Transdermal Drug Delivery Systems (TDDS): Recent Advances and Failure Modes.

Transdermal drug delivery systems (TDDS), commonly refered to as "patches", present a nonintrusive technique to provide medication without the need for invasive procedures. These products adhere to the skin and gradually release a specific dosage of medicine at a defined rate into the bloodstream. Compared with other methods of drug delivery, TDDS offer benefits such as reduced invasiveness, convenience for patients, and avoidance of the metabolic processes that occur when drugs are orally consumed. Throughout time, TDDS have been used to provide medications for various medical conditions (such as nicotine, fentanyl, nitroglycerin, and clonidine), and their potential for delivering biologics is currently being explored. This review investigates the current literature on the drug delivery efficacy of medical TDDS through the transdermal route. Additionally, the review addresses potential risks and failure modes associated with TDDS design and development as well as strategies for mitigating such risks. A thorough understanding of failure modes provides a blueprint to mitigate failure and produce high-quality efficacious therapeutics.

3D printed microneedles: revamping transdermal drug delivery systems.

One of the advancements of the transdermal drug delivery system (TDDS) is the development of microneedles (MNs). These micron-sized needles are used for delivering various types of drugs to address the disadvantage of other transdermal techniques as well as oral drug delivery systems. MNs have high patient acceptance due to self-administration with minimally invasive and pain compared to the parenteral drug delivery. Over the years, various methods have been adopted to evolve the MNs and make them more cost-effective, accurate, and suitable for multiple applications. One such method is the 3D printing of MNs. The development of MN platforms using 3D printing has been made possible by improved features like precision, printing resolution, and the feasibility of using low-cost raw materials. In this review, we have tried to explain various types of MNs, fabrication methods, materials used in the formulation of MNs, and the recent applications that utilize 3D-printed MNs.

Transdermal microneedle patches as a promising drug delivery system for anti-obesogenic molecules.

Obesity, characterized by excessive storage of lipids, has become a global pandemic with high incidence levels, and its forecast is not encouraging. Currently, there are different strategies to treat obesity; however, these conventional methods have various limitations. Lifestyle changes may result in poor outcomes due to the complexity of obesity causes, pharmaceutic treatments produce severe side effects, and bariatric surgery is highly invasive. In the search for alternative treatments to fight obesity, transdermal drug delivery systems of anti-obesogenic molecules have gained particular attention. However, the diffusion of molecules through the skin is the main drawback due to the characteristics of different layers of the skin, principally the stratum corneum and its barrier-like behavior. In this sense, microneedles patches (MP) have emerged to overcome this limitation by piercing the skin and allowing drug delivery inside the body. Although MP have been studied for some years, it was not until about 2017 that their potential as anti-obesogenic treatment was reported. This article aims to summarize and analyze the strategies employed to produce MP and to embed the active molecules against obesity. Special attention is focused on the microneedle's material, geometry, array, and additional delivery strategies, like nanoencapsulation. MP are a promising tool to develop an easy-access treatment, avoiding the digestive tract and with the capacity to enhance the anti-obesogenic activity by delivering one or more active molecules.

Multifunctional Ionic Hydrogel-Based Transdermal Delivery of 5-Fluorouracil for the Breast Cancer Treatment.

Transdermal drug delivery systems (TDDS) are a promising and innovative approach for breast cancer treatment, offering advantages such as noninvasiveness, potential for localized and prolonged drug delivery while minimizing systemic side effects through avoiding first-pass metabolism. Utilizing the distinctive characteristics of hydrogels, such as their biocompatibility, versatility, and higher drug loading capabilities, in the present work, we prepared ionic hydrogels through synergistic interaction between ionic liquids (ILs), choline alanine ([Cho][Ala]), and choline proline ([Cho][Pro]) with oleic acid (OA). ILs used in the study are biocompatible and enhance the solubility of 5-fluorouracil (5-FU), whereas OA is a known chemical penetration enhancer. The concentration-dependent (OA) change in morphological aggregates, that is, from cylindrical micelles to worm-like micelles to hydrogels was formed with both ILs and was characterized by SANS measurement, whereas the interactions involved were confirmed by FTIR spectroscopy. The hydrogels have excellent mechanical properties, which studied by rheology and their morphology through FE-SEM analysis. The in vitro skin permeation study revealed that both hydrogels penetrated 255 times ([Cho][Ala]) and 250 times ([Cho][Pro]) more as compared to PBS after 48 h. Those ionic hydrogels exhibited the capability to change the lipid and keratin arrangements within the skin layer, thereby enhancing the transdermal permeation of the 5-FU. Both ionic hydrogels exhibit excellent biocompatibility with normal cell lines (L-132 cells) as well as cancerous cell lines (MCF-7 cells), demonstrating over 92% cell viability after 48 h in both cell lines. In vitro, the cytotoxicity of the 5-FU-loaded hydrogels was evaluated on MCF-7 and HeLa cell lines. These results indicate that the investigated biocompatible and nontoxic ionic hydrogels enable the transdermal delivery of hydrophilic drugs, making them a viable option for effectively treating breast cancer.

