Initial Burst Release Of Drug Research Articles

Studies on Hydroxyapatite/Polyurethane Scaffold Containing Drug-loaded Microspheres for Bone Tissue Engineering

To explore and develop scaffold for bone regeneration or tissue engineering with the capacity of controlled drug delivery, the feasibility of hydroxyapatite/polyurethane (HA/PU) scaffold containing drug-loaded microspheres for controlled drug delivery system was demonstrated. Ciprofloxacin hydrochlorid as a model drug was encapsulated in ethyl cellulose (EC) microspheres, which were subsequently incorporated into HA/PU composite scaffold to generate an antibiotic drug delivery system. The results show that EC microspheres are uniformly distributed in the HA/PU scaffold matrix and display no significant effect on the pore structure of the scaffold. Compared with incorporating ciprofloxacin hydrochlorid into scaffolds directly, embedding microspheres into scaffolds significantly reduces the initial burst drug release and extends the release time of drug delivery. In vitro drug delivery tests and antibacterial activity tests prove that drug-loaded microsphere/scaffold system has good drug delivery properties and effective antibacterial properties. These results suggest that the novel drug-loaded microsphere/ scaffold composites developed in this study is a good candidate scaffold with the function of bone repair and infection treatment for bone tissue engineering.

Prolonged intragastric drug delivery mediated by Eudragit® E-carrageenan polyelectrolyte matrix tablets.

Interpolyelectrolyte (IPE) complexation between carrageenan (CG) and Eudragit E (EE) was studied in 0.1 M HCl and was used to develop floating matrix tablets aimed to prolong gastric-residence time and sustain delivery of the loaded drug. The optimum EE/CG IPE complexation weight ratio (0.6) was determined in 0.1 M HCl using apparent viscosity measurements. The IPE complex was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. Metronidazole matrix tablets were prepared by direct compression using EE, CG, or hybrid EE/CG with ratio optimal for IPE complexation. Corresponding effervescent tablets were prepared by including Na bicarbonate as an effervescent agent. Tablets were evaluated for in vitro buoyancy and drug release in 0.1 M HCl. Both CG and EE-CG effervescent matrices (1:2 drug to polymer weight ratio, 60 mg Na bicarbonate) achieved fast and prolonged floating with floating lag times less than 30 s and floating duration of more than 10 h. The corresponding EE effervescent matrices showed delayed floating and rapid drug release, and completely dissolved after 3 h of dissolution. CG matrices showed an initial burst drug release (48.3±5.0% at 1 h) followed by slow drug release over 8 h. EE-CG matrices exhibited sustained drug release in almost zero-order manner for 10 h (68.2±6.6%). The dissolution data of these matrices were fitted to different dissolution models. It was found that drug release followed zero-order kinetics and was controlled by the superposition of the diffusion and erosion.

Solutions for Lipophilic Drugs: A Biodegradable Polymer Acting as Solvent, Matrix, and Carrier to Solve Drug Delivery Issues

The purpose of this study was to investigate the polyester hexylsubstituted poly(lactide) (hexPLA) as a possible solvent for lipophilic substances and excipient for pharmaceutical formulations. HexPLA is a biodegradable and semi-solid polymer, which allows the incorporation of active substances by simple mixing and local or systemic application to the patient through injection. The solvent behavior of hexPLA was investigated by adding the lipophilic dye Sudan III to the polymer matrix and optical monitoring of the dissolution process over time by microscopy. As a drug, the antipsychotic compound haloperidol was analyzed for its solubility in hexPLA of different molecular weights by preparing saturated solutions, and measuring the amount of incorporated drug with UV spectroscopy. The influence of the rate of solubilized to suspended drug on the burst release behavior of haloperidol from hexPLA-formulations was investigated in release tests. It is demonstrated that hexPLA dissolves both lipophilic substances, Sudan III and Haloperidol. In the molecular weight range between 2,000 g/mol and 10,000 g/mol, a lower molecular weight hexPLA resulted in a higher incorporation capacity for haloperidol. By changing from a suspension formulation of haloperidol to a solution formulation, the initial burst release established for classical PLA and PLGA systems could be minimized. HexPLA is shown to be a potent solvent and excipient for lipophilic drugs, allowing the initial burst of drug release to be modified and controlled.

