Transdermal Research Articles

Transdermal Drug Delivery System: An Emphasis on Transdermal Patches

Transdermal drug delivery system was presented to overcome the difficulties of drug delivery especially oral route. A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. It promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of delivery system such as oral, topical, i.v., i.m., etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. The main disadvantage to transdermal delivery systems stems from the fact that the skin is a very effective barrier, as a result, only medications whose molecules are small can easily penetrate the skin, so it can be delivered by this method. This review article describes the overall introduction of transdermal patches including type of transdermal patches, method of preparation of transdermal patches and factor affecting etc.

P-511 Prolonging the time of vaginal progesterone supplementation does not improve pregnancy outcomes after day 6 blastocyst transfer

Abstract Study question Does the administration of vaginal progesterone for 6 days improve pregnancy outcomes when transferring day 6 blastocysts, as opposed to 5 days of progesterone treatment? Summary answer We observed similar pregnancy outcomes after 5 and 6 days of vaginal progesterone supplementation following day 6 blastocyst transfer in oocyte recipient cycles. What is known already Progesterone administration promotes the final phase of endometrial preparation for embryo transfer. However, the optimal duration of progesterone transformation still remains unknown. The implantation potential of blastocysts formed at different timepoints is also contentious, as blastocysts on day 6 have been linked to poorer clinical outcomes compared to their day 5 counterparts. It is unclear whether this effect stems from an intrinsic impaired implantation capacity of slow-developing blastocysts, or a displaced window of implantation (WOI). It has been hypothesized that 6 days of progesterone administration may improve clinical outcomes after frozen day 6 blastocyst transfer. Study design, size, duration Retrospective cohort study of oocyte recipients undergoing single day 6 blastocyst transfer, between January 2020 and December 2022. This study compared two groups: day 6 blastocysts transferred after 5 days of progesterone administration (n = 284) and day 6 embryo transfers performed after 6 days of progesterone administration (n = 69). Participants/materials, setting, methods Our study included oocyte recipients who underwent a single embryo transfer of a day 6 blastocyst and hormonal replacement treatment for endometrial preparation with vaginal external progesterone administration (800mg/24h) for either 5 or 6 days prior to embryo transfer. Outcomes were analyzed using unpaired t-test or Fisher’s test and logistic regression. Multivariate models were adjusted for oral or transdermal estrogen administration and endometrial thickness on the day of embryo transfer. P-values <0.05 were considered significant. Main results and the role of chance Mean maternal age was 43.5 years, while patients had a mean BMI of 25.1. Mean days of estrogen therapy prior to embryo transfer were 22.4, with 75.3% of patients using transdermal estrogen administration, and achieving a mean endometrial thickness of 9.6 mm on the day of transfer. Mean progesterone levels on the day of transfer were 11.9 ng/ml. Thirty-seven percent of the day 6 blastocysts were of high quality. None of the demographic or cycle characteristics were significantly different between the study groups. When considering outcomes of day 6 blastocyst transfers, we found no significant differences in biochemical (26.33% vs 20.13%, p = 0.343), clinical (22.06% vs 17.46%, p = 0.49) and ongoing (14.64% vs 9.52%, p = 0.41) pregnancy rates between 5 and 6 days of progesterone administration. Our adjusted analysis further corroborated these results. Limitations, reasons for caution The retrospective nature of the study and low number of transfers performed after 6 days of progesterone treatment warrant careful interpretation. This study only evaluated endometrial preparation by vaginal progesterone administration in oocyte recipients and cannot be extrapolated to other routes of progesterone administration or other patient populations. Wider implications of the findings Poorer reproductive outcomes associated with the transfer of day 6 blastocysts appear to be related to a reduced implantation capacity of slow-developing embryos rather than a displaced WOI due to rising progesterone. WOI appears wider than assumed, as prolonged progesterone transformation times had no effect on pregnancy outcomes. Trial registration number Not applicable

Polymeric Microarray Patches for Enhanced Transdermal Delivery of the Poorly Soluble Drug Olanzapine.

