Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids.

Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their in vitro performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid-liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can, in vivo, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.

Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions.

Poor solubility of drug candidates is a well-known and thoroughly studied challenge in the development of oral dosage forms. One important approach to tackle this challenge is the formulation as an amorphous solid dispersion (ASD). To reach the desired biopharmaceutical improvement a high supersaturation has to be reached quickly and then be conserved long enough for absorption to take place. In the presented study, various formulations of regorafenib have been produced and characterized in biorelevant in-vitro experiments. Povidone-based formulations, which are equivalent to the marketed product Stivarga®, showed a fast drug release but limited stability and robustness after that. In contrast, HPMCAS-based formulations exhibited excellent stability of the supersaturated solution, but unacceptably slow drug release. The attempt to combine the desired attributes of both formulations by producing a ternary ASD failed. Only co-administration of HPMCAS as an external stabilizer to the rapidly releasing Povidone-based ASDs led to the desired dissolution profile and high robustness. This optimized formulation was tested in a pharmacokinetic animal model using Wistar rats. Despite the promising in-vitro results, the new formulation did not perform better in the animal model. No differences in AUC could be detected when compared to the conventional (marketed) formulation. These data represent to first in-vivo study of the new concept of external stabilization of ASDs. Subsequent in-vitro studies revealed that temporary exposure of the ASD to gastric medium had a significant and long-lasting effect on the dissolution performance and externally administered stabilizer could not prevent this sufficiently. By applying the co-administered HPMCAS as an enteric coating onto Stivarga tablets, a new bi-functional approach was realized. This approach achieved the desired tailoring of the dissolution profile and high robustness against gastric medium as well as against seeding.

Effect of hydrocolloid coatings (Basil seed gum, xanthan, and methyl cellulose) on the mass transfer kinetics and quality of fried potato strips.

In this research, the effect of different temperatures (160, 180, and 190 °C) and hydrocolloid coatings (Basil seed gum [BSG], xanthan gum [XG], methylcellulose [MC], BSG-XG, and BSG-MC mixtures) were investigated on the physicochemical properties (oil uptake, moisture loss, color, microscopic structure, activation energy, and texture), mass transfer kinetic of fried potato strips in deep-fat frying, and oil partitions using frying and postfrying cooling phase. An increase in frying time reduced the moisture content and hardness of potato strips; however, the oil content and color difference increased. The oil content in the coated samples had lower rates than that in the noncoated ones. The treated samples using BSG-xanthan mixture (50:50) and BSG had the lowest oil uptake at 0.13% and 0.14% Dry basis (d.b.), respectively. The maximum and minimum values of effective moisture diffusivity were measured in control and samples coated with BSG-XG and BSG, respectively. As frying temperature increased, the specific rate of oil uptake increased and the equilibrium oil content decreased. Overall, BSG-XG mixture-coated potato strips can be used as a promising product due to absorbing the lowest oil rate and being similar to the control in terms of organoleptic properties.

Fermentable Fibers Enhance Aspects of Innate and Adaptive Immunity in Piglets infected with Salmonella Typhimurium.

OBJECTIVE: To test the hypothesis that fermentable fiber prevents Salmonella typhimurium infection-associated symptoms by enhancing innate and adaptive immune system in neonatal pigs. METHODS: Two-d-old piglets (n=120) were randomized to receive either a nutritionally complete sow milk replacer formula (CON), or supplemented with methylcellulose (MCEL-non-fermentable), soy polysaccharides (SPS-moderately fermentable), or fructooligosaccharides (FOS-highly fermentable). On d7, piglets received an oral gavage of S. typhimurium-798, and continued receiving the same diets up to 48h post-infection. Ileal mucosal samples were obtained for further analyses. RESULTS: A reduction in chloride secretion was observed in FOS when compared to other diets (p<0.0003). The number of ileal sulfo-acidomucins was higher (p<0.05) in FOS before infection compared with other diets. NFkB was inhibited in FOS following infection (p<0.05), when compared with CON. IL-1ß expression was increased at 4h post-infection (p<0.05) in CON; however, this response was attenuated in the fiber groups. IL-6 expression was higher (p<0.05) in CON post- infection, higher in SPS at 24h (p<0.05), but unchanged in MCEL and FOS when compared to pre-infection values. FOS had a higher expression of neutrophil-chemoattractant IL-8 before infection (p<0.05) compared to other groups. CONCLUSION: The reduction in chloride secretion, proinflammatory cytokines expression and NFkB activation, and increased number of sulfo-acidomucins, and IL-8 expression in the fiber groups, indicates that the degree of fermentability impacts the innate and adaptive immune system, and could be the mechanisms by which dietary fibers reduce S. typhimurium infection-associated-symptoms in neonatal pigs and apply these results to infants.

