Objectives: This study evaluated the potential of sustainably sourced, plant-based homopolymers derived from citronellol as an alternative to the traditional emollients used in pharmaceutical, cosmetic, and personal care products. With increasing emphasis on environmentally friendly ingredients and manufacturing processes, this study assessed the efficacy of these homopolymers in semi-solid and emulsion-based formulations. Methods: The analyses focused on physicochemical, sensory, biophysical, and neurosensory characteristics. Results: The results demonstrated that emulsions containing sustainable homopolymers maintained viscoelastic stability, preserving rheological properties over time under varying conditions. These formulations showed comparable structural and functional stability to those with traditional emollients while offering skin hydration, moisture retention, and elasticity, with reduced transepidermal water loss. Sensory evaluations highlighted positive user acceptance, with participants favoring the skin feel and in-use qualities of these emulsions over synthetic alternatives. Neurosensory analyses confirmed the strong visual appeal of the product packaging, capturing user attention effectively. Conclusions: These findings underline the capability of plant-based homopolymers to replace traditional emollients while providing significant consumer appeal and sustainability benefits. This study establishes their potential as viable components in the development of more eco-friendly topical formulations for the pharmaceutical, cosmetic, and personal care industries.

Aging reduces NAD+ levels, affecting metabolism. Traditional studies are destructive, limiting tracking. We present a non-invasive optical method with NMN-coated microneedles and multiphoton microscopy to monitor NAD+ shifts in real-time, validated in keratinocytes and mouse skin.

Typical clinical “in use” conditions for topical semisolids involve their application as a thin film, often with rubbing that can induce metamorphic stress. Yet, product quality and performance tests often characterize the manufactured product, and may not consider product metamorphosis (e.g., shear history) during dispensing and administration. This work sought to elucidate how such metamorphosis might alter product quality and performance. We evaluated the effect of “in use” stresses on drug crystal metamorphosis in acyclovir creams by optical microscopy. The amount of dissolved acyclovir was determined by separation of the cream base by ultra-centrifugation and quantification by HPLC. IVPT was undertaken on Zovirax® US and Aciclostad® comparing static and “in use” application of a finite dose. A mechanistic IVPT study was also conducted to understand the influence of acyclovir particle size reduction by “in use” rubbing on skin permeation. Reduction in acyclovir particle size was seen after “in use” rubbing with increases in the amount of dissolved acyclovir after rubbing (30 and 60 s) compared to static for both products. “In use” application resulted in significantly higher acyclovir permeation from both products. The mechanistic IVPT study proved the role of product metamorphosis. These results highlight the role of metamorphosis of product microstructure and its influence on performance.

PURPOSE:To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). METHODS:Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. RESULTS:A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. CONCLUSIONS:This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies.

3D printing of microneedles (μNDs) for transdermal therapy has the potential to enable patient personalization based on the target disease, site of application, and dosage requirements. To convert this concept to reality, it is necessary that the 3D printing technology can deliver high resolution, an affordable cost, and large print volumes. With the introduction of benchtop 4K and 8K 3D printers, it is now possible to manufacture medical devices like μNDs at sufficient resolution and low cost. In this research, we systematically optimized the 3D printing design parameters such as resin viscosity, print angle, layer height, and curing time to generate customizable μNDs. We have also developed an innovative 3D coating microtank device to optimize the coating method. We have applied this to the development of novel μNDs to deliver an established NAD+ precursor molecule, nicotinamide mononucleotide (NMN). A methacrylate-based polymer photoresin (eSun resin) was diluted with methanol to adjust the resin viscosity. The 3D print layer height of 25 μm yielded a smooth surface, thus reducing edge-ridge mismatches. Printing μNDs at 90° to the print platform yielded 84.28 ± 2.158% (n = 5) of the input height thus increasing the tip sharpness (48.52 ± 10.43 μm, n = 5). The formulation containing fluorescein (model molecule), sucrose (viscosity modifier), and Tween-20 (surface tension modifier) was coated on the μNDs using the custom designed microtank setup, and the amount deposited was determined fluorescently. The dye-coated μND arrays inserted into human skin (in vitro) showed a fluorescence signal at a depth of 150 μm (n = 3) into the skin. After optimization of the 3D printing parameters and coating protocol using fluorescein, NMN was coated onto the μNDs, and its diffusion was assessed in full-thickness human skin in vitro using a Franz diffusion setup. Approximately 189 ± 34.5 μg (5× dipped coated μNDs) of NMN permeated through the skin and 41.2 ± 7.53 μg was left in the skin after 24 h. Multiphoton microscopy imaging of NMN-coated μND treated mouse ear skin ex vivo demonstrated significantly (p < 0.05) increased free-unbound NADPH and reduced fluorescence lifetime of NADPH, both of which are indicative of cellular metabolic rates. Our study demonstrates that low-cost benchtop 3D printers can be used to print high-fidelity μNDs with the ability to rapidly coat and release NMN which consequently caused changes in intracellular NAD+ levels.

