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Poly (lactic-co-glycolic acid) (PLGA) in situ-forming implants are well-established drug delivery systems for controlled drug release over weeks up to months. To prevent initial burst release, which is still a major issue associated with PLGA-based implants, drugs attached to particulate carriers have been encapsulated. Unfortunately, former studies only investigated the resulting release of the soluble drugs and hence missed the potential offered by particulate drug release. In this study, we developed a system capable of releasing functional drug-carrying particles over a prolonged time. First, we evaluated the feasibility of our approach by encapsulating silica particles of different sizes (500 nm and 1 μm) and surface properties (OH or NH 2 groups) into in situ-forming PLGA implants. In this way, we achieved sustained release of particles over periods ranging from 30 to 70 days. OH-carrying particles were released much more quickly when compared to NH 2 -modified particles. We demonstrated that the underlying release mechanisms involve size-dependent diffusion and polymer-particle interactions. Second, particles that carried covalently-attached ovalbumin (OVA) on their surfaces were incorporated into the implant. We demonstrated that OVA was released in association with the particles as functional entities over a period of 30 days. The released particle-drug conjugates maintained their colloidal stability and were efficiently taken up by antigen presenting cells. This system consisting of particles incorporated into PLGA-based in situ-forming implants offers the dual advantage of sustained and particulate release of drugs as a functional unit and has potential for future use in many applications, particularly in single-dose vaccines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO 3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.

The objective of this study was to prepare ibuprofen enteric-coated sustained-release pellets (IB-SRPs) and codeine phosphate immediate-release pellets (CP-IRPs) to play a synergistic role in analgesia. The pellets were developed by extrusion-spheronization and fluidized bed coating technology. The single-factor investigation was used to determine the optimal prescription and process. The sustained-release membrane of IB-SRPs was water-insoluble ethyl cellulose (EC), triethyl citrate (TEC) was used as plasticizer, and hydroxypropyl methylcellulose (HPMCP) was chose as porogen. Besides, the immediate-release layer of CP-IRPs was gastric-soluble coating film. The ibuprofen and codeine phosphate compound capsules (IB-CP SRCs) were prepared by IB-SRPs and CP-IRPs packed together in capsules with the optimum doses of 200 and 13 mg, respectively. The prepared pellets were evaluated by scanning electron microscopy and dissolution test. Pharmacokinetic studies in beagle dogs indicated that the optimized IB-CP SRCs had smaller individual differences and better reproducibility comparing with commercial available tablets. Additionally, IB-CP SRCs achieved consistency with in vivo and in vitro tests. Therefore, IB-CP SRCs could play a great role in rapid and long-term analgesic.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

The compaction of multiple-unit pellet system (MUPS) is a challenging process due to the ease of coat damage under high compression pressure, thereby altering drug release rates. To overcome this, cushioning excipients are added to the tablet formulation. Excipients can be processed into pellets/granules and freeze-dried to increase their porosity and cushioning performance. However, successful formation of pellets/granules has specific requirements that limit formulation flexibility. In this study, a novel top-down approach that harnessed bulk freeze-drying milling was explored to avoid the challenges of pelletization/granulation. Aqueous dispersions containing 20%, w/w hydroxypropyl methylcellulose (HPMC), partially pregelatinised starch or polyvinylpyrrolidone alone, and with lactose (Lac) in 1:1 ratio, were freeze-dried and then milled to obtain particulate excipients for characterization and evaluation of their cushioning performance. This study demonstrated that bulk freeze-drying milling is a versatile method for developing excipients that are porous and directly compressible. The freeze-drying process modified the materials in a unique manner which could impart cushioning properties. Compared to unprocessed excipients, the freeze-dried products generally exhibited better cushioning effects. The drug release profile of drug-loaded pellets compacted with freeze-dried Lac-HPMC excipients was similar to that of the uncompacted drug-loaded pellets (f 2 value = 51.7), indicating excellent cushioning effects. It was proposed that the specific balance of brittle and plastic nature of the freeze-dried Lac-HPMC composite conferred greater protective effect to the drug-loaded pellets, making it advantageous as a cushioning excipient.

Most peptide drugs have short half-lives, necessitating frequent injections that may induce skin sensitivity reactions; therefore, versatile prolonged-release delivery platforms are urgently needed. Here, we focused on an oxidatively and thermally responsive recombinant elastin-like polypeptide with periodic cysteine residues (cELP), which can rapidly and reversibly form a disulfide cross-linked network in which peptide can be physically incorporated. As a model for proof of concept, we used enfuvirtide, an antiretroviral fusion-inhibitor peptide approved for treatment of human immunodeficiency virus (HIV) infection. cELP was mixed with enfuvirtide and a small amount of hydrogen peroxide (to promote cross-linking), and the soluble mixture was injected subcutaneously. The oxidative cross-linking generates a network structure, causing the mixture to form a hydrogel in situ that serves as an enfuvirtide depot. We fabricated a series of enfuvirtide-containing hydrogels and examined their stability, enfuvirtide-releasing profile and anti-HIV potency in vitro. Among them, hydrophobic cELP hydrogel provided effective concentrations of enfuvirtide in blood of rats for up to 8 h, and the initial concentration peak was suppressed compared with that after injection of enfuvirtide alone. cELP hydrogels should be readily adaptable as platforms to provide effective depot systems for delivery of other anti-HIV peptides besides enfuvirtide., Statement of Significance: In this paper, we present an anti-HIV peptide delivery system using oxidatively and thermally responsive polypeptides that contain multiple periodic cysteine residues as an injectable biomaterial capable of in situ self-gelation, and we demonstrate its utility as an injectable depot capable of sustained release of anti-HIV peptides. The novelty of this work stems from the platform employed to provide the depot encapsulating the peptide drugs (without chemical conjugation), which consists of rationally designed, genetically engineered polypeptides that enable the release rate of the peptide drugs to be precisely controlled., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Current endeavor was aimed towards monitoring percent weight build-up during functional coating process on drug-layered pellets. Near-infrared (NIR) spectroscopy is an emerging process analytical technology (PAT) tool which was employed here within quality by design (QbD) framework. Samples were withdrawn after spraying every 15-Kg cellulosic coating material during Wurster coating process of drug-loaded pellets. NIR spectra of these samples were acquired using cup spinner assembly of Thermoscientific Antaris II, followed by multivariate analysis using partial least squares (PLS) calibration model. PLS model was built by selecting various absorption regions of NIR spectra for Ethyl cellulose, drug and correlating the absorption values with actual percent weight build up determined by HPLC. The spectral regions of 8971.04 to 8250.77 cm -1 , 7515.24 to 7108.33 cm -1 , and 5257.00 to 5098.87 cm -1 were found to be specific to cellulose, where as the spectral region of 6004.45 to 5844.14 cm -1 was found to be specific to drug. The final model gave superb correlation co-efficient value of 0.9994 for calibration and 0.9984 for validation with low root mean square of error (RMSE) values of 0.147 for calibration and 0.371 for validation using 6 factors. The developed correlation between the NIR spectra and cellulose content is useful in precise at-line prediction of functional coat value and can be used for monitoring the Wurster coating process.

