Formulation and Evaluation of Oleanolic Acid Loaded Transdermal Patches

Compared with traditional oral and injection administration, the transdermal administration of traditional Chinese medicine has distinctive characteristics and advantages, which can avoid the “first pass effect” of the liver and the destruction of the gastrointestinal tract, maintain a stable blood concentration, and prolong drug action time. However, the basic theory and technology research in transdermal drug delivery are relatively limited at present, especially regarding research on new carriers of transdermal drug delivery and pharmacokinetic studies of the skin, which has become a bottleneck of transdermal drug delivery development. Triptolide is one of the main active components of Tripterygium wilfordii, which displays activities against mouse models of polycystic kidney disease and pancreatic cancer but its physical properties and severe toxicity limit its therapeutic potential. Due to the previously mentioned advantages of transdermal administration, in this study, we performed a detail analysis of the pharmacokinetics of a new transdermal triptolide delivery system. Triptolide nanoemulsion gels were prepared and served as new delivery systems, and the ex vivo characteristics were described. The metabolic characteristics of the different triptolide transdermal drug delivery formulations were investigated via skin–blood synchronous microdialysis combined with LC/MS. A multiscale modeling framework, molecular dynamics and finite element modeling were adopted to simulate the transport process of triptolide in the skin and to explore the pharmacokinetics and mathematical patterns. This study shows that the three−layer model can be used for transdermal drug delivery system drug diffusion research. Therefore, it is profitable for transdermal drug delivery system design and the optimization of the dosage form. Based on the drug concentration of the in vivo microdialysis measurement technology, the diffusion coefficient of drugs in the skin can be more accurately measured, and the numerical results can be verified. Therefore, the microdialysis technique combined with mathematical modeling provides a very good platform for the further study of transdermal delivery systems. This research will provide a new technology and method for the study of the pharmacokinetics of traditional Chinese medicine transdermal drug delivery. It has important theoretical and practical significance in clarifying the metabolic transformation of percutaneous drug absorption and screening for appropriate drugs and dosage forms of transdermal drug delivery.

BackgroundHepatic first-pass metabolism and poor therapeutic efficiency at targeted region are the endemic problems of new drug molecules. Thus, comprehensive research has been carried out on the novel vesicular drug delivery systems in nanotechnology from the last few years. These nano-carrier systems have developed to overcome the limitations that are associated with hepatic first-pass metabolism in conventional oral dosage forms and the barrier properties of the lipid bilayer in stratum corneum via transdermal drug delivery for improving the bioavailability of various drugs.Main bodyIn recent years, several targeted vesicular drug delivery carriers are developing like liposomes, niosomes, proniosomes, transferosomes, ethosomes, and electrosomes. Among them, niosomes and proniosomes are to be better carriers to increase therapeutic efficiency and bioavailability by reducing the side effects and acting as a promising approach for transdermal drug delivery. Both are non-ionic surfactant-based vesicles and are amphiphilic. This article concisely reviews the possible mechanisms within niosomes and pronisomes to enhance transdermal drug delivery, types, composition, preparation techniques, characterizations, and its applications.ConclusionAs per the researches done in the formulation of various nano-carrier systems through transdermal approach for the enhancement of bioavailability, it can be stated that the hepatic first pass metabolism can be reduced as well as therapeutic efficiency can be increased by many folds compared to their oral marketed formulations.

