pinecone/core-2020-05-10-deduplication huggingface dataset:
Microneedle assisted micro-particle delivery from gene guns: experiments using skin-mimicking agarose gel

This article was published in the serial Journal of Pharmaceutical Sciences [© Wiley Periodicals, Inc. and the American Pharmacists Association]. The definitive version is available at: http://dx.doi.org/10.1002/jps.23835A set of laboratory experiments has been carried out to determine if micro-needles (MNs) can enhance penetration depths of high-speed micro-particles delivered by a type of gene gun. The micro-particles were fired into a model target material, agarose gel, which was prepared to mimic the viscoelastic properties of porcine skin. The agarose gel was chosen as a model target as it can be prepared as a homogeneous and transparent medium with controllable and reproducible properties allowing accurate determination of penetration depths. Insertions of various MNs into gels have been analysed to show that the length of the holes increases with an increase in the agarose concentration. The penetration depths of micro-particle were analysed in relation to a number of variables, namely the operating pressure, the particle size, the size of a mesh used for particle separation and the MN dimensions. The results suggest that the penetration depths increase with an increase of the mesh pore size, because of the passage of large agglomerates. As these particles seem to damage the target surface, then smaller mesh sizes are recommended; here, a mesh with a pore size of 178 μm was used for the majority of the experiments. The operating pressure provides a positive effect on the penetration depth, that is it increases as pressure is increased. Further, as expected, an application of MNs maximises the micro-particle penetration depth. The maximum penetration depth is found to increase as the lengths of the MNs increase, for example it is found to be 1272 ± 42, 1009 ± 49 and 656 ± 85 μm at 4.5 bar pressure for spherical micro-particles of 18 ± 7 μm diameter when we used MNs of 1500, 1200 and 750 μm length, respectively
Control of Protein Particle Formation During Ultrafiltration/Diafiltration Through Interfacial Protection

ABSTRACTThis study investigates the mechanism of protein particle formation during ultrafiltration/diafiltration (UF/DF), finding that agitation drives particle formation by promoting protein-interface adsorption and desorption. Low conductivity and the presence of surfactant reduced the level of particle formation in small-scale stirring studies, and the same trends were observed in pumping and UF/DF. Polysorbate 80 (PS80) and hydroxypropyl-β-cyclodextrin (HPβCD) reduced particle formation in UF/DF by factors of 15 and 4, respectively. Measurements of conformational stability, colloidal stability, and surface tension demonstrated that PS80 protects against particle formation by preventing protein-interface adsorption, low conductivity improves the colloidal stability of the protein, and the mechanism of action of HPβCD remains unclear. This work demonstrates that interfacial adsorption–desorption of the protein during UF/DF is the principal cause of particle formation, that the level of surfactant-free particle formation depends on the colloidal stability of the protein, and that the inclusion of surfactant greatly reduces in-process particle formation during UF/DF
The Influence of Drug Physical State on the Dissolution Enhancement of Solid Dispersions Prepared Via Hot-Melt Extrusion: A Case Study Using Olanzapine

ABSTRACTIn this study, we examine the relationship between the physical structure and dissolution behavior of olanzapine (OLZ) prepared via hot-melt extrusion in three polymers [polyvinylpyrrolidone (PVP) K30, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) 6:4, and Soluplus® (SLP)]. In particular, we examine whether full amorphicity is necessary to achieve a favorable dissolution profile. Drug–polymer miscibility was estimated using melting point depression and Hansen solubility parameters. Solid dispersions were characterized using differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. All the polymers were found to be miscible with OLZ in a decreasing order of PVP>PVPVA>SLP. At a lower extrusion temperature (160°C), PVP generated fully amorphous dispersions with OLZ, whereas the formulations with PVPVA and SLP contained 14%–16% crystalline OLZ. Increasing the extrusion temperature to 180°C allowed the preparation of fully amorphous systems with PVPVA and SLP. Despite these differences, the dissolution rates of these preparations were comparable, with PVP showing a lower release rate despite being fully amorphous. These findings suggested that, at least in the particular case of OLZ, the absence of crystalline material may not be critical to the dissolution performance. We suggest alternative key factors determining dissolution, particularly the dissolution behavior of the polymers themselves. © 2014 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1214–1223, 201
Functional Evaluation and Characterization of a Newly Developed Silicone Oil-Free Prefillable Syringe System