The objective of this study was to investigate whether different dispensing processes can alter the physicochemical and structural (Q3) attributes of a topical cream product, and potentially alter its performance. Acyclovir cream, 5

Depression is one of the most disabling diseases globally, with a high disease burden that generates high direct and indirect costs. The incidence of depression is twofold higher in adult women than in men. Biological and psychosocial factors constitute the pathophysiological bases of the condition and due to the complexity of the condition, current understanding is that the “treatment strategy must be multimodal”. The objective of this study was to measure the effect of introducing the frequent use of makeup on improving depressive symptoms in adult women of medium–low purchasing power Participants with the targeted profile who did not frequently use makeup were selected and randomised to receive (test group) or not (control group) stimuli and makeup products intended for encouraging the frequent use of makeup. The Zung Depression Self-Assessment Scale was used to assess depressive symptoms, with additional assessments on self-image perception using the mirror test and salivary cortisol level. The results demonstrated a sustained reduction in depressive symptoms (8.3 percentage points reduction in the Average Zung Index; P < 0.05), with a significant improvement in self-image perception (25

Objective: This study aimed to develop a holobiont tablet with rapid dispersibility to provide regulation of the microbiota, virucidal activity, and skin barrier protection. Methods: A 23 factorial experiment was planned to define the best formulation for the development of the base tablet, using average weight, hardness, dimensions, swelling rate, and disintegration time as parameters to be analyzed. To produce holobiont tablets, the chosen base formulation was fabricated by direct compression of prebiotics, postbiotics, and excipients. The tablets also incorporated solid lipid nanoparticles containing postbiotics that were obtained by high-pressure homogenization and freeze-drying. The in vitro virucidal activity against alpha-coronavirus particles (CCoV-VR809) was determined in VERO cell culture. In vitro analysis, using monolayer cells and human equivalent skin, was performed by rRTq-PCR to determine the expression of interleukins 1, 6, 8, and 17, aquaporin-3, involucrin, filaggrin, FoxO3, and SIRT-1. Antioxidant activity and collagen-1 synthesis were also performed in fibroblast cells. Metagenomic analysis of the skin microbiome was determined in vivo before and after application of the holobiont tablet, during one week of continuous use, and compared to the use of alcohol gel. Samples were analyzed by sequencing the V3–V4 region of the 16S rRNA gene. Results: A handrub tablet with rapid dispersibility was developed for topical use and rinse off. After being defined as safe, the virucidal activity was found to be equal to or greater than that of 70% alcohol, with a reduction in interleukins and maintenance or improvement of skin barrier gene markers, in addition to the reestablishment of the skin microbiota after use. Conclusions: The holobiont tablets were able to improve the genetic markers related to the skin barrier and also its microbiota, thereby being more favorable for use as a hand sanitizer than 70% alcohol.