The concept of a carbon nanotube microneedle array is explored in this thesis from multiple perspectives including microneedle fabrication, physical aspects of transdermal delivery, and in vivo transdermal drug delivery experiments. Starting with standard techniques in carbon nanotube (CNT) fabrication, including catalyst patterning and chemical vapor deposition, vertically-aligned carbon nanotubes are utilized as a scaffold to define the shape of the hollow microneedle. Passive, scalable techniques based on capillary action and unique photolithographic methods are utilized to produce a CNT-polymer composite microneedle. Specific examples of CNT-polyimide and CNT-epoxy microneedles are investigated. Further analysis of the transport properties of polymer resins reveals general requirements for applying arbitrary polymers to the fabrication process. The bottom-up fabrication approach embodied by vertically-aligned carbon nanotubes allows for more direct construction of complex high-aspect ratio features than standard top-down fabrication approaches, making microneedles an ideal application for CNTs. However, current vertically-aligned CNT fabrication techniques only allow for the production of extruded geometries with a constant cross-sectional area, such as cylinders. To rectify this limitation, isotropic oxygen etching is introduced as a novel fabrication technique to create true 3D CNT geometry. Oxygen etching is utilized to create a conical geometry from a cylindrical CNT structure as well as create complex shape transformations in other CNT geometries. CNT-polymer composite microneedles are anchored onto a common polymer base less than 50 µm thick, which allows for the microneedles to be incorporated into multiple drug delivery platforms, including modified hypodermic syringes and silicone skin patches. Cylindrical microneedles are fabricated with 100 µm outer diameter and height of 200-250 µm with a central cavity, or lumen, diameter of 30 µm to facilitate liquid drug flow. In vitro delivery experiments in swine skin demonstrate the ability of the microneedles to successfully penetrate the skin and deliver aqueous solutions. An in vivo study was performed to assess the ability of the CNT-polymer microneedles to deliver drugs transdermally. CNT-polymer microneedles are attached to a hand actuated silicone skin patch that holds a liquid reservoir of drugs. Fentanyl, a potent analgesic, was administered to New Zealand White Rabbits through 3 routes of delivery: topical patch, CNT-polymer microneedles, and subcutaneous hypodermic injection. Results demonstrate that the CNT-polymer microneedles have a similar onset of action as the topical patch. CNT-polymer microneedles were also vetted as a painless delivery approach compared to hypodermic injection. Comparative analysis with contemporary microneedle designs demonstrates that the delivery achieved through CNT-polymer microneedles is akin to current hollow microneedle architectures. The inherent advantage of applying a bottom-up fabrication approach alongside similar delivery performance to contemporary microneedle designs demonstrates that the CNT-polymer composite microneedle is a viable architecture in the emerging field of painless transdermal delivery.

Transdermal drug delivery carried out a promising carrier in the transport of drugs to get direct access across the skin deep into the systemic circulation. Transdermal drug delivery have a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. It gives attraction to many researchers due to various biomedical advantages. Due to the limitation of oral drug delivery system and the pain related with the use of needles in case of injections, drug delivery research has tremendously oriented towards the transdermal route. Delivery of drugs via transdermal route has proved to be the convenient route for various clinical implications. The objective of the present review is to focus on newly innovations in transdermal drug delivery systems which can create a platform for the research and development of pharmaceutical drug dosage form for efficient transdermal delivery. In this review, we tell about different types of microneedles are described and their methods of fabrication. Microneedles can be fabricated in different forms like hollow, solid, and dissolving. There are also hydrogel-forming microneedles. In relation to hydrogel-forming microneedles, special attention, these are innovative microneedles which does not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Regulatory authorities approved several microneedles for clinical uses are also examined. The last part of this review discusses concerns and challenges regarding microneedles use.

With the administration of lidocaine,the discomfort caused by injection is counterproductive to the effect of pain relief.Rapid local transdermal anesthetic is desirable to avoid the pain caused by invasive procedures.Transdermal lidocaine products such as EMLA(R)cream and Lidoderm,Lidosite,SonoPrepTM,and SyneraTM are commercially available.The physical methods are used in these products.They could shorten the onset time and relief the pain at certain extent.This review summarizes mechanisms and applications of rapid transdermal delivery of local anesthetic by physical methods. Key words: Transdermal drug delivery system ; Local anesthetic:Lidocaine ; Iontophoresis ; Sonophoresis ;

Transdermal Drug Delivery Systems (TDDS) represent a significant advancement in therapeutic administration by allowing drugs to bypass the gastrointestinal system and first-pass hepatic metabolism, enhancing patient compliance, and enabling sustained drug release. However, traditional TDDS face limitations, including resistance from the skin's natural barrier and limited efficacy in delivering large or hydrophilic molecules. Microneedle (MN) technology offers a breakthrough solution, using minimally invasive micron-sized needles to bypass the stratum corneum, facilitating efficient drug delivery without significant pain or discomfort. This review explores the evolution and recent advancements in microneedle technology, highlighting its role in overcoming the limitations of conventional TDDS. Microneedles have been shown to enhance drug bioavailability, reduce side effects, and expand the range of deliverable therapeutics, including vaccines, insulin, and genetic materials. The development of bioinspired 4D microneedles further extends their application to diagnostics and cosmetic treatments, positioning MNs as a versatile tool in modern medicine. Key sections of the review focus on the types of microneedles—solid, coated, dissolving, hollow, and hydrogel-forming—and their respective fabrication methods, materials, and drug delivery mechanisms. The review also discusses the challenges related to scaling up production, ensuring consistent quality, and regulatory hurdles in achieving clinical approval. Future directions include the integration of microneedles with nanotechnology, combination therapies, and sustainable design, particularly in developing regions where biodegradable materials may address environmental and disposal concerns. The potential for microneedle technology to revolutionize transdermal drug delivery, diagnostics, and therapeutic monitoring is significant, with ongoing research paving the way for multifunctional applications that can reshape patient care and treatment modalities.

