Selection of Silica Type and Amount for Flowability Enhancements via Dry Coating: Contact Mechanics Based Predictive Approach.

PURPOSE: To investigate the effect of dry coating the amount and type of silica on powder flowability enhancement using a comprehensive set of 19 pharmaceutical powders having different sizes, surface roughness, morphology, and aspect ratios, as well as assess flow predictability via Bond number estimated using a mechanistic multi-asperity particle contact model. METHOD: Particle size, shape, density, surface energy and area, SEM-based morphology, and FFC were assessed for all powders. Hydrophobic (R972P) or hydrophilic (A200) nano-silica were dry coated for each powder at 25%, 50%, and 100% surface area coverage (SAC). Flow predictability was assessed via particle size and Bond number. RESULTS: Nearly maximal flow enhancement, one or more flow category, was observed for all powders at 50% SAC of either type of silica, equivalent to 1 wt% or less for both the hydrophobic R972P or hydrophilic A200, while R972P generally performed slightly better. Silica amount as SAC better helped understand the relative performance. The power-law relation between FFC and Bond number was observed. CONCLUSION: Significant flow enhancements were achieved at 50% SAC, validating previous models. Most uncoated very cohesive powders improved by two flow categories, attaining easy flow. Flowability could not be predicted for both the uncoated and dry coated powders via particle size alone. Prediction was significantly better using Bond number computed via the mechanistic multi-asperity particle contact model accounting for the particle size, surface energy, roughness, and the amount and type of silica. The widely accepted 200 nm surface roughness was not valid for most pharmaceutical powders.

Preparation of Free-Flowing Spray-Dried Amorphous Composites Using Neusilin®.

A highly porous additive, Neusilin®, with high adsorption capability is investigated to improve bulk properties, hence processability of spray-dried amorphous solid dispersions (ASDs). Griseofulvin (GF) is applied as a model BCS class 2 drug in ASDs. Two grades of Neusilin®, US2 (coarser) and UFL2 (finer), were used as additives to produce spray-dried amorphous composite (AC) powders, and their performance was compared with the resulting ASDs without added Neusilin®. The resulting AC powders that included Neusilin® had greatly enhanced flowability (flow function coefficient (FFC) > 10) comparable to larger particles (100 µm) yet had finer particle size (< 50 µm), hence retaining the advantage of fast dissolution rate of finer sizes. Dissolution results demonstrated that achieved GF supersaturation for AC powders with Neusilin® was as high as 3 times that of crystalline GF concentration and was achieved within 30 min. In addition, 80% of drug was released within 4 min. The flowability improvement for AC powders with Neusilin® was more significant as compared to spray-dried ASDs without Neusilin®. Thus, the role of Neusilin® in flowability improvement was evident, considering that spray-dried AC with Neusilin® UFL2 has higher FFC than ASDs having a similar size. Lastly, the AC powders retained a fully amorphous state of GF after 3-month ambient storage. The overall results conveyed that the improved flowability and dissolution rate could outweigh the loss of drug loading resulted by addition of Neusilin®.

Decoding Fine API Agglomeration as a Key Indicator of Powder Flowability and Dissolution: Impact of Particle Engineering.

PURPOSE: Fine API agglomeration and its mitigation via particle engineering, i.e., dry coating, remains underexplored. The purpose was to investigate agglomeration before and after dry coating of fine cohesive APIs and impact on powder processability, i.e., flowability (FFC), bulk density (BD), and dissolution of BCS Class II drugs. METHOD: Ibuprofen (three sizes), fenofibrate, and griseofulvin (5-20 µm), before and after dry coating with varying amounts of hydrophobic (R972P) or hydrophilic (A200) nano- silica, were assessed for agglomeration, FFC, BD, surface energy, wettability, and dissolution. The granular Bond number (Bog), a dimensionless parameter, evaluated through material-sparing particle-scale measures and particle-contact models, was used to express relative powder cohesion. RESULTS: Significant powder processability improvements after dry coating were observed: FFC increased by multiple flow regimes, BD increased by 25-100%, agglomerate ratio (AR) reduction by over an order of magnitude, and greatly enhanced API dissolution rate even with hydrophobic (R972P) silica coating. Scrutiny of particle-contact models revealed non-triviality in estimating API surface roughness, which was managed through the assessment of measured bulk properties. A power-law correlation was identified between AR and Bog and subsequently, between AR and FFC & bulk density; AR below 5 ensured improved processability and dissolution. CONCLUSION: Agglomeration, an overlooked material-sparing measure for powder cohesiveness, was a key indicator of powder processability and dissolution. The significant agglomerate reduction was possible via dry coating with either silica type at adequate surface area coverage. Reduced agglomeration after dry coating also countered the adverse impact of increased surface hydrophobicity on dissolution.