Presence of metallic components in transdermal drug delivery systems and risk of skin burns. / [Artículo traducido] Presencia de partículas metálicas en parches transdérmicos de medicamentos y riesgo de quemaduras.

OBJECTIVE: Skin burns are associated with the presence of metallic components in transdermal drug delivery systems during Magnetic Resonance Imaging, cardioversion or defibrillation procedures. The aim of the study was to review the presence of metallic components in marketed products of transdermal drug delivery systems in Spain. METHOD: For each presentation, the summary of product characteristics was reviewed. If the information was not provided, manufacturers were contacted. RESULTS: We identified 59 marketed products of transdermal drug delivery systems of 12 different active substances. 59.3% of patches contained metallic components or their presence could not be ruled out. Information regarding the need to remove the patch was only included in 8 summaries of product characteristics (13.6%). A table was elaborated and included the following aspects: product, active substance, manufacturer, need to remove the patch before the exposure to magnetic or electric fields and references. CONCLUSION: More than a half of the patches at the time of the study contained metals or their absence could not be confirmed by the manufacturer. However, this information was only included in 13.6% of summaries of product characteristics.

Construction of various lipid carriers to study the transdermal penetration mechanism of sinomenine hydrochloride.

OBJECTIVE: To investigate the transdermal mechanisms and compare the differences in transdermal delivery of Sinomenine hydrochloride (SN) between solid lipid nanoparticles (SLN), liposomes (LS), and nanoemulsions (NE). METHODS: SN-SLN, SN-LS and SN-NE were prepared by ultrasound, ethanol injection and spontaneous emulsification, respectively. FTIR, DSC, in vitro skin penetration, activation energy (Ea) analysis were used to explore the mechanism of drug penetration across the skin. RESULTS: The particle size and encapsulation efficiency were 126.60 nm, 43.23 ± 0.48%(w/w) for SN-SLN, 224.90 nm, 78.31 ± 0.75%(w/w) for SN-LS, and 83.22 nm, 89.01 ± 2.16%(w/w) for SN-LS. FTIR and DSC showed the preparations had various levels of impacts on the stratum corneum's lipid structure which was in the order of SLN > NE > LS. Ea values of SN-SLN, SN-LS, and SN-NE crossing the skin were 2.504, 1.161, and 2.510 kcal/mol, respectively. CONCLUSION: SLN had a greater degree of alteration on the skin cuticle, which allows SN to permeate skin more effectively.

Rhamnose-PEG-induced supramolecular helices: Addressing challenges of drug solubility and release efficiency in transdermal patch.

Transdermal drug delivery systems (TDDS) demand both high drug loading capacity and efficient delivery. In order to improve both simultaneously, this study aims to develop a novel rhamnose-induced pressure-sensitive adhesive (HPR) by dispersing the drug in the supramolecular helical structure. Ten model drugs, categorized as acidic and basic compounds, were chosen to understand the characteristics of the HPR and its inner mechanism. Notably, it enhanced drug loading by 1.41 to 5 times over commercially available pressure-sensitive adhesives Duro-Tak@ 87-4098 and Duro-Tak@ 87-2287, in addition to increasing drug release efficiency by a factor of about 5. Pharmacokinetic evaluation demonstrated that the HPR group had >4-fold (Tulobuterol TUL) and 3-fold (Diclofenac DIC) more area under the blood drug concentration curve (AUC) than the commercial TUL and DIC patches in the absence of added excipients and a significantly prolonged mean residence time (MRT) of >4-fold (TUL) and 3-fold (DIC), demonstrating the potential for highly efficacious and prolonged dosing. Furthermore, its safety and mechanical properties meet the requisite standards. Mechanistic inquiries unveiled that both acidic and basic drugs establish hydrogen bonds with HPR and become encapsulated within supramolecular helical structures. The supramolecular helical structures, significantly elevated both the enthalpy of the drug-HPR and entropy of the drugs release, thereby substantially enhancing drug delivery efficiency. In summary, HPR enabled a significant simultaneous enhancement of drug loading and drug delivery, which, together with its unique spatial structure, would contribute to the development of TDDS. In addition, the establishment of rhamnose-induced supramolecular helical structures would provide innovative pathways for different drug delivery systems.

