Disposable Dosators Intended for Dry Powder Delivery to Mice.

Dry powder inhalers offer numerous advantages for delivering drugs to the lungs, including stable solid-state drug formulations, device portability, bolus metering and dosing, and a propellant-free dispersal mechanism. To develop pharmaceutical dry powder aerosol products, robust in vivo testing is essential. Typically, initial studies involve using a murine model for preliminary evaluation before conducting formal studies in larger animal species. However, a significant limitation in this approach is the lack of suitable device technology to accurately and reproducibly deliver dry powders to small animals, hindering such models' utility. To address these challenges, disposable syringe dosators were developed specifically for intrapulmonary delivery of dry powders in doses appropriate for mice. These dosators load and deliver a predetermined amount of powder obtained from a uniform bulk density powder bed. This discrete control is achieved by inserting a blunt needle to a fixed depth (tamping) into the powder bed, removing a fixed quantity each time. Notably, this dosing pattern has proven effective for a range of spray-dried powders. In experiments involving four different model spray-dried powders, the dosators demonstrated the ability to achieve doses within the range of 30 to 1100 µg. The achieved dose was influenced by factors such as the number of tamps, the size of the dosator needle, and the specific formulation used. One of the key benefits of these dosators is their ease of manufacturing, making them accessible and cost-effective for delivering dry powders to mice during initial proof-of-concept studies. The disposable nature of the dosators facilitates use in animal procedure rooms, where cleaning and refilling reusable systems and weighing materials is inconvenient. Thus, developing disposable syringe dosators has addressed a significant hurdle in murine dry powder delivery for proof-of-concept studies, enabling researchers to conduct more accurate and reproducible preliminary studies in small animal models for pulmonary drug delivery.

Preparation Strategies of the Anti-Mycobacterial Drug Bedaquiline for Intrapulmonary Routes of Administration.

Mycobacterium tuberculosis (M.tb) has infected one-quarter of the world's population and led to the deaths of 1.6 million individuals in 2021 according to estimates from the World Health Organization. The rise in prevalence of multidrug-resistant and extensively drug-resistant M.tb strains coupled with insufficient therapies to treat such strains has motivated the development of more effective treatments and/or delivery modalities. Bedaquiline, a diarylquinoline antimycobacterial agent, effectively targets mycobacterial ATP synthase but may lead to systemic complications upon oral delivery. Targeted delivery of bedaquiline to the lungs represents an alternative strategy to harness the sterilizing benefits of the drug against M.tb while mitigating off-target side effects. Two pulmonary delivery modalities were developed herein, including dry powder inhalation and liquid instillation. Despite bedaquiline's poor water solubility, spray drying was performed in predominantly aqueous conditions (≥80%) to avoid a closed-loop, inert system. Aerosols of spray-dried bedaquiline with L-leucine excipient outperformed spray-dried bedaquiline alone, demonstrating superior fine particle fraction metrics (~89% of the emitted dose below <5 µm), suitable for inhalation therapies. Furthermore, the use of a 2-hydroxypropyl-ß-cyclodextrin excipient allowed a molecular dispersion of bedaquiline in an aqueous solution for liquid instillation. Both delivery modalities were successfully administered to Hartley guinea pigs for pharmacokinetic analysis and were well-tolerated by the animals. Intrapulmonary liquid delivery of bedaquiline led to adequate serum absorption and appropriate peak serum concentrations of the drug. The liquid formulation was superior in systemic uptake compared to the powder formulation. The predominant route via which M.tb bacilli enter the body is aerosol droplets that are deposited onto airway surfaces. For this reason, we believe that further studies should focus on inhalation or intrapulmonary therapies that target the site of entry and primary site of infection for M.tb.

Fabrication of polyethylene terephthalate (PET) nanoparticles with fluorescent tracers for studies in mammalian cells.

Fluorescent nanoparticles (NPs) comprising polyethylene terephthalate (PET) with a hydrodynamic diameter of 158 ± 2 nm were synthesized in a bottom-up approach. Concentration-dependent uptake and cytotoxicity of PET NPs in macrophages are shown. The fabrication of well-characterized NPs, derived from high-commodity polymers, will support future studies to assess effects on biological systems.

Influence of peripheral hydrogen bonding on the mechanical properties of photo-cross-linked star-shaped poly(D,L-lactide) networks.

Four-arm, star-shaped poly(D,L-lactide) (PDLLA) oligomers of controlled molar mass and narrow molar mass distribution were successfully synthesized by use of an ethoxylated pentaerythritol initiator. Derivatization of the terminal hydroxyl groups with either methacrylic anhydride (MAAH) or 2-isocyanatoethyl methacrylate (IEM) to yield PDLLA-M (M = methacrylate end group) and PDLLA-UM (UM = urethane methacrylate end group), respectively, was monitored by in situ Fourier transform infrared (FTIR) spectroscopy. Photo-cross-linking of the functional oligomers yielded networks with high gel contents (>95%). The glass transition temperature (T(g)) of these networks was strongly dependent on prepolymer molar mass, and networks based on low molar mass precursors were more rigid than the networks obtained from higher molar mass oligomers. The tensile strength (TS) and Young's modulus of the PDLLA-M samples, approximately 7 and 17 MPa, respectively, were significantly lower than the values of 19 MPa (TS) and 113-354 MPa (Young's modulus) for the PDLLA-UM samples. The introduction of terminal hydrogen-bonding sites that were adjacent to the photo-cross-linking site resulted in higher performance poly(lactide)-based bioadhesives.