Mosquito-borne diseases affect millions of people worldwide each year, and the use of a topically applied insect repellent is an economically viable preventative health practice. The general objective of this work was to encapsulate citronella oil (CO) in a nanostructured lipid carrier (NLC) to formulate a topical repellent with a long duration of efficacy on the skin and a good safety profile based on minimizing skin penetration. In the studied CO, the main chemical constituents of geraniol, citronellal, and citronellol were identified and subsequently used as markers for the in vitro skin permeation testing (IVPT). An optimal NLC encapsulating CO formulation was developed and had an average particle size of 350 nm. The NLC was then formulated in combination with CO at ratios of 2:1, 1:1, and 1:2 CO:NLC-CO as oil-in-water (O/W) emulsions and compared to CO in the same O/W emulsion base (all at 10% CO in the final O/W topical formulation). The markers geraniol, citronellol, and citronellal were detected in all samples tested F1 (10% CO in O/W emulsion) and F3 (10% CO/NLC-CO 1:1 in O/W emulsion). Even the percentages of F3 markers were higher than F1. The recovery of the percentage balance (based on the total remaining on the skin surface, on the skin, and penetrated through the skin to the receptor) of geraniol, citronellol, and citronellal markers for F1 and F3 was 7.70% and 11.96%; 25.51% and 31.89%; and 5.09% and 4.40%, respectively. The nanoparticle lipid solid forms a repellent reservoir on the skin surface, releasing the active ingredients slowly through volatilization, extending the repellent action, and reducing permeation through the skin. It is possible to assume that the remaining 92.30% and 88.03%; 74.49% and 68.11%; and 94.10% and 95.60% of geraniol, citronellol, and citronellal markers of F1 and F3, respectively, were lost to evaporation. In the in vivo efficacy test carried out with the Aedes aegypti mosquito, F3 was the optimal formulation, providing the greatest repellent action compared to free oil in O/W emulsion. Thermal analysis showed that the NLC-CO raised the boiling point of the encapsulated CO compared to the free oil, suggesting that the controlled release of the CO was a possible mechanism for its prolonged effect. We concluded that the nanocarriers developed with CO were stable and provided improved mosquito-repellent efficacy with minimal skin penetration of the CO actives over 24 h. Indeed, regardless of whether the CO was applied as free oil, a 1:1 mixture of CO (pure/free oil) or NLC-CO applied in an O/W emulsion can be considered safe for topical application due to minimal skin penetration.

Numerous products and minimally-invasive procedures are available to reduce cellulite. However, there are a limited number of tools to evaluate the effects of these interventions and some are relatively complex to implement. ObjectiveThis study evaluated the reliability of a standardized grading system for scoring the overall severity of cellulite on the posterior thigh. The study evaluated inter-rater and intra-rater (test/re-test) reliability of the method and engaged in an iterative process to develop a reliable method to evaluate changes in the appearance of cellulite. MethodsThere were two stages in the validation process. The first stage was an open process without evaluator training. The second stage was a more controlled process with training given and moderator involvement to review grade selections. In the first stage, inter-rater reliability was examined across five evaluators who were asked to evaluate 24 photographs (right thighs) based on a cellulite graded severity chart. During the second stage, the same photographs were examined by paired evaluators who had received additional training. Scores were independently moderated by a third person. The inter-rater reliability and intra-rater reliability over a 4-week interval were evaluated using intraclass correlation coefficients (ICCs). ResultsTwenty-four female participants (18-51 years, mean 31.68 +/- 9.03 years) with a mean BMI of 29.04 +/- 6.52 participated in the trial. Five female evaluators completed the initial evaluations. In stage 1, the inter-rater reliability (ICC2,5) was 0.838 (95%CI:0.700-0.922) and test/retest ICC3,1 values ranged from 0.360-0.990. In stage 2, the inter-rater reliability for 2 evaluators improved to 0.978 (95%CI:0.948-0.991), and the test/retest reliability of the moderated scoring method improved to 0.993 (95%CI:0.983-0.997). ConclusionThe iterative process developed a simple and reliable method of rating cellulite severity, with excellent inter-and intra-rater reliability, based on evaluating images of cellulite against a standard set of graded severity images. A reliable method of assessing cellulite severity is essential for undertaking future clinical trials to evaluate cellulite treatments.

Resveratrol (RSV) is a natural product with multiple biological benefits including anticancer properties. Unfortunately, its biological benefits are limited by its low bioavailability and rapid hepatic metabolism and degradation in the body. The aim of this study was to develop an effective delivery system for RSV that would enhance the plasmatic stability and decrease the metabolism rate of RSV through a dual strategy of chemical modification and nanoparticle formulation. The effectiveness of this strategy was tested for the application of RSV anticancer treatment in a mouse cancer model. Chemical modification of RSV was achieved by conjugating RSV to a low molecular weight co-polymer mPEG-PLA. This conjugated RSV together with free RSV were formulated into mPEG-PLA nanoparticles (conjugated RSV NPs). These NPs showed a stable plasma stability profile and decreased liver metabolism rate compared to nanoparticles encapsulating free RSV in mPEG-PLA (encapsulated RSV NPs) and free RSV alone. However, in vitro cell studies using B16-F10 cancer cells showed that conjugated RSV NPs were less effective compared to encapsulated RSV NPs, possibly due to the lack of biotransformation of conjugated RSV to the active form RSV in the simple cell studies. To study the actual effect of our strategy, an in vivo C57BL/6J mouse model with subcutaneous B16-F10 melanoma using intraperitoneal administration was used to reveal the relationship between the improved plasma stability and reduced liver metabolism rate of RSV in conjugated RSV NPs, and suppression of the tumour growth in mice. In vivo, a better tumour suppression trend with conjugated RSV NPs was noted. Our study suggests that the use of chemical conjugation with NP formulation is an effective strategy to reduce the degradation and metabolism rate of RSV and consequently increase the antitumour activity of RSV in vivo. This strategy has potential to be further developed for the suppression of early growth of tumours with no side effects.