Transdermal delivery over the past decade has become the field of interest for drug delivery due to its various advantages such as no first-pass metabolism, increased drug bioavailability, and easy administration. Different vesicle systems like ethosomes, liposomes, niosomes, and transferosomes along with particle systems like lipid nanoparticles, polymeric nanoparticles, carbon nanotubes, and fullerenes have been developed. These vesicles and particle systems have been developed using various easy and effective methods like cold injection method, rotary film evaporation, thin film hydration, high shear homogenization, solvent extraction method, and many more. These drug delivery systems are a very effective and feasible option for transdermal drug delivery and further developments can be made to increase their use. This article explains in detail the preparation methods and applications for these drug delivery systems.

Transdermal drug delivery systems of indapamide have been formulated by using solvent casting method. Monolithic systems were prepared by using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC) polymers by incorporating glycerine and dibutyl phthalate as plasticizers, respectively. All the patches were uniform with respect to physicochemical and scanning electron microscopy (SEM) evaluation. Th e in vitro drug release studies indicated that HPMC containing fi lms have shown better release than that of EC containing fi lms without any permeation enhancer. A total of eight monolithic systems were prepared by using a drug polymer ratio of 1:4 and incorporated diff erent vegetable oils as permeation enhancers in diff erent concentrations. Th e prepared systems released the drug in the following order: F3 > F4 > F7 > F5 > F8 > F6 > F1 > F2. Th e various permeation parameters such as fl ux, permeability coeffi cient, enhancement ratio and diff usion rate constants were determined for all the formulations. Th e maximum fl ux of 9.08 × 102 mg/ cm2 h was observed with HPMC monolithic system containing 30% w/w olive oil. A signifi cant improvement of fl ux was observed in the following order: olive oil > linseed oil > sunfl ower oil > cottonseed oil > coconut oil > castor oil. Further improvement of fl ux was observed, when 30% w/w olive oil was applied directly onto the skin prior to the studies. Th e in vitro release studies revealed that the release was sustained up to 24 h and it follows zero-order kinetics. All the fi lms were found to be stable at 37°C and 45°C with respect to their physical parameters and drug content. Key words: EC, HPMC, linseed oil, olive oil, permeation enhancers, sunfl ower oil, transdermal

Aim: The main objective of the current investigation was to develop and evaluate the microemulsion based transdermal gel for isradipine, poorly water soluble and low bioavailable drug. Materials and Methods: Saturation solubility studies of the drug were conducted in various solvents and oils. Oleic acid, Tween 80 and Transcutol P were selected as oil phase, surfactant and cosurfactants, respectively, as the drug was having highest solubility in these solvents. The pseudo-ternary phase diagrams were constructed using water titration method by varying surfactant to the co-surfactant (Smix) ratio as 1:1, 1:2, 1:3, 2:1, and 3:1. Microemulsion formulations ratios were selected from the constructed pseudo-ternary phase diagrams. Results and Discussion: Microemulsion prepared with oil to Smix ratio of 1:9 (F9) was found to be stable with the globule size of 50.4 ± 3.54, and has more % of drug diffusion of 88.4 ± 1.9% within 6 h and has been selected for the preparation of microemulsion based gel (MEBG) using carbopol 934 as gelling agent. The prepared gel has shown 96.74 ± 2.8% drug releases in 8 h which was higher than control gel. In vivo pharmacokinetic studies conducted in rabbits revealed that the bioavailability of MEBG was increased 5.4 times compared to oral suspension. Conclusion: This demonstrates avoidance of first pass metabolism and oral degradation and indicates the effective management of plasma profile of isradipine when it is administered as MEBG through transdermal route.

Transdermal drug administration is a method of administering medication through the skin that is non-intrusive, offering an innovative and hopeful alternative to traditional oral and injection methods. Advancements in skin penetration technology have enabled the transdermal administration of various anticancer medications, including lipophilic or hydrophilic compounds, offering a new approach to cancer treatment. Research has explored innovative platforms for cancer treatment, such as erythrocytes, vesicles, and exosomes. The most efficient approach is the transdermal drug delivery system. This review investigates various transdermal delivery techniques beyond the pharmaceutical sector in relation to cancer treatment. Techniques include iontophoresis, electroporation, sonophoresis, microneedles, transdermal patches, or vesicular systems like liposomes, niosomes, transferosomes, ethosomes, transethosomes, nanoparticles, carbon nanotubes, quantum dots, as well as nanofibers, which have been used to improve transdermal distribution and their use in cancer treatment. Additionally, a roadmap is presented to guide development strategies, highlighting the multiple applications of transdermal drug administration systems for cancer therapy.