Antibiotic loaded bone cements are used as drug delivery systems for the treatment of periprosthetic joint infections. They can be loaded with antibiotics during industrial component production (premixing) and during cement preparation (manually blending). Although double premixed antibiotic loaded bone cements are available, manually blending of a gentamicin premixed antibiotic loaded bone cement with vancomycin is still popular. We compared in vitro antibiotic elution and compressive strength of 0.5 g gentamicin premixed bone cement (PALACOS® R + G), 0.5 g gentamicin premixed bone cement (PALACOS® R + G) manually blended with 2.0 g vancomycin, 0.5 g gentamicin and 2.0 g vancomycin premixed bone cement (COPAL® G + V), 1 g gentamicin and clindamycin premixed bone cement (COPAL® G + C) and bone cement without an antibiotic (PALACOS® R) as control. Antibiotic concentration measurements were performed for 6 weeks and then compression strength was tested. Concentrations of gentamicin showed no significant differences between PALACOS® R + G, PALACOS® R + G with vancomycin and COPAL G® + V. After 48 h COPAL G® + C produced significantly higher gentamicin concentrations than the other formulations. After 12 h PALACOS® R + G with vancomycin produced significantly higher vancomycin concentrations, but had the lowest compression strength. We found no influence of vancomycin addition on gentamicin elution, irrespectively of the loading method. However, the manually vancomycin blended ALBC produced higher vancomycin concentrations. Compression strength after aging is reduced by loading with vancomycin.

The objective of this work was to develop self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system for liver cancer chemotherapy and studied the release profiles of doxorubicin (Dox) from different depot formulations. Tri-block copolymers of poly(ε-caprolactone), poly(D,L-lactide) and poly(ethylene glycol) named PLECs were successfully used as a biodegradable material to encapsulate Dox as the injectable local drug delivery system. Depot formation and encapsulation efficiency of these depots were evaluated. Results show that depots could be formed and encapsulate Dox with high drug loading content. For the release study, drug loading content (10, 15 and 20% w/w) and polymer concentration (25, 30, and 35% w/v) were varied. It could be observed that the burst release occurred within 1-2 days and this burst release could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. The degradation at the surface and cross-section of the depots were examined by Scanning Electron Microscope (SEM). In addition, cytotoxicity of Dox-loaded depots and blank depots were tested against human liver cancer cell lines (HepG2). Dox released from depots significantly exhibited potent cytotoxic effect against HepG2 cell line compared to that of blank depots. Results from this study reveals an important insight in the development of injectable drug delivery system for liver cancer chemotherapy. Schematic diagram of self-forming doxorubicin-loaded polymeric depots as an injectable drug delivery system and in vitro characterizations. (a) Dox-loaded PLEC depots could be formed with more than 90% of sustained-release Dox at 25% polymer concentration and 20% Dox-loading content. The burst release occurred within 1-2 days and could be reduced by physical mixing of hydroxypropyl-beta-cyclodextrin (HP-β-CD) into the depot system. (b) Dox released from depots significantly exhibited potent cytotoxic effect against human liver cancer cell lines (HepG2 cell line) compared to that of blank depots., ((c) Dox-loaded depots showed bulk erosion with hollow core at day 60.)

Implant infections remain a major healthcare problem due to the prolonged hospitalisation period required to disrupt and treat bacterial biofilm formation, and the need for additional surgery to remove/replace the infected implant, which if not removed in a timely manner may lead to sepsis. Although localised drug administration, via an implanted scaffold, has shown promise in a clinical setting, the ideal scaffold cross-linking (to initially withstand the aggressive infection environment) and drug (to be effective against infection) have yet to be identified. In this work, in the first instance, the biochemical, biophysical, and biological properties of collagen sponges as a function of various concentrations (0.625%, 1.0%, 2.5%, 5.0%, and 10.0%) of hexamethylene diisocyanate were assessed. Data presented illustrate that hexamethylene diisocyanate at 0.625% concentration was able to effectively stabilise collagen scaffolds, as judged by the reduction in free amines, adequate resistance to collagenase digestion, reduction in swelling, increase in denaturation temperature, suitable mechanical properties, and appropriate cytocompatibility. Subsequently, collagen scaffolds stabilised with 0.625% hexamethylene diisocyanate were loaded with variable concentrations (0, 10, 100, and 500 μg ml -1 ) of Cefaclor and Ranalexin. Both drugs exhibited similar loading efficiency, release profile, and cytocompatibility. However, only collagen scaffolds loaded with 100 μg ml -1 Cefaclor exhibited adequate antibacterial properties against both 10 6 and 10 8 colony-forming units per ml of both Escherichia coli and Staphylococcus epidermidis.

In the United States, long standing deep infections of joint arthroplasty, such as total knee and total hip replacements, are treated with two-stage exchange. This requires the removal of the prior implant, placement of an antibiotic eluting spacer block made of polymethylmethacrylate (PMMA), followed by re-implantation of a new implant after treatment with intravenous antibiotics for six to eight weeks. Unfortunately, the use of PMMA as a spacer material has limitations in terms of mechanical and drug-eluting properties. PMMA is brittle and elutes most of the antibiotics within the first few days. Furthermore, the polymerization reaction for PMMA is highly exothermic, thereby limiting the use to heat-stable antibiotics. We hypothesize that the use of a 3D printed polymeric liner made of polylactic acid (PLA) would overcome the limitations of PMMA because it is a stronger and a less brittle material than PMMA. Furthermore, the liner can also act as a controlled drug delivery vehicle by using built in reservoirs and a network of micro-channels as well as by incorporating antibiotics directly into the polymer during manufacturing stage. Finally, the liner can be 3D printed according to the anatomy of the patient and thereby has the potential to transform the manner in which periprosthetic joint infections are currently treated., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study was to develop mucoadhesive pellets on a thiolated pectin base using the extrusion-spheronization technique. Thiolation of pectin was performed by esterification with thioglycolic acid. The molecular weight and thiol group content of the pectins were determined. Pellets containing pectin, microcrystalline cellulose, and ketoprofen were prepared and their mucoadhesive properties were evaluated through a wash-off test using porcine intestinal mucosa. The in vitro ketoprofen release was also evaluated. Thiolated pectin presented a thiol group content of 0.69 mmol/g. Thiolation caused a 13% increase in polymer molecular weight. Pellets containing thiolated pectin were still adhering to the intestinal mucosa after 480 min and showed a more gradual release of ketoprofen. Conversely, pellets prepared with nonthiolated pectin showed rapid disintegration and detached after only 15 min. It can be concluded that thiolated pectin-based pellets can be considered a potential platform for the development of mucoadhesive drug delivery systems for the oral route., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Peripheral nerve injury is one of common traumas. Although injured peripheral nerves have the capacity to regenerate, axon regeneration proceeds slowly and functional outcomes are often poor. Pharmacological enhancement of regeneration can play an important role in increasing functional recovery. In this study, we developed a novel electrospun nanofiber sheet incorporating methylcobalamin (MeCbl), one of the active forms of vitamin B12 homologues, to deliver it enough locally to the peripheral nerve injury site. We evaluated whether local administration of MeCbl at the nerve injury site was effective in promoting nerve regeneration. Electrospun nanofiber sheets gradually released MeCbl for at least 8weeks when tested in vitro. There was no adverse effect of nanofiber sheets on function in vivo of the peripheral nervous system. Local implantation of nanofiber sheets incorporating MeCbl contributed to the recovery of the motor and sensory function, the recovery of nerve conduction velocity, and the promotion of myelination after sciatic nerve injury, without affecting plasma concentration of MeCbl., Statement of Significance: Methylcobalamin (MeCbl) is a vitamin B12 analog and we previously reported its effectiveness in axonal outgrowth of neurons and differentiation of Schwann cells both in vitro and in vivo. Here we estimated the effect of local administered MeCbl with an electrospun nanofiber sheet on peripheral nerve injury. Local administration of MeCbl promoted functional recovery in a rat sciatic nerve crush injury model. These sheets are useful for nerve injury in continuity differently from artificial nerve conduits, which are useful only for nerve defects. We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In this study, a multiparticulate matrix system was produced, containing two different active pharmaceutical ingredients (APIs): enalapril-maleate and hydrochlorothiazide. The critical control points of the process were investigated by means of factorial design. Beside the generally used microcrystalline cellulose, ethylcellulose was used as matrix former to achieve modified drug release ensured by diffusion. The matrix pellets were made by extrusion-spheronization using a twin-screw extruder. Some pellet properties (aspect ratio, 10% interval fraction, hardness, deformation process) were determined. The aim of our study was to investigate how the two different APIs with different solubility and particle size influence the process. The amount of the granulation liquid plays a key role in the pellet shaping. A higher liquid feed rate is preferred in the pelletization process.