Transdermal drug delivery is an alternative route of administration that offers avoidance of the associated drawbacks of orally and parenterally administered hydrophobics. However, owing to the extremely specific set of physicochemical characteristics required for passive transdermal drug permeation, the development of marketed transdermal products containing poorly soluble drugs has been severely limited. Microarray patches (MAPs) are a type of transdermal patch that differ from the traditional patch design due to the presence of tiny, micron-sized needles that permit enhanced drug permeation on their application surface. To date, MAPs have predominantly been used to deliver hydrophilic compounds. However, this work challenges this trend and focuses on the use of MAPs, in combination with commonly utilized solubility-enhancing techniques, to deliver the hydrophobic drug olanzapine (OLP) across the skin. Specifically, cyclodextrin (CD) complexation and particle size reduction were employed in tandem with hydrogel-forming and dissolving MAPs, respectively. In vivo experimentation using a female Sprague-Dawley rat model confirmed the successful delivery of OLP from hydrogel-forming MAPs (Cmax = 611.13 ± 153.34 ng/mL, Tmax = 2 h) and dissolving MAPs (Cmax = 690.56 ± 161.33 ng/mL, Tmax = 2 h) in a manner similar to that of oral therapy in terms of the rate and extent of drug absorption, as well as overall drug exposure and bioavailability. This work is the first reported use of polymeric MAPs in combination with the solubility-enhancing techniques of CD complexation and particle size reduction to successfully deliver the poorly soluble drug OLP via the transdermal route. Accordingly, this paper provides significant evidence to support an expansion of the library of molecules amenable to MAP-mediated drug delivery to include those that exhibit poor aqueous solubility.

Transdermal Flunixin Meglumine as a Pain Relief in Donkeys: A Pharmacokinetics Pilot Study.

Recent approval of transdermal flunixin meglumine (FM) (Banamine®) in cattle has opened the door for the drug's potential application in other species. Transdermal FM could provide a safe and effective form of pain relief in donkeys. In order to evaluate the pharmacokinetics and effects of FM on anti-inflammatory biomarkers in donkeys, a three-way crossover study design was employed. In total, 6 healthy donkeys were administered transdermal (TD) FM at a dosage of 3.3 mg/kg, and oral (PO) and intravenous (IV) doses of 1.1 mg/kg body weight. Blood samples were collected over 96 h to determine the concentration of flunixin, 5OH flunixin, and eicosanoids (TXB2 and PGF2 alpha) using LC-MS/MS. The results indicated that both flunixin and 5OH flunixin were detectable in blood samples collected during TD. The elimination of the drug was slower following the TD route compared to PO and IV. TD administration significantly decreased TXB2 levels in non-stimulated serum from 1 to 96 h post-administration, while IV and PO resulted in TXB2 reduction for 1 to 8 h. A significant reduction in PGF2 alpha was observed in PO and IV 1 h after administration, while TD resulted in a gradual decline from 4 to 72 h. The study concluded that the off-label use of transdermal FM at 3.3 mg/kg could be effective in controlling inflammation in donkeys.

Optimization of Potential Nanoemulgels for Boosting Transdermal Glimepiride Delivery and Upgrading Its Anti-Diabetic Activity.

Transdermal drug delivery has been widely adopted as a plausible alternative to the oral route of administration, especially for drugs with poor systemic bioavailability. The objective of this study was to design and validate a nanoemulsion (NE) system for transdermal administration of the oral hypoglycemic drug glimepiride (GM). The NEs were prepared using peppermint/bergamot oils as the oil phase and tween 80/transcutol P as the surfactant/co-surfactant mixture (Smix). The formulations were characterized using various parameters such as globule size, zeta potential, surface morphology, in vitro drug release, drug-excipient compatibility studies, and thermodynamic stability. The optimized NE formulation was then incorporated into different gel bases and examined for gel strength, pH, viscosity, and spreadability. The selected drug-loaded nanoemulgel formulation was then screened for ex vivo permeation, skin irritation, and in vivo pharmacokinetics. Characterization studies revealed the spherical shape of NE droplets with an average size of ~80 nm and a zeta potential of -11.8 mV, which indicated good electrokinetic stability of NE. In vitro release studies revealed enhanced drug release from the NE formulation compared to the plain drug. GM-loaded nanoemulgel showed a 7-fold increment in drug transdermal flux compared to plain drug gel. In addition, the GM-loaded nanoemulgel formulation did not elicit any signs of inflammation and/or irritation on the applied skin, suggesting its safety. Most importantly, the in vivo pharmacokinetic study emphasized the potential of nanoemulgel formulation to potentiate the systemic bioavailability of GM, as manifested by a 10-fold rise in the relative bioavailability compared to control gel. Collectively, transdermal NE-based GM gel might represent a promising alternative to oral therapy in the management of diabetes.