Abstract Background/Aims Treatment of knee osteoarthritis (OA) focuses on reducing pain and improving function. Transdermal NSAID formulations have been developed as an alternative approach to reduce pain and sensitisation around the OA affected joint whilst avoiding some of the risks associated with oral NSAID administration. The aim of the study was to evaluate clinical outcomes following short-term (48 hours) administration of transdermal ibuprofen (5% w/v) from a wearable patch that incorporated a patented diamagnetic repulsion technology to enhance drug delivery, in comparison to placebo. Methods Double-blind, repeated measures, crossover design. Two study periods (48 hr each); diamagnetically enhanced ibuprofen or placebo, randomised. Participants: 24 (6 male: 18 female, mean age 66) people with painful knee OA. Patch applications: 6 x 4-5 hour patch applications over a 48 hour period. Active patches contained 5% ibuprofen in a gel reservoir with magnetized backing. Placebo patches had identical appearance but no ibuprofen and non-magnetized backing. Primary outcome measures: VAS for pain on movement (STS X3), WOMAC pain score, WOMAC function score. Results: Conclusion The active device containing ibuprofen (5%) and magnetophoresis technology produced a significantly greater reduction in pain and improvement in function than the placebo device. This was particularly the case for movement related pain. The reduction in pain was apparent with both VAS pain ratings and WOMAC pain score. There was also a clear improvement in function based on the WOMAC function score. The number needed to treat (NNT) for a 50% reduction in movement related pain was 2.2 and for resting pain 3.4. There were no major adverse events recorded during the study. Disclosure J. Summers: None. T. Wright: None. H. Benson: None. P. Moss: None. G. Tsadilas: None. J. Edwards: None. R. Will: None.

Epithelial surfaces protect exposed tissues in the body against intrusion of foreign materials, including xenobiotics, pollen and microbiota. The relative permeability of the various epithelia reflects their extent of exposure to the external environment and is in the ranking: intestinal≈ nasal ≥ bronchial ≥ tracheal > vaginal ≥ rectal > blood-perilymph barrier (otic), corneal > buccal > skin. Each epithelium also varies in their morphology, biochemistry, physiology, immunology and external fluid in line with their function. Each epithelium is also used as drug delivery sites to treat local conditions and, in some cases, for systemic delivery. The associated delivery systems have had to evolve to enable the delivery of larger drugs and biologicals, such as peptides, proteins, antibodies and biologicals and now include a range of physical, chemical, electrical, light, sound and other enhancement technologies. In addition, the quality-by-design approach to product regulation and the growth of generic products have also fostered advancement in epithelial drug delivery systems.

Purpose The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products. Methods CRM, a laser-based method, combining chemically-selective analysis and high resolution imaging, is used for the evaluation of different commercially available topical acyclovir creams. Results We show that CRM enables the spatially resolved analysis of microstructural features of semisolid products and provides insights into drug distribution and polymorphic state as well as the composition and arrangement of excipients. Further, we explore how CRM can be used to monitor phase separation and to study skin penetration and the interaction with fresh and cryopreserved excised human skin tissue. Conclusion This study presents a comprehensive overview and illustration of how CRM can facilitate several types of key analyses of semisolid topical formulations and of their interaction with their biological target site, illustrating that CRM is a useful tool for research, development as well as for quality testing in the pharmaceutical industry. Graphical abstract

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human stratum corneum. The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the stratum corneum.

