Transdermal Drug Delivery Research Articles

Design of scalable manufacturing process for the production of biodegradable polymeric microneedles for protein transdermal drug delivery

Introduction. Dissolving polymeric microneedles are attractive drug delivery system especially for vaccine delivery. Still there are a lot of obstacles in developing scalable manufacturing process of them.Aim. To develop a scalable manufacturing process for producing polymeric dissolving microneedles, which can enable keeping protein activity during manufacturing process.Materials and methods. Microneedles were produced from aqua solution of 20 % w.v. pullulan and 3 % w.v. polyvinyl alcohol by casting in hollow negative polyethylene terephthalate mold. Human serum albumin was chosen as a model protein for this investigation.Results and discussion. There were chosen the mode of mold filling and microneedle drying process, which can guarantee keeping of protein activity during manufacturing process.Conclusion. The designed technology can be easily scaled up and used for producing vaccine drug delivery systems, because it doesn’t contain any restraining processes.

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.

A Comprehensive Review of Transdermal Patch Delivery Systems

In order to overcome the difficulties associated with administering medication, especially orally, the application of medication transdermal administration technique Was developed. Transdermal patches are an a sticky a medication-infused patch and put to the skin to provide a certain quantity delivering medicine transdermally entering the blood. It promotes the recuperation process when a body part is injured. By using a membrane that is permeable to cover a supply of medicine or by liquefying small layers of drugs imbedded within the glue with body heata transdermal application allows for a managed delivery of medicine to the individual. One advantages of transdermal medicine delivery above alternative kinds of administration, like current, i.v., and i.m., or oral, is that the remedy offers a regulated The medication's release.

Biofabrication of aminated nanocellulose reinforced polyvinyl alcohol/chitosan nanofibrous scaffold for sustained release of diltiazem hydrochloride

In the modern environment conscious era, there has been a huge demand for the effective green method to fabricate biomaterials for sustained transdermal release of diltiazem hydrochloride to treat hypertension and cardiac failure. In this vein, the present study explores the amination of waste jute sourced nanocellulose (ANC) and its effect as a reinforcing filler to design electrospun polyvinyl alcohol (PVA)/chitosan based polymeric nanofibrous scaffold for drug delivery. The characterization results of FTIR (Fourier Transform Infrared Spectroscopy) confirm the successful chemical modification of nanocellulose (NCC). SEM (Scanning Electron Microscopy) results indicate the morphological modifications in ANC due to grafting. ANC enhances the mechanical properties of scaffold and sustains the release of the loaded drug to 67.89±3.39% as compared to the pure PVA/chitosan scaffold of 92.63±4.63% over a period of 72 h as shown by the results of in-vitro drug release study. Moreover, the incorporation of 0.5 % ANC improves the anti-bacterial activity against both gram-positive (97.4±4.87%, reduction in viable cells count) and gram-negative bacteria (98.5±4.93%, reduction in viable cells count). Further, the skin irritation and MTT assay authenticate the biocompatibility of the developed scaffold. The overall findings hence prove the efficacy of the engineered scaffold as a potential transdermal patch for sustained drug delivery applications.

A Review on Topical Gels as Drug Delivery System

The skin serves as a formidable barrier to drug penetration, primarily due to the stratum corneum. For successful transdermal drug delivery, the drug must overcome this barrier and reach the target site in sufficient concentrations. Drug molecules can penetrate the skin via the transcellular, intercellular, and appendageal pathways. The extent of drug permeation is influenced by factors such as the physicochemical properties of the drug, the nature of the vehicle, and the condition of the skin. Gels, being hydrophilic, can enhance drug permeation by increasing the hydration of the stratum corneum. Permeation enhancers, which reversibly alter the structure of the stratum corneum, can also improve drug permeation. Recent advancements in topical gel drug delivery include the use of nanotechnology, stimuli-responsive gels, combination therapy, natural polymers, and biodegradable materials. The delivery of biomolecules through the skin remains a challenge, and strategies such as iontophoresis, microneedles, and nanocarriers are being investigated. 3D printing technology enables the personalized fabrication of gels with precise drug dosing and customized release profiles. Despite significant advancements, challenges such as limited drug permeability, potential for skin irritation, and the need for long-term stability studies persist. Future research should focus on developing innovative strategies to overcome these challenges and optimize the performance of topical gels, involving the exploration of new drug-polymer combinations, advanced drug delivery technologies, and in silico modeling tools