In addition to excellent biocompatibility and mechanical performance, the new generation of bone and craniofacial implants are expected to proactively contribute to the regeneration process and dynamically interact with the host tissue. To this end, integration and sustained delivery of therapeutic agents has become a rapidly expanding area. The incorporated active molecules can offer supplementary features including promoting oteoconduction and angiogenesis, impeding bacterial infection and modulating host body reaction. Major limitations of the current practices consist of low drug stability overtime, poor control of release profile and kinetics as well as complexity of finding clinically appropriate drug dosage. In consideration of the multifaceted cascade of bone regeneration process, this research is moving towards dual/multiple drug delivery, where precise control on simultaneous or sequential delivery, considering the possible synergetic interaction of the incorporated bioactive factors is of utmost importance. Herein, recent advancements in fabrication of synthetic load bearing implants equipped with various drug delivery systems are reviewed. Smart drug delivery solutions, newly developed to provide higher tempo-spatial control on the delivery of the pharmaceutical agents for targeted and stimuli responsive delivery are highlighted. The future trend of implants with bone drug delivery mechanisms and the most common challenges hindering commercialization and the bench to bedside progress of the developed technologies are covered., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In the literature there are some publications about the effect of impeller and chopper speeds on product parameters. However, there is no information about the effect of temperature. Therefore our main aim was the investigation of elevated temperature and temperature distribution during pelletization in a high shear granulator according to process analytical technology. During our experimental work, pellets containing pepsin were formulated with a high-shear granulator. A specially designed chamber (Opulus Ltd.) was used for pelletization. This chamber contained four PyroButton-TH® sensors built in the wall and three PyroDiff® sensors 1, 2 and 3cm from the wall. The sensors were located in three different heights. The impeller and chopper speeds were set on the basis of 3 2 factorial design. The temperature was measured continuously in 7 different points during pelletization and the results were compared with the temperature values measured by the thermal sensor of the high-shear granulator. The optimization parameters were enzyme activity, average size, breaking hardness, surface free energy and aspect ratio. One of the novelties was the application of the specially designed chamber (Opulus Ltd.) for monitoring the temperature continuously in 7 different points during high-shear granulation. The other novelty of this study was the evaluation of the effect of temperature on the properties of pellets containing protein during high-shear pelletization., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol(®) 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.

Biofunctionalized nanofibers with a desired biological function can be used as a tissue engineering scaffold due to their small fiber diameters and porous structure. In the present study, poly(ɛ-caprolactone)/poly(m-anthranilic acid) nanofibers were biofunctionalized with covalent immobilization of bone morphogenetic protein-2 (BMP-2) through 1-ethyl-3-(dimethyl-aminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide activation. Fourier transform infrared analysis of the nanofiber surfaces confirmed the successful immobilization. The amount of immobilized BMP-2 was determined with bicinchoninic acid protein assay. The nanofibers before and after BMP-2 immobilization were non-cytotoxic and enhanced the attachment and proliferation of Saos-2 cells. Biofunctionalization of nanofibers with BMP-2 promoted in vitro osteogenic activity. The alkaline phosphatase activity and calcium mineralizatio of cells after 14 days of in vitro culture were enhanced on nanofibers with immobilized BMP-2., (© The Author(s) 2016.)

Stent insertion and chemical agents of ethylene diamine tetraacetic acid and sodium cholate for dissolving common bile duct stone diseases through extra biliary tract infusion have been believed a relatively effective therapeutics for the clinical symptom. Core-shell nanofibers produced by co-axial electrospinning to deliver chemical drugs, biomacromolecules, genes and even cells have been reported for various advanced drug delivery system and tissue engineering applications. In the present study, poly (lactide-co-ɛ-caprolactone) (PLCL) core-shell nanofiber-coated film of stent, loaded with ethylene diamine tetraacetic acid and sodium cholate in core layer, was fabricated by co-axial electrospinning for treating gallstone disease. Image of laser scanning confocal microscopy and transmission electron microscopy demonstrated core-shell structure of drug-loaded nanofiber. Fourier transform infrared spectra and the thermogravimetric analysis proved ethylene diamine tetraacetic acid and sodium cholate to be successfully loaded in nanofibers. Morphology of nanofibers after a period of degradation still keeps good shape. Drugs can continuously release for around five days, which was proved significant effectiveness for dissolving gallstone. Besides, unobvious cytotoxicity was exhibited from MTT results and cell kept good morphology in vitro research. The present coated stent showed a bright prospect for dissolving the biliary stone., (© The Author(s) 2016.)

