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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.

Chemotherapy is commonly used in cancer treatment, following resection surgery to reduce recurrence. Systemic administration results in severe side effects, therefore, the concept of drug-eluting implants was adopted, especially biodegradable scaffolds to eliminate the need for additional procedures for removal. Polycaprolactone (PCL) and Poly(lactide-co-glycolide) (PLGA) are biodegradable polymers that showed potential in extended-release drug delivery systems. Their blends combine their benefits, particularly mechanical properties, degradation, and drug release profiles. However, blending these polymers without risking phase separation is challenging. This research presents the development of solvent-cast films composed of different ratios of PCL: PLGA. The blending efficiency was assessed by Fourier Transform Infrared analysis and thermal assessments such as differential scanning calorimetry and thermogravimetric analysis. As PCL is a slow-degrading polymer, the addition of PLGA increased its degradation rate. 5-Fluorouracil (5FU) was used as a model drug and loaded to the blended films, the influence of the ratio of PLGA, percentage of plasticizer, and 5FU loading on the drug release profile was investigated. It was evident that formulations with higher PLGA and plasticizer concentrations showed a reduced burst effect whereas higher 5FU loading resulted in an increased rate of release. Refereed/Peer-reviewed

Refereed/Peer-reviewed While the global market for veterinary products has been expanding rapidly, there is still a lack of specialist knowledge of equine pharmaceutics. In many cases, the basic structure of the gastrointestinal tract (GIT) and integumentary system of the horse shares similarities with those of humans. Generally, the dosage form developed for humans can be repurposed to deliver equine medications; however, due to physiological variation, the therapeutic outcomes can be unpredictable. This is an area that requires more research, as there is a clear deficiency in literature precedence on drug delivery specifically for horses. Through a careful evaluation of equine anatomy and physiology, novel drug delivery systems (NDDSs) can be developed to adequately address many of the medical ailments of the horse. In addition to this, there are key considerations when delivering oral, topical, and parenteral drugs to horses, deriving from age and species variation. More importantly, NDDSs can enhance the duration of action of active drugs in animals, significantly improving owner compliance; and ultimately, enhancing the convenience of product administration. To address the knowledge gap in equine pharmaceutical formulations, this paper begins with a summary of the anatomy and physiology of the equine gastrointestinal, integumentary, and circulatory systems. A detailed discussion of potential dosage-form related issues affecting horses, and how they can be overcome by employing NDDSs is presented.

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 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 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.

Topical patches containing 5-fluorouracil (5-FU) are a feasible alternative to overcome the shortcomings of commercial cream for the treatment of non-melanoma skin cancer (NMSC). Plasticizers are a critical component of drug-in-adhesive (DIA) patches as they can significantly affect the mechanical, adhesive and drug release characteristics of the patches. Eudragit® E (EuE) is a methacrylate-based cationic copolymer capable of producing flexible and adhesive films for topical application. In this study, the effect of plasticizers on the mechanical, adhesive and 5-FU release characteristics of EuE-based patches was comprehensively evaluated. While the elongation at break (%) and adhesion of the films were significantly increased with increasing triacetin, dibutyl sebacate (DBS) and triethyl citrate (TEC) concentrations, the tensile strength showed an inverse relationship. EuE plasticized with 40% triacetin, 30% DBS or 40% w/w TEC produced elastic and adhesive films most suitable for topical application. In vitro release studies of the 5-FU-loaded patches demonstrated an initial burst release pattern during the first 10 min followed by a slow release over 120 min. In summary, this study provides important information on effect of plasticizers for preparation of EuE-based patches with desired mechanical, adhesive and release characteristics of 5-FU towards their potential application in the treatment of NMSC. Refereed/Peer-reviewed

The combination of 5-fluorouracil (5-FU) and cisplatin (Cis) has been used for the treatment of many cancers. The combination demonstrates synergy and improved clinical outcomes encouraging developing a formulation with both drugs. An analytical procedure is essential for formulation studies; however, no method has been reported for the concurrent determination and quantification of both 5-FU and Cis to date. A novel, simple, accurate, and precise HPLC method was developed using a C18 column (250 mm × 4.6 mm, 5 µm) and mobile phase composed of 0.5 mM sodium dodecyl sulfate: methanol (98:2, v/v), adjusted to pH 2.5 with phosphoric acid. A flow rate of 0.5 mL/min was applied and a photodiode array was utilized for detection and the retention times were 9.89 min (265 nm) for 5-FU and 5.36 min (210 nm) for Cis. Validation procedures were performed, and the method was found to be linear at ranges of 0.9–60.0 µg/mL for 5-FU and 6.0–60.0 µg/mL for Cis. The limits of detection (LOD) and quantitation (LOQ) were 0.10 and 0.25 µg/mL for 5-FU and 2.00 and 4.00 µg/mL for Cis, respectively. Other parameters such as precision, selectivity, robustness, and stability results were within acceptable limits. The method was applied to a model co-eluting film and its release profile was studied. Additionally, the method's greenness was evaluated by four assessment tools namely the national environmental method index (NEMI), analytical eco scale assessment (ESA), green analytical procedure index (GAPI), and Analytical GREEnness Metric Approach and Software (AGREE). The results demonstrated compliance with green analytical chemistry (GAC) practices. This research acts as a step towards further investigation of drug stability under different stress conditions and quantification of the intact drugs in presence of their degradation products. Refereed/Peer-reviewed