Efficacy of orally administered porcine epidemic diarrhea vaccine-loaded hydroxypropyl methylcellulose phthalate microspheres and RANKL-secreting L. lactis.

Here, we examined the efficacy of are combinant subunit antigen-based oral vaccine for preventing porcine epidemic diarrhea virus (PEDV). First, we generated a soluble recombinant partial spike S1 protein (aP2) from PEDV in E. coli and then evaluated the utility of aP2 subunit vaccine-loaded hydroxypropyl methylcellulose phthalate microspheres (HPMCP) and RANKL-secreting L. lactis (LLRANKL) as a candidate oral vaccine in pregnant sows. Pregnant sows were vaccinated twice (with a 2 week interval between doses) at 4 weeks before farrowing. Titers of virus-specific IgA antibodies in colostrum, and neutralizing antibodies in serum, of sows vaccinated with HPMCP (aP2) plus LL RANKL increased significantly at 4 weeks post-first vaccination. Furthermore, the survival rate of newborn suckling piglets delivered by sows vaccinated with HPMCP (aP2) plus LL RANKL was similar to that of piglets delivered by sows vaccinated with a commercial killed porcine epidemic diarrhea virus (PED) vaccine. The South Korean government promotes a PED vaccine program (live-killed-killed) to increase the titers of IgA and IgG antibodies in pregnant sows and prevent PEDV. The oral vaccine strategy described herein, which is based on a safe and efficient recombinant subunit antigen, is an alternative PED vaccination strategy that could replace the traditional strategy, which relies on attenuated live oral vaccines or artificial infection with virulent PEDV.

In situ microemulsion-gel obtained from bioadhesive hydroxypropyl methylcellulose films for transdermal administration of zidovudine.

This study aims to develop in situ microemulsion-gel (ME-Gel) obtained from hydroxypropyl methylcellulose (HPMC) films for transdermal administration of Zidovudine (AZT). Firstly, HPMC films containing propylene glycol (PG) and eucalyptus oil (EO) were obtained and characterized. Later, a pseudo-ternary phase diagram composed of water, EO, tween 80 and PG was obtained and one microemulsion (ME) with a similar proportion of the film components was obtained. ME was transformed in ME-Gel by the incorporation of HPMC. Finally, HPMC films were hydrated with Tween 80 solution to yield in situ ME-Gel and its effect on AZT skin permeation was compared with HPMC film hydrated with water (F5hyd). The results showed that the ME and ME-Gel presented a droplet size of 16.79 and 122.13 µm, respectively, polydispersity index (PDI) < 0.39 and pH between 5.10 and 5.40. The incorporation of HPMC resulted in viscosity about 2 times higher than the use of ME. The presence of AZT did not alter the formulation properties. The in situ ME-Gel promoted a two-fold increase in the permeated amount of AZT compared to F5hyd. The results suggest that it was possible to obtain an ME-Gel in situ from HPMC films and that its effect on transdermal permeation of AZT was significant.

Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype.

