pinecone/core-2020-05-10-deduplication huggingface dataset:
An adsorption chromatography assay to probe bulk particle transport through hydrogels

Biopolymer-based hydrogels such as mucus and the basal lamina play a key role in biology, where they control the exchange of material between different compartments. They also pose a barrier that needs to be overcome for successful drug delivery. Characterizing the permeability properties of such hydrogels is mandatory for the development of suitable drug delivery vectors and pharmaceutics. Here, we present an experimental method to measure bulk particle transport through hydrogels. We validate our assay by applying it to mucin hydrogels and show that the permeability properties of these mucin hydrogels can be modulated by polymer density and pH, in agreement with previous results obtained from single particle tracking. The method we present here is easy to handle, inexpensive, and high-throughput compatible. It is also a suitable platform for the design and screening of drugs that aim at modifying the barrier properties of hydrogels. This system can also aid in the characterization and development of synthetic gels for a range of biomedical applications.National Institutes of Health (U.S.) (Grant P50-GM068763)National Institutes of Health (U.S.) (Grant P30-ES002109
Production and characterization of carbamazepine nanocrystals by electrospraying for continuous pharmaceutical manufacturing

In this paper, an electrospray technique followed by annealing at high temperatures was developed to produce nanocrystals of carbamazepine (CBZ), a poorly water-soluble drug, for continuous pharmaceutical manufacturing process. Electrospraying solutions of CBZ in methanol obeys the expected scaling law of current, which is I ∼ Q[superscript 1/2] (I, electrical current; Q, flow rate), for liquids with sufficiently high conductivity and viscosity. Lower flow rates during electrospraying were preferred to produce smaller diameters of monodisperse, dense CBZ nanoparticles. CBZ nanoparticles were predominantly amorphous immediately after electrospraying. Crystallization of CBZ nanoparticles was accelerated by annealing at high temperatures. CBZ nanocrystals with the most stable polymorph, form III, were obtained by annealing at 90°C, which is above the transition temperature, 78°C, for the enantiotropic CBZ form III and form I. The solubility and dissolution rates of CBZ nanocrystals increased significantly as compared with those of CBZ bulk particles. Therefore, electrospray technology has the potential to produce pharmaceutical dosage forms with enhanced bioavailability and can readily be integrated in a continuous pharmaceutical manufacturing process.Novartis-MIT Center for Continuous Manufacturin
A Novel Long-Acting Human Growth Hormone Fusion Protein (VRS-317): Enhanced In Vivo Potency and Half-Life

ABSTRACT:A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS-317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was threefold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4mg/kg VRS-317 (equivalent to 0.26mg/kg rhGH) caused a sustained pharmacodynamic response for 1month equivalent to 0.05mg/kg/day rhGH (1.4mg/kg rhGH total over 28days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observations in these animal studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Associatio
Suppository formulations as a potential treatment for nephropathic cystinosis.

Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of all the organs. It is treated by the 6-h oral administration of the aminothiol, cysteamine, which has an offensive taste and smell. In an attempt to reduce this frequency and improve the treatment, cysteamine-containing polyethylene glycol suppositories were prepared and evaluated for dissolution and stability. The results demonstrated that cysteamine release was complete after 30 min, and that there was a uniform drug distribution within the formulations. Twelve-month stability tests highlighted a potential incompatibility among some excipients, although stability was demonstrated for the cysteamine suppositories up to 6 months. These suppositories may provide a useful alternative to the current oral therapy for cystinosis.Cystinosis Foundation, UK ; TENOVUS, Scotlan
Conjugating drug candidates to polymeric chains does not necessarily enhance anti-influenza activity

Using the plaque reduction assay, relatively simple bicyclic quinone molecules, as well as multiple copies thereof covalently attached to a long polyglutamate-based polymeric chain, were examined as new inhibitors of various naturally occurring strains of influenza A virus. The polymer-conjugated inhibitors were found to have a far greater potency (for some as high as two orders of magnitude when a long spacer arm was employed) than their corresponding parent molecules against the human Wuhan influenza strain. However, such polymeric inhibitors failed to exhibit higher potency compared with their small molecule predecessors against the human Puerto Rico and avian turkey influenza strains. These observations, further explored by means of molecular modeling, reveal the previously unrecognized unpredictability of the benefits of multivalency, possibly because of poor accessibility of the viral targets to polymeric agentsNational Institutes of Health (U.S.) (Grant U01-AI074443
Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches

