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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 170  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2351 journals]
  • Development and Characterization of a Dry Powder Formulation for
           Anti-Tuberculosis Drug Spectinamide 1599
    • Abstract: Purpose Human tuberculosis (TB) is a global health problem that causes nearly 2 million deaths per year. Anti-TB therapy exists, but it needs to be administered as a cocktail of antibiotics for six months. This lengthy therapy results in low patient compliance and is the main reason attributable to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Methods One alternative approach is to combine anti-TB multidrug therapy with inhalational TB therapy. The aim of this work was to develop and characterize dry powder formulations of spectinamide 1599 and ensure in vitro and in vivo delivered dose reproducibility using custom dosators. Results Amorphous dry powders of spectinamide 1599 were successfully spray dried with mass median aerodynamic diameter (MMAD) = 2.32 ± 0.05 μm. The addition of L-leucine resulted in minor changes to the MMAD (1.69 ± 0.35 μm) but significantly improved the inhalable portion of spectinamide 1599 while maintaining amorphous qualities. Additionally, we were able to demonstrate reproducibility of dry powder administration in vitro and in vivo in mice. Conclusions The corresponding systemic drug exposure data indicates dose-dependent exposure in vivo in mice after dry powder intrapulmonary aerosol delivery in the dose range 15.4 - 32.8 mg/kg.
      PubDate: 2019-07-18
  • Item Response Model Adaptation for Analyzing Data from Different Versions
           of Parkinson’s Disease Rating Scales
    • Abstract: Purpose The aim of this work was to allow combination of information from recent and historical trials in Parkinson’s Disease (PD) by developing bridging methodology between two versions of the clinical endpoint. Methods A previously developed Item Response Model (IRM), that described longitudinal changes in Movement Disorder Society (MDS) sponsored revision of Unified Parkinson’s Disease Rating Scale (UPDRS) [MDS–UPDRS] data from the De Novo PD cohort in Parkinson’s Progression Markers Initiative, was first adapted to describe baseline UPDRS data from two clinical trials, one in subjects with early PD and another in subjects with advanced PD. Assuming similar IRM structure, items of the UPDRS version were mapped to those in the MDS-UPDRS version. Subsequently, the longitudinal changes in the placebo arm of the advanced PD study were characterized. Results The parameters reflecting differences in the shared items between endpoints were successfully estimated, and the model diagnostics indicated that mapping was better for early PD subjects (closer to De Novo cohort) than for advanced PD subjects. Disease progression for placebo in advanced PD patients was relatively shallow. Conclusion An IRM able to handle two variants of clinical PD endpoints was developed; it can improve the utilization of data from diverse sources and diverse disease populations.
      PubDate: 2019-07-17
  • Challenging the CNS Targeting Potential of Systemically Administered
           Nanoemulsion Delivery Systems: a Case Study with Rapamycin-Containing Fish
           Oil Nanoemulsions in Mice
    • Abstract: Purpose Despite extensive preclinical investigations, in-vivo properties and formulation characteristics that improve CNS drug delivery following systemic dosing of nanoemulsions remain incompletely understood. Methods The CNS targeting potential of systemically administered nanoemulsions was evaluated by formulating rapamycin containing fish oil nanoemulsions, and testing the combined effect of formulation characteristics such as the circulation half-life and particle size distribution, on CNS delivery of rapamycin containing fish oil nanoemulsions in mice. Results Results generated with rapamycin nanoemulsions suggested that circulation half-life and particle size distribution did not impact the brain targeting efficiency of rapamycin containing fish oil nanoemulsions. Further, in the absence of any improvement in the systemic exposures of rapamycin, nanoemulsions did not outperform their aqueous counterpart with respect to the extent of CNS drug delivery. Conclusions Our findings confirm that BBB penetration, which primarily depends on intrinsic drug-related properties, may not be significantly improved following encapsulation of drugs in nanoemulsions. Graphical The CNS targeting potential of systemically administered nanoemulsions was investigated by formulating various rapamycin containing fish oil nanoemulsions associated with different formulation characteristics such as the circulation half-life and particle size distribution. The targeting efficiency (TE) defined as the ratio of the brain exposures to the accompanying systemic exposures of rapamycin was estimated for each formulation following IV dosing in mice.