ABSTRACTThe functionality of a newly developed silicone oil-free (SOF) syringe system, of which the plunger stopper is coated by a novel coating technology (i-coating™), was assessed. By scanning electron microscopy observations and other analysis, it was confirmed that the plunger stopper surface was uniformly covered with the designed chemical composition. A microflow imaging analysis showed that the SOF system drastically reduced both silicone oil (SO) doplets and oil-induced aggregations in a model protein formulation, whereas a large number of subvisible particles and protein aggregations were formed when a SO system was used. Satisfactory container closure integrity (CCI) was confirmed by means of dye and microorganism penetration studies. Furthermore, no significant difference between the break loose and gliding forces was observed in the former, and stability studies revealed that the SOF system could perfectly show the aging independence in break loose force observed in the SO system. The results suggest that the introduced novel SOF system has a great potential and represents an alternative that can achieve very low subvisible particles, secure CCI, and the absence of a break loose force. In particular, no risk of SO-induced aggregation can bring additional value in the highly sensitive biotech drug market. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association
Small-Angle X-ray Scattering Screening Complements Conventional Biophysical Analysis: Comparative Structural and Biophysical Analysis of Monoclonal Antibodies IgG1, IgG2, and IgG4

ABSTRACTA crucial step in the development of therapeutic monoclonal antibodies is the selection of robust pharmaceutical candidates and screening of efficacious protein formulations to increase the resistance toward physicochemical degradation and aggregation during processing and storage. Here, we introduce small-angle X-ray scattering (SAXS) to characterize antibody solution behavior, which strongly complements conventional biophysical analysis. First, we apply a variety of conventional biophysical techniques for the evaluation of structural, conformational, and colloidal stability and report a systematic comparison between designed humanized IgG1, IgG2, and IgG4 with identical variable regions. Then, the high information content of SAXS data enables sensitive detection of structural differences between three IgG subclasses at neutral pH and rapid formation of dimers of IgG2 and IgG4 at low pH. We reveal subclass-specific variation in intermolecular repulsion already at low and medium protein concentrations, which explains the observed improved stability of IgG1 with respect to aggregation. We show how excipients dramatically influence such repulsive effects, hence demonstrating the potential application of extensive SAXS screening in antibody selection, eventual engineering, and formulation development. © 2014 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1701-1710, 201
Modifying the Release Properties of Liposomes Toward Personalized Medicine

ABSTRACTSurfactant-liposome interactions have historically been investigated as a simplified model of solubilization and breakdown of biological membranes by surfactants. In contrast, our goal was to utilize surfactants to modify the encapsulation and release properties of liposomes. The ability to manufacture one liposomal formulation, which could be modified by the addition of a surfactant to support a wide range of release profiles, would provide greater flexibility than manufacturing multiple batches of liposomes, each differing in composition and with its own specific release profile. A liposomal ciprofloxacin formulation was modified by the addition of various surfactants. These formulations were characterized in terms of liposome structure by cryo-TEM imaging, vesicle size by dynamic light scattering, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance. The addition of polysorbate 20 or polysorbate 80 to liposomal ciprofloxacin, in a hypotonic environment, resulted in a concentration-dependent loss of encapsulated drug, and above 0.4% polysorbate 20, or 0.2% polysorbate 80, a modified IVR profile as well. This study demonstrates that the encapsulation and release properties of a liposomal formulation can be modified postmanufacture by the addition of judiciously chosen surfactants in combination with osmotic swelling of the liposomes and may support a personalized approach to treating patients. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1851-1862,201
Infrared Thermography for Monitoring of Freeze-Drying Processes: Instrumental Developments and Preliminary Results

ABSTRACTCoupling an infrared (IR) camera to a freeze dryer for on-line monitoring of freeze-drying cycles is described for the first time. Normally, product temperature is measured using a few invasive Pt-100 probes, resulting in poor spatial resolution. To overcome this, an IR camera was placed on a process-scale freeze dryer. Imaging took place every 120 s through a Germanium window comprising 30,000 measurement points obtained contact-free from −40°C to 25°C. Results are presented for an empty system, bulk drying of cheese slurry, and drying of 1 mL human serum in 150 vials. During freezing of the empty system, differences of more than 5°C were measured on the shelf. Adding a tray to the empty system, a difference of more than 8°C was observed. These temperature differences probably cause different ice structures affecting the drying speed during sublimation. A temperature difference of maximum 13°C was observed in bulk mode during sublimation. When drying in vials, differences of more than 10°C were observed. Gradually, the large temperature differences disappeared during secondary drying and products were transformed into uniformly dry cakes. The experimental data show that the IR camera is a highly versatile on-line monitoring tool for different kinds of freeze-drying processes. © 2014 European Union 103:2088–2097, 201
Sucrose esters increase drug penetration, but do not inhibit P-glycoprotein in Caco-2 intestinal epithelial cells

