Initial Release Phase Research Articles

The role of partial area under the curve and maximum concentrations in assessing the bioequivalence of long-acting injectable formulation of exenatide_A sensitivity analysis

To ensure therapeutic equivalence between the long-acting injectable (LAI) products, additional PK metrics other than Cmax and AUC were considered necessary. However, regarding the selection of additional PK metrics for bioequivalence (BE) assessment of exenatide LAI, a discrepancy existed between EMA's and USFDA's product-specific guidance. The EMA recommends that both the maximum plasma concentration in the initial-release phase (Cmax,1) and the extended-release phase (Cmax,2) should be determined. Nevertheless, the USFDA recommends the use of the partial area under the curve (i.e., the area under the curve from week 4 to the last sampling point; pAUC4w-t). The focus of this study was to compare the sensitivity of different PK metrics, including Cmax,1, Cmax,2, pAUC4w-t, early and late pAUC metrics truncated at different time points (three, four, five, six and seven weeks), to formulation-related parameters and pharmacodynamic (PD) markers of glycemic control. A sensitivity analysis was conducted using the published PK/PD model of exenatide LAI. The results indicated that Cmax,1 and Cmax,2 exhibited comparable sensitivities. AUC4w-t was sensitive to changes in detecting the differences in formulation-related parameters and PD markers of glycemic control, but did not provide superior sensitivity performance compared to Cmax,1 and Cmax,2. Among all tested PK metrics, AUC7w-t was found to be the most sensitive. The optimal cut-off time point for the pAUC should be set at the time of maximum plasma concentration in the extended-release phase (approximately 6–7 weeks). These results may provide useful insights into the selection of appropriate PK metrics for BE determination of exenatide LAI.

Doxorubicin-Loaded Multivesicular Liposomes (DepoFoam) as a Sustained Release Carrier Intended for Locoregional Delivery in Cancer Treatment: Development, Characterization, and Cytotoxicity Evaluation.

Despite the advantages of direct intratumoral (IT) injection, the relatively rapid withdrawal of most anti-cancer drugs from the tumor due to their small molecular size limits the effectiveness of this method of administration. To address these limitations, recently, increasing attention has been directed to using slow-release biodegradable delivery systems for IT injection. This study aimed to develop and characterize a doxorubicin-loaded DepoFoam system as an efficient controlled-release carrier to be employed for locoregional drug delivery in cancer treatment. Major formulation parameters, including the molar ratio of cholesterol to the main lipid [Chol/egg phosphatidylcholine (EPC)], triolein (TO) content, and lipid-to-drug molar ratio (L/D), were optimized using a two-level factorial design approach. The prepared batches were evaluated for encapsulation efficiency (EE) and percentage of drug release (DR) after 6 and 72 hours as dependent variables. The optimum formulation (named DepoDOX) was further evaluated in terms of particle size, morphology, zeta potential, stability, Fourier-transform infrared spectroscopy, in vitro cytotoxicity, and hemolysis. The analysis of factorial design indicated that TO content and L/D ratio had a negative effect on EE; between these two, TO content had the greatest effect. The TO content was also the most significant component, with a negative effect on the release rate. The ratio of Chol/EPC showed a dual effect on the DR rate. Using a higher percentage of Chol slowed down the initial release phase of the drug; nevertheless, it accelerated the DR rate in the later slow phase. DepoDOX were spherical and honeycomb-like structures (≈ 9.81 μm) with a desired sustained release profile, as DR lasted 11 days. Its biocompatibility was confirmed by the results of cytotoxicity and hemolysis assays. The in vitro characterization of optimized DepoFoam formulation demonstrated its suitability for direct locoregional delivery. DepoDOX, as a biocompatible lipid-based formulation, showed appropriate particle size, high capability for encapsulating doxorubicin, superior physical stability, and a markedly prolonged DR rate. Therefore, this formulation could be considered a promising candidate for locoregional drug delivery in cancer treatment.