      PubDate: 2019-07-11
  • Targeting KRAS Mutant Lung Cancer Cells with siRNA-Loaded Bovine Serum
           Albumin Nanoparticles
    • Abstract: Purpose KRAS is the most frequently mutated gene in human cancers. Despite its direct involvement in malignancy and intensive effort, direct inhibition of KRAS via pharmacological inhibitors has been challenging. RNAi induced knockdown using siRNAs against mutant KRAS alleles offers a promising tool for selective therapeutic silencing in KRAS-mutant lung cancers. However, the major bottleneck for clinical translation is the lack of efficient biocompatible siRNA carrier systems. Methods Bovine serum albumin (BSA) nanoparticles were prepared by desolvation method to deliver siRNA targeting the KRAS G12S mutation. The BSA nanoparticles were characterized with respect to their size, zeta potential, encapsulation efficiency and nucleic acid release. Nanoparticle uptake, cellular distribution of nucleic acids, cytotoxicity and gene knock down to interfere with cancer hallmarks, uncontrolled proliferation and migration, were evaluated in KRAS G12S mutant A459 cells, a lung adenocarcinoma cell line. Results BSA nanoparticles loaded with siRNA resulted in nanoparticles smaller than 200 nm in diameter and negative zeta potentials, displaying optimal characteristics for in vivo application. Encapsulating and protecting the siRNA payload well, the nanoparticles enabled transport to A549 cells in vitro, could evade endosomal entrapment and mediated significant sequence-specific KRAS knockdown, resulting in reduced cell growth of siRNA transfected lung cancer cells. Conclusions BSA nanoparticles loaded with mutant specific siRNA are a promising therapeutic approach for KRAS-mutant cancers.
      PubDate: 2019-07-09
  • Correction to: Impact of Buffer, Protein Concentration and Sucrose
           Addition on the Aggregation and Particle Formation during Freezing and
    • Abstract: The statement in the caption to Fig. 1 “Data taken from reference (38).” (Kolhe P, Holding E, Lary A, Chico S, Singh SK. Large-scale freezing of biologics: understanding protein and solute concentration changes in a Cryovessel-part 2. Biopharm International. 2010;23(7):40–9) is erroneous.
      PubDate: 2019-07-08
  • Utility of High Resolution NMR Methods to Probe the Impact of Chemical
           Modifications on Higher Order Structure of Monoclonal Antibodies in
           Relation to Antigen Binding
    • Abstract: Purpose An understanding of higher order structure (HOS) of monoclonal antibodies (mAbs) could be critical to predicting its function. Amongst the various factors that can potentially affect HOS of mAbs, chemical modifications that are routinely encountered during production and long-term storage are of significant interest. Methods To this end, two Pfizer mAbs were subjected to forced deamidation stress for a period of eight weeks. Samples were aliquoted at various time points and high resolution accurate mass liquid chromatography-mass spectrometry (LC-MS/MS) was performed using low-artifact trypsin digestion (LATD) peptide mapping to identify and quantify chemical modifications. 2D backbone amide and sidechain methyl NMR spectra were acquired to gauge the effect of HOS changes upon chemical modification. Differential scanning calorimetry was also performed to assess the effect of thermal stability of mAbs upon modification. Finally, functional studies via target-binding based ELISA were performed to connect HOS changes to any loss of potency. Results The extent of deamidation in the mAb domains were quantified by LC-MS/MS. The HOS changes as obtained from 2D NMR were mostly localized around the affected sites leaving the overall structure relatively unchanged. The antigen-antibody binding of the mAbs, in spite of deamidation in the Fab region, remains unchanged. Conclusion This case study provides an integrated approach of relating chemical modifications in mAb domains with possible changes in HOS. This can be potentially used to assess a possible loss of potency within the structure-function paradigm of proteins in an orthogonal manner.
      PubDate: 2019-07-01
  • Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone
           Nanoparticles for the Treatment of Glioblastoma
    • Abstract: Purpose Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma. Methods MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated. Results MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route. Conclusions Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.