Methylcellulose (MC; 0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. When administered by the oral (PO) route, MC is considered a Food and Drug Administration "generally recognized as safe" compound. Yet, there is limited data pertaining to the tolerability and impact on model fidelity of repeated intraperitoneal administration of 0.5% MC. Chronic administration of high-concentration MC (2%-2.5%) has been used to induce anemia, splenomegaly, and lesions in multiple organ systems in several preclinical species. Histopathological findings from a diagnostic pathologic analysis of a single mouse from our laboratory with experimentally induced chronic seizures that had received repeated intraperitoneal administration of antiseizure drugs delivered in MC revealed similar widespread lesions. This study thus tested the hypothesis that chronic administration of intraperitoneal, but not PO, MC incites histologic lesions without effects on preclinical phenotype. Male CF-1 mice (n = 2-14/group) were randomized to receive either 6 weeks of twice weekly 0.5% MC or saline (intraperitoneal or PO) following induction of chronic seizures. Histology of a subset of mice revealed lesions in kidney, liver, mediastinal lymph nodes, mesentery, aorta, and choroid plexus only in intraperitoneal MC-treated mice (n = 7/7). Kindled mice that received MC PO (n = 5) or saline (intraperitoneal n = 6, PO n = 3) had no lesions. There were no effects of intraperitoneal MC treatment on body weight, appearance, seizure stability, or behavior. Nonetheless, our findings suggest that repeated intraperitoneal, but not PO, MC elicits systemic organ damage without impacting the model phenotype, which may confound interpretation of investigational drug-induced histologic lesions. SIGNIFICANCE STATEMENT: Methylcellulose (0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. Herein, we demonstrate that repeated administration of 0.5% methylcellulose by the intraperitoneal, but not oral, route results in systemic inflammation and presence of foam-laden macrophages but does not impact the behavioral phenotype of a rodent model of neurological disease.

An enhanced charge-driven intranasal delivery of nicardipine attenuates brain injury after intracerebral hemorrhage.

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Comparison of the effect of mitomycin C and bevacizumab-methylcellulose mixture on combined phacoemulsification and non-penetrating deep sclerectomy surgery on the intraocular pressure (a clinical trial study).

PURPOSE: Comparison of the effect of mitomycin C (MMC) versus bevacizumab-methylcellulose mixture (BMM) on combined phacoemulsification and non-penetrating deep sclerectomy surgery on the intraocular pressure in patients with open-angle glaucoma was made. METHODS: The current study is a controlled, randomized, double-blind clinical trial. Thirty-eight patients were enrolled, with a total of 40 eyes, and underwent a combined phacoemulsification and non-penetrating deep sclerectomy surgery from 2016 to 2017. MMC with concentration of 0.2 mg/mL for 2 min was used for 20 eyes before separating the scleral flap, and 0.3 mL of BMM (bevacizumab 1.25 mg incorporated into 2% methylcellulose) was injected subconjunctivally following surgery. The success rate of surgery was categorized as complete, relative and failure. Fisher's exact, Mann-Whitney U and Chi-square tests were employed to data analysis. A p value < 0.05 was supposed significant. RESULTS: Patients had the same distribution in terms of age, sex, type of glaucoma and type of cataract. Patients were followed up for a mean of 6 months. The mean intraocular pressure before surgery in the MMC group was 24.85 ± 2.83 mmHg with 3.2 ± 0.523 anti-glaucoma drugs, which reached 13.75 ± 3.552 mmHg with 0.15 ± 0.489 anti-glaucoma drugs at the latest visit. The average intraocular pressure before surgery in the BMM group was 24.45 ± 2.48 mmHg with 2.9 ± 0.641 anti-glaucoma drugs, which reached 15.40 ± 3.267 mmHg with 0.25 ± 0.55 anti-glaucoma drug at the last follow-up. The intraocular pressure was notably lower in the MMC group than BMM group 6 months after surgery. There was not a significant difference from the aspect of success rate and failure rate among the two groups at the 6-month follow-up (p = 0.135). DISCUSSION: Based on the results of this study, MMC and bevacizumab-methylcellulose both seem to be effective in the success of combined phacoemulsification and non-penetrating deep sclerectomy surgery, but MMC decreases intraocular pressure in patients at 6 months post-surgery.

A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect.

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.

Effectiveness of hyaluronic acid/carboxymethylcellulose in preventing adhesive bowel obstruction after laparoscopic radical cystectomy.