Reduced Fine API Agglomeration After Dry Coating for Enhanced Blend Uniformity and Processability of Low Drug Loaded Blends.

PURPOSE: The impact of dry coating on reduced API agglomeration remains underexplored. Therefore, this work quantified fine cohesive API agglomeration reduction through dry coating and its impact on enhanced blend uniformity and processability, i.e., flowability and bulk density of multi-component blends API loading as low as 1 wt%. METHODS: The impact of dry coating with two different types and amounts of silica was assessed on cohesion, agglomeration, flowability, bulk density, wettability, and surface energy of fine milled ibuprofen (~ 10 µm). API agglomeration, measured using Gradis/QicPic employing gentler gravity-based dispersion, resulted in excellent size resolution. Multi-component blends with fine-sized excipients, selected for reduced segregation potential, were tested for bulk density, cohesion, flowability, and blend content uniformity. Tablets formed using these blends were tested for tensile strength and dissolution. RESULT: All dry coated ibuprofen powders exhibited dramatic agglomeration reduction, corroborated by corresponding decreased cohesion, unconfined yield strength, and improved flowability, regardless of the type and amount of silica coating. Their blends exhibited profound enhancement in flowability and bulk density even at low API loadings, as well as the content uniformity for the lowest drug loading. Moreover, hydrophobic silica coating improved drug dissolution rate without appreciably reducing tablet tensile strength. CONCLUSION: The dry coating based reduced agglomeration of fine APIs for all three low drug loadings improved overall blend properties (uniformity, flowability, API release rate) due to the synergistic impact of a minute amount of silica (0.007 wt %), potentially enabling direct compression tableting and aiding manufacturing of other forms of solid dosing.

A systematic review of covered balloon-expandable stents for treating aortoiliac occlusive disease.

OBJECTIVE: To evaluate and compare studies reporting the outcomes of the use of covered balloon-expandable (CBE) stents for the treatment of aortoiliac occlusive disease. METHODS: A systematic literature search was conducted to identify studies that investigated the use of CBE stents for the treatment of aortoiliac occlusive disease and were published between 2000 and 2019. Baseline demographic data, procedural variables, and long-term outcomes were extracted from publications for analysis. RESULTS: A total of 15 published articles about 14 studies were included in the review. Of these, eight studies were prospective clinical trials and six studies were retrospective real-world studies. The articles included data regarding five different CBE stents, namely, the iCast/Advanta V12, Viabahn VBX, BeGraft, LifeStream, and JOSTENT. Lesion severity was higher in real-world studies, with more TransAtlantic Inter-Society Consensus Classification class D lesions and a higher percentage of occlusions. All studies showed high rates of technical success and patency over the course of 12 months. Long-term data were only available for the iCast/Advanta V12 device, which had a primary patency rate of 74.7% at 5 years. CONCLUSIONS: CBE stents are a viable treatment option for patients with complex aortoiliac lesions because of their high rates of technical success and favorable patency across all devices at 12 months. However, long-term data are only available for a single device, the iCast/Advanta V12. The results of using this device were favorable over the course of 5 years.

iCAST Balloon-Expandable Covered Stent for Iliac Artery Lesions: 3-Year Results from the iCARUS Multicenter Study.