Transdermal Drug Delivery System of Linagliptin Sustained-release Microparticle Gels: In vitro Characterization and In vivo Evaluation.

BACKGROUND: Linagliptin (LNG) exhibits poor bioavailability and numerous side effects, significantly limiting its use. Transdermal drug delivery systems (TDDS) offer a potential solution to overcome the first-pass effect and gastrointestinal reactions associated with oral formulations. OBJECTIVE: The aim of this study was to develop LNG microparticle gels to enhance drug bioavailability and mitigate side effects. METHODS: Linagliptin hyaluronic acid (LNG-HA) microparticles were prepared by spray drying method and their formulation was optimized via a one-factor method. The solubility and release were investigated using the slurry method. LNG-HA microparticle gels were prepared and optimised using in vitro transdermal permeation assay. The hypoglycaemic effect of the LNG-HA microparticle gel was examined on diabetic mice. RESULTS: The results indicated that the LNG-HA microparticle encapsulation rate was 84.46%. Carbomer was selected as the gel matrix for the microparticle gels. Compared to the oral API, the microparticle gel formulation demonstrated a distinct biphasic release pattern. In the first 30 minutes, only 43.56% of the drug was released, followed by a gradual release. This indicates that the formulation achieved a slow-release effect from a dual reservoir system. Furthermore, pharmacodynamic studies revealed a sustained hypoglycemic effect lasting for 48 hours with the LNG microparticle gel formulation. CONCLUSION: These findings signify that the LNG microparticle gel holds significant clinical value for providing sustained release and justifies its practical application.

Presence of metallic components in transdermal drug delivery systems and risk of skin burns.

OBJECTIVE: Skin burns are associated with the presence of metallic components in transdermal drug delivery systems during Magnetic Resonance Imaging, cardioversion, or defibrillation procedures. The aim of the study was to review the presence of metallic components in marketed products of transdermal drug delivery systems in Spain. METHOD: For each pharmaceutical form, the summary of product characteristics was reviewed. If the information was not provided, manufacturers were contacted. RESULTS: We identified 59 marketed products of transdermal drug delivery systems of 12 different active substances. 59.3% of patches contained metallic components or their presence could not be ruled out. Information regarding the need to remove the patch was only included in 8 summaries of product characteristics (13.6%) A table was elaborated and included the following aspects: product, active substance, manufacturer, need to remove the patch before the exposure to magnetic or electric fields, and references. CONCLUSION: More than a half of the patches at the time of the study contained metals or their absence could not be confirmed by the manufacturer. However, this information was only included in 13.6% of summaries of product characteristics.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis.

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Dual-Pulsed Laser Ablation of Oyster Shell Producing Novel Thin Layers Deposed to Saccharomyces cerevisiae.

Dual-pulsed (DPL) laser deposition using oyster shells as targets was studied in order to find out if this method can replace the use of high-power pulsed lasers. Aspects related to changes in the morphological structure of the thin layer but also to the chemical composition of the obtained thin layer were analyzed and compared with the target as well as with the thin layers obtained with a higher power pulsed laser in a single-pulsed (SPL) regime. Orthorhombic structures were noticed with Scanning Electron Microscopy for the thin film obtained in DPL mode compared to the irregular particles obtained in SPL mode. The deacetylation process during ablation was evidenced by Fourier Transform Infrared spectroscopy, resulting in chitosan-based thin films. The effect of the obtained thin films of chitosan on the cells of baker's yeast (Saccharomyces cerevisiae) was studied. Restoration of the yeast paste into initial yeast was noticed mainly when the hemp fabric was used as support for the coating with yeas which was after that coated with chitosan thin film produced by DPL method.

Integrated Device Based on a Sudomotor Nanomaterial for Sweat Detection.