This is the accepted version of the following article: OLATUNJI, O. ... et al, 2013. Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches. Journal of Pharmaceutical Sciences, 102 (4), pp. 1209 - 1221, which has been published in final form at: http://dx.doi.org/10.1002/jps.23439Insertion behaviour of microneedle (MN) arrays depends upon the mechanical properties of the skin and, MN geometry and distribution in an array. In addressing this issue, this paper studies MN array insertion mechanism into skin and provides a simple quantitative basis to relate the insertion force with distance between two MNs. The presented framework is based on drawing an analogy between a beam on an elastic foundation and mechanism of needle insertion, where insertion force is separated into different components. A theoretical analysis indicates that insertion force decreases as interspacing increases. For a specified skin type, insertion force decreased from 0.029 to 0.028N/MN when interspacing at MN tip was increased from 50μm (350μm at MN base) to 150μm (450μm at MN base). However, dependence of insertion force seems to decrease as the interspacing is increased beyond 150μm. To assess the validity of the proposed model, a series of experiments was carried out to determine the force required for skin insertion of MN. Experiments performed at insertion speed of 0.5 and 1.0mm/s yielded insertion force values of 0.030 and 0.0216N, respectively, for 30μm interspacing at MN base (330μm interspacing at tip) and 0.028 and 0.0214N, respectively, for 600μm interspacing at MN base (900μm interspacing at tip). Results from theoretical analysis and finite element modelling agree well with experimental results, which show MN interspacing only begins to affect insertion force at low interspacing (<150μm interspacing at MN base). This model provides a framework for optimising MN devices, and should aid development of suitable application method and determination of force for reliable insertion into skin. © 2013 Wiley Periodicals, Inc
A Triple-Transgenic Immunotolerant Mouse Model

ABSTRACTAvoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1116-1124, 201
Characterization of hybrid materials by means of inverse gas\ud
chromatography and chemometrics

The surface properties of hybrid materials (potential carriers for sustained release of active\ud
agents) have been examined by inverse gas chromatography (IGC). A nonsteroidal antiinflammatory\ud
agent – ibuprofen was used as a model for active compound. The following\ud
parameters have been used to characterize the interactions between the constituents of the\ud
hybrid material and the active agent: dispersive component of the surface free energy D\ud
S g , KA\ud
and KD parameters describing the acidity and basicity, respectively, and Flory-Huggins\ud
parameter '\ud
23 c (the magnitude of interactions). Principal component analysis (PCA) and the\ud
procedure based on sum of ranking differences (SRD) were applied for selection of hybrid\ud
materials and parameters for characterization of these materials. One loose cluster found by\ud
PCA grouping of hybrid materials is refined by SRD analysis: SRD grouping indicates three\ud
groups having somewhat dissimilar properties
Comparison of  in vitro – in vivo  extrapolation of biliary clearance using an empirical scaling factor versus transport‐based scaling factors in sandwich‐cultured rat hepatocytes

Biliary clearance (CL b ) is often underestimated by  in vitro – in vivo  extrapolation from sandwich‐cultured hepatocytes (SCHs). The objective of this study was to compare the performance of a universal correction factor with transporter‐based correction factors in correcting underestimation of CL b . The apparent  in vitro  CL b  of a training set of 21 compounds was determined using the SCH model and extrapolated to apparent  in vivo  CL b  (CL b, app ). A universal correction factor (10.2) was obtained by a linear regression of the predicted CL b, app  and observed  in vivo  CL b  of training set compounds and applied to an independent test set ( n  = 20); the corrected CL b  predictions of 13 compounds were within twofold error of observed values. Furthermore, two transporter‐based correction factors (Organic anion transporting polypeptides/multidrug‐resistance‐related protein 2 and diffusion/P‐glycoprotein) were estimated by linear regression analysis of training set compounds. The applications of the two correction factors to the test set resulted in improved prediction precision. In conclusion, both the universal correction factor and transporter‐based correction factors provided reasonable corrections of CL b  values, which are often underestimated by the SCH model. The use of transporter‐based correction factors resulted in an even greater improvement of predictions for compounds with intermediate‐to‐high CL b  values. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2837–2850, 201
Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants

By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective.Martin Family Society of Fellows for SustainabilityNational Institutes of Health (U.S.) (Grant U01-AI074443
In Vitro Protein Binding of Liraglutide in Human Plasma Determined by Reiterated Stepwise Equilibrium Dialysis

ABSTRACTLiraglutide is a human glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It is based on human GLP-1 with the addition of a 16-carbon fatty acid, which facilitates binding to plasma proteins, thus prolonging the elimination half-life and allowing once-daily administration. It has not been possible to quantify liraglutide protein binding by ultrafiltration (the usual method of choice), as the lipophilic molecule becomes trapped in the filter membrane. Therefore, the aim of this study was to develop a methodology that could determine the extent of liraglutide binding to plasma proteins in vitro. We report here the details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding. The assay allowed quantification of liraglutide binding to proteins in purified plasma protein solutions and human plasma samples and was effective at plasma dilutions as low as 5%. At a clinically relevant liraglutide concentration (104pM), greater than 98.9% of liraglutide was bound to protein. Specific binding to human serum albumin and α1-acid glycoprotein was 99.4% and 99.3%, respectively. The novel methodology described herein could have an application in the quantification of plasma protein binding of other highly lipophilic drug molecules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2882–2888, 201
An experimental study of microneedle-assisted microparticle delivery

This article was published in the serial \ud
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.23665A set of well-defined experiments has been carried out to explore whether microneedles (MNs) can enhance the penetration depths of microparticles moving at high velocity such as those expected in gene guns for delivery of gene-loaded microparticles into target tissues. These experiments are based on applying solid MNs that are used to reduce the effect of mechanical barrier function of the target so as to allow delivery of microparticles at less imposed pressure as compared with most typical gene guns. Further, a low-cost material, namely, biomedical-grade stainless steel microparticle with size ranging between 1 and 20 μm, has been used in this study. The microparticles are compressed and bound in the form of a cylindrical pellet and mounted on a ground slide, which are then accelerated together by compressed air through a barrel. When the ground slide reaches the end of the barrel, the pellet is separated from the ground slide and is broken down into particle form by a mesh that is placed at the end of the barrel. Subsequently, these particles penetrate into the target. This paper investigates the implications of velocity of the pellet along with various other important factors that affect the particle delivery into the target. Our results suggest that the particle passage increases with an increase in pressure, mesh pore size, and decreases with increase in polyvinylpyrrolidone concentration. Most importantly, it is shown that MNs increase the penetration depths of the particles
Modeling the Physiological Factors That Affect Drug Delivery from a Nipple Shield Delivery System to Breastfeeding Infants

ABSTRACTAn apparatus was designed to mimic lactation from a human breast. It was used to determine the influence of milk fat content and flow rate, and suction pulse rate of a breastfeeding infant upon the release of a model compound from a nipple shield delivery system (NSDS). The NSDS would be worn by a mother to deliver drugs and nutrients to her infant during breastfeeding. Sulforhodamine B dye (SB) was used as model compound and formulated as a dispersible tablet to be placed within the NSDS. Increasing suction pulse rate from 30 to 120 pulses/min  clearly correlated with increased cumulative release of SB for the same volume of milk passed through the NSDS. No distinct correlation was found between flow rates (1, 5, and 8mL/min) and SB release, possibly because of competing factors controlling release rate at different flow rates. A highly similar SB release rate into two fat content fluids (2.9 and 4.2wt%) was observed for identical flow conditions. This proof of concept study outlines a novel method to mimic lactation from a breast, and future studies will lead to effective methods to identify key physiological factors that influence drug release from a NSDS
Nondestructive evaluation of Polymer Coating Structures on Pharmaceutical Pellets using Full Field Optical Coherence Tomography

