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Sangseo Kim,1 Sadikalmahdi Abdella,1 Fatima Abid,1 Franklin Afinjuomo,1 Souha H Youssef,1 Amy Holmes,1 Yunmei Song,1 Sachin Vaidya,2 Sanjay Garg1 1Centre for Pharmaceutical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5000, Australia; 2Central Adelaide Local Health Network, The Queen Elizabeth Hospital, Woodville, SA, 5011, AustraliaCorrespondence: Sanjay Garg, Tel +61 8 8302 1575, Email Sanjay.garg@unisa.edu.auBackground: Imiquimod (IMQ) is an immunomodulating drug that is approved for the treatment of superficial basal cell carcinoma, actinic keratosis, external genital warts and perianal warts. However, IMQ cream (Aldara®) has several drawbacks including poor skin permeation, local toxicity, and compromised patient compliance as a topical pharmacological option.Methods: Our research aimed to develop and optimize nanostructured lipid carriers (NLCs) containing IMQ for the first time using a hybrid design of experiments approach. The optimized formulation was then incorporated into a matrix-type topical patch as an alternative dosage form for topical application and evaluated for IMQ deposition across different skin layers in comparison to the performance of the commercial product. Additionally, our work also attempted to highlight the possibility of implementing environment-friendly practices in our IMQ-NLCs formulation development by reviewing our analytical methods and experimental designs and reducing energy and solvent consumption where possible.Results: In this study, stearyl alcohol, oleic acid, Tween® 80 (polysorbate 80), and Gelucire® 50/13 (Stearoyl polyoxyl-32 glycerides) were selected for formulation development. The formulation was optimized using a 2k factorial design and a central composite design. The optimized formulation achieved the average particle size, polydispersity index, and zeta potential of 75.6 nm, 0.235, and – 30.9 mV, respectively. Subsequently, a matrix-type patch containing IMQ-NLCs was developed and achieved a statistically significant improvement in IMQ deposition in the deeper skin layers. The IMQ deposition from the patch into the dermis layer and receptor chamber was 3.3 ± 0.9 μg/cm2 and 12.3 ± 2.2 μg/cm2, while the commercial cream only deposited 1.0 ± 0.8 μg/cm2 and 1.5 ± 0.5 μg/cm2 of IMQ, respectively.Conclusion: In summary, IMQ-NLC-loaded patches represent great potential as a topical treatment option for skin cancer with improved patient compliance.Keywords: imiquimod, nanostructured lipid carrier, design of experiments, topical patches, skin cancer, greenness evaluation

Background Otitis externa is a commonly diagnosed dermatological disorder in canines. The pathogens primarily involved in canine otitis externa (COE) include Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Proteus mirabilis, and Malassezia pachydermatis. As COE tends to be superficial, medications delivered topically are often effective and practical in managing the condition. As such, there is a wide variety of approved topical products currently available in the market. The efficacy of topical dosage forms can be dependent on various factors such as the pharmacology of active constituents and the physicochemical properties of the formulation, including pH, viscosity, spreadability, and bio-adhesion. Currently, there is a lack of published literature available on the optimal properties of topical COE products. In this study, we compared the physicochemical properties of nine commercially available otic veterinarian products in Australia used clinically to manage COE. Results Based on our comparative analysis, the pH (6.26 ± 0.04) of an aqueous-based product was similar to a healthy dog’s external auditory canal. Products containing polymers exhibited higher viscosity and bio-adhesion. Spreadability was inversely related to viscosity and Osurnia ® a product with high viscosity demonstrated the lowest spreadability. Aqueous-based otic products showed better syringebility whereas oil-based systems required higher force to expel the products. Variability in droplet size was noted. Derm Otic, Baytril Otic, and Aurizon Ear Drops had the lower standard deviation which indicates they would give a more consistent dose. Conclusions Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.

Technological advancements have created infinite opportunities and rendered our life easier at several fronts. Nonetheless, the environment has suffered the aftermaths of modernization. Ironically, the pharmaceutical industry was found to be a significant contributor to environmental deterioration. To tackle this issue, continuous eco-evaluation of newly introduced technologies is crucial. Three-dimensional printing (3DP) is rapidly establishing its routes in different industries. Interestingly, 3DP is revolutionising the production of pharmaceuticals and is regarded as a promising approach for the fabrication of patient-centric formulations. Despite the increasing applications in the pharmaceutical field, tools that evaluate the environmental impacts of 3DP are lacking. Energy and solvent consumption, waste generation, and disposal are the main associated factors that present major concerns. For the first time, we are proposing a quantitative tool, the index of Greenness Assessment of Printed Pharmaceuticals (iGAPP), that evaluates the greenness of the different 3DP technologies used in the pharmaceutical industry. The tool provides a colour-coded pictogram and a numerical score indicating the overall greenness of the employed printing method. Validation was performed by constructing the greenness profile of selected formulations produced using the different 3DP techniques. This tool is simple to use and indicates the greenness level of the procedures involved, thereby creating an opportunity to modify the processes for more sustainable practices. Refereed/Peer-reviewed