The aim of the research was to investigate the complete process of pellet production in a Wurster fluidized bed coater in order to determine the main factors affecting the migration phenomenon of a soluble API through the ethycellulose film coating (Surelease®) and hence the long-term stability of the controlled release pellets. Guaifenesin (GFN), as BCS class I model drug, was layered on sugar spheres using a binder-polymer solution containing the dissolved GFN. The drug loaded pellets were then coated with Surelease®. The influence of drug loading (4.5-20.0% w/w), curing conditions (40-60°C and dynamic-static equipment), coating level (12-20% theoretical weight gain) and composition of the binder-layering solution (hypromellose versus Na alginate) on process efficiency (RSDW%), GFN content uniformity (RSDC%), GFN solid state (DSC and XRD) and pellet release profiles was evaluated. The effectiveness of the Surelease film was strongly affected by the ability of GFN to cross the coating layer and to recrystallize on the pellet surface. Results indicated that this behaviour was dependent on the polymer used in the binder-layering solution. Using hypromellose as polymer, GFN recrystallized on the coated pellet surface at both drug loadings. The curing step was necessary to stabilize the film effectiveness at the higher drug loading. Increasing the coating level delayed but did not prevent the GFN diffusion. Replacing hypromellose with Na alginate, reduced the migration of GFN through the film to a negligible amount even after six months of storage and the curing step was not necessary to achieve stable controlled release profiles over storage., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Development of an intraocular lens (IOL) as a drug delivery device has been pursued for many years and is a promising concept in modern cataract surgery. Common postoperative conditions such as posterior capsule opacification (PCO), intraocular inflammation or the rare but severe complications of cataract surgery like endophthalmitis are potential therapeutic targets for a drug-eluting IOL. There are three techniques of pharmacological IOL modification: Firstly, surface modification of the IOL ("coating"); secondly, IOL optic modification ("soaking") and lastly, loading the IOL haptics with a slow release system. The last option does not interfere with the IOL optics at all. Therefore, a broad spectrum of pharmacological agents needs to be assessed in preclinical and clinical studies to determine which agent/IOL combination is safe and efficient. For pharmacological PCO prophylaxis, erufosine-loaded IOLs are of great clinical interest. Heparin-coated IOLs might become clinically relevant for attenuation of intraocular inflammation after cataract surgery and cefuroxime-loaded IOLs for endophthalmitis prophylaxis., (Georg Thieme Verlag KG Stuttgart · New York.)

Platelet-rich plasma (PRP) has been used for different applications in human and veterinary medicine. Many studies have shown promising therapeutic effects of PRP; however, there are still many controversies regarding its composition, properties, and clinical efficacy. The aim of this study was to evaluate the influence of different platelet concentrations on the rheological properties and growth factor (GF) release profile of PRP-gels. In addition, the viability of incorporated bone marrow-derived human mesenchymal stem cells (MSCs) was investigated. PRP (containing 1000 × 10(3), 2000 × 10(3), and 10,000 × 10(3) platelets/μL) was prepared from human platelet concentrates. Platelet activation and gelification were achieved by addition of human thrombin. Viscoelastic properties of PRP-gels were evaluated by rheological studies. The release of GFs and inflammatory proteins was measured using a membrane-based protein array and enzyme-linked immunosorbent assay. MSC viability and proliferation in PRP-gels were assessed over 7 days by cell viability staining. Cell proliferation was examined using DNA quantification. Regardless of the platelet content, all tested PRP-gels showed effective cross-linking. A positive correlation between protein release and the platelet concentration was observed at all time points. Among the detected proteins, the chemokine CCL5 was the most abundant. The greatest release appeared within the first 4 h after gelification. MSCs could be successfully cultured in PRP-gels over 7 days, with the highest cell viability and DNA content found in PRP-gels with 1000 × 10(3) platelets/μL. The results of this study suggest that PRP-gels represent a suitable carrier for both cell and GF delivery for tissue engineering. Notably, a platelet concentration of 1000 × 10(3) platelets/μL appeared to provide the most favorable environment for MSCs. Thus, the platelet concentration is an important consideration for the clinical application of PRP-gels.

Significant research has focused on investigating the potential of hydrogels in various applications and, in particular, in medicine. Specifically, hydrogels that are biodegradable lend promise to many therapeutic and biosensing applications. Endonucleases are critical for mechanisms of DNA repair. However, they are also known to be overexpressed in cancer and to be present in wounds with bacterial contamination. In this work, we set out to demonstrate the preparation of DNA-enabled hydrogels that could be degraded by nucleases. Specifically, hydrogels were prepared through the reaction of dibenzocyclooctyne-functionalized multi-arm poly(ethylene glycol) with azide-functionalized single-stranded DNA in aqueous solutions via copper-free click chemistry. Through the use of this method, biodegradable hydrogels were formed at room temperature in buffered saline solutions that mimic physiological conditions, avoiding possible harmful effects associated with other polymerization techniques that can be detrimental to cells or other bioactive molecules. The degradation of these DNA-cross-linked hydrogels upon exposure to the model endonucleases Benzonase(®) and DNase I was studied. In addition, the ability of the hydrogels to act as depots for encapsulation and nuclease-controlled release of a model protein was demonstrated. This model has the potential to be tailored and expanded upon for use in a variety of applications where mild hydrogel preparation techniques and controlled material degradation are necessary including in drug delivery and wound healing systems.

In this study, we proposed a potential method for the preparation of a magnesium-based medical device for local drug delivery and controlled corrosion. A magnesium surface was modified with 3-aminopropyltrimethoxy silane, and the resulting surface was then coated with drug-loaded nanoparticles made of poly (lactic-co-glycolic acid) via electrophoretic deposition. The drug-loaded nanoparticles (i.e., Tr_NP) exhibited a size of 250 ± 67 nm and a negative zeta potential of -20.9 ± 2.75 mV. The drug was released from the nanoparticles in a sustained manner for 21 days, and this did not change after their coating on the silane-modified magnesium. The silane-modified surface suppressed magnesium corrosion. When immersed in phosphate buffered saline at pH 7.4, the average rate of hydrogen gas generation was 0.41-0.45 ml/cm(2)/day, compared to 0.58-0.6 ml/cm(2)/day from a bare magnesium surface. This corrosion profile was not significantly changed after nanoparticle coating under the conditions employed in this work. The in vitro cell test revealed that the drug released from the coating was effective during the whole release period of 21 days, and both the silane-modified surface and carrier nanoparticles herein were not cytotoxic., (© The Author(s) 2015.)

To assess the effect of basic fibroblast growth factor-binding extracellular matrix (bFGF-ECM) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation on acute myocardial infarction (AMI) and explore the underlying mechenisms. Rabbit hearts were processed by decellularization with sodium dodecyl sulfate (SDS) perfusion, heparin immobilization, bFGF-binding and homogenization, for preparation of bFGF-binding cardiac ECM suspension (bFGF-ECM). Thereafter, the characteristics of bFGF release were analyzed in vitro. Following ligation of the mid-third of the left anterior descending artery, the rabbits were divided into a control group (no treatment), BMSCs group (BMSCs transplantation), bFGF-ECM group (bFGF-ECM implantation), and BMSCs + bFGF-ECM group (BMSCs and bFGF-ECM implantation). Apoptosis and differentiation of implanted BMSCs, and the left ventricular (LV) remodeling and function were assessed. The ex vivo proliferation, apoptosis, migration and differentiation of BMSCs were determined after exposure to bFGF and/or ECM. The ECM could sustainably release bFGF. 24 h and 6 weeks after the operation, improved viability and differentiation of the implanted BMSCs, as well as inhibited dilatation and preserved function of the left ventricle (LV), were significant in the BMSCs  +  bFGF-ECM group compared with other groups (P < 0.05), although BMSCs and ECM-bFGF groups also showed better results than control group (P < 0.05). Additionally, ECM and bFGF showed a synergistic effect on BMSCs proliferation, viability, migration and differentiation. The combination of bFGF-binding ECM and BMSCs implantation may promote myocardial regeneration and LV function, and become a new strategy for the treatment of AMI.