Polyphenol and Flavonoid Stability of Wild Blueberry (Sideroxylon mascatense) during Air- and Freeze-Drying and Storage Stability as a Function of Temperature

Būt (Sideroxylon mascatense) is an indigenous wild blueberry found in Oman. It has a very short season and is commonly preserved by drying. The aims of this study were to determine the physico-chemical characteristics and stability of phytochemicals (i.e., polyphenols and flavonoids) in the berries during drying (i.e., freeze-drying at -40 °C and air-drying at 60 and 90 °C) and the polyphenol stability of the dried berries as a function of storage temperature (i.e., 90, 70, 60, 40, 20, and -20 °C). The moisture content of fresh berry flesh was 64.5 g/100 g sample (wet basis). The crude protein and fat contents were higher in the seeds than in the flesh. Glucose and fructose were the main sugars and their concentrations were highest in the sample air-dried at 60 °C. The initial total polyphenol content (TPC) and total flavonoid content (TFC) of the flesh were 2.009 mg gallic acid equivalent (GAE)/g dry-solids and 0.199 mg catechin equivalent (CE)/g dry-solids, respectively. The samples air-dried at 90 °C and freeze-dried at -40 °C had higher TPC (i.e., 2.638 mg GAE/g dry-solids) and TFC (i.e., 0.395 mg CE/g dry-solids), respectively. There was a significant difference between the TPC and TFC of fresh and dried wild berries (p < 0.05). The freeze-dried wild berries retained a high TPC compared to the air-dried samples. The polyphenol storage stability of freeze-dried wild berries at different storage temperatures showed two phases: an initial release phase followed by a decay phase. The polyphenol storage stability was modeled using the Peleg model and the kinetic parameters were correlated with the storage temperature.

The Effect of Odour Valence and Odour Detection Threshold on the Withholding and Cancellation of Reach-to-Press Responses

IntroductionWithholding uninitiated actions and cancelling ongoing ones are two main components of response inhibition, a key element of the executive control. Inhibitory performance is sensitive to emotional contexts elicited by subliminal and supraliminal visual material. However, whether stimuli from other sensory modalities, such as odours, would equally modulate response inhibition remains unclear. Here, we aimed to assess the effect of task-irrelevant odours as a function of their valence and threshold on both action withholding and action cancellation of reach-to-press movements.MethodThirty-two healthy participants performed a Go/No-Go task that included the presentation of pleasant (orange) and unpleasant (trimethyloxazole) odour primes at supra- and sub-threshold levels; clean air was included as a control condition. The reach-to-press responses were composed of an initial release phase and a subsequent reaching phase.ResultsOnly the supra-threshold pleasant (vs. control) odour impaired action withholding. Moreover, the pleasant (vs. control) odour—presented at both sub- and supra-threshold levels—elicited more accurate Go responses, whereas the sub- and supra-threshold pleasant and unpleasant (vs. control) odours triggered faster responses in the release phase. Additionally, only the supra-threshold pleasant (vs. unpleasant) odour impaired action cancellation in the reaching phase. Furthermore, reaching responses were slower following the supra-threshold unpleasant (vs. control) odour.ConclusionsOur findings extend the sparse literature on the impact of odour stimuli on goal-directed behaviour, highlighting the role of both odour valence and threshold in the modulation of response inhibition.ImplicationsDetermining the mechanisms by which odour stimuli modulate response inhibition lays the foundations for research on odour-triggered disinhibition.

Effect of implant formation on drug release kinetics of in situ forming implants

In situ forming implants are attractive long-acting implant dosage forms due to their: i) ability to control drug release; ii) simple manufacturing process; and iii) minimally invasive administration. In situ forming implants are typically made of a drug, solvent, and a biocompatible polymer that controls drug release. Once injected in the subcutaneous tissue, they form solid depots through solvent/non-solvent exchange and phase separation of the biodegradable polymer (such as poly (lactic-co-glycolic acid), PLGA and poly (lactic acid), PLA). However, the mechanism of implant formation and the changes in their microstructure that determine drug release behavior are not fully understood. Furthermore, there is no standardized in vitro release testing method for in situ forming implants due to limitations in recreating bio-relevant and reproducible implant formation in vitro with controllable implant shape, dimensions and surface-to-volume ratio. In the present study, bio-relevant implant formation was recreated in vitro by testing five different methods to determine their effect on drug release kinetics, reproducibility, and internal microstructure formation. The leuprolide acetate formulation Eligard® was used as a model in situ-forming implant, consisting of lyophilized leuprolide acetate, and PLGA dissolved in N-methyl pyrrolidone. The results revealed that the in vitro implant formation method is a crucial step in the dissolution testing process that significantly impacts the release profile of in situ forming implants. An implant formation method that utilizes dissolvable polyvinyl alcohol (PVA) films allowed for initial drug burst release control by modulating implant dimensions (i.e. surface area) and resulted in reproducible in vitro release profiles. In addition, implant formation was shown to affect the internal microstructure of in situ forming implant and was the main factor controlling the release profile which consisted of an initial release phase followed by a release plateau (lag phase) and then a second erosion-controlled release phase.