In vitro percutaneous penetration test overview.

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug-in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades-results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

Co-Amorphous Versus Deep Eutectic Solvents Formulations for Transdermal Administration.

Transdermal administration can be considered as an interesting route to overcome the side-effects inherent to oral intake. Designing topical formulations with maximum drug efficiency requires the optimization of the permeation and the stability of the drug. The present study focuses on the physical stability of amorphous drugs within the formulation. Ibuprofen is commonly used in topical formulations and then was selected as a model drug. Additionally, its low Tg allows easy, unexpected recrystallization at room temperature with negative consequence on skin penetration. In this study, the physical stability of amorphous ibuprofen was investigated in two types of formulations: (i) in terpenes-based deep eutectic solvents (DES) and (ii) in arginine-based co-amorphous blends. The phase diagram of ibuprofen:L-menthol was mainly analyzed by low-frequency Raman spectroscopy, leading to the evidence of ibuprofen recrystallization in a wide range of ibuprofen concentration. By contrast, it was shown that amorphous ibuprofen is stabilized when dissolved in thymol:menthol DES. Forming co-amorphous arginine-ibuprofen blends by melting is another route for stabilizing amorphous ibuprofen, while recrystallization was detected in the same co-amorphous mixtures obtained by cryo-milling. The mechanism of stabilization is discussed from determining Tg and analyzing H-bonding interactions by Raman investigations in the C=O and O-H stretching regions. It was found that recrystallization of ibuprofen was inhibited by the inability to form dimers inherent to the preferential formation of heteromolecular H-bonding, regardless of the glass transition temperatures of the various mixtures. This result should be important for predicting ibuprofen stability within other types of topical formulations.

Effect of microneedle roller on promoting transdermal absorption of crossbow-medicine liquid via transdermal administration of Traditional Chinese Medicine and the safety of crossbow-medicine needle therapy: An experimental study

Ethnopharmacology relevanceCrossbow-medicine needle therapy (microneedle roller combined with crossbow-medicine) is one of the external treatment methods of Miao Medicine in China. It is a way of combining acupuncture with Chinese herbal medicine, which is widely used in clinical treatment of pain. Aim of the studyTo observe the transdermal absorption promoting effect of microneedle roller via transdermal administration, and to discuss the transdermal absorption characteristics and the safety of crossbow-medicine needle therapy. MethodsBased on the determination of the content of the main components of crossbow-medicine prescription in our previous research, the present experiment was conducted in-vitro and in-vivo experiments and the skin of rats was used as the penetration barrier. For in-vitro experiment, the modified Franz diffusion cell method was used to determine the transdermal absorption rate and 24h cumulative transdermal absorption amount of the active ingredients of crossbow-medicine liquid. For in-vivo experiment, tissue homogenization was applied to compare the skin retention amount and plasma concentration of crossbow-medicine liquid absorbed at different time points via the aforementioned two modes of administration. Furthermore, the effect of crossbow-medicine needle on the morphological structure of rat skin stratum corneum was detected by hematoxylin-eosin (HE) staining. The safety of crossbow-medicine needle therapy was evaluated according to the scoring criteria of the skin irritation test. Results1. In-vitro experiment: In the microneedle-roller group and crossbow-medicine liquid application group, the effect of transdermal delivery was identified in all the four ingredients of anabasine, chlorogenic acid, mesaconitine and hypaconitine. The 24h cumulative transdermal absorption amount and transdermal absorption rate of each ingredient in microneedle-roller group were significantly higher than those in crossbow-medicine liquid application group (all P < 0.05). 2. In-vivo experiment: Both microneedle-roller and crossbow-medicine liquid application could promote the transdermal absorption of the active ingredients of the drug in the skin and retain in the skin structure. After 8h of administration, the total retention amount of anabasine, chlorogenic acid, mesaconitine and hypaconitine in the skin of rats in the former group was significantly higher than that in the latter group (all P < 0.05). 3. HE staining: In the blank group, the stratum corneum showed an evenly zonal distribution on the active epidermis, and had a close connection with the epidermis, without exfoliation or cell dissociation of the stratum corneum. The crossbow-medicine liquid group had a relatively complete stratum corneum, with a small proportion of exfoliation or cell dissociation, loose arrangement and loose connection with the epidermis. In the microneedle-roller group, the skin had pore channels, and the stratum corneum was loose and exfoliated, which showed zonal distribution in a free state and a high degree of separation. The crossbow-medicine needle group had loose the stratum corneum, broken and exfoliated, which was separated from the active epidermis and showed zonal distribution in a free state. 4.Safety: No obvious erythema, edema and skin protuberance were observed in the skin of rats treated with microneedle roller, crossbow-medicine liquid and crossbow-medicine needle. Additionally, the skin irritative response score was 0. ConclusionMicroneedle roller can promote the transdermal absorption of crossbow-medicine liquid, and crossbow-medicine needle therapy has good safety.