      PubDate: 2019-07-01
  • Generation, Characterization, and Quantitative Bioanalysis of
           Drug/Anti-drug Antibody Immune Complexes to Facilitate Dedicated In Vivo
    • Abstract: Purpose Immunogenicity against biotherapeutics can lead to the formation of drug/anti-drug-antibody (ADA) immune complexes (ICs) with potential impact on safety and drug pharmacokinetics (PK). This work aimed to generate defined drug/ADA ICs, characterized by quantitative (bio) analytical methods for dedicated determination of IC sizes and IC profile changes in serum to facilitate future in vivo studies. Methods Defined ICs were generated and extensively characterized with chromatographic, biophysical and imaging methods. Quantification of drug fully complexed with ADAs (drug in ICs) was performed with an acid dissociation ELISA. Sequential coupling of SEC and ELISA enabled the reconstruction of IC patterns and thus analysis of IC species in serum. Results Characterization of generated ICs identified cyclic dimers, tetramers, hexamers, and larger ICs of drug and ADA as main IC species. The developed acid dissociation ELISA enabled a total quantification of drug fully complexed with ADAs. Multiplexing of SEC and ELISA allowed unbiased reconstruction of IC oligomeric states in serum. Conclusions The developed in vitro IC model system has been properly characterized by biophysical and bioanalytical methods. The specificity of the developed methods enable discrimination between different oligomeric states of ICs and can be bench marking for future in vivo studies with ICs.
      PubDate: 2019-06-28
  • An Effective Technology for the Development of Immediate Release Solid
           Dosage Forms Containing Low-Dose Drug: Fused Deposition Modeling 3D
    • Abstract: Purpose Fabrication of immediate release (IR) tablet formulations with rapid release profile via fused deposition modeling 3D printing (FDM 3DP) is a challenge. The aims of this study were to prepare IR tablets with different dissolution profiles and to increase their in vitro dissolution rates by making physical modifications on them. Pramipexole was used as the model low-dose drug. Methods Polymeric filaments were prepared with six different combinations of Eudragit EPO and poly(ethylene) oxide by hot melt extrusion and 3D tablets were produced using an FDM printer. Characterization studies for the filaments and tablets were carried out. The printability of the filaments was also evaluated using a novel mechanical characterization method. Tablet formulation with optimum dissolution profile was chosen and physical modifications (infill %, shape change and thickness) on this formulation were made. Results Low-dose pramipexole loading filaments and 3D tablets were homogenously prepared. The printability of the filaments was related to their flexibility. With the physical modifications, the drug release completion time of the tablets reduced to 5 min. Conclusions The same rapid release profiles with conventional IR tablets can be reached by making only physical changes on 3D tablets without using any filling or disintegrating agents.
      PubDate: 2019-06-27
  • Recent Treatment Advances and the Role of Nanotechnology, Combination
           Products, and Immunotherapy in Changing the Therapeutic Landscape of Acute
           Myeloid Leukemia
    • Abstract: Acute myeloid leukemia (AML) is the most common acute leukemia that is becoming more prevalent particularly in the older (65 years of age or older) population. For decades, “7 + 3” remission induction therapy with cytarabine and an anthracycline, followed by consolidation therapy, has been the standard of care treatment for AML. This stagnancy in AML treatment has resulted in less than ideal treatment outcomes for AML patients, especially for elderly patients and those with unfavourable profiles. Over the past two years, six new therapeutic agents have received regulatory approval, suggesting that a number of obstacles to treating AML have been addressed and the treatment landscape for AML is finally changing. This review outlines the challenges and obstacles in treating AML and highlights the advances in AML treatment made in recent years, including Vyxeos®, midostaurin, gemtuzumab ozogamicin, and venetoclax, with particular emphasis on combination treatment strategies. We also discuss the potential utility of new combination products such as one that we call “EnFlaM”, which comprises an encapsulated nanoformulation of flavopiridol and mitoxantrone. Finally, we provide a review on the immunotherapeutic landscape of AML, discussing yet another angle through which novel treatments can be designed to further improve treatment outcomes for AML patients.
      PubDate: 2019-06-24
  • Model-based analysis of treatment effects of paclitaxel microspheres in a
           microscopic peritoneal carcinomatosis model in mice
    • Abstract: Purpose Paclitaxel (PTX)-loaded genipin-crosslinked gelatin microspheres (GP-MS) are a prolonged IP delivery system under development for the treatment of peritoneal minimal residual disease (pMRD). Here, we show the use of a pharmacokinetic-pharmacodynamic (PKPD) modelling approach to inform the formulation development of PTX-GP-MS in a mice pMRD model. Methods PTX blood concentrations and survival data were obtained in Balb/c Nu mice receiving different single IP doses (7.5 and/or 35 mg/kg) of PTX-ethanolic loaded GP-MS (PTXEtOH-GP-MS), PTX-nanosuspension loaded GP-MS (PTXnano-GP-MS), and immediate release formulation Abraxane®. A population PK model was developed to characterize the PTX blood concentration pattern and to predict PTX concentrations in peritoneum. Afterwards, PKPD relationships between the predicted peritoneal or blood concentrations and survival were explored using time-to-event modelling. Results A PKPD model was developed that simultaneously describes the competing effects of treatment efficacy (driven by peritoneal concentration) and toxicity (driven by blood concentration) of PTX on survival. Clear survival advantages of PTXnano-GP-MS over PTXEtOH-GP-MS and Abraxane® were found. Simulations of different doses of PTXnano-GP-MS demonstrated that drug-induced toxicity is high at doses between 20 and 35 mg/kg. Conclusions The model predicts that the dose range of 7.5-15 mg/kg of PTXnano-GP-MS provides an optimal balance between efficacy and safety.
