal model was established. The experiments of paw swelling, histopathology and X-ray examination showed that dissolving microneedles significantly alleviated paw condition, reduced the serum concentrations of proinflammatory cytokines, and inhibited synovial tissue damage in AIA rats. These results indicate that the DMNPs we prepared can deliver TMP safely, effectively and conveniently, providing a basis for the percutaneous treatment of RA. Schematic illustration of TMP-loaded dissolving microneedle patch for RA treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Ketorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug, when given orally causes gastrointestinal disturbances. Its transdermal drug delivery may reduce such side effects associated with them. The present investigation was aimed at evaluating the efficiency of various penetration enhancers for improved permeation of KT through the skin. Materials and Methods: A concentration of 1 mg/mL of the drug solution with enhancers was used to evaluate diffusion through the rat skin using a Franz diffusion cell assembly. 20 different penetration enhancers were selected for this study. Results: Saturated fatty acids like stearic and palmitic acid were found to increase the permeation rate of the drug to a great extent whereas unsaturated fatty acid viz. oleic acid exhibited maximum permeation. Increase in permeability efficiency of various penetration enhancers was observed in the following order: Oleic acid > stearic acid > palmitic acid > isopropyl myristate > tween 80 > span 80 > span 40 > span 20 > l-limonene > l-menthol > fenchone > α-pinene > urea > dimethyl sulfoxide (DMSO) > triton X-100 > tween 20 > dimethyl formamide > acetone > control > citric acid > ascorbic acid. Ascorbic acid and citric acid had no effect on permeation rate. Conclusion: The results revealed that the permeation of KT through the skin can maximally be enhanced using oleic acid-an unsaturated fatty acid. [ABSTRACT FROM AUTHOR]

The main objective of this research work was to fabricate and evaluate adhesive matrix-type transdermal patches of buflomedil hydrochloride, employing different ratios of pressure sensitive adhesives (PSAs) by solvent casting technique. The adhesive matrix-type transdermal patches were evaluated by theirin vitrophysicochemical properties such as thickness, moisture content, weight variation, drug content uniformity, etc. The effects of PSAs ratio, drug loading, and concentration of permeation enhancer were evaluated thoroughly.Ex vivoskin permeation studies with kinetic modeling of adhesive matrix patches were systematically evaluated. Based on the above observations, the best optimized buflomedil hydrochloride-loaded adhesive matrix-type transdermal patch was further characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction study, and differential scanning calorimetry analyses. Drug containing adhesive matrix patches showed sustained release property without showing any incompatibility in adhesive matrix system. Hence, adhesive matrix-type transdermal patches of buflomedil hydrochloride can be used as a potential carrier for sustained transdermal delivery of hydrophilic drugs like buflomedil hydrochloride. [ABSTRACT FROM PUBLISHER]

To enhance skin permeability to medicine, the argon-fluoride excimer laser (ArF laser) was used to partially ablate the stratum corneum. Skin permeability to dextran (20 kDa) was studied in the Yucatan micro-pig skin in vitro. The cumulative amount of dextran permeating across the full-thickness skin was not detected for 30 h in the unirradiated skin; we obtained up to 90.5 microg/cm2 in laser-irradiated skin. In the case where the total laser energy was kept constant at 7.1 J/cm2, permeability was mainly influenced by laser fluence rather than laser pulses. Many granular structures of about 2 microm were found on the stratum corneum surface of ablated skin. Size and density of these structures were changed according to irradiation conditions. Skin permeability may be estimated by these structural changes. Our partial stratum corneum ablation by ArF laser could be suitable for transdermal drug delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] • Quantitative structure-activity relationships that related formation and skin permeation of drug-ILs to counterions physicochemical parameters were developed. • Charge assisted hydrogen bond and van der Waals interaction undermined ionic interactions, which caused low T g values of drug-ILs. • Skin permeability of drug-ILs were enhanced by increasing conformational disorder and phase transition of lipid bilayers. Though ionic liquids (ILs) as novel enhancers had garnered wide attention, detailed studies elucidating molecular design of drug-ILs were missing and mechanisms of their formation and skin permeation were still lacking. Herein, we systematically investigated effects of counterions structures on formation and skin permeation of drug-ILs. Firstly, effects of counterions on formation of drug-ILs were dependent on polarizability, molecular weight (M.W.) and polar surface area of counterions. It was caused by strong charge assisted hydrogen bond and van der Waals interactions revealed through FT-IR, X-ray photoelectron spectroscopy and molecular docking, which undermined ionic interactions and reduced total interaction strength, thereby produced lower lattice energy. Then, skin permeability of drug-ILs had a good parabola relationship with M.W., polarizability and log P of counterions. The underlying mechanism was the increased drug miscibility with stratum corneum, which caused conformational disorder and phase transition of lipid bilayers characterized by ATR-FTIR, DSC and confocal laser scanning microscopy. Finally, the drug-ILs proved to be non-irritating using in vivo skin erythema analysis. In conclusion, the quantitative structure-activity relationship models based on counterions structure to predict formation and skin permeation of drug-ILs were developed, which provided basic theory for design of drug-ILs with high permeation-enhancing efficiency. [ABSTRACT FROM AUTHOR]