PURPOSE: To evaluate safety and effectiveness of the iCAST Covered Stent for treatment of iliac artery atherosclerotic lesions. MATERIALS AND METHODS: The iCARUS trial (ClinicalTrials.gov Identifier: NCT00593385) was a single-arm, prospective, multicenter study that enrolled 152 per protocol subjects at 25 sites in the United States and Germany. Subjects with multiple lesions and/or stents were eligible. The primary endpoint was the composite rate of death within 30 days, target lesion revascularization (TLR) within 9 months, or restenosis at 9 months after procedure. Secondary endpoints included major adverse vascular events (MAVEs), primary patency, freedom from TLR, and clinical success. RESULTS: Device and acute procedural success were achieved in 98.7% and 92.7% of cases, respectively. MAVE rate was 4.6% at 30 days. The 9-month primary composite endpoint rate was 8.1% (10/123), which was below the performance goal of 16.57%. Nine-month primary patency, defined as continuous flow without revascularization, bypass, or target limb amputation, was 96.4%. Freedom from TLR at 9 months and 3 years was 97.2% and 86.6%, respectively. Early clinical success was seen in 88.7% of subjects at 30 days with sustained clinical benefit in 72.4% of subjects at 3 years. CONCLUSIONS: The iCARUS study demonstrated that the iCAST Covered Stent was safe and effective for treatment of atherosclerotic iliac artery lesions with sustained clinical benefit out to 3 years.

Convective Drying Kinetics of Polymer Strip Films Loaded with a BCS Class II Drug.

Polymer strip film is a promising dosage form for oral delivery of poorly water-soluble drugs. Drying is an important step in the production of polymer strip films with significant effects on critical quality attributes (CQAs). In this study, a custom-made batch drying setup was used to study convective drying kinetics of wet polymer strip films loaded with dry-coated micronized griseofulvin (GF) at various drying conditions. A rate-based semi-empirical model was formulated and parameters were estimated by integral method of analysis using a coupled optimizer-ordinary differential equation solver. Despite its simplicity with three parameters, the model could fit the experimental data very well for all drying conditions, which enabled us to examine the effects of air velocity, temperature, and initial wet film thickness on drying kinetics quantitatively. The modeling results clearly delineate a drying mechanism with constant-rate and falling-rate periods. One set of kinetic parameter estimates reasonably predicted the drying kinetics for two different wet film thicknesses in the selected process conditions, which demonstrates the predictive capability of the model. After reporting the limitations of the semi-empirical model, upon future modification and refinement, its potential use in drying process development and process control was highlighted.

Sustained Release of Poorly Water-Soluble Drug from Hydrophilic Polymeric Film Sandwiched Between Hydrophobic Layers.

This proof-of-concept study explores the feasibility of using a drug-loaded hydrophilic polymeric layer sandwiched between two hydrophobic layers for improving film drug load while achieving sustained release of poorly water-soluble drug. Such films having total thickness in range ~ 146-250 µm were prepared by slurry-based casting using hydrophilic hydroxypropyl methylcellulose (HPMC) as matrix layer containing fenofibrate (FNB) as the model drug, encased between two very thin rate-limiting layers of 10 µm each of hydrophobic poly-ɛ-caprolactone (PCL). Film precursor slurry consisted of HPMC with plasticizer and water along with micronized FNB powders, which were dry-coated with hydrophilic silica. Characterization techniques demonstrated the presence of homogeneously dispersed crystalline FNB in films. The films are very thin and hence two-dimensional; hence, average drug load per unit area in range ~ 5 to ~ 9 mg/cm2 could be achieved by altering the thickness of the drug matrix layer. Drug amount and drug content uniformity were measured through assay of ten circular samples ~ 0.712 cm2 in area punched out using a circular-shaped punch tool. Drug release rate was investigated using USP IV flow-through cell and surface dissolution imaging system. Thinner films followed Fickian diffusion, and thicker films followed non-Fickian anomalous diffusion. Overall, the application of middle layer thickness could be used as a tool to manipulate drug load without the need for altering its formulation or precursor preparation by changing its thickness, hence achieving relatively high drug loading yet having sustained release of drug.

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement.

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 µm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

An Intensified Vibratory Milling Process for Enhancing the Breakage Kinetics during the Preparation of Drug Nanosuspensions.