Physical-Chemical Characterization of Octreotide Encapsulated in Commercial Glucose-Star PLGA Microspheres.

Sandostatin LAR (SLAR) is an injectable long-acting release (LAR) microsphere formulation for octreotide based on a biodegradeable glucose star copolymer of d,l-lactic and glycolic acids (PLGA-glu), which is primarily used for the treatment of patients with acromegaly. There currently is no generic SLAR approved in the United States despite expiration of patent coverage. To understand better this important formulation, SLAR was assessed for its composition and physical-chemical properties. Octreotide release kinetics was monitored under physiological conditions over 56 days together with several bioerosion parameters [mass loss, water uptake, pH of release media, polymer molecular weight (Mw), and confocal microscopy after BODIPY uptake]. A significant increase in the amount of released peptide occurred after day 14. After 1 day of incubation in PBST, octreotide was not extractable completely from SLAR during 2 h of the extraction process, but complete extraction was accomplished after 24 h, which suggested that strong and noncovalent PLGA-octreotide interactions occurred beginning in the initial release phase. Leuprolide is considered as a cationic peptide competitor for octreotide-PLGA interactions and its presence in the release medium resulted in more continuous octreotide release from SLAR, which was linearly correlated with the mass loss from the polymer (i.e., an indication of erosion-controlled release). These data strongly suggest that octreotide forms a salt with acid end groups of linear PLGA chains that are either present as impurities in, and/or produced by the degradation of, the PLGA-Glu. This salt is expected to catalyze octreotide acylation and extend peptide release beyond that driven by erosion control. The characterization studies of physicochemical properties of SLAR described here could be useful for the development and regulatory evaluation of generic octreotide microspheres as well as new polymer formulations, in which the polymer strongly interacts with encapsulated peptides.

Adsorption study of bovine serum albumin onto multiwalled carbon nanotubes

Carbon nanotubes (CNTs) exhibit interesting physical and chemical properties that are useful for biomedical applications. In this work, the adsorption of bovine serum albumin by multi-walled carbon nanotubes modified with mixed H2SO4/HNO3 was investigated. The minimum time to reach adsorption equilibrium was determined to be 6 h for pristine MWCNTs and for MWCNTs with a modified surface. The maximum adsorption capacities of BSA on the pristine and treated MWCNTs were 532.56 and 771.87 mg/g, respectively. Both the Langmuir and Freundlich isotherms were well fitted to the adsorption data and could best describe the behavior of the adsorption process. The modified surface of the MWCNTs exhibited higher absorbability than the pristine MWCNTs because the modified MWCNTs possessed a greater surface area and large amounts of oxygen-containing functional groups. Moreover, the release characteristics of BSA with MWCNTs exhibited a relatively rapid initial release phase, followed by a phase involving a sustained release. The study could be used for prolonged drug release model in medical applications.

Chitosan-Alginate Nanoparticle System Efficiently Delivers Doxorubicin to MCF-7 Cells

A chitosan-alginate nanoparticle system encapsulating doxorubicin (DOX) was prepared by a novel ionic gelation method using alginate as the crosslinker. These nanoparticles were around 100 nm in size and more stable with higher positive zeta potential and had higher % encapsulation efficiency (95%) than DOX loaded chitosan nanoparticles (DOX Csn NP) crosslinked with sodium tripolyphosphate (STPP). FTIR spectroscopy and thermogravimetric analysis revealed successful loading of DOX.In vitrodrug release showed an initial release phase followed by slow release phase with higher cumulative release obtained with DOX loaded chitosan-alginate nanoparticles (DOX Csn-Alg NP). Thein vitrocytotoxicity of DOX released from the two nanoparticle systems showed a notable difference on comparison with that of free DOX on the MCF-7 cell line. The SRB assay, AO/EB staining, and fluorescence uptake study indicated that free DOX only showed dose dependent cytotoxicity, whereas both dose and time dependency were exhibited by the two sets of NPs. While both systems show sustained release of DOX, from the cell viability plots, DOX Csn-Alg NPs showed their superiority over DOX Csn NPs. The results obtained are useful for developing DOX Csn-Alg NPs as a sustained release carrier system for DOX.