Use of xanthan and its binary blends with synthetic polymers to design controlled release formulations of buccoadhesive nystatin tablets

Various buccoadhesive nystatin tablets formulations containing xanthan, carbopols (934P, 971P, 974P), PVP K30 or PEG 6000 or their binary blends were prepared. The powders were compressed into tablets at a constant compression pressure. Drug release behaviour, swelling and erosion indices and strength of bioadhesion in vitro to a biological membrane were investigated. The interaction between nystatin and polymers was investigated by DSC and FT-IR. Tablets containing the different types of carbopol alone consistently showed an initial burst release of drug, whereas this was not observed for matrices containing xanthan or xanthan-carbopol. The presence of PEG in xanthan-containing formulations induced an increase in dissolution rate; however, in the absence of xanthan the amount of drug release from a PEG matrix was reduced to < 15% over 8 h dissolution. The presence of PVP increased the dissolution rate of nystatin due to the relative hydrophilicity of PVP. The presence of calcium ions induced a more rigid gel in the xanthan matrix as a result of interaction between the polymer and calcium ions. Xanthan can be used in potential mucoadhesive formulations containing nystatin to produce a controlled release of the drug and the outcomes of this work may provide a suitable strategy for matrix selection to provide more efficacious treatment alternatives for candidiasis and other disease processes for significant patient populations.

Release profile characteristics of biodegradable-polymer-coated drug particles fabricated by dual-capillary electrospray

This study describes one-step synthesis of coated particles by a dual-capillary electrospray (ES) system to produce monodisperse PLGA-coated drug particles. Different from a single-capillary ES system, the dual-capillary ES system separates drug and coating material, i.e., PLGA, solutions in two separate flow channels formed by two co-axially aligned capillaries and produce particles with the core(drug)-shell(PLGA) structure. No emulsion process is involved in the ES process. Our study shows that the studies system can achieve nearly 100% drug encapsulation efficiency with the proper system setting. Through the variation of PLGA concentration and the electrical conductivity of spray solutions, monodisperse PLGA-coated drug particles with sizes ranging from 165 nm to 1.2 μm were prepared. The drug release rates of prepared particles show that the small particles released the drug more rapidly than large ones. The SEM images of different release timing also show that the penetration of water into particles increases with the decrease of particle size, resulting in the fast particle swelling and eventually rupturing. This result demonstrates that the drug release profile can be controlled by tuning the particle size. We also observed two unique characteristics from the release behavior of drug-loaded PLGA particles produced by the dual-capillary ES system. One is that PLGA particles with the sizes smaller than 1 μm in diameter rupture before they were degraded and the drug release profile is therefore dominated by the penetration of water and drug diffusion. The other characteristic is that the core–shell structure of drug-loaded PLGA particles minimizes the initial burst release of drug. It is because the drug is fully encapsulated in the core of particles (without the surface drug loading).

Design and In Vitro Evaluation of Novel Sustained-Release Double-Layer Tablets of Lornoxicam: Utility of Cyclodextrin and Xanthan Gum Combination

The objective of the present study was to develop new directly compressed, double-layer tablets (DLTs) of lornoxicam, a highly potent nonsteroidal anti-inflammatory drug with short half-life, that are characterized by initial burst drug release in the stomach and comply with the release requirements of sustained-release products. Each of the proposed DLTs is composed of a fast-release layer and a sustained-release layer, anticipating rapid drug release that starts in the stomach to rapidly alleviate the symptoms and continues in the intestine to maintain protracted analgesic effect. An amorphous, freeze-dried inclusion complex of lornoxicam with hydroxypropyl-beta-cyclodextrin, present in 1:2 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of lornoxicam in the stomach and assure rapid onset of its analgesic effect. Xanthan gum (XG), a hydrophilic matrix-forming agent, was integrated in the sustained-release layer to provide appropriate sustainment of drug release. The weight ratios between the sustained-release layer and fast-release layer present in DLTs were adjusted to reach optimal formulations. DLTs composed of sustained-release layer (40% XG) to fast-release layer in 2:1 weight ratio and those composed of sustained-release layer (50% XG) to fast-release layer in 1:1 weight ratio showed the desired release profile. The drug contained in the fast-release layer showed an initial burst drug release of more than 30% of its drug content during the first 30 min of the release study followed by gradual release of the drug for a period of 8 h.