      PubDate: 2019-06-24
  • High Pressure Nebulization (PIPAC) Versus Injection for the
           Intraperitoneal Administration of mRNA Complexes
    • Abstract: Purpose Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique delivering drugs into the abdominal cavity as an aerosol under high pressure. It is hypothesized to have advantages such as enhancing tissue uptake, distributing drugs homogeneously within the closed and expanded abdominal cavity and higher local concentration of drugs in the peritoneal cavity. However, the clinical trials of PIPAC so far are limited to liquid chemotherapeutic solution, and the applicability of biomolecules (such as mRNA, siRNA and oligonucleotide) is not known. We aimed to investigate the feasibility of administrating mRNA lipoplexes to the peritoneal cavity via high pressure nebulization. Methods We firstly investigated the influences of nebulization on physicochemical properties and in vitro transfection efficiency of mRNA lipoplexes. Then, mRNA lipoplexes were delivered to healthy rats through intravenous injection, intraperitoneal injection and PIPAC, respectively. Results mRNA lipoplexes can withstand the high pressure applied during the PIPAC procedure in vitro. Bioluminescence localized to the peritoneal cavity of rats after administration by IP injection and nebulization, while intravenous injection mainly induced protein expression in the spleen. Conclusion This study demonstrated that local nebulization is feasible to apply mRNA complexes in the peritoneal cavity during a PIPAC procedure.
      PubDate: 2019-06-24
  • Heat Enhanced Follicular Delivery of Isotretinoin to the Skin
    • Abstract: Purpose The aim of this work was to evaluate the use of short durations of externally applied heat with chemical penetration enhancers to improve delivery of isotretinoin to the skin and in particular via the follicular route. Methods A range of chemical penetration enhancers were screened for their ability to improve isotretinoin delivery into human skin with heat using infinite dose, Franz cell experiments conducted in a water bath at a higher temperature to simulate heated conditions. Following this a prototype external heating system was developed that provided short durations of heat and its ability to improve delivery of finite doses into the skin and hair follicles was assessed. Results The magnitude of the effect of heat on drug delivery was influenced by the choice of vehicle with changes in isotretinoin flux across skin ranging from not statistically significant to 25 fold increases with heat in the infinite dose studies. The prototype heating system provided significant increases in the total delivery of isotretinoin into the skin from an optimised vehicle. Drug distribution in the skin revealed significant increases in isotretinoin delivery to the hair follicles, and deeper skin layers, but not to the stratum corneum, providing strong evidence that the enhancement in delivery occurred mainly via the hair follicles. Conclusion These data indicate that the use of short durations of heat combined with chemical penetration enhancers offers a valuable strategy for improving the delivery of drugs such as isotretinoin to the skin via the hair follicles. Graphical Schematic illustration of the sodium thiosulphate heating system on a Franz diffusion cell and the subsequent impact of a short burst of heat on the delivery of isotretinoin into human skin.
      PubDate: 2019-06-21
  • Non-Propellant Foams of Green Nano-Silver and Sulfadiazine: Development
           and In Vivo Evaluation for Burn Wounds
    • Abstract: Purpose A non-propellant based foam (NPF) system was developed incorporating the antibiotics, pectin capped green nano-silver and sulfadiazine (SD) for the topical treatment of burn wounds as a convenient alternative to the existing therapies. Methods NPF were prepared using various surfactants and oils forming a nanoemulsion. Anti-microbial studies by resazurin microtitre assay, ex vivo diffusion, in vivo skin permeation and deposition studies, and acute irritation studies were carried out. NPF was applied onto secondary thermal wounds manifested on mice models followed by macroscopic and histological examinations. Results NPF had an average globule size of <75 nm. The viscosity was ~10 cP indicating the feasibility of expulsion from the container upon actuation. With no skin irritation, the foams showed a higher skin deposition of SD. A high contraction and an evident regeneration of the skin tissue upon treatment with NPF indicated a good recovery from the thermal injury was apparent from the histology studies. Conclusion NPF represents an alternative topical formulation that can be employed as a safe and effective treatment modality for superficial second degree (partial thickness) burn wounds. With a minimal requirement of mechanical force, the no-touch application of NPF makes it suitable for sensitive and irritant skin surfaces.
