Mechanistic insights derived from retardation and peak broadening of particles up to 200 nm in diameter in electrophoresis in semidilute polyacrylamide solutions

Rigid spherical particles in the size range of 5-200 nm diameter were subjected to capillary zone electrophoresis (CZE) in semidilute solutions of uncross-linked polyacrylamide of M(r) 5, 7 and 18 x 10(6) (PA-5, -7 and -18, respectively) of varying concentrations up to 1.6% and at field strengths varying from 68 to 270 V/cm. For all particles under study, the experimental Ferguson plots, log(mobility) vs. polymer concentration, permit a linear approximation. Their slope, the retardation coefficient KR = delta log (mobility)/delta (concentration), for particles smaller than 30 nm in diameter increased with particle size in PA-5 and -7 independently of electric field strength and polymer M(r). The KR of particles of 30 nm in diameter or more was found to be independent of particle size at the lowest field strength used but to decrease with it at the higher values of field strength. The decrease was parallel but shifted to higher values of retardation when the polymer M(r) increased from 5 to 7 x 10(6). With a decreasing ratio of average mesh size of the polymer network, zeta, to particle radius, R, the approach to "continuity" of the polymeric medium (zeta/R < 1) with both increasing particle size and polymer concentration does not result in the retardation behavior expected according to the macroscopic (bulk) viscosity of the solution. These experimental observations were hypothetically interpreted in terms of a transition to a retardation mechanism comprising the formation of a polymer depletion layer near the particle surface--polymer solution interface. Peak width exhibited an overall increase with PA-7 concentration for all particles studied. For particles of 30 nm in diameter or less, the increase was steepest when the radius of the particle was approximately commensurate with zeta at a given polymer concentration. For the largest particle, 205 nm in diameter, peak broadening with polymer concentration was found to correlate linearly with peak asymmetry. CZE of the particles in PA-18 solutions revealed abnormal behavior, with both mobility and peak width remaining near-constant up to a concentration of 0.08% and sharply declining at higher concentrations. The decline of relative mobility is the same-for the entire particle size range used, while peak width declines in direct relation to particle size.     

Release kinetics of coated, donut-shaped tablets for water soluble drugs

Coated, donut-shaped tablets (CDST) were designed to achieve parabolic and linear drug release profiles. When rapidly erodible polymers (HPMC E3, HPC, PEG8000, PEOs (Mw=100000 and 200000)) were used, the release profiles of diltiazem HCl from the tablets becomes parabolic whereas zero-order release was achieved by using slowly erodible polymers (HPMC E5, HPMC E15, PEO (Mw=300000)). Drug release from the rapidly erodible polymers was governed by the pure erosion of the polymer while both polymer erosion and drug diffusion controlled drug release from the slowly erodible polymers. As drug loading was increased from 10% to 39% w/w, the drug release rate from CDST based on HPMC E3 became faster and parabolic whereas that from CDST based on HPMC E5 was linear. The slowly erodible polymer (HPMC E5) provided parabolic release profiles when drug loading was greater than 49% w/w. In this case, drug release mechanisms likely shifted from a combination of polymer erosion and drug diffusion to pure polymer erosion due to the enhancement of polymer erosion by faster influx of water. As drug solubility decreased from 61.6% w/v (diltiazem HCl), 1.0% w/v (theophylline), to 0.5% w/v (nicardipine HCl), the drug release rate from CDST based on HPMC E3 decreased due to polymer erosion mechanism but there was little difference in release rate from CDST based on HPMC E5 due to the greater contribution of drug diffusion to drug release kinetics along with polymer erosion. As expected, the drug release rate of diltiazem HCl from HPMC E3 and E5 was significantly influenced by stirring rate and hole size.     

Distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans in various sizes of airborne particles

We investigated the particle size distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) in atmospheric samples collected at four sites. The largest amounts of particle-bound PCDD/F were found on small particles with aerodynamic diameters (dae) of less than 1.1 microns that accounted for over 50% of the total PCDD/F, contributing mostly to the toxicity and providing over 47% of the total TEQs (Toxicity Equivalents) loading. PCDF showed about twice the concentration of the PCDD in the total TEQs. The total PCDD/F concentration for accumulation mode particles (dae < 1.1 microns) ranged from 8.2 to 16 pg/m3 and that on coarse particles (dae > 1.1 microns) from 3.5 to 8.6 pg/m3. Five to eight percent of the total PCDD/F was found on large particles of dae > 7 microns. It was observed that the PCDD/F homologue profiles on large particles were different from the small particles and the fraction of less chlorinated PCDD/F in the homologue groups increased with increasing particle size. The reentrainment of soil particles including PCDD/F did not significantly influence the PCDD/F on the large particles. Two plausible mechanisms, the mass transfer of the gas phase PCDD/F on the particle surface and the contribution of the large size fly ash emitted from incinerators are proposed to explain the observed PCDD/F homologues partitioning among particle size fractions.     

Particle Destabilization in Highway Runoff to Optimize Pollutant Removal

Sedimentation column studies and simulations using particle size distribution suggest that low removal efficiencies of smaller particles in highway runoff would be obtained using sedimentation if coagulation-flocculation is not performed. Coagulation-flocculation studies, using metal salts (alum and ferric chloride) and one organic polymer in three molecular weights, were evaluated over the 2004–2005 storm seasons. Only the first flush or approximately the first hour of runoff was coagulated. Efficiencies were quantified with particle size distribution measurements and turbidity. Results with low dosages of metal salts were ineffective and did not improve water quality. High dosages of metal salts using a sweep floc mechanism were effective in dramatically lowering runoff turbidity, but resulted in large quantities of sludge production and required pH control. A cationic organic polymer at low dosages (<10?mg/L) was effective in coagulating highway runoff and reducing particle charge. Extended mixing time was required to achieve low turbidities ( ～ 5 NTU). A combination of organic polymer, followed by small doses of alum (<10?mg/L), reduced mixing time and produced high quality effluent.     

