Poly(glycerol sebacate) (PGS) is a biodegradable, elastomeric polymer that has been explored for applications including tissue engineering, drug delivery, and wound repair. Despite its promise, its biomedical utility is limited by its rapid, and largely fixed, degradation rate. Additionally, its preparation requires prolonged curing at high temperatures, rendering it incompatible with heat-sensitive molecules, complex device geometries, and high-throughput production. In this study, we synthesized methacrylated PGS (PGS-M), imparting the ability to rapidly photocross-link the polymer. Increasing the degree of methacrylation was found to slow PGS-M degradation; PGS-M (5.5kDa) disks with 21% methacrylation lost 40.1 ± 11.8% of their mass over 11 weeks in vivo whereas 47% methacrylated disks lost just 14.3 ± 1.4% of their mass over the period. Daunorubicin release from PGS-M occurred in a linear fashion without a substantial initial burst. Further, increasing the degree of methacrylation extended the release of encapsulated drug. After 60 days, 21%, 27%, and 47% methacrylated disks with the same drug loading (w/w) released 56.8 ± 5.4%, 15.1 ± 0.4%, and 15.4 ± 0.3% of encapsulated drug, respectively. Importantly, the 27% and 47% methacrylated disks consistently released ~ 0.25% (w/w) of encapsulated drug per day with no burst release. Histological evaluation also suggested that PGS-M is biocompatible, eliciting limited inflammation and fibrous encapsulation when implanted subcutaneously. This report presents the first long-term in vitro studies and first in vivo studies using PGS-M and demonstrates the ability to tune PGS-M degradation rate, use PGS-M to encapsulate drug, and obtain sustained drug release over months.

Human cells, such as fibroblasts and particularly human mesenchymal stem cells (hMSCs), represent a promising and effective therapeutic tool for a range of cell-based therapies used to treat various diseases. The effective delivery of therapeutic cells remains a challenge due to limitations in targeting, invasiveness, and cell viability. To address these challenges, we developed a microneedle (MN) system for minimally invasive cell delivery with high cellular stability. The MN system comprises a core of gelatin methacryloyl (GelMA) hydrogel embedded with fibroblasts, encased in a polylactic-co-glycolic acid (PLGA) shell that enhances structural integrity for efficient skin penetration. The fabrication process involves UV-crosslinking of the GelMA hydrogel with cells, optimizing both cell encapsulation and structural strength. This MN system achieves over 80% cell viability after seven days in vitro, with the conventional GelMA formulation providing superior stability and cellular outcomes. This platform's ability to ensure sustained cell viability presents promising implications for future applications in regenerative medicine, wound healing, and localized treatments for skin conditions. This MN system opens new avenues for cell-based therapies, offering a versatile and scalable solution for therapeutic cell delivery.

Ocular diseases have a major impact on patient's vision and quality of life, with approximately 2.2 billion people have visual impairment worldwide according to the findings from the World Health Organization (WHO). The eye is a complex organ with unique morphology and physiology consisting of numerous ocular barriers which hinders the entry of exogenous substances and impedes drug absorption. This in turn has a substantial impact on effective drug delivery to treat ocular diseases, especially intraocular disorders which has consistently presented a challenge to eye care professionals. The most common method of delivering medications to the eye is topical instillation of eye drops. Although this approach is a viable option for treating many ocular diseases remains a major challenge for the effective treatment of posterior ocular conditions. Up till now, incessant efforts have been committed to design innovative drug delivery systems with the hopes of potential clinical application. Modern developments in nanocarrier's technology present a potential chance to overcome these obstacles by enabling targeted delivery of the loaded medication to the eyes with improved solubility, delayed release, higher penetration and increased retention. This review covers the anatomy of eye with associated ocular barriers, ocular diseases and administration routes. In addition it primarily focuses on the latest progress and contemporary applications of ophthalmic formulations providing specific insight on nanostructured drug delivery carriers reported over the past 5 years highlighting their values in achieving efficient ocular drug delivery to both anterior and posterior segments. Most importantly, we outlined in this review the macro and nanotechnology based ophthalmic drug formulations that are being patented or marketed so far for treating ocular diseases. Finally, based on current trends and therapeutic concepts, we highlighted the challenges faced by novel ocular drug delivery systems and provided prospective future developments for further research in these directions. We hope that this review will serve as a source of motivation and ideas for formulation scientists in improving the design of innovative ophthalmic formulations.