      PubDate: 2019-06-19
  • Folate Conjugated Double Liposomes Bearing Prednisolone and Methotrexate
           for Targeting Rheumatoid Arthritis
    • Abstract: Purpose This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA). Methods To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance. Results fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6 nm in size with 0.109 PDI, 8.01 ± 0.3 mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24 h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints. Conclusions The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.
      PubDate: 2019-06-19
  • Inhaler Spray Investigation Using High-Speed Phase-Contrast X-Ray and
           Schlieren Imaging
    • Abstract: Purpose The first pressurised metered dose inhaler (pMDI) was introduced in 1956. Even with excellent inhaler technique typically only 20% of the dose deposits in the lungs where needed. It is hoped that a better understanding of the initial plume formation and expansion during dose release can help improve modelling, devices and ultimately transport to the lungs. We have used two high-speed imaging techniques to investigate the transient dose event. Methods Synchrotron phase-contrast X-Ray imaging is a technique that is sensitive to variations in the refractive index of materials in the X-ray region. Similarly, Schlieren imaging is an optical technique sensitive to the refractive index gradients which are often present in pMDI plumes due to gas density variations. We have combined and synchronised both techniques to investigate three commercial pMDIs actuators during dose release for various actuator/formulation combinations. Results We have observed temporal phases of propellant flowing in the orifice channel. At early times flash boiling takes place and drives gas emission, steep plume density gradients and liquid jets/droplets at the orifice. Evaporating liquid is present in the sump long after the dose is finished. Regional counter-flow is seen in plumes emitted into a mouth-throat geometry. Conclusions As the foamy liquid-vapour mixture is forced out of the sump and into the orifice the liquid walls of the bubbles break into fragments which are forced out of the sump and tend to form a liquid-gas flow in the orifice channel. The period of high density plume observed by the schlieren technique corresponds to flash-boiling-driven liquid exiting the orifice channel.
      PubDate: 2019-06-18
  • Development of β-elemene and Cisplatin Co-Loaded Liposomes for Effective
           Lung Cancer Therapy and Evaluation in Patient-Derived Tumor Xenografts
    • Abstract: Purpose β-elemene and cisplatin combined chemotherapy currently is one of the most important settings available for lung cancer therapy in China. However, the clinical outcome is limited by their pharmacokinetic drawbacks. On the other hand, most of nanomedicines have failed in clinical development due to the huge differences between heterogeneous clinical tumor tissues and homogenous cell-derived xenografts. In this work, we fabricated a β-elemene and cisplatin co-loaded liposomal system to effectively treat lung cancer. Method In vitro cytotoxicity of co-loaded liposomes was studied by MTT, trypan and Hoechst/PI staining, and western blot in A549, A549/DDP, and LCC cells. In vivo antitumor efficacy was evaluated in cell-derived and clinically relevant patient-derived xenografts. Results Co-loaded liposomes were more cytotoxic to cancer cells, especially than the combination of single-loaded liposomes, benefiting from their simultaneous drug internalization and release. As a result, they exhibited desirable therapeutic outcome in both cell-derived and patient-derived xenografts. Conclusion β-elemene and cisplatin co-loaded liposomes are a clinically promising candidate for effective lung cancer therapy.