In this study, the enteric-coated delayed-release pellets of duloxetine hydrochloride (DLX) were formulated using a fluidized bed coater. Three separate layers, the drug layer, the barrier layer, and the enteric layer, were coated onto inert core pellets. Among the three formulations (F1-F3), the dissolution profiles of formulation F2 were most similar to those of the marketed product, with similarity and difference factors of 83.99 and 3.77, respectively. In addition, pharmacokinetic parameters of AUC, C(max), T(max), t(1/2), K(el), and MRT of DLX for the developed formulation (F2) did not differ significantly from those for the marketed product in beagle dogs, suggesting that they were bioequivalent. Our results demonstrated that the in vitro dissolution data resembled the in vivo performance of the drug. Therefore, this study has a positive scope for further scale up and development of the formulation for achievement of the generic product.

There is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TEC in vitro and to cure methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

In tissue engineering, most polymeric scaffolds should degrade along with the formation of the new tissues. Therefore, it is necessary to look into the in vivo degradation of scaffolds. In this study, a fluorescent perylenediimide-cored (PDI-cored) dendritic star macromolecule bearing multiple amines (d-p48) was incorporated into biodegradable polyester nanofibrous scaffolds by eletrospinning as an indicator. The polyester/d-p48 blend nanofibers could emit strong red fluorescence when they were irradiated under exciting light. Initially, using slowly degradable polyester, poly(L-lactide) (PLLA)/d-p48 nanofibers were soaked in phosphate buffered saline for various lengths of time to determine the possible diffusing release of d-p48 macromolecule from nanofibers. The PLLA/d-p48 nanofibers were then implanted subcutaneously into mice and left for up to 2 weeks. In both cases, no undesirable release of the incorporated d-p48 macromolecule was detected, and the nanofibers were clearly visualized in vivo by fluorescence microscopy. Using a fast degradable polyester, poly(lactide-co-glycolide) (PLGA)/d-p48 nanofibers were electrospun and implanted subcutaneously to determine the possibility of monitoring in vivo degradation by fluorescence during 12 weeks. The results showed that the location and the contour of PLGA/d-p48 nanofibrous scaffolds could be clearly visualized using an animal fluorescent imaging system. The fluorescent intensities decreased gradually with the degradation of the scaffolds. No side effects on liver and kidney were found during the detection. This study indicates that the fluorescent PDI-cored dendritic star macromolecule can be used as a stable bioimaging indicator for biodegradable aliphatic polyesters in vivo.

Gelatin hydrogels have been designed and prepared for the controlled release of the transforming growth factor (TGF-b1) and the platelet-derived growth factor (PDGF-BB). PRP (Platelet rich plasma) contains many growth factors including the PDGF and TGF-b1. The objective of this study was to evaluate the regeneration of periodontal tissue following the controlled release of growth factors in PRP. For the periodontal ligament cells and osteoblast, PRP of different concentrations was added. The assessment of DNA, mitochondrial activity and ALP activity were measured. To evaluate the TGF-β1 release from PRP incorporated gelatin sponge, amounts of TGF-β1 in each supernatant sample were determined by the ELISA. Transplantation experiments to prepare a bone defect in a rat alveolar bone were an implanted gelatin sponge incorporated with different concentration PRP. In DNA assay and MTT assay, after the addition of PRP to the periodontal ligament cells and osteoblast, the cell count and mitochondrial activity had increased the most in the group with the addition of 5  ×  PRP. In the ALP assay, after the addition of PRP to the periodontal ligament cells, the cell activity had increased the most in the group with the addition of 3  ×  PRP. In the transplantation, the size of the bone regenerated in the defect with 3  ×  PRP incorporated gelatin sponge was larger than that of the other group.

Cortical neural prostheses (CNPs) hold great promise for paralyzed patients by recording neural signals from the brain and translating them into movement commands. However, these electrodes normally fail to record neural signals weeks to months after implantation due to inflammation and neuronal loss around the implanted neural electrodes. Sustained local delivery of neurotrophins from biocompatible coatings on CNPs can potentially promote neuron survival and attract the nearby neurons to migrate toward the electrodes to increase neuron density at the electrode/brain interface, which is important for maintaining the recording quality and long-term performance of the implanted CNPs. However, sustained release of neurotrophins from biocompatible ultrathin coatings is very difficult to achieve. In this study, we investigated the potential of several biocompatible natural polyanions including heparin, dextran sulfate, and gelatin to form layer-by-layer (LbL) assembly with positively charged neurotrophin nerve growth factor (NGF) and its model protein lysozyme, and whether sustained release of NGF and lysozyme can be achieved from the nanoscale thin LbL coatings. We found that gelatin, which is less negatively charged than heparin and dextran sulfate, showed the highest efficacy in loading proteins into the LbL films because other interactions in addition to electrostatic interactions were involved in LbL assembly. Sustained release of NGF and lysozymes for approximately 2 weeks was achieved from the gelatin-based LbL coatings. Released NGF maintained the bioactivity to stimulate neurite outgrowth from PC12 cells. Gelatin is generally recognized as safe by the FDA. Thus, the biocompatible LbL coating developed in this study is highly promising to be used for implanted CNPs to improve their long-term performance in human patients.

Topographical features of biomaterials are able to modulate cell attachment, spreading and differentiation. The addition of growth factors to implantable biomaterials can modify these cellular responses, enhancing their therapeutic potential. The aim of this research is to establish the influence of biomorphic silicon carbide ceramics (bioSiCs) surface topography on the proliferation and osteoblastic differentiation of mesenchymal stem cells and the potential synergistic effect of the ceramic porous structure together with vascular endothelial growth factor loading (VEGF) on the surface mediated osteoblastic differentiation. Three porous bioSiCs with important differences in their microstructure were obtained from different natural precursors. Samples loaded with or without VEGF through ionic interactions were cultured with human umbilical vein endothelial cells (HUVEC) or bone marrow derived mesenchymal stem cells (hMSCs). Cell behaviour and protein activity with regard to bioSiC porous structure and surface properties were analysed. An in vivo model (Chick Chorioallantoic Membrane; CAM) was used to assess the capability of the VEGF loaded systems to promote angiogenesis. Experimental data show that loaded systems were able to control the release of VEGF for up to 15 d ensuring the activity of the protein, increasing the proliferation of HUVECs and the formation of new blood vessels in the CAM. It was found that the selection of bioSiCs with a higher pore size promoted a higher concentration of osteoblastic differentiation markers of MSCs cultured on the surface of bioSiCs. Furthermore, the addition of VEGF to the systems was able to promote a faster osteoblastic differentiation according to the qPCR results, suggesting a synergy between both the surface properties and the controlled release of the growth factor. The VEGF loaded sapelli bioSiC was found to be the most promising material for bone tissue engineering applications.