Brain targeting of zolmitriptan via transdermal terpesomes: statistical optimization and in vivo biodistribution study by 99mTc radiolabeling technique

Zolmitriptan (ZT) is a potent second generation triptan, commonly administered to alleviate migraine attacks. ZT suffers various limitations; massive hepatic first pass metabolism, P-gp efflux transporters susceptibility, and limited (≈40%) oral bioavailability. Transdermal route of administration could be explored to enhance its bioavailability. A 23.31 full factorial design was constructed to developed twenty-four ZT loaded terpesomes via thin film hydration technique. The influence of drug: phosphatidylcholine ratio, terpene type, terpene concentration and sodium deoxycholate concentration on the characterization of the developed ZT-loaded terpesomes was assessed. Particle size (PS), zeta potential (ZP), ZT entrapment efficiency (EE%), drug loading (DL%) and drug released percentages after 6 h (Q6h) were the selected dependent variables. Further morphological, crystallinity, and in-vivo histopathological studies were conducted for the optimum terpesomes (T6). 99mTc-ZT and 99mTc-ZT-T6 gel were radio-formulated for in-vivo biodistribution studies in mice following transdermal application of 99mTc-ZT-T6 gel, relative to 99mTc-ZT oral solution. T6 terpesomes [comprising ZT and phosphatidylcholine (1:15), cineole (1% w/v) and sodium deoxycholate (0.1% w/v)] were optimum with respect to spherical PS (290.2 nm), ZP (-48.9 mV), EE% (83%), DL% (3.9%) and Q6h (92.2%) with desirability value of 0.85. The safety of the developed T6 terpesomes was verified by the in-vivo histopathological studies. 99mTc-ZT-T6 gel showed maximum brain concentration (5 ± 0.1%ID/ g) with highest brain to blood ratio of 1.92 ± 0.1 at 4 h post transdermal application. Significant improvement of ZT brain relative bioavailability (529%) and high brain targeting efficiency (315%) were revealed with 99mTc-ZT-T6 gel, which confirmed successful ZT delivery to the brain. Terpesomes could be safe, successful systems capable of improving ZT bioavailability with high brain targeting efficiency.Graphical

Preparation, characterization, and pharmacokinetic assessment of metformin HCl loaded transfersomes co-equipped with permeation enhancer to improve drug bioavailability via transdermal route

Preparation, characterization, and pharmacokinetic assessment of metformin HCl loaded transfersomes co-equipped with permeation enhancer to improve drug bioavailability via transdermal route

Therapeutic potential of microneedles based delivery systems for the management of atopic dermatitis

Atopic Dermatitis (AD) is a diverse skin condition with a range of shapes, localization, and progression of the disease. Even though its pathophysiology is multifaceted and not entirely comprehended, it appears to be the consequence of a mix of environmental and genetic variables that cause skin barrier disruption, dermal and systemic immunological imbalance, a significant hereditary influence, and skin microbiome dysbiosis. AD is now a major global health concern owing to its rising incidence over the past few decades. For topical distribution of numerous medications, nano-based formulations have been widely investigated during the past decade. Nanoparticles have been used for transdermal applications but their distribution over stratum corneum(SC), the primary skin barrier, is still difficult. Recent advancements in microneedle array (MN) technology, particularly the use of nanoparticles (NPs) that transport both lipophilic and hydrophilic medicinal drugs, have shown promise in the administration of a variety of formulations. Microneedles (MNs) are the devices that physically penetrate the stratum corneum to effectively traverse the epidermal barrier producing minor invasion and improving patient medication adherence. These are the microscale methods to significantly widen range of medications available for transdermal administration. The current work focuses on the developments associated with the use of microneedles and nanoparticles for efficient penetration of numerous drugs. The review also focuses on the significance of microneedles in treating atopic dermatitis, and various microneedles under preclinical and clinical studies have been summarised along with regulatory challenges and toxicity issues.