Analgesic Efficiency of Transdermal Patches of Fentanyl and Diclofenac in Impacted Mandibular Third Molar Surgery - A Comparative Study

Analgesic Efficiency of Transdermal Patches of Fentanyl and Diclofenac in Impacted Mandibular Third Molar Surgery - A Comparative Study

Contribution of chemical permeation enhancers to the process of transdermal drug delivery: Adsorption, microscopic interactions, and mechanism

Transdermal drug delivery (TDD) has attracted widespread attention because of the advantage of its non-invasive nature, easy self-administration, and low side effects. The key to this pathway of drug delivery is how to overcome the barrier of the lipid matrix in the stratum corneum (SC). In this work, molecular dynamics (MD) were employed to investigate the adsorption of thyrotropin-releasing hormone (TRH) on the SC, and the effects of three different chemical permeation enhancers (ethanol (ETOH), carveol (CAV), and borneol (BOR)) on the SC were analyzed. The results showed that ETOH hardly altered the order of lipids in the SC, while CAV and BOR disrupted the morphology of the SC. The primary target of CAV was the CHOL in SC, which not only disrupted the ordered arrangement of CHOL, but also “extracted” CHOL from SC. The thickness distribution of SC became more inhomogeneous in the presence of CAV and BOR, which facilitated the penetration of drug molecules. Compared to no chemical permeation enhancers, the free energy of permeation in the presence of chemical permeation enhancers was less than 4–10 kcal mol−1, which suggested that chemical permeation enhancers were more favorable for the permeation of drugs from viewpoints of thermodynamics. All the results provided theoretical insights into the effect of chemical permeation enhancers on the transdermal permeation of drugs.

Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

Optimizing the Dosing Regimen During Rotation From Subcutaneous to Transdermal Administration of Fentanyl

ContextSubcutaneous (SC) administration of fentanyl allows for rapid dose titration to treat urgent cancer-related pain. After establishing the optimal fentanyl dose, patients typically rotate towards transdermal (TD) fentanyl patches. Continuing the SC fentanyl up to 12h after application of the patch led to elevated fentanyl concentrations and fentanyl-related toxicities. Based on these findings, and simulations using a pharmacokinetic (PK) model, SC fentanyl administration was discontinued immediately following the application of the patch. ObjectivesTo validate the fentanyl rotation schedule by assessing the PK equivalence in fentanyl exposure before and after rotation. MethodsPK samples and clinical data were prospectively collected from 12 hours prior to rotation until 12 hours after rotation in patients with cancer-related pain undergoing fentanyl rotation. ResultsBetween December 2021 and September 2023, 29 evaluable patients were enrolled in the study. The 90% confidence interval (CI) of the geometric mean ratio between the post- over pre-rotation area under the curve (AUC) fell within the prespecified 0.8–1.25 equivalence interval (90% CI 1.05–1.16). Patient-reported intensity of both nausea (P = 0.047) and transpiration (P = 0.034) decreased post-rotation. Pain intensity and other adverse events did not differ significantly pre and post-rotation. One patient needed adjustment of opioid therapy 40 hours after rotation due to fentanyl-related toxicities. ConclusionThe updated rotation scheme, implying a 1:1 dose conversion and discontinuation of SC fentanyl directly after rotation, resulted in equivalent fentanyl exposure pre and post-rotation. Moreover, the dosing regimen showed to be safe and efficacious during rotation. The new dosing regimen when rotating from SC to TD fentanyl can be effectively and safely implemented in routine palliative care.