As poly L-lactic acid (PLLA) is a polymer with good biocompatibility and biodegradability, we created a new tissue adhesive (TA), pre-polymerized allyl 2-cyanoacrylate (PACA) mixed with PLLA in an effort to improve biocompatibility and mechanical properties in healing dermal wound tissue. We determined optimal mixing ratios of PACA and PLLA based on their bond strengths and chemical structures analyzed by the thermal gravimetric analysis (TGA) and Fourier transform infrared (FT-IR) spectroscopy. In vitro biocompatibility of the PACA/PLLA was evaluated using direct- and indirect-contact methods according to the ISO-10993 cytotoxicity test for medical devices. The PACA/PLLA have similar or even better biocompatibility than those of commercially available cyanoacrylate (CA)-based TAs such as Dermabond® and Histoacryl®. The PACA/PLLA were not different from those exposed to Dermabond® and Histoacryl® in Raman spectra when biochemical changes of protein and DNA/RNA underlying during cell death were compared utilizing Raman spectroscopy. Histological analysis revealed that incised dermal tissues of rats treated with PACA/PLLA showed less inflammatory signs and enhanced collagen formation compared to those treated with Dermabond® or Histoacryl®. Of note, tissues treated with PACA/PLLA were stronger in the tensile strength compared to those treated with the commercially available TAs. Therefore, taking all the results into consideration, the PACA/PLLA we created might be a clinically useful TA for treating dermal wounds., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In terms of ocular drug delivery, biodegradable implant systems have several advantages including the ability to provide constant drug concentration at the target site, no necessity for surgical removal, and minimum systemic side effects. Cyclosporin A (CsA) is a neutral, hydrophobic, cyclic peptide of amino acids that frequently used for dry eye disease treatment. The aim of this study was to develop a nanoparticle-loaded implant system for sustained-release CsA delivery following subconjunctival implantation. Poly(lactide-co-glycolide) (85:15) or poly-ε-caprolactone (PCL) were used to prepare two different nanoparticle formulations. These nanoparticles loaded into PCL or poly(lactide-co-caprolactone) implant formulations were prepared by two different methods, which were molding and electrospinning. Size and zeta potential of nanoparticles were determined and the morphology of the formulations were investigated by scanning electron microscopy. CsA-loading efficiencies were calculated and the in vitro degradation and in vitro release studies were performed. MTT test was also performed using L929 fibroblast cells to evaluate the cytotoxicity of the formulations. PCL-PCL-NP-I formulation was implanted to Swiss Albino mice with induced dry eye syndrome to evaluate the efficacy. In vitro release studies showed that the release from the formulations continues between 30 and 60 days, and the cell viability was found to be 77.4%-99.0%. In vivo studies showed that healing is significantly faster in the presence of the selected implant formulation. Results indicated that nanodecorated implants are promising ocular carriers for controlled-release CsA application., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

The procedure described in this study provides a platform technology for rapidly dissolving, single-dosed cryopellets. The different steps during cryopellet production were investigated, covering droplet generation, droplet freezing in liquid nitrogen (LN₂) as well as cryopellet properties. With the setup developed, uniform droplets between 4 and 14 μL were produced. The freezing behavior was similar to approaches reported in the literature. A weight loss reported for droplets frozen in LN₂ could not be confirmed. Mechanical stability as observed with texture analysis as well as dissolution time increased with increasing solid content. All cryopellets immediately disintegrated when in contact with the dissolution medium. The dissolution times of amorphous sucrose and trehalose-based cryopellets at different solid content levels were comparable. Crystalline mannitol cryopellets showed in general a higher dissolution time. The formation of δ-mannitol potentially makes the cryopellets suitable as an intermediate product for tableting., (© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Injectable hydrogels are an important class of biomaterials, and they have been widely used for controlled drug release. This study evaluated an injectable hydrogel formed in situ system by the reaction of a polyethylene glycol derivative with α,β-polyaspartylhydrazide for local cancer chemotherapy. This pH-responsive hydrogel was used to realize a sol-gel phase transition, where the gel remained a free-flowing fluid before injection but spontaneously changed into a semisolid hydrogel just after administration. As indicated by scanning electron microscopy images, the hydrogel exhibited a porous three-dimensional microstructure. The prepared hydrogel was biocompatible and biodegradable and could be utilized as a pH-responsive vector for drug delivery. The therapeutic effect of the hydrogel loaded with doxorubicin (DOX) after intratumoral administration in mice with human fibrosarcoma was evaluated. The inhibition of tumor growth was more obvious in the group treated by the DOX-loaded hydrogel, compared to that treated with the free DOX solution. Hence, this hydrogel with good syringeability and high biodegradability, which focuses on local chemotherapy, may enhance the therapeutic effect on human fibrosarcoma.

The antibiotic compound, rifampicin (RFP), was loaded into porous reinforced β-tricalcium phosphate (β-TCP) scaffolds using three different solution adsorption methods. This resulted in drug delivery systems (DDS) generated by vacuum adsorption (VA), dynamic adsorption (DA), and static adsorption (SA). In vitro examination of the drug loading and release profiles of the DDS indicated that the unit mass of RFP loaded into the scaffold by the VA method (0.44 mg/g) was higher than that achieved by SA (0.42 mg/g) or DA (0.38 mg/g) (P < 0.05). The mechanical strength had no significant change after RFP-loading (P > 0.05). Moreover, there were no significant differences among the mechanical strength of three β-TCP DDS generated by loading RFP using SA, DA, and VA (P > 0.05). In vitro release testing showed an initial burst release of RFP from the three different DDS within the first 3 h and in the first 51 h, the cumulative release of RFP from VA-DDS, DA-DDS, and SA-DDS had reached 56.2, 83.6, and 88.6 %, respectively. Complete RFP release had occurred from VA-DDS, DA-DDS, and SA-DDS after 23, 17, and 15 days, respectively. As the VA-DDS method showed improved RFP loading and a more sustained drug release, this method is recommended for solution adsorption drug loading into porous β-TCP scaffolds to form a DDS.

Polypeptide-based degradable polyplexes attracted considerable attention in drug delivery systems. Polysaccharides including cyclodextrin (CD), dextran, and chitosan (CS) were readily grafted with cationic poly(aspartic acid)s (PAsps). To further enhance the transfection performances of PAsp-based polyplexes, herein, different types of ligand (folic acid, FA)-functionalized degradable polyplexes were proposed based on the PAsp-grafted chitosan-cyclodextrin conjugate (CCPE), where multiple β-CDs were tied on a CS chain. The FA-functionalized CCPE (i.e., CCPE-FA) was obtained via a host-guest interaction between the CD units of CCPE and the adamantane (Ad) species of Ad-modified FA (Ad-FA). The resulting CCPE/pDNA, CCPE-FA/pDNA, and ternary CCPE-FA/CCPE/pDNA (prepared by layer-by-layer assembly) polyplexes were investigated in detail using different cell lines. The CCPE-based polyplexes displayed much higher transfection efficiencies than the CS-based polyplexes reported earlier by us. The ternary polyplexes of CCPE-FA/CCPE/pDNA produced excellent gene transfection abilities in the folate receptor (FR)-positive tumor cells. This work would provide a promising means to produce highly efficient polyplexes for future gene therapy applications.