Preparation and evaluation of microspheres prepared from novel polyester-ibuprofen conjugates blended with non-conjugated ibuprofen

A novel polyester, poly(glycerol-adipate-co-ω-pentadecalactone) (PGA-co-PL), was conjugated with a model drug, ibuprofen, through the free hydroxyl groups of the former and the free carboxyl group of the latter at various levels of substitution. The conjugated material was processed into microspheres by both emulsion solvent evaporation and spray-drying methods. Samples of conjugated material were also blended with non-conjugated drug and the microspheres produced were evaluated by various methods. Morphologically, the microspheres produced were satisfactory. However, there was some initial burst drug release from all samples, probably due to the presence of non-conjugated drug. Subsequent drug release was very slow due to the relative stability of the covalent bonding of the drug–polyester conjugate. Stability tests showed that storage at high relative humidity resulted in increased burst release.

Functionally gradient chitosan/hydroxyapatite composite scaffolds for controlled drug release

This study explored the potential of chitosan/hydroxyapatite (HA) composites to act as a controlled drug delivery system by developing functional scaffolds with a gradient of structure and drug concentration. Firstly, a porous composite scaffold was prepared and tetracycline hydrochloride (TCH) was impregnated in the scaffold as a model drug. The pore size of the scaffold was negatively dependent on the HA content and ranged about 40-250 microm. Subsequently, a porous chitosan/HA composite layer without drug was coated on the scaffold to create a gradient drug concentration in the specimen. The in vitro drug-release test demonstrated that the porous layer without drug on the outer surface of the scaffold significantly reduced the initial burst of drug release and extended the release period. Finally, a successive and dense chitosan/HA composite layer endowed the scaffold with a sustained, drug-release pattern without any initial drug burst. These findings confirmed the high effectiveness of the hybrid scaffolds in regulating the release of drugs, and hence their capability to serve as a temporary drug carrier in tissue regeneration. These functional scaffolds also have potential application to the delivery of some bioactive molecules such as growth factors.

Analysis of initial burst in PLGA microparticles

Background: This review addresses recent advances in the understanding of the mechanisms that underlie burst release and strategies developed to control burst from poly(lactide-co-glycolide) (PLGA) microparticle formulations. While the initial burst release of drug is not always detrimental, excessive drug release in the burst phase may be toxic, and irregularity in the amount of drug released (e.g., from batch to batch) is not acceptable. Many drugs that are good candidates for sustained release treatments are not miscible in PLGA and common microparticle processing solvents, and, as a result, suffer from excessive initial burst release. Objective: The aim of this review is to provide an update on research to understand the mechanisms that underlie burst release of drugs from PLGA microparticles, and strategies developed to control burst. Methods: This review focuses on literature published since 2004. Results: Strategies to control burst release fall into two general categories. First are efforts to improve the miscibility of drug and polymer by altering the composition of the formulation, for example by altering the salt form of the drug. Secondly, processing methods may be altered (increasing the rate of solvent removal, for example) to prevent drug–polymer separation. The goal of most strategies is to reduce or eliminate burst release, so that the encapsulated drug may be maximally retained in the delivery system for long-term delivery.

Antimicrobial activity and local release characteristics of chlorhexidine diacetate loaded within the dental copolymer matrix, ethylene vinyl acetate

In vitro results are presented for a novel oral drug-delivery system ultimately intended for treatment of oral infections in immunocompromised patients. Test samples of ethylene vinyl acetate copolymer (EVA) containing chlorhexidine diacetate (CDA) showed desirable antimicrobial properties and steady, slow release into aqueous and other media after an initial burst of drug release in the first day of liquid exposure. By washing away this initial burst, the proposed mouthguard device should be capable of sustained delivery of locally effective CDA concentrations far below systemically toxic levels. A prolonged room temperature shelf-life of at least 1 year, and effectivity against a wide range of oral bacteria and Candida species was demonstrated. Drug loaded films showed a top-to-bottom asymmetry in drug release, but good lateral homogeneity, and a linear relationship between initial CDA loading concentration (from 0.63 to 10 wt %) and days 3-14 release rates in a static aqueous environment. The EVA matrix containing CDA appears to possess many suitable properties for localized oral delivery of sustained antimicrobial activity.