If it can be effectively delivered to its site of action, α-mangostin has potential in development of novel cosmeceuticals due to its melanogenesis-blocking activity. The aim of this study was to develop an ultra-small unilamellar carrier system for α-mangostin and to evaluate its effect as an anti-age-spot serum on humans in vivo. The ultra-small unilamellar carrier bases were optimized using a 25 factorial design, with five factors (virgin coconut oil, soy lecithin, Tween 80, and stirring duration and speed) and two levels (low and high); response of droplet size was analyzed using Design Expert 12®. The anti-spot examination was conducted via capturing digital images of the human skin after topical application of an α-mangostin-loaded ultra-small unilamellar carrier at night for two consecutive weeks. The results thereof were analyzed using Motic Live Imaging 3.0 and a standard red, green, and blue score. The optimized serum formula was confirmed with a composition of 2.3% virgin coconut oil, 1% lecithin, and 28.3% Tween 80 (polysorbate 80) at a stirring speed of 1500 revolutions per minute for 15 min. Incorporation of 3% α-mangostin to the optimized base formula produced an ultra-small unilamellar carrier globule size of 16.5 nm, with zeta potential of −25.8 mV and a polydispersion index of 0.445. Physical characterization of an α-mangostin-loaded ultra-small unilamellar carrier comprised 90.94% transmittance, a pH value of 6.5, a viscosity of 38 cP, specific gravity of 1.042 g/mL and 72.46% entrapment efficiency. A transmission electron microscope confirmed spherical nanosized droplets in the system. Topical application of an α-mangostin-loaded ultra-small unilamellar carrier at night for 2 consecutive weeks demonstrated anti-age-spot activity shown through a significant reduction in intensity and area of spots in human volunteers (p < 0.05).

Microneedles (µND) are promising devices that can be used to transport a wide variety of active compounds into the skin. To serve as an effective delivery system, µND must pierce the human stratum corneum (~10–20 µm), without breaking or buckling during penetration. In the current review, we discuss both the anatomical features and biomechanical properties of skin in order to understand the local environment and resistive forces relevant to µNDs insertion. Of particular importance are the factors that affect µND insertion, such as their geometry and material composition, as these can be manipulated in the design and development phase to optimise skin insertion. We review the research relevant to µND and how this interacts with skin properties. We have also reviewed the most commonly used skin drug diffusion modelling used to predict drug behaviour from µNDs, and discussed the current challenges faced by µNDs to enter clinical trials and provide positive clinical outcomes.

Dissolvable transdermal microneedles (μND) are promising micro-devices used to transport a wide selection of active compounds into the skin. To provide an effective therapeutic outcome, μNDs must pierce the human stratum corneum (~10 to 20 μm), without rupturing or bending during penetration, then release their cargo at the predetermined area and time. The ability of dissolvable μND arrays/patches to sufficiently pierce the skin is a crucial requirement, which depends on the material composition, μND geometry and fabrication techniques. This comprehensive review not only provides contemporary knowledge on the μND design approaches, but also the materials science facilitating these delivery systems and the opportunities these advanced materials can provide to enhance clinical outcomes.

Topically applied products may target sites in one or more different skin layers, the skin appendages, and underlying tissues. Identifying the specific target region and formulating to deliver the therapeutic compound to that target is a key objective in topical product design. The skin surface is the target for cosmetics, sunscreens, and insect repellents, so the aim is to target actives to the skin surface with minimal absorption to deeper skin layers. The key target region for the majority of topically applied products is the viable epidermis and dermis, and sites targeted include nerves, keratinocytes, melanocytes, Langerhans cells, and hair follicles. Deeper tissues associated with muscles and joints may also be targeted, such as topical products for musculoskeletal pain and inflammation. Transdermal products target the systemic circulation. This chapter focuses on the rationale, mechanism, and application of the formulation approaches to topical and transdermal drug delivery.

Repeated long-term exposure to ultraviolet radiation causes skin aging and increased risk of skin cancer, whereas acute exposure can cause sunburn and significant discomfort. Strategies that have been demonstrated to protect the skin, including the regular use of efficient sunscreens, are heavily promoted by cancer prevention organizations and can provide better health outcomes for individuals and cost savings for health care systems. Consequently, sunscreen actives are present in many cosmetic and personal care products, as well as "beach sunscreen" products. In all cases the advice is to apply liberally, well before expected sun exposure. Sunscreens are used to protect against solar ultraviolet radiation. Sunscreen products are typically formulated to provide high skin substantivity. It is therefore important that in vitro experiments are designed to assess both permeation through the skin and penetration into/retention in the skin over the time course of topical application.