The compositions of sweat and blood are related. Therefore, sweat is an ideal noninvasive test body fluid that could replace blood for linear detection of many biomarkers, especially blood glucose. However, access to sweat samples remains limited to physical exercise, thermal stimulation, or electrical stimulation. Despite intensive research, a continuous, innocuous, and stable method for sweat stimulation and detection has not yet been developed. In this study, a nanomaterial for a sweat-stimulating gel based on the transdermal drug delivery system is presented, which transports acetylcholine chloride into the receptors of sweat glands to achieve the function of biological stimulation of skin sweating. The nanomaterial was applied to a suitable integrated sweat glucose detection device for noninvasive blood glucose monitoring. The total amount of evaporated sweat enabled by the nanomaterial is up to 35 µL·cm-2 for 24 h, and the device detects up to 17.65 µM glucose under optimal conditions, showing stable performance regardless of the user's activity level. In addition, the in vivo test was performed and compared with several studies and products, which showed excellent detection performance and osmotic relationship. The nanomaterial and associated integrated device represent a significant advance in continuous passive sweat stimulation and noninvasive sweat glucose measurement for point-of-care applications.

Development of a Microfluidic Formatted Ultrasound-Controlled Monodisperse Lipid Vesicles' Hydrogel Dressing Combined with Ultrasound for Transdermal Drug Delivery System.

Transdermal drug delivery system (TDDS) has attracted much attention in the pharmaceutical technology area. However, the current methods are difficult to ensure penetration efficiency, controllability, and safety in the dermis, so its widespread clinical use has been limited. This work proposes an ultrasound-controlled monodisperse lipid vesicles (U-CMLVs) hydrogel dressing, which combines with ultrasound to form TDDS. Using microfluidic technology, prepare size controllable U-CMLVs with high drug encapsulation efficiency and quantitative encapsulation of ultrasonic response materials, and even uniform mix them with hydrogel to prepare the required thickness of dressings. The high encapsulation efficiency can ensure sufficient dosage of the drugs and further realize the control of ultrasonic response through quantitative encapsulation of ultrasound-responsive materials. Using high frequency (5 MHz, 0.4 W cm-2 ) and low frequency (60 kHz, 1 W cm-2 ) ultrasound to control the movement and rupture of U-CMLVs, the contents not only penetrate the stratum corneum into the epidermis but also break through the bottleneck of penetration efficiency, and deep into the dermis. These findings provide the groundwork for deep, controllable, efficient, and safe drug delivery through TDDS and lay a foundation for further expanding its application.

Bacterial cellulose-based composites as vehicles for dermal and transdermal drug delivery: A review.

In recent years, a significant amount of drugs have been taken orally, which are not as effective as desired. To solve this problem, bacterial cellulose-based dermal/transdermal drug delivery systems (BC-DDSs) with unique properties such as cell compatibility, hemocompatibility, tunable mechanical properties, and the ability to encapsulate various therapeutic agents with the controlled release have been introduced. A BC-dermal/transdermal DDS reduces first-pass metabolism and systematic side effects while improving patient compliance and dosage effectiveness by controlling drug release through the skin. The barrier function of the skin, especially the stratum corneum, can interfere with drug delivery. Few drugs can pass through the skin to reach effective concentrations in the blood to treat diseases. Due to their unique physicochemical properties and high potential to reduce immunogenicity and improve bioavailability, BC-dermal/transdermal DDSs are widely used to deliver various types of drugs for disease treatment. In this review, we describe the different types of BC-dermal/ transdermal DDSs, along with a critical discussion of the advantages and disadvantages of these systems. After the general presentation, the review is focused on recent advances in the preparation and applications of BC-based dermal/transdermal DDSs in various types of disease treatment.

Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy.

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.

Ethosomes as dermal/transdermal drug delivery systems: applications, preparation and characterization.

Transdermal drug delivery systems (TDDSs) have gained substantial attention during the last decade. TDDS are versatile delivery systems in which active components are delivered to skin for local effects or systemic delivery of active pharmaceutical through the skin. Overcoming stratum corneum is the most challenging step of delivering drugs through the skin. Lipid-based vesicular delivery systems due to the capability of the delivery of both hydrophilic and hydrophobic drugs are becoming more popular during the recent years. Ethosomes are innovative, biocompatible, biodegradable and non-toxic form of lipid-based vesicles that efficiently enable to entrap drugs of various physicochemical properties. These are other forms of liposome which contain high amounts of ethanol in their structure that enabling ethosomes to efficiently penetrate through deeper layers of skin. Ethosomes have various compositions based on their type but are mainly composed of phospholipids, ethanol, water and the active components. Ethosomes are easily manufactured and they are superior compared to liposomes in terms of different aspects due to the presence of ethanol. The purpose of this review is to thoroughly focus on various aspects of ethosomes, including mechanism of penetration, advantages and disadvantages, characterisation and applications.