Biodegradable hydrophobic–hydrophilic hybrid hydrogels: swelling behavior and controlled drug release

The objective of this work was to investigate a new family of hydrophobic–hydrophilic biodegradable hybrid hydrogels as drug carriers. A series of hydrophobic–hydrophilic biodegradable hybrid hydrogels was formulated via photo means from hydrophobic three-arm poly (ε-caprolactone) maleic acid (PGCL-Ma) and hydrophilic dextran maleic acid (Dex-Ma) precursors over a wide range of the two precursors' feed ratio (PGCL-Ma/Dex-Ma at 100:0, 70:30, 50:50, 30:70 and 0:100). A low-molecular-weight and hydrophilic drug, the α-7 agonist cocaine methiodide, was used as the model drug for the release study from the hybrid hydrogels in pH 7.4 phosphate buffer solution at 37°C. The swelling data of these hybrid hydrogels depended on the hydrophobic to hydrophilic precursors' feed ratio, and there were several-fold differences in swelling ratios between a pure hydrophilic Dex-Ma and a pure hydrophobic PGCL-Ma hydrogels. The presence of the hydrophobic PGCL-Ma component significantly reduced the initial burst swelling of the hybrid hydrogels. Depending on the two precursors' feed ratios, the swelling data during the early period obeyed either Fickian diffusion (for 50:50 PGCL-Ma/Dex-Ma hydrogel), non-Fickian or anomalous transport (for 70:30 and 100:0 PGCL-Ma/Dex-Ma), or relaxation-controlled (for 30:70 and 0:100 PGCL-Ma/Dex-Ma). A wide range of cocaine methiodide release profiles was achieved by controlling hydrophobic to hydrophilic precursors' feed ratios. Initial drug burst release was significantly reduced as the concentration of the hydrophobic PGCL-Ma component increased in the hybrid hydrogels. The bulk of cocaine methiodide released during the 160-h period was via diffusion-controlled mechanism, while degradation-controlled mechanism dominated thereafter.

Cellular uptake and cytotoxicity of shell crosslinked stearic acid-grafted chitosan oligosaccharide micelles encapsulating doxorubicin

Stearic acid-grafted chitosan oligosaccharide (CSO-SA) with 3.48% amino-substituted degree (SD%) was synthesized by coupling reaction. The CSO-SA could self-aggregate to form micelle with a critical micelle concentration (CMC) at 0.035 mg/mL in the aqueous phase. The CSO-SA self-aggregate micelles indicated spatial structure with multi-hydrophobic core. One CSO-SA chain could form 2.8 hydrophobic cores. Cellular uptakes of CSO-SA micelles by using A549, LLC, and SKOV3 cells as model tumor cell lines showed the faster cellular internalization of CSO-SA micelles, and the cellular uptakes on the LLC and SKOV3 cells were higher than that on the A549 cells. Doxorubicin (DOX) was then used as a model drug to incorporate into CSO-SA micelles. To reduce the initial burst drug release from CSO-SA micelles loading DOX (CSO-SA/DOX), the shell of CSO-SA micelles was crosslinked by glutaraldehyde. The shell crosslinking of CSO-SA micelles reduced the micelle size and surface potential, but it did not significantly affect the cellular uptake and drug encapsulation efficiency of CSO-SA micelles. The cellular inhibition experiments demonstrated that the cytotoxicity of DOX was increased by the encapsulation of CSO-SA micelles. CSO-SA/DOX displayed the best antitumor efficacy in SKOV3 cell line due to the higher cellular uptake percentage of CSO-SA micelles and the lower sensitivity of free drug to the cells. The cytotoxicities of shell crosslinked CSO-SA/DOX were highly enhanced in all cell lines than those of unmodified CSO-SA/DOX.

Fabrication of drug-loaded biodegradable microcapsules for controlled release by combination of solvent evaporation and layer-by-layer self-assembly

The initial burst release of drug from polymer microparticles remains an unsolved problem. Here, we deposited polysaccharides on drug-loaded microspheres using layer-by-layer self-assembly to produce core–shell microparticles for sustained drug release. The ibuprofen (IBU)-loaded poly(3-hydroxybutyrate -co-3-hydroxyvalerate) (PHBV) microparticles were fabricated by conventional solvent evaporation. The processing parameters, such as pH of water phase, drug/polymer ratio, polymer type, and emulsifier concentration, were optimized according to the encapsulation efficiency and drug loading as pH 4.0, drug/polymer ratio = 10/50 (wt), HV in PHBV = 6 wt.%, and PVA concentration = 1% (w/v). The multilayer shells of chitosan (CHI)/sodium alginate (ALG) and poly(diallyldimethylammonium chloride) (PD)/sodium poly(styrenesulfonate) (PSS) were formed on the IBU-loaded PHBV microparticles using layer-by-layer self-assembly. The in vitro release experiments revealed that, as for the microparticles with three CHI/ALG bilayer shells, the initial burst release of IBU from the microparticles was significantly suppressed and the half release time was prolonged to 62 h from 1 h for the microparticles without coverage. The compact CHI/ALG multilayer film was observed with an atomic force microscopy (AFM) due to the matched distance of charges along the CHI chain and those along the ALG chains. The present combination for encapsulating drug-loaded microparticles demonstrates an effective way to prolong the drug release with reduced initial burst.