Tizanidine HCl (TZN) is an FDA-approved medication for treating spasticity. However, its oral administration presents obstacles to its efficacy, as it has a short duration of action and a low rate of absorption into the circulation (less than 40%) due to its rapid breakdown in the liver. In addition, its hydrophilic properties limit its capacity to cross the blood-brain barrier, thereby prohibiting it from reaching the central nervous system, where it can exert its intended therapeutic effects. Furthermore, diet-dependent absorption leads to fluctuations in bioavailability. Thus, this work aimed to create TZN-loaded chitosan-coated emulsomes (TZN-CTS-EMS) for intranasal administration, bypassing hepatic metabolism and boosting brain bioavailability. TZN-CTS-EMS were made using a thin film hydration approach. The influence of the independent parameters on the vesicle characteristics was examined and optimized using a Box-Behnken experimental methodology. The optimized formulation expected by the experimental design exhibited a greater desirability factor, characterized by a smaller particle size (127.63 nm), higher encapsulation efficiency (67.36%), and higher zeta potential (32.49 mV). As a result, it was chosen for additional in vivo assessment. Histopathological examinations showed no structural injury or toxicity to the nasal mucosa. Compared to intranasal TZN solution (TZN-SOL), the pharmacokinetics analysis demonstrated that intranasal TZN-CTS-EMS had a relative bioavailability of 191.9% in the plasma and459.3% in the brain. According to these findings, intranasal administration of the optimized TZN-CTS-EMS may represent a viable, noninvasive substitute for effective TZN delivery to brain tissues, potentially leading to improved safety and pharmacological efficiency.

Despite being the most widely prescribed formulation, oral formulations possess several limitations such as low adherence, low bioavailability, high toxicity (in the case of anticancer drugs), and multiple-time administration requirements. All these limitations can be overcome by long-acting injectables. Improved adherence, patient compliance, and reduced relapse have been observed with long-acting formulation which has increased the demand for long-acting injectables. Drugs or peptide molecules with oral bioavailability issues can be easily delivered by long-acting systems. This review comprehensively addresses the various technologies used to develop long-acting injections with a particular focus on hydrophilic drugs and large molecules as well as the factors affecting the choice of formulation strategy. This is the first review that discusses the possible technologies that can be used for developing long-acting formulations for hydrophilic molecules along with factors which will affect the choice of the technology. Furthermore, the mechanism of drug release as well as summaries of marketed formulations will be presented. This review also discusses the challenges associated with the manufacturing and scale-up of the long-acting injectables.

The present study aimed to synthesize tiotropium bromide (TIO)-loaded generation 5 polyamidoamine dendrimers (TIO-PAMAM-G5-DMs) using a solvent-free microwave assisted synthesis (MAS) for the treatment of pulmonary acidosis, a condition associated with decreased blood pH due to bronchoconstriction. The encapsulation of TIO into PAMAM-G5-DMs was achieved using MAS Michael addition and amidation reactions, following green chemistry principles. The DMs demonstrated particle size of 460.68 ± 1.38nm, entrapment efficiency of 92.4 ± 0.44%, controlled release profiles of 90.4 ± 0.62% and 76 ± 0.84% in media of pH 6.8 and 7.4, respectively, and high buffering capacity (25 mL/pH units) using a proton sponge effect for the release of the drug into the system as compared to the conventional formulation. A synergistic rat model was used to compare the pharmacokinetics (PK) of marketed and DM-based formulations. The results showed a mean Cmax of 1987 ng/mL, tmax of 6h, AUC of 10013863.5 ng.h/mL, and t½ of 18.59h, respectively. The DMs exhibited low cytotoxicity, good biocompatibility, and higher IC50 value (> 10µg) on human lung epithelial cell line BEAS-2B. Thus, our study introduces a cutting-edge alternative approach for treating pulmonary acidosis using PAMAM-DMs with proton sponge effect.