MICRONEEDLES ASSISTED ENHANCEMENT OF TRANSDERMAL DELIVERY OF CURCUMIN THROUGH ORGANOGEL FORMULATION

Curcumin is a natural compound found in turmeric and has been shown to have anti-inflammatory and antioxidant properties. Topical delivery of curcumin through an organic emulsion-based gel can effectively target inflammation at specific sites on the body. The current study aims to formulate Pluronic based organogel of curcumin, whose absorption is further assisted by microneedles technology. Nine organogel formulations were prepared and optimized by 32 full factorization model to fix the ratio of lecithin[A] and Pluronic[B] concentration in order to get optimum drug release after 2 hours (Q2) and maximum release of drug after 8 hours (Q8). The in-vitro study through the Franz diffusion cell indicated a significant impact of Pluronic F-127 concentration on the release of drug. As increased concentration of Pluronic increased the viscosity of formulations which ultimately retarded the release of drug. Based on Design of Experiment (DoE) study, optimized batch containing 6.5% lecithin and 20.6% Pluronic was further studied for microneedle assisted ex-vivo skin permeation through rat skin. Permeation without microneedle poration was around 70.26% after 8 hours, which was significantly increased (around 25%) after microneedle treatment of the skin. The results indicated promising application microneedle assisted skin permeation as a non-invasive and controlled delivery of curcumin through the transdermal route. Further, in-vivo studies are recommended to further establish this promising concept, targeting a variety of inflammatory conditions, including arthritis, psoriasis, and eczema, etc., through non-invasive transdermal drug delivery systems.

Permeability of Skin-Mimicking Cell Coatings by Polymers of Complex Architecture Based on Polyoxazolines

In the scope of drug delivery, the transdermal route is desirable because it provides attainable therapeutic concentrations and has minimal systemic side effects. To make the skin a feasible route for the delivery of therapeutic agents, the biggest challenge is overcoming its natural coating. In this paper, we investigate the effect of the architectures (homopolymer vs. block copolymer vs. hybrid block–graft copolymer) of several amphiphilic polymeric derivatives of poly(2-oxazoline) on skin permeability. The block copolymers are composed of a hydrophobic poly(2-oxazoline) block and a hydrophilic PEG block. The hybrid block–graft copolymers are obtained by grafting hydrophobic side chains of polycaprolactone to a poly(2-oxazoline) backbone. We used the commercially available EpiDerm™ by MatTek, composed of human epidermal cells, as a model of human skin. Two parameters of skin permeation are reported: penetration rate and lag time. We hypothesize that the skin permeation characteristics correlate with the critical micelle concentration and particle size of the studied polymers, while both parameters are a function of the complex architectures of the presented macromolecular constructs. While homopolymer poly(2-oxazolines) show the least permeation, the block copolymers demonstrate partial permeation. The hybrid block–graft copolymers exhibited full penetration through the model skin samples.

Transdermal Drug Delivery System

A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into systemic circulation. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of medication delivery such as oral, topical, intravenous, intramuscular, etc. is that the patch provides a controlled release of the medication into the patient, usually through either a porous membrane covering a reservoir of medication or through body heat melting thin layers of medication embedded in the adhesive. Transdermal drug delivery offers controlled release of the drug into the patient, it enables a steady blood level profile, resulting in reduced systemic side effects and, sometimes, improved efficacy over other dosage forms. The main objective of transdermal drug delivery system is to deliver drugs into systemic circulation through skin at predetermined rate with minimal inter and intrapatient variations. Transdermal drugs are self- contained, discrete dosage form. It delivers a drug through intact skin at a controlled rate into the systemic circulation. Delivery rate is controlled by the skin or membrane in the delivery system. It is a sophisticated complex drug delivery system which is difficult to formulate. It requires specialized manufacturing process/equipment. The materials of construction, configuration and combination of the drug with the proper cosolvent, excipient, penetration enhancer, and membrane are carefully selected and matched to optimize adhesive properties and drug delivery requirements. Several transdermal products and applications include hormone replacement therapy, management of pain, angina pectoris, smoking cessation and neurological disorders such as Parkinson's disease. Formulated to deliver the drug at optimized rate into the systemic circulation should adhere to the skin for the expected duration should not cause any skin irritation and/or sensitization, enhancing bioavailability via bypassing first pass metabolism, minimizing pharmacokinetic peaks and troughs, improving tolerability and dosing increasing patient compliance in continuous delivery. This review article provides an overview of TDDS, its advantages over conventional dosage forms, Limitations, various components of Transdermal patches, types of Transdermal patches, methods of preparation and Ideal requirements for TDDS, regulatory issues over transdermal drug delivery, its physicochemical methods of evaluation, therapeutic uses and recent advances in transdermal drug delivery system.1

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone)

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study’s primary outcome is the rate of pregnancy in couples during the study’s 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. ImplicationsThe development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.