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Development and Evaluation of PLGA Nanoparticle-Loaded Organogel for the Transdermal Delivery of Risperidone.

A transdermal delivery approach may circumvent the limitations associated with the oral use of risperidone (RIS), an atypical antipsychotic drug. The current study focuses on the utilization of poloxamer (pluronic) lecithin organogel (PLO), a suitable transdermal vehicle, and a biodegradable nanoparticulate system of PLGA with the potential to deliver RIS in an efficient way. PLGA nanoparticles were fabricated using different ratios of the polymer and surfactant. The optimization was performed principally on the basis of particle size and entrapment efficiency (EE). The developed PLGA nanoparticles were spherical, sized around 109 nm with negative charge (−9.3 mv) and enhanced drug entrapment efficiency (58%). The in vitro drug release study of lyophilized nanoparticles showed a sustained pattern. Statistical analysis confirmed that there was a significant difference (p < 0.05) between the nanoparticle-loaded PLO gel and conventional drug formulations in terms of drug release and ex vivo permeation across rat skin (three-fold). The results confirm enhanced drug release and permeation through the skin at 72 h. Hence, the investigated formulation could be a better alternative to the conventional route for improving patient compliance.

Structural analysis and simulation of solid microneedle array for vaccine delivery applications.

This paper promotes a basic, quick, stature adaptable, and direct approach to selecting exceptionally suitable materials in polyethylene glycol diacrylate (PEGDA) and silicon for microneedle fabrication. Researchers and scientists are facing challenges in readily selecting biocompatible materials for microneedle fabrication. Solid porous silicon and PEGDA microneedles are particularly biocompatible and desirable for vaccine delivery by the transdermal vaccine delivery method if microneedle arrays are fabricated successfully using lithography techniques as they belong to enhanced patient concurrence and well-being. Moreover, silicon and PEGDA microneedles are the ultimate for conveying coronavirus vaccines. In this work, we applied the ANSYS workbench tool to investigate the properties of triangular pyramidal-shaped solid silicon and PEGDA microneedle array to perform structural analysis on microneedle for estimating the capability of an array of needles to enter and convey vaccines along with the skin. These outcomes demonstrated that microneedles of porous silicon are better than polymers such as PEGDA as far as mechanical strength and capacity to convey drugs. Buckling was anticipated as the fundamental method to estimate the failure of microneedles and finally, by analysis, it was clear that buckling does not impact the potential of the silicon microneedle needle array. Silicon and PEGDA microneedles are penetrated against human skin surfaces in explicit dynamics by utilizing the ANSYS tool to select the best material. Along these lines, the current strategy can work with silicon and PEGDA microneedles for useful applications. The von Mises stresses generated by applying loads on silicon and PEGDA arrays were greater than the skin resistance of 3.18 MPa and suitable for skin insertion. Silicon microneedles are sustained due to buckling but PEGDA needles fail if the loading is more than 0.1 N. Vaccination can be provided to humans if needle arrays are fabricated based on this approach and design analysis and considering parameters.

Characterization of Drug Release from Mesoporous SiO2-Based Membranes with Variable Pore Structure and Geometry.

Transdermal drug delivery systems (TDDSs) play important roles in therapy due to distinct advantages over other forms and types of drug application. While common TDDS patches mainly consist of polymeric matrices so far, inorganic carriers show numerous advantages such as high mechanical stability, possible re-use and re-loading of drugs, and a broad chemical compatibility with therapeutically relevant compounds and chemical enhancers. Mesoporous glasses can be prepared in different monolithic shapes, and offer a particularly wide range of possible pore volumes, pore diameters, and specific surface areas. Further, they show high loading capacities and favorable physical, technical, and biological properties. Here, we explored for the first time monolithic SiO2-based carriers as sustained release systems of therapeutic drugs. In an ideally stirred vessel as model system, we systematically analyzed the influence of pore diameter, pore volume, and the dimensions of glass monoliths on the loading and sustained release of different drugs, including anastrozole, xylazine, imiquimod, levetiracetam, and flunixin. Through multilinear regression, we calculated the influence of different parameters on drug loading and diffusion coefficients. The systematic variation of the mesoporous glass properties revealed pore volumes and drug loading concentrations, but not pore diameter or pore surface area as important parameters of drug loading and release kinetics. Other relevant effectors include the occurrence of lateral diffusion within the carrier and drug-specific properties such as adsorption. The structure-property relationships derived from our data will allow further fine-tuning of the systems according to their desired properties as TDDS, thus guiding towards optimal systems for their use in transdermal drug applications.