Optimized Prefetching Scheme to Support VCR-Like Operations in P2P VoD Applications with Guided Seeks

In Peer-to-Peer (P2P) Video-on-Demand (VoD) streaming systems, supporting free VCR operations is challenging. Prefetching is a good way to improve user experience of VCR interactivity. But most existing P2P VoD prefetching schemes are proposed aimed at those popular videos with large amount of log data, without considering the situation that the videos are unpopular or the popular videos are in their initial phase of release. In this situation, these schemes cannot support user VCR interactivity very well. To address this issue, we propose a new optimized prefetching scheme, called Hybrid Anchor Scheme (HAS), in which fixed anchors and dynamic anchors are merged together. The dynamic anchors are generated based on association rule and segments popularity. Through combining the way of sequential prefetching according to weight of segments and the way of several rounds prefetching, we implement HAS effectively. Extensive simulations validate the proposed prefetching scheme provide shorter seeking latency compared to other prefetching schemes.

Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction

The use of arterial stents and other medical implants as a delivery platform for surface immobilized gene vectors allows for safe and efficient localized expression of therapeutic transgenes. In this study we investigate the use of hydrolyzable cross-linkers with distinct kinetics of hydrolysis for delivery of gene vectors from polyallylamine bisphosphonate-modified metal surfaces. Three cross-linkers with the estimated t1/2 of ester bonds hydrolysis of 5, 12 and 50 days demonstrated a cumulative 20%, 39% and 45% vector release, respectively, after 30 days exposure to physiological buffer at 37 °C. Transgene expression in endothelial and smooth muscles cells transduced with substrate immobilized adenovirus resulted in significantly different expression profiles for each individual cross-linker. Furthermore, immobilization of adenoviral vectors effectively extended their transduction effectiveness beyond the initial phase of release. Transgene expression driven by adenovirus-tethered stents in rat carotid arteries demonstrated that a faster rate of cross-linker hydrolysis resulted in higher expression levels at day 1, which declined by day 8 after stent implantation, while inversely, slower hydrolysis was associated with increased arterial expression at day 8 in comparison with day 1. In conclusion, adjustable release of transduction-competent adenoviral vectors from metallic surfaces can be achieved, both in vitro and in vivo, through surface immobilization of adenoviral vectors using hydrolyzable cross-linkers with structure-specific release kinetics.

Fabrication and characterization of DNA-loaded zein nanospheres

BackgroundParticulates incorporating DNA are promising vehicles for gene delivery, with the ability to protect DNA and provide for controlled, localized, and sustained release and transfection. Zein, a hydrophobic protein from corn, is biocompatible and has properties that make it a promising candidate material for particulate delivery, including its ability to form nanospheres through coacervation and its insolubility under physiological conditions, making it capable of sustained release of encapsulated compounds. Due to the promise of this natural biomaterial for drug delivery, the objective of this study was to formulate zein nanospheres encapsulating DNA as the therapeutic compound, and to characterize size, charge, sustained release, cell cytotoxicity and cellular internalization of these particles.ResultsZein nanospheres encapsulating DNA were fabricated using a coacervation technique, without the use of harsh solvents or temperatures, resulting in the preservation of DNA integrity and particles with diameters that ranged from 157.8 ± 3.9 nm to 396.8 ± 16.1 nm, depending on zein to DNA ratio. DNA encapsulation efficiencies were maximized to 65.3 ± 1.9% with a maximum loading of 6.1 ± 0.2 mg DNA/g zein. The spheres protected encapsulated DNA from DNase I degradation and exhibited sustained plasmid release for at least 7 days, with minimal burst during the initial phase of release. Zein/DNA nanospheres demonstrated robust biocompatibility, cellular association, and internalization.ConclusionsThis study represents the first report on the formation of zein particles encapsulating plasmid DNA, using simple fabrication techniques resulting in preservation of plasmid integrity and tunable sizes. DNA encapsulation efficiencies were maximized to acceptable levels at higher zein to DNA ratios, while loading was comparable to that of other hydrophilic compounds encapsulated in zein and that of DNA incorporated into PLGA nano- and microspheres. The hydrophobic nature of zein resulted in spheres capable of sustained release of plasmid DNA. Zein particles may be an excellent potential tool for the delivery of DNA with the ability to be fine-tuned for specific applications including oral gene delivery, intramuscular delivery, and in the fabrication of tissue engineering scaffolds.

