Small Molecule Topical Ophthalmic Formulation Development-Data Driven Trends & Perspectives from Commercially Available Products in the US.

Topical ophthalmic drug product development is a niche research domain as the drug formulations need to be designed to perform in the unique ocular physiological conditions. The most common array of small molecule drug formulations intended for topical ophthalmic administration include solutions, suspensions, emulsions, gels, and ointments. The formulation components such as excipients and container closure are unique to serve the needs of topical ophthalmic delivery compared to other parenteral products. The selection of appropriate formulation platform, excipients, and container closure for delivery of drugs by topical ophthalmic route is influenced by a combination of factors like physicochemical properties of the drug molecule, intended dose, pharmacological indication as well as the market trends influenced by the patient population. In this review, data from literature and packaging inserts of 118 reference listed topical ophthalmic medications marketed in the US are collected and analyzed to identify trends that would serve as a guidance for topical ophthalmic formulation development for small molecule drugs. Specifically, the topics reviewed include current landscape of the available small molecule topical ophthalmic drug products in the US, physicochemical properties of the active pharmaceutical ingredients (APIs), formulation platforms, excipients, and container closure systems.

Imaging of Liposomes by Negative Staining Transmission Electron Microscopy and Cryogenic Transmission Electron Microscopy.

Morphological characteristics of liposomes, such as size and lamellarity directly impact their quality and biological performance of encapsulated drug. Gaining insights into these parameters may also help ensure identification and utilization of most efficient process parameters for liposomes manufacturing. Direct imaging of such self-assembling colloidal structures, although challenging, is feasible through transmission electron microscopy (TEM) which uses nanometer scale wavelength of electrons for illumination, enabling an accurate assessment of the morphological characteristics of liposomes. This chapter will provide background information on the working principle and general sample preparation procedure for the two most commonly used TEM techniques for imaging liposomes, viz. negative staining transmission electron microscopy and cryogenic transmission electron microscopy.

Intra-articular interleukin-1 receptor antagonist (IL1-ra) microspheres for posttraumatic osteoarthritis: in vitro biological activity and in vivo disease modifying effect.

BACKGROUND: Interleukin-1 receptor antagonist (IL-1 ra) can be disease-modifying in posttraumatic osteoarthritis (PTOA). One limitation is its short joint residence time. We hypothesized that IL-1 ra encapsulation in poly (lactide-co-glycolide) (PLGA) microspheres reduces IL-1 ra systemic absorption and provides an enhanced anti-PTOA effect. METHODS: IL-1 ra release kinetics and biological activity: IL-1 ra encapsulation into PLGA microsphere was performed using double emulsion solvent extraction. Lyophilized PLGA IL-1 ra microspheres were resuspended in PBS and supernatant IL-1 ra concentrations were assayed. The biological activity of IL-1 ra from PLGA IL-1 ra microspheres was performed using IL-1 induced lymphocyte proliferation and bovine articular cartilage degradation assays. Systemic absorption of IL-1 ra following intra-articular (IA) injection of PLGA IL-1 ra or IL-1 ra: At 1, 3, 6, 12 and 24 h following injection of 50 µl PLGA IL-1 ra (n = 6) or IL-1 ra (n = 6), serum samples were collected and IL-1 ra concentrations were determined. Anterior cruciate ligament transection (ACLT) and IA dosing: ACLT was performed in 8-10 week old male Lewis rats (n = 42). PBS (50 µl; n = 9), IL-1 ra (50 µl; 5 mg/ml; n = 13), PLGA IL-1 ra (50 µl; equivalent to 5 mg/ml IL-1 ra; n = 14) or PLGA particles (50 µl; n = 6) treatments were performed on days 7, 14, 21 and 28 following ACLT. Cartilage and synovial histopathology: On day 35, animal ACLT joints were harvested and tibial cartilage and synovial histopathology scoring was performed. RESULTS: Percent IL-1 ra content in the supernatant at 6 h was 13.44 ± 9.27 % compared to 34.16 ± 12.04 %, 47.89 ± 12.71 %, 57.14 ± 11.71 %, and 93.90 ± 8.50 % at 12, 24, 48 and 72 h, respectively. PLGA IL-1 ra inhibited lymphocyte proliferation and cartilage degradation similar to IL-1 ra. Serum IL-1 ra levels were significantly lower at 1, 3, and 6 h following PLGA IL-1 ra injection compared to IL-1 ra. Cartilage and synovial histopathology scores were significantly lower in the PLGA IL-1 ra group compared to PBS and PLGA groups (p < 0.001). CONCLUSIONS: IL-1 ra encapsulation in PLGA microspheres is feasible with no alteration to IL-1 ra biological activity. PLGA IL-1 ra exhibited an enhanced disease-modifying effect in a PTOA model compared to similarly dosed IL-1 ra.