A new multimodal paradigm for biomarkers longitudinal monitoring: a clinical application to women steroid profiles in urine and blood

BackgroundMost current state-of-the-art strategies to generate individual adaptive reference ranges are designed to monitor one clinical parameter at a time. An innovative methodology is proposed for the simultaneous longitudinal monitoring of multiple biomarkers. The estimation of individual thresholds is performed by applying a Bayesian modeling strategy to a multivariate score integrating several biomarkers (compound concentration and/or ratio). This multimodal monitoring was applied to data from a clinical study involving 14 female volunteers with normal menstrual cycles receiving testosterone via transdermal route, as to test its ability to detect testosterone administration. The study samples consisted of urine and blood collected during 4 weeks of a control phase and 4 weeks with a daily testosterone gel application. ResultsIntegrating multiple biomarkers improved the detection of testosterone gel administration with substantially higher sensitivity compared with the distinct follow-up of each biomarker, when applied to selected urine and serum steroid biomarkers, as well as the combination of both. Among the 175 known positive samples, 38% were identified by the multimodal approach using urine biomarkers, 79% using serum biomarkers and 83% by combining biomarkers from both biological matrices, whereas 10%, 67% and 64% were respectively detected using standard unimodal monitoring. Significance and noveltyThe detection of abnormal patterns can be improved using multimodal approaches. The combination of urine and serum biomarkers reduced the overall number of false-negatives, thus evidencing promising complementarity between urine and blood sampling for doping control, as highlighted in the case of the use of transdermal testosterone preparations. The generation in a multimodal setting of adaptive and personalized reference ranges opens up new opportunities in clinical and anti-doping profiling. The integration of multiple parameters in a longitudinal monitoring is expected to provide a more complete evaluation of individual profiles generating actionable intelligence to further guide sample collection, analysis protocols and decision-making in clinics and anti-doping.

Acacetin-loaded microemulsion for transdermal delivery: preparation, optimization and evaluation

Context Acacetin is reported as a potential drug candidate for the treatment of atrial fibrillation. However, clinical applications are limited by poor water solubility, limited ethanol solubility, and extremely low oral bioavailability. Objective The present study prepared and evaluated acacetin-loaded microemulsion (ME) to achieve efficient pharmacokinetics together with no or minimal invasiveness for transdermal delivery. Materials and methods The formulation of ME was determined by the water titration method based on solubility results. The optimized formulation was achieved by the simplex lattice experiment design. The optimized ME formulations FA, FB and FC (FA with 10% and 50% DMSO as enhancers, respectively) were evaluated by ex vivo permeation with Franz diffusion cell and excised mice skin. In vivo pharmacokinetic studies were also performed at 8 mg/kg in rats within 6 h by transdermal administration. Results The optimal ME (FA) was comprised of 12.2% caprylic acid decanoate monoditriglyceride (MCF-NF), 39.8% Smix (RH40: Trans = 2:1 w/w) and 48% water, respectively. Acacetin-loaded FA with particle size 36.0 ± 3.6 nm and drug solubility 803.7 ± 32.1 mg/g was prepared. FB had significantly higher cumulative amounts and higher AUC0-∞ (196.6 ± 11.0 min × μg/mL, p < 0.05) than that FA alone (121.4 ± 33.1 min × μg/mL). Discussion and conclusions The formulation of ME combined with the penetration enhancer can effectively improve the solubility and percutaneous absorption efficiency of acacetin, providing a new option for the non-invasive delivery of acacetin.