Chronic wounds present significant challenges with high morbidity and mortality. A cost-effective dressing that can absorb large exudate volumes, is hemostatic and therapeutically active is of current interest. This study compares two crosslinking approaches on composite scaffolds comprising fish collagen (FCOL), hyaluronic acid (HA) and sodium alginate (SA) by respectively targeting HA and SA. Crosslinking involved reacting HA with polyethylene glycol diglycidyl ether (PEGDE)/itaconic acid (IT) (IPC scaffolds) or SA with calcium chloride (CC scaffolds) and the crosslinked gels (with/without BSA) freeze-dried. Selected optimized formulations were loaded with basic fibroblast growth factor (b-FGF) as medicated scaffold dressings. NMR and FTIR spectroscopies (crosslinking/component interactions), SEM (morphology), texture analysis (mechanical strength/adhesion), and exudate handling were used to characterize the physico-chemical properties of the scaffolds. Protein (BSA) release profiles, hemostasis, biocompatibility and wound closure were assessed using HPLC, whole blood and methyl thiazolyl tetrazolium (MTT) and scratch assays respectively. The CC SA:FCOL:HA scaffolds showed improved mechanical strength, porosity, water vapor transmission rate, retained structural integrity after absorbing 50% exudate and promoted cell proliferation. The IPC scaffolds showed enhanced structural integrity, excellent hemostasis, retained three times more exudate than non-crosslinked scaffolds and provided acceptable pore size for cell adhesion and proliferation. The results show potential of CC and IPC SA:FCOL:HA scaffolds as medicated dressings for delivering proteins to chronic wounds. The study's significance lies in their potential use as multifunctional, multi-targeted and therapeutic dressings to overcome challenges with chronic wounds and use as delivery platforms for other therapeutic agents for chronic wound healing.

Coated microneedles (MNs) have several disadvantages, including limited drug doses, decreased skin puncture ability due to drug coating, and a risk of clogging and infection due to repeated application. We aimed to fabricate a dissolving bird-bill MN (dBB MN) with a vertical groove between two thin plate-shaped needles and needle pedestal. Moreover, we evaluated its ability to transdermally deliver a large-molecular-weight insulin into the systemic circulation. Hydrogels with various concentrations of polyvinylpyrrolidone (PVP) or sodium hyaluronate (HA) were prepared, and dBB MN arrays were fabricated by micromolding under negative pressure for potential mass production. The needle height of the dBB MN was at the maximum when the hydrogel was 25 w/w% PVP, with a viscosity of 8-9Pa∙s. Furthermore, the buckling force of dBB MNs made from 25 w/w% PVP was 130.6 ± 51.0 mN, which increased to 195.6 ± 65.3 mN when insulin was added at 1 w/w%. The skin insertion ability of dBB MN was investigated using swain skin, with micro-holes were confirmed on the skin surface. dBB MN showed biphasic dissolution in the skin; the plate-shaped needles were immediately dissolved within 10min, while the needle pedestal was slowly dissolved over 180min. The blood glucose concentration in diabetic rats decreased slowly and significantly after a 3-h application of the insulin-loaded dBB MN array. Therefore, the dBB MN array demonstrated sufficient ability to puncture skin and transdermally deliver a large-molecular-weight drug into the systemic circulation. These findings suggest that the dBB MN array holds promise as a minimal invasive drug delivery platform, with potential applications in improving patient adherence and expanding access to essential therapies, particularly in resource-limited settings.