Full field optical coherence tomography (FF-OCT) using a conventional LED light source and a CMOS camera has been developed for characterising coatings on small pellet samples. A set of en-face images covering an area of 700µm x 700µm were taken over a depth range of 166 µm. The three-dimensional structural information, such as the coating thickness and uniformity, was subsequently obtained by analysis of the recorded en-face images. Drug loaded pharmaceutical sustained release pellets with two coating layers and of a sub-millimetre diameter were studied to demonstrate the usefulness of the developed system. We have shown that both coatings can be clearly resolved and the thickness was determined to be 40 µm and 50 µm for the outer and inner coating layers, respectively. It was also found that the outer coating layer is relatively uniform whilst the inner coating layer has many particle-like features. X-ray Computed Microtomography (X?CT) measurements carried out on the same pellet sample confirmed all these findings. The presented FF-OCT approach is inexpensive and has better spatial resolution compared to other non-destructive analysis techniques such as terahertz pulsed imaging, and is thus considered advantageous for the quantitative analysis of thin coatings on small pellet samples.This is the pre-peer reviewed version of the following article: Li, C., Zeitler, J. A., Dong, Y. and Shen, Y.-C. (2014), Non-Destructive Evaluation of Polymer Coating Structures on Pharmaceutical Pellets Using Full-Field Optical Coherence Tomography. J. Pharm. Sci., 103: 161-166. doi: 10.1002/jps.23764, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/jps.23764/abstrac
Sustained Release of Naltrexone from Poly(N-Isopropylacrylamide) Microgels

The release of the opioid antagonist naltrexone from neutral poly(N-isopropylacrylamide) (PNIPAAM)microgels and negatively
charged PNIPAAM microgels containing acrylic acid groups (PNIPAAM-co-PAA) has been studied at various microgel and drug concentrations.
The release curves were found to be well represented by the Weibull equation. The release rates were observed to be dependent
on the microgel concentration. At most conditions, the release from the charged microgels was slower than for the neutral microgels. In
addition, the charged microgels exhibited a release lag time, which was dependent on the microgel concentration. No significant lag time
could be observed for the neutral microgels. Increasing the naltrexone concentration did not significantly affect the release rates from
the neutral microgels, but the release from the charged microgels became faster. The microgels did not exhibit any significant cytotoxic
effect on HeLa cells at the tested concentrations.Norwegian Research Counci
Development and Characterization of an In Vitro Release Assay for Liposomal Ciprofloxacin for Inhalation

AbstractA novel method was developed and optimized to measure the in vitro release (IVR) of two liposomal ciprofloxacin formulations under development to treat lung infection. The release agent, bovine serum, has components that interact with liposomes to cause the encapsulated drug to be released. The precision and accuracy of the method were characterized. The method has a nearly linear release phase initially, which then approaches a plateau value after 2–4h. The robustness of the method was verified over a range of release agent and liposomal concentrations, and in response to changes in incubation temperature, buffer pH, and storage containers of serum. For this “sample and separate” IVR method, there is less than 2% release at the T = 0 time point, indicating negligible artifactual release before analysis. For both inhaled liposomal ciprofloxacin products, the plateau value represents 100% release of the encapsulated drug. The key elements of this IVR method may prove useful for characterization of other liposomal products as well. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:314–327, 201
Understanding the Relationship Between Biotherapeutic Protein Stability and Solid–Liquid Interfacial Shear in Constant Region Mutants of IgG1 and IgG4

AbstractRelative stability of therapeutic antibody candidates is currently evaluated primarily through their response to thermal degradation, yet this technique is not always predictive of stability in manufacture, shipping, and storage. A rotating disk shear device is proposed that produces defined shear conditions at a known solid–liquid interface to measure stability in this environment. Five variants of IgG1 and IgG4 antibodies were created using combinations of two discrete triple amino acid sequence mutations denoted TM and YTE. Antibodies were ranked for stability based on shear device output (protein decay coefficient, PDC), and compared with accelerated thermal stability data and the melting temperature of the CH2 domain (Tm1) from differential scanning calorimetry to investigate technique complimentarity. Results suggest that the techniques are orthogonal, with thermal methods based on intramolecular interaction and shear device stability based on localized unfolding revealing less stable regions that drive aggregation. Molecular modeling shows the modifications’ effects on the antibody structures and indicates a possible role for Fc conformation and Fab-Fc docking in determining suspended protein stability. The data introduce the PDC value as an orthogonal stability indicator, complementary to traditional thermal methods, allowing lead antibody selection based on a more full understanding of process stability