Evaluation of ibuprofen-loaded microspheres prepared from novel copolyesters

The utility of two novel linear random copolyesters to encapsulate and control the release of ibuprofen, via microspheres, was investigated. Various manufacturing parameters, including temperature, disperse phase volume and polymer:ibuprofen ratios were altered during the microsphere production. The effects of these changes on the morphological characteristics of the microspheres, yield, drug loading, encapsulation efficiency and drug release rates were examined. The diameter of the microspheres ranged from 36 to 89 μm and showed both smooth and ridged surfaces. Microsphere diameter was probably determined by the internal phase volume, while surface morphology was controlled by manufacturing temperature. Greater encapsulation efficiency was obtained by increasing the polymer:ibuprofen ratio and by reducing the internal phase volume. For all batches there was an initial burst drug release into phosphate buffer (pH 7.4) over the first 2–4 h, which was followed by a much slower release rate over the remaining time period. Drug release rates during both these phases were dependent upon the amount and nature of the polymer in the microspheres, noting that the more hydrophilic polymer provided faster release rates. Ibuprofen solubility appeared to play a dominant role in controlling release, although both encapsulation efficiency and microsphere morphology were also contributing factors.

Application of USP Apparatus 4 and In Situ Fiber Optic Analysis to Microsphere Release Testing

Introduction In the past 15 years,the number of novel drug dosage forms such as controlled release (CR) parenterals (microspheres, liposomes,stents,and other implants) entering to the U.S. market has increased (1). These products can deliver drugs at a desired rate over periods of several days to months. It is essential to develop discriminatory in vitro release testing methods and standards for these delivery systems. In vitro release methods are necessary to monitor batch-to-batch variability,evaluate any process or manufacturing change,ensure the clinical performance of the drug i.e. safety and efficacy and determine a relationship between the in vitro and in vivo release data. Standard dissolution methods are inappropriate for CR parenterals since:these were designed for oral and transdermal products; they utilize large volumes of media,and often require separation of the delivery system from the release media for analysis. Methods of in vitro release testing that are currently used for CR parenterals include membrane diffusion,sample-and-separate, in situ and continuous flow (2). USP apparatus 1 (basket),2 (paddle) and 4 (flow through) have been used for microspheres and other dispersed systems. Sample-and-separate methods have been used where samples are taken from USP Apparatus 2 and the dispersed phase is isolated by centrifugation or filtration. In addition to the official USP Apparatus,other methods such as miniaturized methods and dialysis sacs have been used for CR dispersed systems. Since most of these products are small volume parenterals,miniaturized methods have been designed where the samples are placed into small vials instead of one-liter vessels. Problems with this method include violation of sink conditions,sample aggregation due to limited agitation,and disruption of the delivery system during centrifugation or filtration (e.g. coalescence of emulsion droplets,or aggregation of liposomes) in sample-and-separate methods leading to inaccuracy in the release data. A recent AAPS-EUFEPS workshop report (2003) on “Assuring Quality and Performance of Sustained and Controlled Release Parenterals”stated that there is a need for standards for in vitro release testing methods for controlled release parenterals with respect to apparatus, media,sampling interval,and temperature,and also acknowledged that guidance on in vivo release testing of these products and development of in vitro-in vivo relationships/prediction is necessary (1). In vitro release testing methods for poly (lactic-co-glycolic acid) (PLGA) microspheres are discussed herein. The 2003 AAPS-EUFEPS workshop report recommended the use of USP Apparatus 4 for in vitro release testing of CR microspheres (1). USP Apparatus 4,which is a flow through method that includes a pump,flow-through cells,water bath and media reservoir,was designed as an in vitro dissolution method for controlled release oral powders,granules,and solid dispersions. The specifications with respect to cell size of this apparatus are described in the US Pharmacopeia (3). USP Apparatus 4 can be operated under different conditions such as open or closed system mode;different flow rates and temperatures. The diversity of available cell types allows application to a wide range of dosage forms. Since the reservoir volume is not fixed,media volume can be decreased to accommodate systems where the concentration of drug released would otherwise be below the detection limit (e.g. systems with low drug loading) or increased to allow ease of maintenance of sink conditions for poorly soluble compounds. USP Apparatus 4 also offers flexibility in monitoring release via in situ UV analysis. Such analysis can be achieved without any correction for scattering by the dispersed system or particle accumulation on the probes since the microspheres or other delivery system are isolated Abstract The objective of this study was to determine the applicability of USP Apparatus 4 and in situ fiber optic UV analysis to in vitro release testing of poly (lactic-co-glycolic acid) (PLGA) microspheres. The release of dexamethasone from microspheres prepared with both high and low Mw PLGA was evaluated. Dexamethasone release profiles obtained using USP apparatus 4 were compared with those obtained using a sample-and-separate method. Cumulative release obtained using USP Apparatus 4 was approximately 16% higher over a 30-day period when compared to that obtained using the sample-and-separate method. This difference was attributed to loss of microspheres during separation as well as to microsphere aggregation in the sample-and-separate method. The versatility of USP Apparatus 4 with respect to alteration of flow rate allowed demonstration of diffusion-controlled release from low Mw PLGA microspheres. Fiber optic UV probes used in conjunction with USP Apparatus 4 enabled complete characterization of the initial burst release of drug from the microsphere systems.