As a drug-sparing approach in early development, vibratory milling has been used for the preparation of nanosuspensions of poorly water-soluble drugs. The aim of this study was to intensify this process through a systematic increase in vibration intensity and bead loading with the optimal bead size for faster production. Griseofulvin, a poorly water-soluble drug, was wet-milled using yttrium-stabilized zirconia beads with sizes ranging from 50 to 1500 µm at low power density (0.87 W/g). Then, this process was intensified with the optimal bead size by sequentially increasing vibration intensity and bead loading. Additional experiments with several bead sizes were performed at high power density (16 W/g), and the results were compared to those from wet stirred media milling. Laser diffraction, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and dissolution tests were used for characterization. Results for the low power density indicated 800 µm as the optimal bead size which led to a median size of 545 nm with more than 10% of the drug particles greater than 1.8 µm albeit the fastest breakage. An increase in either vibration intensity or bead loading resulted in faster breakage. The most intensified process led to 90% of the particles being smaller than 300 nm. At the high power intensity, 400 µm beads were optimal, which enhanced griseofulvin dissolution significantly and signified the importance of bead size in view of the power density. Only the optimally intensified vibratory milling led to a comparable nanosuspension to that prepared by the stirred media milling.

Spray drying of drug-swellable dispersant suspensions for preparation of fast-dissolving, high drug-loaded, surfactant-free nanocomposites.

Bioavailability of a poorly soluble drug can be improved by preparing a drug nanosuspension and subsequently drying it into nanocomposite microparticles (NCMPs). Unfortunately, drug nanoparticles aggregate during milling and drying, causing incomplete recovery and slow dissolution. The aim of this study is to investigate the impact of various classes of dispersants on drug dissolution from drug NCMPs, with the ultimate goal of enhancing the bioavailability of poorly water-soluble drugs via high drug nanoparticle loaded, surfactant-free NCMPs. Precursor suspensions of griseofulvin (GF, model drug) nanoparticles in the presence of various dispersants were prepared via wet stirred media milling and spray dried to form the NCMPs. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as a base-line stabilizer/dispersant during milling. Two swellable crosslinked polymers, croscarmellose sodium (CCS) and sodium starch glycolate (SSG), and a conventional soluble matrix former, Mannitol, were used in addition to HPC. Besides being used as-received, CCS was also wet co-milled with GF for two different durations to examine the impact of CCS particle size. Laser diffraction, scanning electron microscopy, powder X-ray diffraction (XRD), UV spectroscopy, NCMP redispersion and dissolution tests were used for characterization. The results show that incorporation of CCS/SSG, preferably wet-milled to a wide particle size distribution, into the spray-dried NCMPs resulted in fast release and dispersion of drug nanoparticle clusters. The swellable dispersants were superior to Mannitol in dissolution enhancement, and could achieve fast release comparable to SDS, demonstrating the feasibility of spray drying to prepare high drug-loaded, surfactant-free nanocomposites.

Preparation of concentrated stable fenofibrate suspensions via liquid antisolvent precipitation.

A major challenge in achieving size stability for relatively high concentration of fine particles from poorly water-soluble drug fenofibrate (FNB) is addressed through T-mixing based liquid antisolvent precipitation in the presence of ultrasonication and judicious use of stabilizers. Multiple stabilizers were screened in a batch mode prior to their continuous formation via T-mixing. In both cases, the stable suspensions maintained their size after 2 days of storage at room temperature, with the smallest particle size of d50: ∼1.2 µm was achieved through a combination of HPMC with SDS or PF-68. The influence of processing parameters, such as sonication energy, sonication probe insert depth and solvent/antisolvent flow rate, on the particle size distribution (PSD) in T-mixing were investigated, to identify optimum processing conditions. Optimal operating and formulation conditions also allowed increase in the drug loading from 0.32% to 4% (w/v), while keeping the median size 2.5 µm. Interestingly, the primary particles observed in the SEM were spherical and under 100 nm in diameter, indicating agglomeration. It was shown that the stabilized particles could be centrifuged and did not show size growth upon resuspension, allowing for increase in the drug loading up to 27% (w/v), which is a significant novel outcome.

Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant-free nanocomposite microparticles incorporating wet-milled swellable dispersants.

Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet-milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose® to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles.

Facilitating direct compaction tableting of fine cohesive APIs using dry coated fine excipients: Effect of the excipient size and amount of coated silica.