BACKGROUND/OBJECTIVE: Adhesive bowel obstruction is one of the most frequent complications after radical cystectomy, prolonging hospital stay and fasting period and increasing medical expenses. This study evaluated the effectiveness of hyaluronic acid/carboxymethylcellulose (HA/CMC) in preventing adhesive bowel obstruction after laparoscopic radical cystectomy. METHODS: Randomized, controlled, single-blinded study was performed. Of 76 patients who underwent laparoscopic radical cystectomy for bladder cancer, 38 received HA/CMC instillation and 38 did not. The primary endpoint was the rate of postoperative adhesive bowel obstruction. The secondary endpoint was the rate of other postoperative outcomes. RESULTS: None of the patients who received HA/CMC instillation experienced postoperative adhesive bowel obstructions, compared with six (15.79%) patients in the control group (p = 0.025). Of the six patients with ileus, two underwent adhesiolysis. There were no significant differences between the two groups in other postoperative outcomes. CONCLUSION: HA/CMC instillation during laparoscopic radical cystectomy may reduce the incidence of postoperative adhesive bowel obstruction without adverse effects.

In vitro and ex vivo studies on diltiazem hydrochloride-loaded microsponges in rectal gels for chronic anal fissures treatment.

Diltiazem hydrochloride, topically applied at 2% concentration, is considered effective for the treatment of chronic anal fissures, although it involves several side effects among which anal pruritus and postural hypotension. To test the hypothesis that a sustained delivery system of diltiazem hydrochloride may be helpful for the treatment of chronic anal fissures, in the present study we evaluated the potential of gels containing diltiazem hydrochloride entrapped in microsponges. Such microsponges were based on Eudragit RS 100 and the effect of some formulation variables was assessed by a 23 full factorial screening design. An optimized formulation of diltiazem hydrochloride microsponges was dispersed in Methylcellulose 2% or Poloxamer 407 20% and the resulting gels (micro-l-diltiazem hydrochloride 2%) were subjected to in vitro drug release, ex vivo permeability and drug deposition after application on porcine rectal mucosa. The results showed a prolonged release up to 24 h from micro-l-diltiazem hydrochloride at 2% in the gels. The permeation tests revealed up to 18% higher drug retention on the mucosal tissue after 24 h by the micro-l-diltiazem hydrochloride 2% gels compared to conventional diltiazem hydrochloride gels at 2%. These results suggest that diltiazem hydrochloride-loaded microsponges dispersed in rectal gels may be useful to overcome some limitations of conventional local chronic anal fissure therapy.

Controlled release strategy designed for intravitreal protein delivery to the retina.

Therapeutic protein delivery directly to the eye is a promising strategy to treat retinal degeneration; yet, the high risks of local drug overdose and cataracts associated with bolus injection have limited progress, requiring the development of sustained protein delivery strategies. Since the vitreous humor itself is a gel, hydrogel-based release systems are a sensible solution for sustained intravitreal protein delivery. Using ciliary neurotrophic factor (CNTF) as a model protein for ocular treatment, we investigated the use of an intravitreal, affinity-based release system for protein delivery. To sustain CNTF release, we took advantage of the affinity between Src homology 3 (SH3) and its peptide binding partners: CNTF was expressed as a fusion protein with SH3, and a thermogel of hyaluronan and methylcellulose (HAMC) was modified with SH3 binding peptides. Using a mathematical model, the hydrogel composition was successfully designed to release CNTF-SH3 over 7 days. The stability and bioactivity of the released protein were similar to those of commercial CNTF. Intravitreal injections of the bioengineered thermogel showed successful delivery of CNTF-SH3 to the mouse retina, with expected transient downregulation of phototransduction genes (e.g., rhodopsin, S-opsin, M-opsin, Gnat 1 and 2), upregulation of STAT1 and STAT3 expression, and upregulation of STAT3 phosphorylation. This constitutes the first demonstration of intravitreal protein release from a hydrogel. Immunohistochemical analysis of the retinal tissues of injected eyes confirmed the biocompatibility of the delivery vehicle, paving the way towards new intravitreal protein delivery strategies.

Rhomboid Intercostal and Subserratus Plane Block: A Cadaveric and Clinical Evaluation.