Transdermal drug delivery has been applied as a safe and efficient delivery system since 1981. TDDS recently accessible to dominate the problems of drug delivery over the oral route. Transdermal film is a therapeutic adhesive film which is used on the skin to deliver a particular amount of drug over the skin as well as systemic circulation. Development of an effective TDDS is dependent to physicochemical properties of drug, excipients and manufacturing possesses. For achieving systemic effect, many new carriers have been established such as Liposomes, Niosomes, Transfersomes, Cubosome and Ethosomes, an enormous request for pharmaceutical and cosmeceutical industry, it has capability to controlled the release of active ingredient, enhance consistency and bioavailability. In this review, we have summarized many physicochemical approaches for transdermal drug delivery system, containing classification of TDDS, enhancing the permeability of drug over the skin, marketed formulation and application of transdermal drug delivery system.

Transdermal drug delivery system through polymeric microneedle: A recent update

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation.

Background: Transdermal drug delivery by means of polymeric microneedles (PMNs) offers the advantage of overcoming some of the disadvantages of oral medication, such as first-pass metabolism, through painless, controlled drug release. Lawsone, isolated from Lawsonia inermis, exhibits reported antioxidant, anti-inflammatory, antimicrobial, and antitumor properties, suggesting its use as a promising candidate for topical application. Objectives: Fabrication and optimization of hyaluronic acid-carboxymethylcellulose (HA-CMC) PMNs loaded with lawsone with respect to enhancing transdermal delivery and understanding release and physicochemical characteristics. Methods: Hyaluronic acid-carboxymethylcellulose-lawsone patches were prepared by micromolding. The Box-Behnken design approach was then utilized to identify the appropriate concentrations of carboxymethylcellulose (CMC) (0.15% to 0.35% w/w), hyaluronic acid (HA) (0.01% to 0.09% w/w), and polyethylene glycol 400 (PEG 400) (0.5% to 1.5% w/w), all of which are dependent on drug release after 90 minutes. Morphological examination was conducted using light and scanning electron microscopy (SEM). The levels of transepidermal water loss (TEWL), drug content, insertion rate, mechanical properties, and release of the patches were assessed. Results: The optimized formulation showed a cumulative release of 59.63% in 90 min, following Higuchi release kinetics. Polymeric microneedles showed uniform morphology, a failure force of 0.48 N, full penetration of 375 μm, and reversible changes in TEWL. Conclusions: Hyaluronic acid-carboxymethylcellulose PMNs offer a promising formulation strategy for the transdermal delivery of lawsone. This preliminary study establishes a biocompatible platform with potential for future development towards anti-inflammatory and antitumor therapies, pending further in vivo validation.

Melanoma is a highly aggressive form of skin cancer with limited therapeutic options. Chemo-photothermal combination therapy has demonstrated potential for effectively treating melanoma, and transdermal administration is considered the optimal route for treating skin diseases due to its ability to bypass first-pass metabolism and enhance drug concentration. However, the stratum corneum presents a formidable challenge as a significant barrier to drug penetration in transdermal drug delivery. Lipid-nanocarriers, particularly cubosomes, have been demonstrated to possess significant potential in augmenting drug permeation across the stratum corneum. Herein, cubosomes co-loaded with doxorubicin (DOX, a chemotherapeutic drug) and indocyanine green (ICG, a photothermal agent) (DOX-ICG-cubo) transdermal drug delivery system was developed to enhance the therapeutic efficiency of melanoma by improving drug permeation. The DOX-ICG-cubo showed high encapsulation efficiency of both DOX and ICG, and exhibited good stability under physiological conditions. In addition, the unique cubic structure of the DOX-ICG-cubo was confirmed through transmission electron microscopy (TEM) images, polarizing microscopy, and small angle X-ray scattering (SAXS). The DOX-ICG-cubo presented high photothermal conversion efficiency, as well as pH and thermo-responsive DOX release. Notably, the DOX-ICG-cubo exhibited enhanced drug permeation efficiency, good biocompatibility, and improved in vivo anti-melanoma efficacy through the synergistic effects of chemo-photothermal therapy. In conclusion, DOX-ICG-cubo presented a promising strategy for melanoma treatment.