The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of APIs. Three APIs, very-cohesive micronized acetaminophen (mAPAP, 7 µm), cohesive acetaminophen (cAPAP, 23 µm), and easy-flowing ibuprofen (IBU, 53 µm), were selected. High DL (60 wt%) binary blends were prepared with different fine-milled MCC-based excipients (ranging 20- 37 µm) with or without A200 silica coating during milling. The blend flowability (flow function coefficient -FFC) and bulk density (BD) of the blends for all three APIs were significantly improved by 1 wt% A200 dry coated MCCs; reaching FFC of 4.28 from 2.14, 7.82 from 2.96, and > 10 from 5.57, for mAPAP, cAPAP, and IBU blends, respectively, compared to the uncoated MCC blends. No negative impact was observed on the tablet tensile strength (TS) by using dry coated MCCs despite lower surface energy of silica. Instead, the desired tablet TS levels were reached or exceeded, even above that for the blends with uncoated milled MCCs. The novelty here is that milled and silica coated fine MCCs could promote DC tableting for cAPAP and IBU blends at 60 wt% DL through adequate flowability and tensile strength, without having to dry coat the APIs. The effect of the silica amount was investigated, indicating lesser had a positive impact on TS, whereas the higher amount had a positive impact on flowability. Thus, the finer excipient size and silica amounts may be adjusted to potentially attain blend DC processability for high DL blends of fine APIs.

Impact of dry coating lactose as a brittle excipient on multi-component blend processability.

Previous work demonstrated the benefits of dry coating fine-grade microcrystalline cellulose (MCC) for enabling direct compression (DC), a favored tablet manufacturing method, due to enhanced flowability while retaining good compactability of placebo and binary blends of cohesive APIs. Here, fine brittle excipients, Pharmatose 450 (P450, 19 µm) and Pharmatose 350 (P350, 29 µm), having both poor flowability and compactability are dry coated with silica A200 or R972P to assess DC capability of multi-component cohesive API (coarse acetaminophen, 22 µm, and ibuprofen50, 47 µm) blends. Dry coated P450 and P350 not only attained excellent flowability and high bulk density but also heightened tensile strength hence processability, which contrasts with reported reduction for dry coated ductile MCC. Although hydrophobic R972P imparted better flowability, hydrophilic A200 better enhanced tensile strength, hence selected for dry coating P450 in multi-component blends that included fine Avicel PH-105. For coarse acetaminophen blends, substantial bulk density and flowability increase without any detrimental effect on tensile strength were observed; a lesser amount of dry coated P450 was better. Increased flowability, bulk density, and tensile strength, hence enhanced processability by reaching DC capability, were observed for 60 wt% ibuprofen50, using only 18 wt% of the dry coated P450, i.e. 0.18 wt% silica in the blend.

Nine-month results of the REFORM study: a prospective, single-arm, multicenter clinical study of the safety and effectiveness of the Formula™ balloon-expandable stent for treatment of renal artery stenosis.

OBJECTIVES: To evaluate the 9-month safety and effectiveness outcomes of the Formula™ balloon-expandable renal stent (Cook Medical, Bloomington, IN) for the treatment of atherosclerotic renal artery stenosis (RAS) following suboptimal angioplasty. BACKGROUND: Atherosclerotic RAS can cause hypertension and ischemic nephropathy. When clinically indicated, an interventional approach with renal angioplasty and stent implantation is the preferred method for revascularization of atherosclerotic renal artery stenoses. METHODS: The REFORM study is a prospective, multicenter, single-arm study of stent implantation following suboptimal PTRA using the Formula stent. One hundred patients with atherosclerotic ostial renal artery lesions =18 mm in length with a >50% residual stenosis following PTA were enrolled. The primary endpoint was 9-month primary patency. RESULTS: The 9-month primary patency rate was 91.7%. The 9-month major adverse event rate was 2.2%. Mean systolic blood pressure was significantly decreased at follow-up (from 150 ± 21 mm Hg at baseline to 141 ± 21 mm Hg at 9 months; P = 0.003). Mean serum creatinine (SCr) level and mean estimated glomerular filtration rate (eGFR) were not significantly different at 9 months. A clinically meaningful improvement in renal function (i.e., =25% increase in eGFR or =0.5 mg/dl decrease in SCr) was observed in 9% of patients at 1 month and 12% of patients at 9 months. A clinically meaningful decline in renal function (i.e., =25% decrease in eGFR or =0.5 mg/dl increase in SCr) was observed in only 3% of patients at 1 month and 7% of patients at 9 months. CONCLUSIONS: The Formula stent was safe and effective in treating atherosclerotic RAS following suboptimal angioplasty.