BACKGROUND AND OBJECTIVES: Fascial plane blocks are rapidly emerging to provide safe, feasible alternatives to epidural analgesia for thoracic and abdominal pain. We define a new option for chest wall and upper abdominal analgesia, termed the rhomboid intercostal and subserratus plane (RISS) block. The RISS tissue plane extends deep to the erector spinae muscle medially and deep to the serratus anterior muscle laterally. We describe a 2-part proof-of-concept study to validate the RISS block, including a cadaveric study to evaluate injectate spread and a retrospective case series to assess dermatomal coverage and analgesic efficacy. METHODS: For the cadaveric portion of the study, bilateral ultrasound-guided RISS blocks were performed on 6 fresh cadavers with 30 mL of 0.5% methylcellulose with india ink. For the retrospective case series, we present 15 patients who underwent RISS block or RISS catheter insertion for heterogeneous indications including abdominal surgery, rib fractures, chest tube-associated pain, or postoperative incisional chest wall pain. RESULTS: In the cadaveric specimens, we identified staining of the lateral branches of the intercostal nerves from T3 to T9 reaching the posterior primary rami deep to the erector spinae muscle medially. In the clinical case series, dermatomal coverage was observed in the anterior hemithorax with visual analog pain scores less than 5 in patients who underwent both single-shot and continuous catheter infusions. CONCLUSIONS: Our preliminary cadaveric and clinical data suggest that RISS block anesthetizes the lateral cutaneous branches of the thoracic intercostal nerves and can be used in multiple clinical settings for chest wall and upper abdominal analgesia.

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery.

Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%. There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation, and the formulation reliably switched between thixotropy and temperature-dependent rheopexy when it was tested in a rheometer under conditions that simulate the ocular surface, including blinking. These properties should ensure that the formulation coats the cornea through blinking of the eyelid and facilitate application of the medication as an eye drop immediately prior to the patient's bedtime. We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. This work paves the way for the introduction of novel products targeting ocular diseases to the market.

Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done "WT".

An account is given of the recent development of the highly viscous complex biopharmaceuticals in relation to syringeability and injectability. The specific objective of this study is to establish a convenient method to examine problem of the injectability for the needle-syringe-formulation system when complex formulations with diverse viscosities are used. This work presents the inter-relationship between needle size, syringe volume, viscosity, and injectability of polymeric solutions having typical viscosities encountered in concentrated biologics, by applying a constant probe crosshead speed on the plunger-syringe needle assembly and continuously recording the force-distance profiles. A computerized texture analyzer was used to accurately capture, display, and store force, displacement, and time data. The force-distance curve and area under the curve are determined, and total work done for complete extrusion of the syringe content was calculated automatically by applying an established Matlab program. Various concentrations (i.e., 0.5-4% w/v of polymeric fluids/dispersions) of polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) with viscosity ranges of 5-100 cP mimicking concentrated monoclonal antibody solutions and complex biopharmaceutical formulations are investigated. Results indicate that calculated values of total work done to completely extrude the syringe content are the most appropriate parameter that describes viscosity-injection force of dispersed formulations. Additionally, the rheological properties of HPMC and PEO fluids in the context of syringeability and injectability are discussed.

Surfactant-free solubilization and systemic delivery of anti-cancer drug using low molecular weight methylcellulose.

Docetaxel, an advanced taxoid, has been widely used as an anti-mitotic agent, but further augmentation of its properties is still required, including improvement in low aqueous solubility. Herein, we report the development of bio-eliminable low molecular weight methylcellulose-based surfactant-free injectable formulation for the delivery of docetaxel. Crude methylcellulose, a hydrophobically modified cellulose derivative, was hydrolyzed by an enzymatic degradation method to obtain low molecular weight methylcellulose (LMwMC). Docetaxel was successfully loaded in micelles with small particle sizes high drug loading and sustained release profile. The in vivo anti-cancer effects of intravenously injected nanoparticle systems in B16F10 melanoma xenograft mice were evaluated and demonstrated a significantly enhanced therapeutic effect with the docetaxel-LMwMC micellar aggregates compared to a commercially available docetaxel, Taxotere®. Surfactant-free solubilization of docetaxel could be a promising delivery method for effective insoluble drug delivery for anti-tumor efficacy.

In vitro investigations on the effects of semi-synthetic, sulphated carbohydrates on the immune status of cultured common carp (Cyprinus carpio) leucocytes.