Comprehensive investigation of niosomal red palm wax gel encapsulating ginger (Zingiber officinale Roscoe): Network pharmacology, molecular docking, In vitro studies and phase 1 clinical trials

Ginger, a Zingeberaceae family member, is notable for its anti-inflammatory properties. This study explores the pharmaceutical mechanisms of ginger and red palm wax co-extract, developing novel niosomal formulations for enhanced transdermal delivery. Evaluations included physical characteristics, drug loading, in vitro release, network pharmacology, molecular docking, and biocompatibility. The niosomal ginger with red palm wax gel (NGPW) exhibited non-Newtonian fluid properties. The optimized niosome formulation (cholesterol: Tween80: Span60 = 12.5: 20: 5 w/w) showed a high yield (93.23 %), high encapsulation efficiency (54.71 %), and small size (264.33 ± 5.84 nm), prolonging in vitro anti-inflammatory activity. Human skin irritation and biocompatibility tests on 1 % NGPW showed favorable cytotoxicity and hemocompatibility results (ISO10993). Network pharmacology identified potential targets, while molecular docking highlighted high affinities between gingerol and red palm wax compounds with TRPM8 and TRPV1 proteins, suggesting pain inhibition via serotonergic synapse pathways. NGPW presents a promising transdermal pain inhibitory drug delivery strategy.

Innovative approaches in characterizing and developing methods for lipoidal vesicular drug delivery systems

Lipoidal vesicular systems, including liposomes, ethosomes, and transferosomes, represent a significant advancement in targeted drug delivery, offering enhanced bioavailability, controlled release, and specific targeting capabilities. This review discusses the types of lipoidal vesicular systems, their methods of characterization, method development, applications, advantages, challenges, and future perspectives. These systems have shown immense potential in diverse therapeutic areas, including cancer therapy, infectious diseases, gene therapy, and transdermal drug delivery. Despite the challenges in stability, scalability, and targeting, ongoing research and technological advancements promise to expand their applications and improve therapeutic outcomes.

A novel transdermal drug delivery system: drug-loaded ROS-responsive ferrocene fibers for effective photoprotective and wound healing activity

The present study proposes an innovative transdermal drug delivery system using ferrocene-incorporated fibers to enhance the bioavailability and therapeutic efficacy of ascorbyl tetraisopalmitate. Using electrospinning technology, the authors created ferrocene polymer fibers capable of highly efficient drug encapsulation and controlled release in response to reactive oxygen species commonly found in wound sites. The approach improves upon previous methods significantly by offering higher drug loading capacities and sustained release, directly targeting diseased cells. The results confirm the potential of ferrocene fibers for localized drug delivery, potentially reducing side effects and increasing patient convenience. The method could facilitate the application of bioactive compounds in medical textiles and targeted therapy.

Fabrication and evaluation of nanoemulsionbased insulin loaded microneedles for transdermal drug delivery.

Aim: Insulin therapy require self-administration of subcutaneous injection leading to painful and inconvenient drug therapy. The aim is to fabricate nanoemulsion (NE)based insulin loaded microneedles with improved bioavailability and patient compliance.Materials & methods: Different ratios of polyvinyl alcohol and polyvinylpyrrolidone as polymers were prepared through micro-molding technique for microneedles. Characterization of were performed using scanning electron microscope, differential scanning calorimetry, Fourier-transform infrared spectroscopy and circular dichroism. Mechanical strength, hygroscopicity and pain perception of these microneedles were also evaluated. Invitro release, permeation and in vivo PK/PD study of NE-based microneedles were conducted.Results: NE-based microneedles of insulin have improved bioavailability and quick response.Conclusion: Microneedles loaded with insulin can be effectively delivered insulin transdermally to treat diabetes with increased convenience and patient compliance.

Mesoporous Silica-Based Membranes in Transdermal Drug Delivery: The Role of Drug Loss in the Skin.