Refereed/Peer-reviewed The age-related loss of circulating estrogen that occurs during the menopausal transition manifests itself through a variety of symptoms including vasomotor (hot flushes and night sweats), genito-urinary syndrome (vaginal dryness and urinary symptoms), sexual dysfunction, mood, and sleep disturbance that often last longer than a decade. Furthermore, reductions in estrogen level increase the risks of chronic complications such as osteoporosis, cardiovascular disease, and cognitive decline among others, thereby affecting the quality of life of women. Although oral estrogens are the most widely used therapy for menopausal symptoms, they suffer from poor bioavailability, and there are concerns over their safety, creating a significant concern to consumers. Mucoadhesive buccal films are an innovative dosage form that offers several advantages including avoidance of the first-pass metabolism, fast onset of action, and importantly, improved patient acceptance In the current work, we developed mucoadhesive estradiol film for hormonal replacement therapy using film-forming polymers. Two approaches, namely, co-solvency and nano-emulsion were evaluated to increase solubility and hence incorporate estradiol, a poorly water-soluble drug, into a formulation made from the hydrophilic polymer/s. The films were characterised for their mechanical and physicochemical properties. In-vitro release study showed that about 80% of the drug was released within 6 min from films prepared by the nano-emulsion approach, whereas it took about 10.5 min to get similar drug release from films prepared by the co-solvency approach. The ex-vivo permeation result indicates that about 15% of the drug permeated across the porcine buccal mucosa in the first 10 h from films prepared by the nano-emulsion approach, while permeation across porcine buccal mucosa was only observed at around 24 h from films prepared by the co-solvency method The nano-emulsion films were evaluated for in vivo performance using a convolution technique using R software. The predicted Cmax and Tmax were found to be 740.74 ng mL−1 and 7 min, respectively, which were higher than previously reported in vivo concentration from oral tablets. The results demonstrated that mucoadhesive film of estradiol based on the nano-emulsion approach could be a promising platform for the delivery of estradiol through the buccal mucosa for the treatment of menopausal symptoms.

Refereed/Peer-reviewed Despite being an effective therapy for menopausal symptoms, the use of oral estrogen is associated with low bioavailability and serious adverse effects of venous thromboembolism. Individualized therapy has been recommended to maximize benefits and curb the adverse effects, but much has not been done in developing formulations that offer flexibility to personalize therapy. In the present study, we employed an innovative 3D printing technology to design and develop bi-layered estradiol film with different infill patterns with an aim of improving bioavailability and facilitating personalized treatment. Hydroxypropyl cellulose (HPC-H) based formulation exhibited suitable rheological properties and was used as a feedstock to fabricate estradiol films with different infill patterns namely honeycomb, rectangular and plain. The back layer was prepared from a hydroxyethyl cellulose-based formulation. The resulting films were subsequently characterized in terms of their physicochemical, mechanical, environmental impact, and release characteristics among others. Films with a plain infill pattern exhibited significantly higher % elongation break and tensile strength. The in vitro drug release study revealed the fastest drug release profile for rectangular infill (96 % within 4 h) and the slowest drug release was observed for the plain infill pattern (∼35 % within 4 h), highlighting the effect of the infill pattern on release kinetics. Films with honeycomb infill patterns were selected for further characterization based on mechanical and in vitro release properties. No interaction between components of the formulation was observed and the absence of crystallinity in the final product was confirmed by Differential Scanning Calorimetry (DSC) and X-Ray Powder Diffraction analyses (XRD). The force of adhesiveness for the film was 0.13 ± 0.03 N. The predicted AUC 0–4 h, Cmax, and Tmax were 144.85 ng·h/mL, 65.97 ng/mL, and 0.83 h for a film (honeycomb infill pattern) loaded with 1 mg of estradiol. The printing process of films with honeycomb and rectangular infill patterns was evaluated as “green” using the index of Greenness Assessment of Printed Pharmaceuticals (iGAPP) tool. Our finding demonstrates the development of bi-layered estradiol film using Pressure assisted microsyringe (PAM) 3D printing and the influence of infill patterns on release kinetics and mechanical properties. The fabricated film not only facilitates the move towards personalized medicine but could also improve the bioavailability of the drugs by bypassing the hepatic first-pass metabolism and decreasing wash-out by the saliva.