Mechanistic evaluation of the glucose-induced reduction in initial burst release of octreotide acetate from poly( d, l-lactide- co-glycolide) microspheres

One major obstacle for development of injectable biodegradable microspheres for controlled peptide and protein delivery is the high initial burst of drug release occurring over the first day of incubation. We describe here the significant reduction in initial burst release of a highly water-soluble model peptide, octreotide acetate, from poly( d, l-lactide- co-glycolide) microspheres by the co-encapsulation of a small amount of glucose (e.g., 0.2% w/w), i.e., from 30±20% burst − glucose to 8±3% + glucose (mean±SD, n=4). This reduction is unexpected since hydrophilic additives are known to increase porosity of microspheres, causing an increase in permeability to mass transport and a higher burst. Using the double emulsion-solvent evaporation method of encapsulation, the effect of glucose on initial burst in an acetate buffer pH 4 was found to depend on polymer concentration, discontinuous phase/continuous phase ratio, and glucose content. Extensive characterization studies were performed on two microsphere batches, ±0.2% glucose, to elucidate the mechanism of this effect. However, no significant difference was observed with respect to specific surface area, porosity, internal and external morphology and drug distribution. Continuous monitoring of the first 24-h release of octreotide acetate from these two batches disclosed that even though their starting release rates were close, the microspheres + glucose exhibited a much lower release rate between 0.2 and 24 h compared to those − glucose. The microspheres + glucose showed a denser periphery and a reduced water uptake at the end of 24-h release, indicating decreased permeability. However, this effect at times was offset as glucose content was further increased to 1%, causing an increase in surface area and porosity. In summary, we conclude that the effect of glucose on initial burst are determined by two factors: (1) increased initial burst due to increased osmotic pressure during encapsulation and drug release, and (2) decreased initial burst due to decreased permeability of microspheres.

Analysis of the initial burst of drug release coupled with polymer surface degradation.

Local pH effect on the release of a model pH-inert hydrophobic drug coupled with polymer degradation is described at the induction phase of biodegradable polymer erosion for better understanding the nature of initial burst of a drug. Using a novel approach with time-of-flight secondary ion mass spectrometry. both surface concentration of Ph3N and degradation kinetics of PLLA are simultaneously and independently determined from a model Ph3N/PLLA (20:80 wt%) blend matrix (t approximately 0.4 microm on 1.0 cm2). In vitro hydrolysis of the model blend matrix is investigated for short-term periods (<24 h) at physiologic pH and temperature and compared to basic pH. The rate of PLLA degradation is accelerated by a factor of approximately 3 when using basic pH in vitro, but the rate of Ph3N accumulation at the surface is accelerated by a factor of approximately 6. A new quantitative method has been developed to examine the earliest stages of polymer degradation and drug release. It was applied to a model system that could not be examined by traditional in vitro methods. For the model system studied the release of a low molecular weight hydrophobic drug at the induction phase of polymer erosion is related to but not singularly dependent on degradation kinetics.