The performance of the standardized extrusion-spheronization technique, operational conditions, formulation parameters and storage of the final product over the bioactivity of papain containing pellets has been evaluated to obtain an insight into the potential of the technique for the manufacture of solid protein formulations. The pellets produced were assayed in terms of biological activity - monitored at each operational stage using N-benzoyl-dl-arginine ρ-nitroanilide as a substrate, and according to the physical properties - evaluated by means of size distribution, apparent density and friability. The produced pellets presented adequate physical and mechanical properties. Monitoring biological activity at each production stage revealed that the most critical steps corresponded to drying and storage, with bioactivity decay ranging from 5 to 30% and 5 to 20% for each process. Dry mixing and extrusion did not hold any influence over papain activity, while wet massing decreased the bioactivity by approximately 0-5% and the spheronization 0-2%. The results varied as a function of the experimental conditions and formulation components. In conclusion, the extrusion--spheronization technique was suitable to produce solid multiparticulate dosage forms for papain, considering the possibility to originate pellets with relatively low bioactivity decay. However, weak points of the technique corresponded to the wet massing and drying stages as well as storage.

In this study, a new co-processed excipient composed of microcrystalline cellulose (MCC), sorbitol, chitosan and Eudragit® E, easily obtained by wet massing, to increase the dissolution rate of active ingredients of low water solubility from pellets prepared by extrusion-spheronization is evaluated. Indomethacin, nifedipine, furosemide, ibuprofen, prednisolone and hydrochlorothiazide are used as model drugs of different solubility. All pellet formulations evaluated showed adequate morphological, flow and mechanical properties. Pellets prepared with the co-processed excipient show a higher drug dissolution rate than those prepared with MCC and even higher than the pure drug powder. The fast drug dissolution and the complete disintegration (<3 min) of the pellets can be explained by the great porosity of the formulations, the high solubility of the sorbitol, the disintegrant capacity of the chitosan and the distribution of the Eudragit® E polymer particles in-between the other components of the co-processed mixture. In conclusion, this new co-processed excipient is very suitable to increase the dissolution rate of poorly soluble drugs from pellets prepared by extrusion-spheronization. Moreover, the drug release rate can be estimated from the Ln of the drug solubility in acidic medium.

Purpose: Salvianolic acid B micro-porous osmotic pump controlled release pellets (SalB-CRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed., Method: Extrusion-spheronization was used to prepare the starter cores containing SalB/MCC/Kollidon®CL-SF/Flowlac®100 of 30:40:15:15 [w/w, The formulation composition of SalB immediate-release pellets (SalB-IRPs)] and complexed with lactose. The pellets were subsequently coated with Surelease aqueous dispersion to achieve controlled-release properties. Furthermore, a single-dose pharmacokinetics study was carried out in New Zealand White (NZW) rabbits., Results: In the starter cores, the lactose content was 25% based on the SalB-IRPs constituent. The optimal coating polymer ratio of Surelease aqueous dispersion and polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymer (EC/PVA-PEG) was found to be 70:30 (w/w, %) with a coating weight of 5%. The prepared SalB-CRPs had similar in vitro release under three different pH release mediums. A good IVIVC was characterized by a high coefficient of determination (r=0.9801). The in vivo study indicated that the maximum plasma concentration (Cmax) of SalB-CRPs was decreased, peak concentration time (Tmax) and mean residence time (MRT) were all prolonged, as that of SalB-IRPs. In addition, the area under concentration-time curve from 0 to 24 h (AUC0-24 h) and 0 to infinity (AUC0-∞) were significantly higher, compared with those of SalB-IRPs., Conclusion: Collectively, these results manifested that SalB-CRPs were likely to be a more suitable formulation in treating cardiovascular disease with improved in vivo retention, decreased plasma drug concentration fluctuation.

Self-emulsifying pellets were prepared using microcrystalline cellulose, emulsions of caprylic/capric triglyceride, and three Cremophors (ELP, RH40, and RH60) at 1.5 and 2.3 weight ratios, and two drugs (furosemide and propranolol) of different lipophilicity. Droplet size, zeta potential (ζ) and viscosity of emulsions, and pellet size, shape, friability, tensile strength, disintegration, and drug migration in pellets were determined. Evaluation of reconstituted emulsions was based on droplet size and ζ. Factorial design and 3-way ANOVA was applied to estimate the significance of the effects of the drug, surfactant and oil/surfactant ratio. It was found that droplet size, viscosity and ζ of emulsions, and size, shape, and friability of pellets were affected by the studied factors and were significant interactions between their effects on pellet size and friability. Migration of drug towards the pellet surface was higher for the less lipophilic furosemide and higher oil content. Linear relationships were found between the emulsion viscosity and the shape parameters of the pellets (for the aspect ratio R (2) = 0.796 for furosemide and R (2) = 0.885 for propranolol and for the shape factor, e R R (2) = 0.740 and R (2) = 0.960, respectively). For all the formulations examined, an exponential relationship was found between migration (M%) and the product of viscosity (η) and solubility of drug in oil/surfactant mixture (S) (M% = 98.1e-0.016 [η•S], R (2) = 0.856), which may be useful in formulation work.

Objective: The dorsal root ganglion is an attractive target for implanting neural electrode arrays that restore sensory function or provide therapy via stimulation. However, penetrating microelectrodes designed for these applications are small and deliver low currents. For long-term performance of microstimulation devices, novel coating materials are needed in part to decrease impedance values at the electrode-tissue interface and to increase charge storage capacity., Approach: Conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and multi-wall carbon nanotubes (CNTs) were coated on the electrode surface and doped with the anti-inflammatory drug, dexamethasone. Electrode characteristics and the tissue reaction around neural electrodes as a result of stimulation, coating and drug release were characterized. Hematoxylin and eosin staining along with antibodies recognizing Iba1 (microglia/macrophages), NF200 (neuronal axons), NeuN (neurons), vimentin (fibroblasts), caspase-3 (cell death) and L1 (neural cell adhesion molecule) were used. Quantitative image analyses were performed using MATLAB., Main Results: Our results indicate that coated microelectrodes have lower in vitro and in vivo impedance values. Significantly less neuronal death/damage was observed with coated electrodes as compared to non-coated controls. The inflammatory response with the PEDOT/CNT-coated electrodes was also reduced., Significance: This study is the first to report on the utility of these coatings in stimulation applications. Our results indicate PEDOT/CNT coatings may be valuable additions to implantable electrodes used as therapeutic modalities.