Refereed/Peer-reviewed Physiologic pH is vital for the normal functioning of tissues and varies in different parts of the body. The varying pH of the body has been exploited to design pH-sensitive smart oral, transdermal and vaginal drug delivery systems (DDS). The DDS demonstrated promising results in hard-to-treat diseases such as cancer and Helicobacter pylori infection. In some cases, a change in pH of tissues or body fluids has also been employed as a useful diagnostic biomarker. This paper aims to comprehensively review the development and applications of pH-sensitive DDS as well as recent advances in the field.

Refereed/Peer-reviewed Three-dimensional (3D) printing is among the rapidly evolving technologies with applications in many sectors. The pharmaceutical industry is no exception, and the approval of the first 3D-printed tablet (Spiratam®) marked a revolution in the field. Several studies reported the fabrication of different dosage forms using a range of 3D printing techniques. Thermosensitive drugs compose a considerable segment of available medications in the market requiring strict temperature control during processing to ensure their efficacy and safety. Heating involved in some of the 3D printing technologies raises concerns regarding the feasibility of the techniques for printing thermolabile drugs. Studies reported that semi-solid extrusion (SSE) is the commonly used printing technique to fabricate thermosensitive drugs. Digital light processing (DLP), binder jetting (BJ), and stereolithography (SLA) can also be used for the fabrication of thermosensitive drugs as they do not involve heating elements. Nonetheless, degradation of some drugs by light source used in the techniques was reported. Interestingly, fused deposition modelling (FDM) coupled with filling techniques offered protection against thermal degradation. Concepts such as selection of low melting point polymers, adjustment of printing parameters, and coupling of more than one printing technique were exploited in printing thermosensitive drugs. This systematic review presents challenges, 3DP procedures, and future directions of 3D printing of thermo-sensitive formulations.

Refereed/Peer-reviewed Inulin’s unique and flexible structure, stabilization/protective effects, and organ targeting ability make it an excellent drug delivery carrier compared to other biodegradable polysaccharides. The three hydroxyl groups attached to each fructose unit serve as an anchor for chemical modification. This, in turn, helps in increasing bioavailability, improving cellular uptake, and achieving targeted, sustained, and controlled release of drugs and biomolecules. This review focuses on the various types of inulin drug delivery systems such as hydrogel, conjugates, nanoparticles, microparticles, micelles, liposomes, complexes, prodrugs, and solid dispersion. The preparation and applications of the different inulin drug delivery systems are further discussed. This work highlights the fact that modification of inulin allows the use of this polymer as multifunctional scaffolds for different drug delivery systems.

Refereed/Peer-reviewed The swine industry has evolved significantly in the recent decades, but this has come at considerable expense to piglet survival. Breeding sows for greater prolificacy has been accompanied by a greater proportion of piglets being born underweight, of lower vigor, and higher susceptibility to early mortality. Inducing sows to farrow during working hours has the potential to increase piglet survivability, but non-therapeutic injectable products are often discouraged on farms. We aimed to design and develop a novel vaginal drug delivery system (NVDDS) that could reliably trigger luteolysis and induce parturition. To achieve this, two vaginal tablets containing the luteolytic agent cloprostenol were formulated to be inserted together: one would release constituents immediately on insertion (immediate release; IR) and the other would release cloprostenol in a controlled manner (controlled release; CR). The two formulations (IR and CR) were evaluated for drug release, swelling and bio-adhesion in conditions simulating the sow vaginal environment. The IR tablet released the drug completely for 5 min whereas the CR tablet took 5 h to release 50% of the drug. Furthermore, the release kinetics were evaluated by fitting the dissolution profiles into different mathematical models. Both IR and CR tablets were best fitted by the Makoid–Banakar model which assumes release by summation of different mechanisms. The performance of the optimized formulations was studied in vivo with 161 Large White x Landrace sows of varying parity (0–5). The sows were assigned to five groups. Group 1 (SI) received a single vulval injection of cloprostenol at 0700 h (n = 32), group 2 (SDI) received the same dose split in two parts, at 0700h and 1300h (n = 33). Group 3 (IRT) animals were administered an IR tablet at 0700h (n = 32), while group 4 (IRCRT) received both IR and CR tablets at 0700 h (n = 33). Group 5 was untreated and served as a control (n = 32). The interval to farrowing was longer (p < 0.001) for controls than for treated sows, but there were no differences among cloprostenol treatments for timing of farrowing. The finding confirms the efficacy of the NVDDS for induction of farrowing in sows.