The rapid emergence of drug resistance, unfavourable immunosuppression and mounting evidence to suggest the deleterious accumulation of drug breakdown residues within animal tissues has driven a strong desire to move away from these current methods of disease control. Some natural products such as ß-glucan, which are extracted from, for example, plants and fungi, are able to modulate the immune system and increase protection against diseases. However, these products are heterogeneous and their effects can be variable thus limiting their applicability and reliability. Carbohydrates were modified via chemical sulphation and these semi-synthetic, sulphated carbohydrates analysed for their immunological activity utilising carp pronephric cells and a carp leucocyte cell line (CLC). A sulphated ß(1,4)-glucan, methyl hydroxyethyl cellulose sulphate (MHCS), demonstrated a stimulatory effect on fish immune cells. MHCS induced a range of bioactive effects in carp leucocyte cells whilst not affecting cell viability when cells were exposed for 24 h at concentrations of 1-150 µgml-1. MHCS stimulated the innate immune system where a significant increase in respiratory burst activity was observed at concentrations 25-250 µgml-1 in comparison to control (sterile water), cellulose ether, MacroGard® and zymosan. Also, under in mock bacterial and viral infection conditions i.e. Lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly(I:C)), MHCS enhanced the immune responses of pronephric cells by stimulating the respiratory burst activity at concentrations 50 and 150 µgml-1. MHCS also enhanced the expression of cytokines including interleukin 1 beta (IL1ß), tumor necrosis factor alpha 1 and 2 (TNFα 1,2), interferons alpha 2 (IFN α2) and inducible nitric oxide synthase (iNOS) in carp pronephric cells. It is proposed that this new semi-synthetic carbohydrate is a potential candidate for the development of a new generation of immunostimulants and adjuvants for use in vaccination strategies in aquaculture.

The effect of vocal fold augmentation on cough symptoms in the presence of glottic insufficiency.

OBJECTIVE: To determine the effect of injection augmentation of the vocal folds on chronic cough symptoms in patients with glottic insufficiency. METHODS: Medical records from 146 consecutive patients who underwent vocal fold injection augmentation by a fellowship-trained laryngologist between 2013 and 2015 were reviewed. Twenty-three patients (12 male) met inclusion criteria of a vocal fold augmentation injection, cough symptoms lasting more than 8 weeks, and glottic insufficiency as determined by shortened closed phase on stroboscopy. Exclusion criteria included lack of cough complaints, diagnosis of vocal fold immobility, previous history of vocal fold augmentation, and incomplete data sets. Data collected included age, gender, pre- and 1-month postinjection Cough Severity Index (CSI) scores, location of injection (unilateral or bilateral), and patient statement of percent change in symptoms that was recorded at 1-month postinjection visit. RESULTS: Paired t test indicated a significant decrease in CSI scores from pre- (m = 18.5) to 1-month postinjection (m = 12.1) (P = 0.004). Eighteen patients (78.2%) reported a 50% or greater improvement in cough symptoms at the 1-month postinjection visit. CONCLUSION: Injection augmentation of the vocal folds in the presence of glottic insufficiency appears to improve cough symptoms, as was reported by CSI in patients who are refractory to other medical and behavioral treatments. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1316-1319, 2018.

Injectable methylcellulose hydrogel containing silver oxide nanoparticles for burn wound healing.

A thermo-sensitive methylcellulose (MC) hydrogel containing silver oxide nanoparticles (NPs) was prepared via one-pot synthesis in which a silver acetate precursor salt (CH3COOAg) induces a salt-out effect in the MC solution. The silver oxide NPs were synthesized in situ from Ag+ ions during the MC hydrogelation, and the residual CH3COO- ions decreased the gelation temperature of the MC solution through the salt-out effect. The gelation behavior of the MC solution varied according to the CH3COOAg content and was monitored. Also, the formation and structure of the silver oxide NPs in the MC hydrogel was confirmed. From the results, silver oxide NPs was successfully incorporated in MC hydrogels, simultaneously, acetate ion which was counter ion of Ag was affected gelation behavior of Ag. Finally, the antimicrobial activity and wound healing effect was examined using the shaking flask method and burn wound test, respectively. The MC hydrogel with silver oxide NPs showed excellent antimicrobial activity and burn wound healing. Therefore, this thermo-responsive MC hydrogel has great potential as an injectable hydrogel for wound regeneration.