The objective of the present study was to evaluate the feasibility of using model drug metoprolol succinate (MS) as a pore former to modify the initial lag phase (i.e., a slow or non-release phase in the first 1-2 h) associated with the drug release from coated pellets. MS-layered cores with high drug-layering efficiency (97% w/w) were first prepared by spraying a highly concentrated drug aqueous solution (60% w/w, 70°C) on non-pareils without using other binders. The presence of MS in ethylcellulose (EC) coating solution significantly improved the coating process by reducing pellets sticking, which often occurs during organic coating. There may be a maximum physical compatibility of MS with EC, and the physical state of the drug in the functional coating layer of EC/MS (80:20) was simultaneously crystalline and non-crystalline (amorphous or solid molecule solution). The lag phase associated with hydroxypropylcellulose (HPC) as a pore former was not observed when MS was used as a pore former. The drug release from EC/MS-coated pellets was pH independent, inversely proportional to the coating levels, and directly related to the pore former levels. The functional coating layer with MS as a pore former was not completely stabilized without curing. Curing at 60°C for 1 day could substantially improve the stability of EC/MS-coated pellets. The physical state of the drug in the free film of EC/MS (85:15) changed partially from amorphous to crystal when cured at 60°C for 1 day, which should be attributed to the incompatibility of the drug with EC.

Fragility fractures can cause significant morbidity and mortality in patients with osteoporosis and inflict a considerable medical and socioeconomic burden. Moreover, treatment of an osteoporotic fracture is challenging due to the decreased strength of the surrounding bone and suboptimal healing capacity, predisposing both to fixation failure and non-union. Whereas a systemic osteoporosis treatment acts slowly, local release of osteogenic agents in osteoporotic fracture would act rapidly to increase bone strength and quality, as well as to reduce the bone healing period and prevent development of a problematic non-union. The identification of agents with potential to stimulate bone formation and improve implant fixation strength in osteoporotic bone has raised hope for the fast augmentation of osteoporotic fractures. Stimulation of bone formation by local delivery of growth factors is an approach already in clinical use for the treatment of non-unions, and could be utilized for osteoporotic fractures as well. Small molecules have also gained ground as stable and inexpensive compounds to enhance bone formation and tackle osteoporosis. The aim of this paper is to present the state of the art on local drug delivery in osteoporotic fractures. Advantages, disadvantages and underlying molecular mechanisms of different active species for local bone healing in osteoporotic bone are discussed. This review also identifies promising new candidate molecules and innovative approaches for the local drug delivery in osteoporotic bone., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Postoperative infections are a major concern in patients that receive implants. These infections generally occur in areas with poor blood flow and pathogens do not always respond to antibiotic treatment. With the latest developments in nanotechnology, the incorporation of antibiotics into prosthetic implants may soon become a standard procedure. The success will, however, depend on the ability to control the release of antibiotics at concentrations high enough to prevent the development of antibiotic-resistant strains. Through additive manufacturing, antibiotics can be incorporated into cementless femoral stems to produce prosthetic devices with antimicrobial properties. With the emerging increase in resistance to antibiotics, the incorporation of antimicrobial compounds other than antibiotics, preferably drugs with a broader spectrum of antimicrobial activity, will have to be explored. This review highlights the microorganisms associated with total hip arthroplasty (THA), discusses the advantages and disadvantages of the latest materials used in hip implants, compares different antimicrobial agents that could be incorporated, and addresses novel ideas for future research.

Gold nanoparticles have utility for in vitro, ex vivo and in vivo imaging applications as well as for serving as a scaffold for therapeutic delivery and theranostic applications. Starting with gold nanoparticles as a core, layer-by-layer degradable polymer coatings enable the simultaneous co-delivery of DNA and short interfering RNA (siRNA). To engineer release kinetics, polymers which degrade through two different mechanisms can be utilized to construct hybrid inorganic/polymeric particles. During fabrication of the nanoparticles, the zeta potential reverses upon the addition of each oppositely charged polyelectrolyte layer and the final nanoparticle size reaches approximately 200nm in diameter. When the hybrid gold/polymer/nucleic acid nanoparticles are added to human primary brain cancer cells in vitro, they are internalizable by cells and reach the cytoplasm and nucleus as visualized by transmission electron microscopy and observed through exogenous gene expression. This nanoparticle delivery leads to both exogenous DNA expression and siRNA-mediated knockdown, with the knockdown efficacy superior to that of Lipofectamine® 2000, a commercially available transfection reagent. These gold/polymer/nucleic acid hybrid nanoparticles are an enabling theranostic platform technology capable of delivering combinations of genetic therapies to human cells., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Microwells fabricated from poly-L-lactic acid (PLLA) were evaluated for their application as an oral drug delivery system using the amorphous sodium salt of furosemide (ASSF) as a model drug. Hot embossing of PLLA resulted in fabrication of microwells with an inner diameter of 240 μm and a height of 100 μm. The microwells were filled with ASSF using a modified screen printing technique, followed by coating of the microwell cavities with a gastro-resistant lid of Eudragit® L100. The release behavior of ASSF from the coated microwells was investigated using a μ-Diss profiler and a UV imaging system, and under conditions simulating the changing environment of the gastrointestinal tract. Biorelevant gastric medium (pH 1.6) was employed, after which a change to biorelevant intestinal release medium (pH 6.5) was carried out. Both μ-Diss profiler and UV imaging release experiments showed that sealing of microwell cavities with an Eudragit® layer prevented drug release in biorelevant gastric medium. An immediate release of the ASSF from coated microwells was observed in the intestinal medium. This pH-triggered release behavior demonstrates the future potential of PLLA microwells as a site-specific oral drug delivery system.

Specific and targeted delivery of medical therapies continues to be a challenge for the optimal treatment of multiple medical conditions. Technological advances permit physicians to target most sites of the body. However, after the intervention, physicians rely on systemic medications that need frequent dosing and may have noxious side effects. A novel system combining the temporal flexibility of systemic drug delivery and the spatial control of injectable biomaterials would improve the spatiotemporal control of medical therapies. Here we present an implantable biomaterial that harnesses in vivo click chemistry to enhance the delivery of suitable small molecules by an order of magnitude. The results demonstrate a simple and modular method to modify a biomaterial with small molecules in vitro and present an example of a polysaccharide modified hours after in vivo implantation. This approach provides the ability to precisely control the moment when biochemical and/or physical signals may appear in an implanted biomaterial. This is the first step towards the construction of a biomaterial that enhances the spatial location of systemic small molecules via in vivo chemical delivery., (Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Bioresorbable polymer stents have been proposed as promising medical implants to avoid long-term safety concerns and other potential issues caused by traditional materials. As an important member, poly(ε-caprolactone) (PCL) was used as the implant matrix with different drug loadings. To better regulate drug release rate, the hydrophilicity of PCL was adjusted by addition of amphiphilic graft copolymers, chitosan-g-poly(ε-caprolactone) (CP). The in vitro release results indicated that the improvement of bulk hydrophilicity could accelerate drug release better than that of surface coating. The optimum additive amount was 25% with CP9. Further study showed that the effect of aspirin molecules displayed no obvious difference to that of CP macromolecules on drug release rate. Moreover, these release profiles were fitted with mathematical models. The similarities were evaluated with similarity factors. Scanning electron microscopy (SEM) images displayed surface/cross-section morphologies of pure PCL and modified implants before and after release., (Copyright © 2014 Elsevier B.V. All rights reserved.)