Modification of the Release Characteristics of Estradiol Encapsulated in PLGA Particles Via Surface Coating

Drug-loaded poly(lactide-co-glycolide) particles (100-4500 nm in diameter) were prepared via the electrospraying method. An extensive study was then carried out to determine the parameters affecting the release profile of estradiol (the drug or active pharmaceutical ingredient) in order to facilitate minimum initial burst release of estradiol. The three most important factors affecting estradiol release were identified as: particle size, coating of the particles with chitosan/gelatin and the concentration of the coating agent. It was shown that coating the particles with chitosan significantly reduced the burst and initial release without affecting the subsequent release profile. This work demonstrates a powerful method of generating drug-loaded polymeric particles with modified release behavior and control over the initial release phase. The surface-modified particles may be useful in controlled therapeutic delivery systems to minimize undesirable side effects.

Phosphate release from waste stabilisation pond sludge: significance and fate of polyphosphate

Net phosphorus removal from waste stabilisation pond (WSP) systems is governed by the rate of phosphorus incorporation into the sludge layer and the rate of phosphorus release from this sludge back to the overlying wastewater. Luxury uptake of phosphorus by microalgae has been shown to occur under WSP conditions in the laboratory; however, the significance of this mechanism and the fate of polyphosphate contained in the settled solids have not previously been investigated. In this work the analysis of sludge samples from three WSP showed that up to 71% of the total phosphorus in the sludge was in the form of polyphosphate. This indicates that polyphosphate accumulation could potentially be an important mechanism for phosphorus sequestration in WSP and challenges the common view that chemical precipitation is the predominant phosphorus removal mechanism in these systems. The release of phosphate from WSP sludge samples was monitored in the laboratory. The samples from two different pond systems had release rates in the order of 4.3 microgP/gTSS.d. However, the third sample which was collected during an algal bloom had a release rate of 12.4 microgP/gTSS.d. Phosphate release from fresh microalgal sludge grown under laboratory conditions was also studied and was shown to have a release rate of 160 microgP/gTSS.d. Analysis of polyphosphate during the experiments on laboratory grown microalgal sludge showed that polyphosphate was indeed degraded resulting in phosphate release. Interestingly, after the initial release phase phosphorus was assimilated by the biomass and some polyphosphate was reformed. It is likely that this is due to bacterial growth in the sludge.

Effect of WOW process parameters on morphology and burst release of FITC-dextran loaded PLGA microspheres

Using fluorescein isothiocyanate labeled dextran (FITC-dextran 40, FD40) as a hydrophilic model compound, microspheres were prepared by a WOW double emulsion technique. Influence of process parameters on microsphere morphology and burst release of FD40 from PLGA microspheres was studied. Internal morphology of microspheres was investigated by stereological method via cryo-cutting technique and scanning electron microscopy (SEM). Drug distribution in microspheres was observed with confocal laser scanning microscopy (CLSM). Polymer nature (RG503 and RG503H) had significant influence on the micro-morphology of microspheres. Increase in continuous water phase volume (W2) led to increased surface porosity but decreased internal porosity. By increasing PVA concentration in the continuous phase from 0.1 to 1%, particle size changed marginally but burst release decreased from 12.2 to 5.9%. Internal porosity of microspheres decreased considerably with increasing polymer concentration. Increase in homogenization speed during the primary emulsion preparation led to decreased internal porosity. Burst release decreased with increasing drug loading but increased with drug molecular weight. Drug distribution in microspheres depended on preparation method. The porosity of microspheres decreased with time in the diffusion stage, but internal morphology had no influence on the release behavior in the bioerosion stage. In summary, surface porosity and internal morphology play a significant role in the release of hydrophilic macromolecules from biodegradable microspheres in the initial release phase characterized by pore diffusion.