Compared to other forms of drug administration, the use of Transdermal Drug Delivery Systems (TDDSs) offers significant advantages, including uniform drug release profiles that contribute to lower side effects and higher tolerability, avoidance of direct exposure to the gastrointestinal tract, better patient compliance due to their non-invasive means of application and others. Mesoporous silica membranes are of particular interest in this regard, due to their chemical stability and their tunable porous system, with adjustable pore sizes, pore volumes and surface chemistries. While this allows for fine-tuning and, thus, the development of optimized TDDSs with high loading capacities and the desired release profile of a given drug, its systemic availability also relies on skin penetration. In this paper, using a TDDS based on mesoporous silica membranes in Franz cell experiments on porcine skin, we demonstrate surprisingly substantial drug loss during skin penetration. Drug passage through porcine skin was found to be dependent on the age and pre-treatment of the skin. pH and temperature were major determinants of drug recovery rates as well, indicating drug loss in the skin by enzymatic metabolization. Regarding the TDDS, higher loading obtained by SO3H surface modification of the mesoporous silica membranes reduced drug loss. Still, high loss rates in the skin were determined for different drugs, including anastrozole, xylazine and imiquimod. We conclude that, beyond the fine-tuned drug release profiles from the mesoporous silica membrane TDDS, remarkably high drug loss in the skin is a major issue for achieving desired skin penetration and, thus, the systemic availability of drugs. This also poses critical requirements for defining an optimal TDDS based on mesoporous silica membranes.

Self‐Nanoformulating Poly(2‐oxazoline) and Poly(2‐oxazine) Copolymers Based Amorphous Solid Dispersions as Microneedle Patch: A Formulation Study

AbstractA pioneering approach in the domain of transdermal drug delivery systems (TDDS) is introduced by using microneedles (MNs) fabricated from an amorphous solid dispersion comprising only a model drug and an amphiphilic block copolymer to form a drug nanoformulation upon MN dissolution. To maximize drug loading and ensure consistent release, a minimalist formulation that achieves 40 wt% drug loading, which is a significant improvement over existing methods, is developed. Using scanning electron microscopy, the morphology of MNs is examined across a spectrum of drug loading ratios, demonstrating the consistency in structure and integrity. Mechanical testing confirms the MNs' proficiency in effective skin penetration. A comparative study on the formation of polymeric micelles underscores the innovative concept of a “nano‐in‐micro drug delivery system”. The results demonstrate that MNs manufactured from an amorphous solid dispersion of drug and amphiphilic block copolymer with ultra‐high loading enhance the availability and release dynamics of hydrophobic drugs, positioning them as a tool for enhancing TDDS. This study sets a new benchmark in the utilization of polymer‐drug nanoformulations for transdermal applications and underscores the capacity for high drug loading and the creation of adaptable drug delivery mechanisms for the studied amphiphilic block copolymer.

PAMAM dendrimers as mediators of dermal and transdermal drug delivery: a review.

Poly(amidoamine) dendrimers have been widely investigated as potential nanomaterials that can enhance the skin permeation of topically applied drugs. This article reviews the studies that have used dendrimers as penetration enhancers and examines the mechanisms by which enhancement is claimed. A wide range of studies have demonstrated that, in certain circumstances and for certain drugs, the incorporation of dendrimers into a topically applied formulation can significantly increase the amount of drug passing into and through the skin. In some cases, dendrimers offered little or no enhancement of skin permeation, suggesting that the drug-dendrimer interaction and the selection of a specific dendrimer were central to ensuring optimal enhancement of skin permeation. Significant interactions between dendrimers and other formulation components were also reported in some cases. Dendrimers offer substantial potential for enhancing drug delivery into and across the skin, putatively by mechanisms that include occlusion and changes to surface tension. However, most of these studies are conducted in vitro and limited progress has been made beyond such laboratory studies, some of which are conducted using membranes of limited relevance to humans, such as rodent skin. Thus, the outcomes and claims of such studies should be treated with caution.

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.