Sucrose fatty acid esters are increasingly used as excipients \ud
in pharmaceutical products, but few data are available on\ud
their toxicity profile, mode of action, and efficacy on \ud
intestinal epithelial models. Three water-soluble sucrose \ud
esters, palmitate (P-1695),\ud
myristate (M-1695), laurate (D-1216), and two reference \ud
absorption enhancers, Tween 80 and Cremophor RH40, were \ud
tested on Caco-2\ud
cells. Caco-2 monolayers formed a good barrier as reflected \ud
by high transepithelial resistance and positive \ud
immunostaining for junctional\ud
proteins claudin-1, ZO-1, and\ud
-catenin. Sucrose esters in nontoxic concentrations \ud
significantly reduced resistance and impedance, and\ud
increased permeability for atenolol, fluorescein, \ud
vinblastine, and rhodamine 123 in Caco-2 monolayers. No \ud
visible opening of the tight\ud
junctions was induced by sucrose esters assessed by \ud
immunohistochemistry and electron microscopy, but some \ud
alterations were seen in\ud
the structure of filamentous actin microfilaments. Sucrose \ud
esters fluidized the plasma membrane and enhanced the \ud
accumulation of efflux\ud
transporter ligands rhodamine 123 and calcein AM in \ud
epithelial cells, but did not inhibit the P-glycoprotein (P-\ud
gp)-mediated calcein AM\ud
accumulation in MES-SA/Dx5 cell line. These data indicate \ud
that in addition to their dissolution-increasing properties \ud
sucrose esters can\ud
enhance drug permeability through both the transcellular and \ud
paracellular routes without inhibiting P-gp
Development and characterization of a novel, antimicrobial, sterile hydrogel dressing for burn wounds : single-step production with gamma irradiation creates silver nanoparticles and radical polymerization

Patients with burn wounds are susceptible to wound infection and sepsis. This research introduces a novel burn wound dressing that contains silver nanoparticles (SNPs) to treat infection in a 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na(+) ) hydrogel. Silver nitrate was dissolved in AMPS-Na(+) solution and then exposed to gamma irradiation to form SNP-infused hydrogels. The gamma irradiation results in a cross-linked polymeric network of sterile hydrogel dressing and a reduction of silver ions to form SNPs infused in the hydrogel in a one-step process. About 80% of the total silver was released from the hydrogels after 72 h immersion in simulated body fluid solution; therefore, they could be used on wounds for up to 3 days. All the hydrogels were found to be nontoxic to normal human dermal fibroblast cells. The silver-loaded hydrogels had good inhibitory action against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Results from a pilot study on a porcine burn model showed that the 5-mM silver hydrogel was efficient at preventing bacterial colonization of wounds, and the results were comparable to the commercially available silver dressings (Acticoat(TM) , PolyMem Silver(®) ). These results support its use as a potential burn wound dressing
Historical Data Analyses and Scientific Knowledge Suggest Complete Removal of the Abnormal Toxicity Test as a Quality Control Test

ABSTRACTIn the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940. The evidence of abnormal toxicity testing as a prediction for harmful batches is highly questionable and lacks a scientific rationale. Numerous reviews of historical ATT results have revealed that no reliable conclusions can be drawn from this QC measure. Modern pharmaceutical manufacturers have thorough control of the manufacturing process and comply with good manufacturing practice rules. Contaminants are appropriately controlled by complying with the validated manufacturing processes and strict QC batch release confirming batch-to-batch consistency. Recognizing that product safety, efficacy, and stability can be ensured with strict QC measures, nowadays most regulatory authorities do not require the ATT for most product classes. In line with the replacement, reduction, and refinement (3Rs) initiative, the test requirement has been deleted from approximately 80 monographs of the European Pharmacopoeia and for the majority of product classes in the United States. For these reasons, it is recommended that the ATT should be consistently omitted world-wide and be removed from pharmacopoeias and other regulatory requirements. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3349–3355, 201
In Vitro Evaluation of Cenderitide‐Eluting Stent I —An Antirestenosis and Proendothelization Approach

