Current State and Opportunities with Long-acting Injectables: Industry Perspectives from the Innovation and Quality Consortium "Long-Acting Injectables" Working Group.

Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval.

Synthesis and Nanofiltration Membrane Performance of Oriented Mesoporous Silica Thin Films on Macroporous Supports.

Silica thin films with accessible hexagonal close-packed (HCP) pores have been deposited on macroporous supports to achieve composite nanofiltration membranes. The properties of these pore channels have been characterized through solvent flux and solute diffusion experiments. A chemically neutral surface (provided by a cross-linked layer of P123 copolymer) for silica thin film synthesis on the alumina macroporous support promotes the alignment of HCP channels vertical to the substrate, where the mesopore templating agent is block copolymer P123 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)). Vertical pore alignment is achieved for thin films (less than ∼100 nm) on a neutral surface and by sandwiching thicker films (∼240 nm) between two chemically neutral surfaces. Solvent flux through the composite membranes is consistent with accessible 10 nm diameter pores. Size selectivity of the membranes is characterized from the permeability of fluorescently tagged solutes (ranging from 4000 to 70 000 Da), where a size cut off occurs at 69 000 Da for the model protein bovine serum albumin. These permeability studies of the nanofiltration membranes serve to demonstrate solute transport in oriented silica thin film membranes and also highlight their versatility for membrane-based separations.

Synthesis of surfactant-templated silica films with orthogonally aligned hexagonal mesophase.

Thin silica films with orthogonally aligned hexagonal close-packed cylindrical structure are synthesized by dip coating silica precursors and poly(ethylene oxide)-polyproplyene oxide (PEO-PPO) triblock surfactants (P123) onto modified glass slides. All films cast from this sol display 2D hexagonal pore structures (a approximately 6.2 nm) under transmission electron microscopy (TEM). However, X-ray diffraction (XRD) shows that confining freshly deposited films between two chemically neutral modified slides completely aligns the pores toward the direction orthogonal to the substrate. Equally effective alignment is obtained by using slides modified with either a random PEO-PPO copolymer or P123 itself. The channels in films cast onto unmodified slides, onto modified slides which are exposed to air, or onto modified slides which are exposed to unmodified glass slides align at least partially parallel to the substrate. Parallel mesophase alignment is also observed in a control experiment with a sol containing the nonionic surfactant template decaethelyne glycol hexadecyl ether (Brij-56) sandwiched between copolymer-modified slides because the surfaces are not chemically neutral toward Brij-56. This study confirms that it is possible to use substrate surface chemistry to control the orientation of mesophases in mixtures of reactive silicates and low molecular weight nonionic surfactant templates.

Generalized coating route to silica and titania films with orthogonally tilted cylindrical nanopore arrays.

We describe a simple, inexpensive coating method to produce thin silica and titania films with surfactant templated, orthogonally tilted cylindrical nanopore arrays. These films can be deposited onto any substrate because orientation of the 2D hexagonally close packed (HCP) mesophases out of the plane of the film is directed by a chemically neutral sacrificial copolymer layer. Orientation of the HCP mesophases through the entire thickness of films cured in open air is achieved by limiting the coating thickness. This generalizes the coating method by making it possible to deposit oriented films on substrates of any curvature and size. We find a critical thickness between 70 and 100 nm, below which the triblock copolymer surfactant-templated HCP phase aligns completely out of the plane of glass and silicon wafer substrates. Above this thickness, the effect of the chemically neutral bottom layer does not propagate across the entire film, and alignment of the HCP mesophases parallel to the (nonpolar) air interface produces a mixed orientation.