A gel plaster in the form of nipple cover: A comfortable and safe transdermal delivery method for mammary hyperplasia

Hyperplasia of mammary glands (HMG) is considered a precancerous condition with a risk of malignant transformation, highlighting the necessity of proactive treatment in the early stages. Transdermal drug delivery offers significant advantages such as painlessness, absence of first-pass effect, and good patient compliance. However, the unique structure of the breast requires transdermal formulations for treating mammary hyperplasia to exhibit higher levels of safety and comfort. We have formulated an ancient topical formula called ’Muxiang Bing,’ comprising traditional Chinese medicines Aucklandiae Radix (AR) and Rehmanniae Radix (RR), for the treatment of HMG. This formula has been transformed into a gel paster in the form of nipple cover for trans-nipple-areola delivery. In our investigations, we observed that the optimal formulation of the Muxiang gel plaster demonstrated enhanced permeation facilitated by AR’s effect on RR. Furthermore, pre-treatment with the Muxiang gel plaster improved mammary tissue morphology, hormone levels, oxidative stress, aberrant cell proliferation, and damage in rat models, thus preventing and ameliorating mammary hyperplasia. The Muxiang gel plaster exhibited low skin irritability in rats, and long-term use did not cause harm to their internal organs or blood cells, indicating its safety and efficacy.

Pretreatment of microneedles enhances passive transdermal administration of pilocarpine and pilocarpine-induced sweat production in humans

The development of an effective transdermal drug delivery protocol to eccrine sweat glands is important for the advancement of research on the human sweating response. We investigated whether microneedle treatment prior to the application of pilocarpine, a hydrophilic and sudorific agent that does not induce sweating due to a limited percutaneous passive diffusion by skin application alone, augments sweat production. We applied three microneedle arrays to forearm skin sites simultaneously (n = 20). Upon removal of the microneedles, 1 % pilocarpine was applied to each site for 5-, 15-, and 30-min for the assessment of sweat gland function. In parallel, pilocarpine was administered by transdermal iontophoresis (5-min) at a separate site. Sweat rate was assessed continuously via the ventilated capsule technique. Pilocarpine augmented sweat rate at the 15- and 30-min periods as compared to the application at 5-min. The sweating responses induced by the 15- and 30-min application of pilocarpine were equivalent to ∼ 80 % of that measured at the iontophoretically treated sites. Notably, we observed a correlation in sweat rate between these two transdermal drug delivery methods. Altogether, our findings show that pre-treatment of microneedle arrays can enhance transdermal delivery efficiency of pilocarpine to human eccrine sweat glands.

Efficacy of transdermal buprenorphine patch for managing withdrawal symptoms in patients with cancer physically dependent on prescription opioids.

The physical dependence on prescription opioids among cancer survivors remains an under-investigated area, with a scarcity of well-designed prospective studies. This single-arm, phase-2 clinical trial in Korea assessed the efficacy and safety of a transdermal buprenorphine patch (TBP) in managing physical dependence on prescription opioids in cancer survivors, as confirmed through the DSM-5 criteria or psychiatric consultation for opioid withdrawal. This study involved a 4-phase treatment protocol of screening, induction/stabilization, discontinuation, and monitoring. The primary outcome was the rate of successful opioid discontinuation, as measured by a negative urine-drug screening at 8 weeks. Key secondary outcomes included the resumption of prescribed opioids, changes in both the Clinical Opioid Withdrawal Scale (COWS) and morphine equivalent daily dose (MEDD), and assessments related to the psychological and physiological aspects of dependence and safety. Thirty-one participants were enrolled. In the intention-to-treat population, the success rate of opioid discontinuation was 58%, with only 2 participants experiencing a resumption of prescribed opioids. Significant reductions were observed in MEDD, which decreased from 98 to 26mg/day (P < .001), and COWS scores, which decreased from 5.5 to 2.8 (P < .001). Desire to use opioids reduced from 7.0 to 3.0 on a 10-point numeric rating scale (P < .001). Toxicities related to TBP were mild and manageable, without severe precipitated withdrawal symptoms. TBP may be considered as an alternative therapeutic option in cancer survivors physically dependent on prescription opioids, especially where sublingual formulations are unavailable.