Controlled drug release from a novel injectable biodegradable microsphere/scaffold composite based on poly(propylene fumarate)

The ideal biomaterial for the repair of bone defects is expected to have good mechanical properties, be fabricated easily into a desired shape, support cell attachment, allow controlled release of bioactive factors to induce bone formation, and biodegrade into nontoxic products to permit natural bone formation and remodeling. The synthetic polymer poly(propylene fumarate) (PPF) holds great promise as such a biomaterial. In previous work we developed poly(DL-lactic-co-glycolic acid) (PLGA) and PPF microspheres for the controlled delivery of bioactive molecules. This study presents an approach to incorporate these microspheres into an injectable, porous PPF scaffold. Model drug Texas red dextran (TRD) was encapsulated into biodegradable PLGA and PPF microspheres at 2 microg/mg microsphere. Five porous composite formulations were fabricated via a gas foaming technique by combining the injectable PPF paste with the PLGA or PPF microspheres at 100 or 250 mg microsphere per composite formulation, or a control aqueous TRD solution (200 microg per composite). All scaffolds had an interconnected pore network with an average porosity of 64.8 +/- 3.6%. The presence of microspheres in the composite scaffolds was confirmed by scanning electron microscopy and confocal microscopy. The composite scaffolds exhibited a sustained release of the model drug for at least 28 days and had minimal burst release during the initial phase of release, as compared to drug release from microspheres alone. The compressive moduli of the scaffolds were between 2.4 and 26.2 MPa after fabrication, and between 14.9 and 62.8 MPa after 28 days in PBS. The scaffolds containing PPF microspheres exhibited a significantly higher initial compressive modulus than those containing PLGA microspheres. Increasing the amount of microspheres in the composites was found to significantly decrease the initial compressive modulus. The novel injectable PPF-based microsphere/scaffold composites developed in this study are promising to serve as vehicles for controlled drug delivery for bone tissue engineering.

Odontoblast transport of sulphate—the in vitro influence of fluoride

The present study reports the development of a culture system for the analysis of 35 S -sulphate release from odontoblasts in vitro. Pulpless longitudinally split rat incisors were cultured in supplemented minimum essential medium (αMEM) with 20 μCi 35 S -sulphate per ml, 20 μCi 3 H -mannitol per ml for 1 h. Teeth were then transferred to fresh unlabelled media and aliquots of media were removed and the level of 35 S -sulphate 3 H -mannitol determined. Results indicated a two phase release of 35 S -sulphate into the media, and comparison with pulp tissue indicated a specific release pattern. Transport of sulphate is essential for correct synthesis and glycosylation of macromolecules such as proteoglycans (PG). Previous studies have shown that post-translational modifications of these proteins can be influenced by excess fluoride, resulting in decreased sulphation and elongation of glycosaminoglycan (GAG) chains. Therefore the influence of fluoride on sulphate transport, using the optimised culture system was also investigated. Inclusion of 6 mM fluoride during pulse labelling caused a significant decrease of 35 S -sulphate ( P<0.0001) during the initial release phase. Inclusion of 3 and 6 mM fluoride only in the post-labelling incubation media resulted in a significant decrease in the release of 35 S -sulphate ( P<0.0001), during the total time course. The influence of fluoride was not dose dependent. Inclusion of a specific chloride channel blocker SITS, into the culture system indicated that 35 S -sulphate transport may in part be via this route. Fluoride would therefore appear to influence the transport of 35 S -sulphate across the odontoblast membrane, potentially via a chloride channel.

