Although strip films are a promising platform for delivery of poorly water-soluble drug particles via slurry casting, the effect of critical material attributes, for example, superdisintegrants (SDIs) on critical quality attributes, including film disintegration time (DT), remains underexplored. A 2-level factorial design is considered to examine the impact of the SDI type (sodium starch glycolate and croscarmellose sodium), their amount, and film thickness. SDIs were used with hydroxypropyl methylcellulose (E15LV) and glycerin solutions along with viscosity matching. Fenofibrate, a model poorly water-soluble drug, was micronized and surface modified via fluid energy milling. Significant decreases in film DT, measured using 3 different methods, were observed due to the addition of SDIs. Percentage reduction in DT was a strong function of SDI amount, and thinner films disintegrated faster. Films with either higher SDI concentrations (>9%) or films under 80 μm, exhibited fast DT (<180 s, European Pharmacopeia). All thin films (50-60 μm) exhibited immediate release (>80% in 10 min). All films achieved good content uniformity, except for those with the lowest amount of SDI, attributed to insufficient viscosity and thickness nonuniformity due to the SDI. Finally, all films achieved adequate mechanical properties, notwithstanding minor negative impact of SDIs.

It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting.

Objective Intervertebral disk degeneration is a prevalent postoperative complication after discectomy, underscoring the need to develop preventative and bioactive treatment strategies that decelerate degeneration and seal annulus fibrosus (AF) defects. Human mesenchymal stem cell–derived exosomes (MSC-Exos) hold promise for cell-free bioactive repair; however, their ability to promote AF repair is poorly understood. The objective of this study was to evaluate the ability of MSC-Exos to promote endogenous AF repair processes and integrate MSC-Exos within a biomaterial delivery system. Design We characterize biophysical and biochemical properties of normoxic (Nx) and hypoxic (Hx) preconditioned MSC-Exos from young, healthy donors and examine their effects on AF cell proliferation, migration, and gene expression. We then integrate a poly(lactic- co-glycolic acid) microsphere (PLGA µSphere) delivery platform within an interpenetrating network hydrogel to facilitate sustained MSC-Exo delivery. Results Hx MSC-Exos led to a more robust response in AF cell proliferation and migration than Nx MSC-Exos and was selected for a downstream protection experiment. Hx MSC-Exos maintained a healthy AF cell phenotype under a TNFα challenge in vitro and attenuated catabolic responses. In all functional assays, AF cell responses were more sensitive to Hx MSC-Exos than Nx MSC-Exos. PLGA µSpheres released MSC-Exos over a clinically relevant timescale without affecting hydrogel modulus or pH upon initial embedment and µSphere degradation. Conclusions This MSC-Exo treatment strategy may offer benefits of stem cell therapy without the need for exogenous stem cell transplantation by stimulating cell proliferation, promoting cell migration, and protecting cells from the degenerative proinflammatory microenvironment.

The effect of particle size on the dissolution behavior of the particles of amorphous solid dispersions (ASDs) of griseofulvin (GF), with 0%-50% Kollidon ® VA 64 as a crystallization inhibitor is investigated. Both the final dissolved GF concentration and the dissolution rate of GF ASDs were found to be inversely proportional to the particle size. The solution concentrations for the smallest (45-75 mm) size group with different polymer loadings were significantly higher than those for the largest (250-355 mm) group regardless of the initial GF amount. Specifically, the dissolution rate of GF ASDs with 50% polymer loading for the finest group was 2.7 times higher than for the largest group under supersaturating conditions. The rates of dissolution and recrystallization were assessed through surface concentration (C s) and Avrami recrystallization rate kinetics, where the solid-state recrystallization was confirmed using Raman spectroscopy. Outcomes indicated that particle size reduction enhanced ASD drug loading by reducing the amount of polymer necessary as finest size ASDs initially dissolve faster, negating their higher recrystallization rate. Kollidon® VA 64 at 30% loading was sufficient to inhibit the GF recrystallization. Overall, the combination of particle size reduction and recrystallization inhibition is effective for improved dissolution behavior of GF ASDs.

Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. Dry coating using high-intensity vibratory mixing is employed to reduce API cohesion and granular Bond number as well as agglomeration as predicted by contact models, hence improve blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~10μm), a model API, was dry coated with nano-silica R972P (20nm), and mixed with Avicel 102. The amount of silica was varied from 0 to 2.74wt%, corresponding to theoretical surface area coverage (SAC) from 0 to 100% respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1.0wt% silica was adequate for API property enhancement; further corroborated by improved CU for 5wt% API blends. Excellent CU was achieved for 3, 5 and 10wt% API loaded blends, where 30min of mixing was found to be acceptable for all three. The CU with dry coated mAPAP was significantly lower and within the acceptable range as compared to control blends without silica, as well as those with silica added during blending. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. Compared to theoretical predictions, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.