NANOSUSPENSIONS: A STRATERGY TO INCREASE THE SOLUBILITY AND BIOAVAILABILITY OF POORLY WATER-SOLUBLE DRUGS

The process that occurs at the molecular level and at the nanoscale is the subject of nanotechnology. Nanotechnology includes nanosuspension. Nanosuspension is a colloidal dispersion of medication particles that are nanometer-sized and stabilized with surfactants. To manufacture and scale up nanosuspensions, conventional size reduction tools such as media mills and high-pressure homogenizers as well as formulation strategies including precipitation, emulsion-solvent evaporation, solvent diffusion, and microemulsion procedures can be successfully used. The main elements to be taken into consideration for the effective manufacture and scale-up of nanosuspensions are maintaining the stability in solution as well as in the solid form, and resuspendability without aggregation. The flexibility for surface modification and mucoadhesion for drug targeting have substantially broadened the scope of this innovative formulation method as a result of the significant improvement in bioavailability. Extensive research is now being done on the use of nanosuspensions in various drug delivery methods, including oral, ophthalmic, brain, topical, buccal, nasal, and transdermal routes. The majority of permeability limiting absorption and hepatic first-pass metabolism associated difficulties that negatively affect bioavailability can be resolved with oral drug delivery of nanosuspension with receptor mediated endocytosis, which is a promising capability. The development of enabling technologies like nanosuspension can address several formulation issues that protein- and peptide-based medicines currently encounter

Transdermal delivery of doxorubicin and methotrexate from polyelectrolyte three layer nanoparticle of graphene oxide/polyethyleneimine/dextran sulphate for chemotherapy: In vitro and in vivo studies

In the present work, novel dual drug loaded - anionic graphene oxide/cationic polyethyleneimine/poly anionic dextran sulfate (GO/PEI/DS) was synthesized by a layer-by-layer self-assembly technique for transdermal anti-cancer drug delivery. Doxorubicin (DOX) was loaded onto folic acid conjugated graphene oxide (GO) and methotrexate (MTX) was loaded onto dextran sulfate (DS). The drug carrier was characterized by fourier transform infrared spectroscopy, x-ray diffraction spectroscopy, dynamic light scattering analysis, scanning electron microscopy, atomic force microscopy, transmission electron microscopy, zeta-potential analysis, drug loading and encapsulation efficiency, equilibrium swelling studies, in vitro drug release studies, hemocompatibility assays, in vitro cytotoxicity assay, skin irritation studies, ex vivo skin permeation studies and in vivo pharmacokinetic studies.The cytotoxicity of synthesized materials was evaluated against MCF-7 breast cancer cells using an MTT assay and apoptosis assay. The synergistic effect of DOX and MTX to inhibit the growth of cancer cells was also confirmed. The final dual drug-loaded carrier showed a cell viability of 36.38 % towards MCF-7 cancer cells while it showed a cell viability of >87.65 % towards normal L929 cell lines. The in vivo pharmacokinetic studies in Wistar rats through oral and transdermal routes of administration, the transdermal route of administration of dual drug-loaded material provided a sustained and prolonged drug existence in the blood circulation system. The mean residence time of drugs in the bloodstream via oral administration was 83.98 ± 3.71 h, while that of the transdermal route of administration was 149.62 ± 6.11 h. The results revealed that the synthesized dual drug-loaded material showed a good pH-dependent controlled and sustained release profile for both DOX and MTX via the transdermal route of administration in comparison with oral delivery.

Therapeutic potential of aromatic plant extracts in Alzheimer's disease: Comprehensive review of their underlying mechanisms.

The aim of this review is to outline recent advancements in the application and mechanistic studies of aromatic plant extracts in Alzhermer`s disease (AD) to demonstrate their value in the management of this disease. AD is a neurodegenerative disease with a complex pathogenesis characterized by severe cognitive impairment. Currently, there are very few drugs available for the treatment of AD, and treatments are primarily focused on symptom relief. Aromatherapy is a traditional complementary alternative therapy that focuses on the prevention and treatment of the disease through the inhalation or transdermal administration of aromatic plant extracts. Over the past few years, studies on the use of aromatic plant extracts for the treatment of AD have been increasing and have demonstrated a definitive therapeutic effect. We systematically summarized in vitro, in vivo, and clinical studies focusing on the potential use of aromatic plant extracts in the treatment of AD in PubMed, ScienceDirect, Google Scholar, and the Chinese National Knowledge Infrastructure from 2000 to 2022. Our literature survey indicatesthat aromatic plant extracts exert anti-AD effects by modulating pathological changes through anti-amyloid, anti-tau phosphorylation, anti-cholinesterase, anti-inflammation, and anti-oxidative stress mechanisms (Figure 1). This review provides a future strategy for the research of novel anti-AD drugs from aromatic plant extracts.