Impact of Silica Dry Coprocessing with API and Blend Mixing Time on Blend Flowability and Drug Content Uniformity.

This paper considers two fine-sized (d50 ∼10 µm) model drugs, acetaminophen (mAPAP) and ibuprofen (Ibu), to examine the effect of API dry coprocessing on their multi-component medium DL (30 wt%) blends with fine excipients. The impact of blend mixing time on the bulk properties such as flowability, bulk density, and agglomeration was studied. The hypothesis tested is that blends with fine APIs at medium DL require good blend flowability to have good blend uniformity (BU). Moreover, the good flowability could be achieved through dry coating with hydrophobic (R972P) silica, which reduces agglomeration of not only fine API, but also of its blends while using fine excipients. For uncoated APIs, the blend flowability was poor, i.e. cohesive regime at all mixing times, and the blends failed to achieve acceptable BU. In contrast, for dry coated APIs, their blend flowability improved to easy-flow regime or better, improving with mixing time, and as hypothesized, all blends consequently achieved desired BU. All dry coated API blends exhibited improved bulk density and reduced agglomeration, attributed to mixing induced synergistic property enhancements, likely due to silica transfer. Despite coating with hydrophobic silica, tablet dissolution was improved, attributed to the reduced agglomeration of fine API.

Enhanced blend uniformity and flowability of low drug loaded fine API blends via dry coating: The effect of mixing time and excipient size.

Although previous research demonstrated improved flowability, packing, fluidization, etc. of individual powders via nanoparticle dry coating, none considered its impact on very low drug loaded blends. Here, fine ibuprofen at 1, 3, and 5 wt% drug loadings (DL) was used in multi-component blends to examine the impact of the excipients size, dry coating with hydrophilic or hydrophobic silica, and mixing times on the blend uniformity, flowability and drug release rates. For uncoated active pharmaceutical ingredients (API), the blend uniformity (BU) was poor for all blends regardless of the excipient size and mixing time. In contrast, for dry coated API having low agglomerate ratio (AR), BU was dramatically improved, more so for the fine excipient blends, at lesser mixing times. For dry coated API, the fine excipient blends mixed for 30 min had enhanced flowability and lower AR; better for the lowest DL having lesser silica, likely due to mixing induced synergy of silica redistribution. For the fine excipient tablets, dry coating led to fast API release rates even with hydrophobic silica coating. Remarkably, the low AR of the dry coated API even at very low DL and amounts of silica in the blend led to the enhanced blend uniformity, flow, and API release rate.

Real-world use of the Impella 2.5 circulatory support system in complex high-risk percutaneous coronary intervention: the USpella Registry.

OBJECTIVES: We report on the real-world, multicenter experience of the Impella 2.5 circulatory support system during high-risk PCI, a subset of the larger USpella Registry. BACKGROUND: Standard of care for most patients with compromised ventricular function with multivessel or high-risk coronary lesions has been coronary artery bypass grafting. In poor operative candidates, high-risk PCI is increasingly considered, despite an increased risk for periprocedural hemodynamic compromise. METHODS: 175 consecutive patients who underwent high-risk PCI with prophylactic support of the Impella 2.5 were evaluated. The primary safety endpoint was the incidence of major adverse cardiac events (MACE) at 30 days. Secondary endpoints included safety and efficacy related to the device and patient outcomes, including survival at 12 months. RESULTS: Overall angiographic revascularization was successful in 99% of patients and in 90% of those with multivessel revascularization, resulting in a reduction of the mean SYNTAX score post-PCI from 36 ± 15 to 18 ± 15 (P < 0.0001) and an improvement of the ejection fraction (from 31 ± 15% to 36 ± 14%, P < 0.0001). In 51% of patients, the functional status improved by one or more NYHA class (P < 0.001). At 30-day follow-up, the rate of MACE was 8%, and survival was 96%, 91%, and 88% at 30 days, 6 months, and 12 months, respectively. CONCLUSIONS: The use of Impella 2.5 in high-risk PCI appeared feasible and safe in the real-world setting. The utilization of the Impella 2.5 was successful, resulting in favorable short- and midterm angiographic, procedural and clinical outcomes.