In Vitro Characterization of Polyorthoester Microparticles Containing Bupivacaine

Laboratory-scale spray-congealing equipment was utilized to fabricate injectable microparticles consisting of polyorthoester and bupivacaine. Operating conditions for the spray-congealing process were optimized to produce microparticles with the desired shape and particle size to yield acceptable syringeability and injectability. Characterizations were performed to determine the chemico-physical properties of polyorthoester before and after microparticle fabrication. Microparticles with different drug loadings and comparable particle sizes were produced, and their in vitro drug-release profiles were determined. The in vitro drug release of microparticles with a high drug loading was markedly faster than those with a low drug loading. This is partially attributed to a more significant initial burst–drug release of the microparticles with a high drug loading. The microparticles have demonstrated the potential to be used for long-acting postsurgery pain management by local injection.

Preparation and Reconstitution of Core-shell Type Nanoparticles of Poly(ε -caprolactone)/Poly(ethyleneglycol)/Poly(ε -caprolactone) Triblock Copolymers

One of the improtant characteristics of core-shell type nanoparticles is the long-term storage and reuse as an aqueous injection solution when required. For this reason, reconstruction of lyophilized core-shell type nanoparticles is considered to be essential . BAB type triblock copolymers differ from AB type diblock copolymers, which contain the A block as a hydrophilic part and the B block as a hydrophobic part. by not being easily redistributed into phosphate-buffered saline (PBS, pH 7.4, 0.1 M). Therefore, lyophilized core-shell type nanoparticles of CEC triblock copolymer were reconstituted using a somication process with a bar-type sonicator in combination with a freezing-thawing process. Soncation for 30s only resuspended CEC nanoparticles in PBS; their particle size distribution showed a monomodal pattern with narrow size distribution. The bimodal size distribution pattern and the aggregates were reduced by further sonication for 120 s but these nanoparticles showed a wide size distribution. The initial burst of drug release was increased by reconstitution process. The reconstitution of CEC core-shell type nanoparticles by freezing-thawing resulted in trimodal distribution pattern and formed aggregates, although freezing-thawing process was easier than sonication . Drug release form CEC nanoparticles prepared by freezing-thawing was slower than from the original dialysis solution. Although core-shell typenanoparticles of CEC triblock copolymers were not easily performed. Cytotoxicity testing of core-shell type nanoparticles of CEC-2 triblock copolymers containing clonazepam (CNZ) was performed using L929 cells. Cytotoxicity of CNZ was decreased by incorporation into nanoparticles.

Acrylic-phosphate glasses composites as self-curing controlled delivery systems of antibiotics.

New antibiotic delivery systems based on self-hardening methyl methacrylate (MMA)/polymethyl methacrylate (PMMA) systems and phosphate glasses (PG) in the system P(2)O(5)-CaO-Na(2)O have been developed. Self-curing formulations were prepared by mixing the solid component containing PMMA beads, different proportions of PG (30-70 wt %) and vancomycin (5 wt %) as antibiotic, with the liquid component made of MMA monomer. Dough and setting times increased with the content of PG but peak temperature decreased to values well below to guarantee the chemical stability of the antibiotic drug, gentamicin or vancomycin. Mechanical properties of the PMMA/PG composites were evaluated in compression test giving rise to values of compressive strength in the range of 100 MPa. The release of vancomycin was analyzed in vitro by immersion of samples in phosphate buffer of pH=7.4. Release profiles were influenced by the content of PG present in the cement. An initial burst of drug release was observed in all cases. The composites with 70 wt % PG released nearly the total amount of drug loaded in a period of 45 days, and those containing 60 wt % PG released the 70% of the vancomycin in the same period of time. However, either the control of the composite with 30 wt % PG released only the 30% of the drug in 10-15 days. The surface of the drug-loaded composites before and after release experiments was analyzed by ESEM. The deposition of some aggregates at certain points of the surface was detected for the specimens immersed in buffer phosphate after 45 days. This material was characterized by FTIR and Raman spectroscopy as an amorphous phosphate formed by calcium ortho and pyrophosphates, and indicates an interaction between the hydrated layer at the place of the glass and the surrounding medium.