      PubDate: 2019-06-18
  • Proton Oriented-“Smart Depot” for Responsive Release of Ca 2+ to
           Inhibit Peptide Acylation in PLGA Microspheres
    • Abstract: Purpose The purpose of this study was to characterize and detail the mechanism of a smart Ca2+ release depot (Ca3(PO4)2) about its ability for sustainable inhibition on peptide acylation within PLGA microspheres. Methods The octreotide acetate release and acylation kinetics were analyzed by RP-HPLC. Changes of Ca2+ concentration and adsorption behavior were determined by a Calcium Colorimetric Assay Kit. The inner pH changes were delineated by a classic pH sensitive probe, Lysosensor yellow/ blue® dextran. Morphological changes of microspheres, adsorption between polymer and additive, transformation of Ca3(PO4)2 were characterized using SEM, FTIR and SSNMR separately. Results Before and after microspheres formulation, the property and effectiveness of Ca3(PO4)2 were investigated. Compared with a commonly used calcium salt (CaCl2), high encapsulation efficiency (96.56%) of Ca3(PO4)2 guarantees lasting effectiveness. In an increasingly acidic environment that simulated polymer degradation, the poorly water-soluble Ca3(PO4)2 could absorb protons and transform into the more and more soluble CaHPO4 and Ca(H2PO4)2 to produce sufficient Ca2+ according to severity of acylation. The corresponding Ca2+ produce capacity fully met the optimum inhibition requirement since the real-time adsorption sites (water-soluble carboxylic acids) inside the degrading microspheres were rare. A sustained retention of three switchable calcium salts and slow release of Ca2+ were observed during the microsphere incubation. FTIR results confirmed the long-term inhibition effect induced by Ca3(PO4)2 on the adsorption between drug and polymer. Conclusions With the presence of the smart Ca2+ depot (Ca3(PO4)2) in the microspheres, a sustainable and long-term inhibition of peptide acylation was achieved.
      PubDate: 2019-06-04
  • Uncommon Peptide Bond Cleavage of Glucagon from a Specific Vendor under
           near Neutral to Basic Conditions
    • Abstract: Purpose The main purposes of this manuscript are to report a surprising and interesting degradation reaction of glucagon from a specific vendor in which glucagon underwent cleavage among several peptide bonds quickly under near neutral to basic conditions, and to propose the root cause of mechanism for the degradation reaction. Methods The degradation reaction was monitored by HPLC and the fragment structures were confirmed by LC-MS. Possible impurities responsible for the degradation were either confirmed or excluded by a variety of techniques such as addition of chelator EDTA and transitional metal ions or separation by ultrafiltration. Results This type of degradation was rarely reported in literature, especially considering its extreme cleavage efficiency. Contamination by a thermostable high molecular impurity (such as a peptidase with molecular weight between 10 and 30 KDa) during the manufacturing process was the main reason for this interesting phenomenon. Conclusions The degradation phenomenon described here could be used as an excellent example showing that products ordered from vendors meeting the rudimentary quality standards might contain impurities which could cause significant degradation. We suggest that a simple solution, i.e. additional tests of stability under real or accelerated conditions by manufacturers and inclusion of the “accelerated stability criteria” in the Certificate of Analysis (CoAs), especially for sensitive biological reagents prone to faster degradation, would be very helpful for avoiding losses for both vendors and users.
      PubDate: 2019-06-03
  • Fibrin Gels Entrapment of a Poly-Cyclodextrin Nanocarrier as a Doxorubicin
           Delivery System in an Orthotopic Model of Neuroblastoma: Evaluation of In
           Vitro Activity and In Vivo Toxicity
    • Abstract: Purpose Fibrin gels (FBGs) are potential delivery vehicles for many drugs, and can be easily prepared from purified components. We previously demonstrated their applicability for the release of different doxorubicin (Dox) nanoparticles used clinically or in an experimental stage, such as its inclusion complex with the amino β-cyclodextrin polymer (oCD-NH2/Dox). Here we extend these studies by in vitro and in vivo evaluations. Methods An in vitro cytotoxicity model consisting of an overlay of a neuroblastoma (NB) cell-containing agar layer above a drug-loaded FBG layer was used. Local toxicity in vivo (histology and blood analysis) was studied in a mouse orthotopic NB model (SHSY5YLuc+ cells implanted into the left adrenal gland). Results In vitro data show that FBGs loaded with oCD-NH2/Dox have a slightly lower cytotoxicity against NB cell lines than those loaded with Dox. Fibrinogen (FG), and Ca2+ concentrations may modify this activity. In vivo data support a lower general and local toxicity for FBGs loaded with oCD-NH2/Dox than those loaded with Dox. Conclusion Our results suggest a possible increase of the therapeutic index of Dox when locally administered through FBGs loaded with oCD-NH2/Dox, opening the possibility of using these releasing systems for the treatment of neuroblastoma.
      PubDate: 2019-06-03
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