ABSTRACTDespite the success that drug‐eluting stents (DESs) have achieved for minimizing in‐stent restenosis (ISR), the antirestenotic agents used in DES have been implicated in delayed endothelial healing and impairment of endothelial functions. Cenderitide (CD‐NP) is a novel antiproliferation chimeric peptide of semiendothelial origin; thus, this paper aims to demonstrate the selectivity aspect of this new peptide via in vitro evaluation on key players in ISR—smooth muscle cells (SMCs) and endothelial cells. The microbicinchoninic acid protein assay was used to investigate the CD‐NP release from films and stents. Cenderitide‐containing films blended with poly(ethylene glycol) and its copolymer exhibited higher release kinetics compared with neat poly(ε‐caprolactone) (PCL) formulation. Cenderitide‐eluting stents (CES) was produced by coating bare metallic stents with CD‐NP entrapped PCL using an ultrasonic spray coater. The investigation of CD‐NP on in vitro cells revealed that CD‐NP inhibits human coronary smooth muscle cells (HCaSMCs) proliferation but exhibits no effects on human umbilical vein endothelial cells (HUVECs) proliferation. Moreover, CD‐NP released up to 7 days displayed inhibitory effects on SMCs proliferation. The CES produced in this work shows that the released CD‐NP inhibits HCaSMCs proliferation but did not hamper HUVECs proliferation in vitro, suggesting that it has potential to reduce ISR without retarding the endothelialization healing in vivo. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3631–3640, 201
Microneedles for Drug Delivery via the Gastrointestinal Tract

Both patients and physicians prefer the oral route of drug delivery. The gastrointestinal (GI) tract, though, limits the bioavailability of certain therapeutics because of its protease and bacteria-rich environment as well as general pH variability from pH 1 to 7. These extreme environments make oral delivery particularly challenging for the biologic class of therapeutics. Here, we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract.National Institutes of Health (U.S.) (Grant EB000244)National Institutes of Health (U.S.) (Grant T32DK7191-38-S1
Effects of Syringe Material and Silicone Oil Lubrication on the Stability of Pharmaceutical Proteins

ABSTRACTCurrently, polymer-based prefillable syringes are being promoted to the pharmaceutical market because they provide an increased break resistance relative to traditionally used glass syringes. Despite this significant advantage, the possibility that barrel material can affect the oligomeric state of the protein drug exists. The present study was designed to compare the effect of different syringe materials and silicone oil lubrication on the protein aggregation. The stability of a recombinant fusion protein, abatacept (Orencia), and a fully human recombinant immunoglobulin G1, adalimumab (Humira), was assessed in silicone oil-free (SOF) and silicone oil-lubricated 1-mL glass syringes and polymer-based syringes in accelerated stress study. Samples were subjected to agitation stress, and soluble aggregate levels were evaluated by size-exclusion chromatography and verified with analytical ultracentrifugation. In accordance with current regulatory expectations, the amounts of subvisible particles resulting from agitation stress were estimated using resonant mass measurement and dynamic flow-imaging analyses. The amount of aggregated protein and particle counts were similar between unlubricated polymer-based and glass syringes. The most significant protein loss was observed for lubricated glass syringes. These results suggest that newly developed SOF polymer-based syringes are capable of providing biopharmaceuticals with enhanced physical stability upon shipping and handling. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:527–535, 201
Solid-state supramolecular synthesis based on the N–H...O heterosynthon: an approach to solve the polymorphism problem in famotidine

Famotidine (FMT), a histamine H2-receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)+ in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)+ side chain. Nonconventional π–stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET: PIP 112-201101-00912)Universidad Nacional de San Luis (SECyT-UNSL Project 2-1612)CNPqFAPESP (09/54035-4
In Vitro Liberation of Indomethacin from Chitosan Gels Containing Microemulsion in Different Dissolution Mediums

ABSTRACT:The objective of this research is to outline the liberation of indomethacin from different chitosan gels containing O/W microemulsion. The influence of surfactant, sodium lauryl sulfate, in two concentrations (0.5% and 0.75%, w/w) was determined in dissolution medium on the release of indomethacin, which was used as poor water-soluble model drug. Chitosan gels were prepared in four different concentrations of chitosan—1%, 1.5%, 2%, and 3% (w/w). Microemulsion enhanced the liberation of the indomethacin from chitosan gels into all dissolution mediums. Adding the surfactant into phosphate-buffered saline decreased the amount of liberated indomethacin from microemulsion, gel mixture, but increased the drug liberation from pure chitosan gels. It was detected that with the increased concentration of chitosan in the samples, the amount of indomethacin liberated (p < 0.05) also increased. A conclusion was drawn that the liberation of indomethacin from chitosan gels was influenced by increased pH of the samples. The high viscosity induced a higher release of indomethacin from 3% (w/w) chitosan hydrogel at pH 5.8 as compared with 3% (w/w) chitosan hydrogel at pH 3.8. The highest percentage of released indomethacin was determined when a mixture of microemulsion gel with higher chitosan content was used. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association