An Investigation of the Mechanism of Release of the Amphoteric Drug Amoxycillin from Poly(d,l-Lactide-co-glycolide) Matrices

Amoxycillin–poly (d,l-lactide-co-glycolide) (PLGA) compacts were prepared by direct compression of both powder mixtures or films in a pre-heated press. Release profiles generally showed two phases separated by an induction period. Thus, both diffusion and polymer degradation mechanisms were involved in drug release, the relative importance of each depending on processing type and drug loading. Drug release parameters for each phase were determined. The fraction of total drug released, in the initial release phase, increased with drug loading and was much larger for compressed physical mixtures than for compressed composites prepared from co-evaporate films. Comparison of the polymer mass loss profiles of drug-loaded and drug-free discs indicated that the presence of the amphoteric drug amoxycillin had little impact on the polymer degradation rate, in contrast to the marked acceleration previously reported for basic drugs. Significant drug degradation occurred and was associated with release at later times. Release data was fitted to an equation accounting for degradation of the drug on release and suggested accelerated amoxycillin degradation during the polymer degradation controlled release phase, consistent with changes in pH in the microenvironment of the eroding compact.

Drug-releasing scaffolds fabricated from drug-loaded microspheres.

Biodegradable scaffolds serve a central role in many strategies for engineering tissue replacements or in guiding tissue regeneration. Typically, these scaffolds function to create and maintain a space and to provide a support for cell adhesion. However, these scaffolds also can serve as vehicles for the delivery of bioactive factors (e.g., protein or DNA) in order to manipulate cellular processes within the scaffold microenvironment. This study presents a novel approach to fabricate tissue-engineering scaffolds capable of sustained drug delivery whereby drug-loaded microspheres are fabricated into structures with controlled porosity. A double-emulsion process was used to fabricate microspheres with encapsulated DNA that retained its integrity and was released from the microspheres within 24 h. These DNA-loaded microspheres subsequently were formed into a nonporous disk or an interconnected open-pore scaffold (>94% porosity) via a gas-foaming process. The disks and scaffolds exhibited sustained plasmid release for at least 21 days and had minimal burst during the initial phase of release. This approach of assembling drug-loaded microspheres into porous and nonporous structures may find great utility in the fabrication of synthetic matrices that direct tissue formation.

Chitosan nanoparticles as delivery systems for doxorubicin

The aim of this paper was to evaluate the potential of chitosan nanoparticles as carriers for the anthracycline drug, doxorubicin (DOX). The challenge was to entrap a cationic, hydrophilic molecule into nanoparticles formed by ionic gelation of the positively charged polysaccharide chitosan. To achieve this objective, we attempted to mask the positive charge of DOX by complexing it with the polyanion, dextran sulfate. This modification doubled DOX encapsulation efficiency relative to controls and enabled real loadings up to 4.0 wt.% DOX. Separately, we investigated the possibility of forming a complex between chitosan and DOX prior to the formation of the particles. Despite the low complexation efficiency, no dissociation of the complex was observed upon formation of the nanoparticles. Fluorimetric analysis of the drug released in vitro showed an initial release phase, the intensity of which was dependent on the association mode, followed by a very slow release. The evaluation of the activity of DOX-loaded nanoparticles in cell cultures indicated that those containing dextran sulfate were able to maintain cytostatic activity relative to free DOX, while DOX complexed to chitosan before nanoparticle formation showed slightly decreased activity. Additionally, confocal studies showed that DOX was not released in the cell culture medium but entered the cells while remaining associated to the nanoparticles. In conclusion, these preliminary studies showed the feasibility of chitosan nanoparticles to entrap the basic drug DOX and to deliver it into the cells in its active form.

Mechanistic aspects of the release of levamisole hydrochloride from biodegradable polymers

The release of levamisole hydrochloride from poly- dl-lactide-co-glycolide compacts prepared at 5, 10 and 20% drug loading using two different particle size fractions of drug (90–125 and 125–250 μm) was investigated. Release profiles were significantly different from those previously reported for compacts prepared using the base form of the drug. Release was found to occur in a biphasic manner, with an initial fast release phase followed by a slower polymer degradation controlled release phase. The drug release profiles were successfully described by a model combining contributions from a first-order initial release phase and a polymer degradation controlled drug release phase. The fraction of drug released in the initial burst phase ( F B) was attributed to the dissolution of drug domains situated at the surface of the polymer–drug compact and this fraction tended to increase with increasing drug particle size, as expected from the model. The increase in F B with increased loading was attributed to the clumping of dispersed drug particles which effectively increased the proportion of drug linked to the compact surface.