Preparation, characterization and in vitro antimicrobial activity of ampicillin-loaded polyethylcyanoacrylate nanoparticles

In this paper, the experimental conditions for preparing ampicillin-loaded polyethylcyanoacrylate (PECA) nanoparticles are described. The effects of drug concentration and surfactant type in the polymerization medium on the particle size distribution and loading capacity were studied. The results of these studies show that only the type of surfactant has an impact on the nanoparticle dimensions. The release rate of ampicillin from PECA nanoparticles at pH 7.4 (extracellular value pH) performed either with and without esterases, show that the drug release is considerably increased in the presence of these exzymes. The results of drug release study at pH 1.1 (simulated gastric juice) are very interesting. This study has evidenced that the 70% of ampicillin is released quickly, while the remaining fraction is firmly incorporated in nanoparticles. The released ampicillin is quickly degraded in acid medium while the entrapped fraction is protected from acid degradation and afterwards, when nanoparticles reach the small intestine, can be readily released in the presence of esterases. This result could be exploited for the oral administration of the ampicillin-PECA system. Finally, studies of antimicrobial activity of prepared systems evidenced that ampicillin-loaded PECA nanoparticles exhibit an activity equal or higher than the free drug.     

Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy

A prototype multiple-drug delivery implant has been developed for the intraocular management of proliferative vitreoretinopathy (PVR). Because of the recurrent nature of the disease, PVR causes blindness in approximately 7% of patients who have undergone retinal re-attachment surgery. The poly(dl-lactide-co-glycolide) 50/50 (PLGA) implant consists of three cylindrical segments, each of which contains one of the following drugs: 5-fluorouridine (5FUrd, an antimetabolite), triamcinolone (Triam, a corticosteroid), and human recombinant tissue plasminogen activator (t-PA, a thrombolytic agent). The device can be inserted through a 20-gauge syringe needle into the vitreous body of the eye. The implant also possesses a PLGA coating over the t-PA-containing terminal segment, which creates a lag-time to deliver t-PA when most needed and to decrease the risk of postoperative bleeding. Two methods of cylinder fabrication were investigated: heat and solvent extrusion. The release behavior of several drugs was examined as a function of the processing variables including: extrusion method, drug loading, polymer molecular weight, and drug particle size. The presence of either the organic solvent (acetone) during processing or a highly water-soluble drug (5FUrd) in the formulation increased the polymer porosity, which in turn, increased the drug release-rate. Drug loading effects were consistent with percolation concepts, and a low-molecular-weight PLGA (e.g., Mw=42000 for inherent viscosity=0.58 dl/g) was desirable to produce controlled release close to one month. Based on pharmacological and pharmacokinetic data of these compounds and our clinical experience with this disease, several design criteria for a combined implant were devised. Optimal cylindrical segments from the formulation studies were selected and combined in series to form a contiguous implant. After successful combination and coating procedures were developed, prototype implants were prepared. From the 3-drug prototype, 5FUrd and Triam were released approximately 1 microgram/day for over 4 weeks and 10-190 microgram/day over 2 weeks, respectively. The solvent-extrusion procedure did not significantly alter the stability of the encapsulated t-PA (>94+/-5% serine protease activity after preparation). After a lag-time of approximately 2 days, t-PA was released active at a rate of approximately 0.2-0.5 microgram/day in approximately 2 weeks. The release characteristics from the combined implant largely met our initial design criteria. Hence, controlled-release implants of this kind may have potential use for intraocular treatment of PVR.     

Differential in vitro hepatic and intestinal metabolism of ifosfamide in the rat

Influence of chitosan molecular weight on drug loading and drug release of drug-loaded chitosan microspheres was studied. Chitosans of 70,000 (LC), 750,000 (MC), and 2,000,000 (HC) molecular weight were employed alone or as mixtures (HC/LC 1:1-1:2 w/w). Ketoprofen (ket) was chosen as the model drug to be encapsulated. Microspheres characterized by different theoretical polymer/drug ratios were prepared (2:1, 1:1, 1:2 w/w). Satisfactory ket contents were obtained for all batches of chitosan microspheres with the theoretical polymer/drug ratio 1:2 w/w; microspheres made of HC/LC (1:2 w/w) were characterized by good drug content and encapsulation efficiency independent by polymer/drug ratio. Prepared chitosan microparticulate delivery systems can modulate ket release within 48 hr. Microspheres consisting of HC/LC (1:2 w/w) were the most suitable formulation in controlling drug release.     

Determination of fracture toughness and bridging tractions from crack-opening displacement measurements in particulate composites of diamond in zinc sulfide

The fracture toughness of zinc sulfide ceramic and a series of ZnS diamond particle composites was studied through measurements of crack opening displacement profiles. Five composites were fabricated using weight fractions of 10, 20 and 30% of 0–1 μm diamond particles, and 10 and 20% of 1–3 μm particles in a ZnS matrix. The cracks were grown using a novel specimen geometry and a loading technique that permitted stable crack growth even in small specimens. The fracture toughness of each material was calculated on the basis of the displacement profiles and the material properties, as opposed to the applied loads and the specimen geometry. The pure zinc sulfide material exhibited nearly ideal brittle behavior, and the toughness measurements agreed closely with other methods. The greatest toughening occurred in the 1–3 μm particle size composites, in which weak bridging tractions (⩽ 100 MPa) over a short distance along the crack (50–100 μm) could explain the reduced displacements near the crack tip. Even smaller size bridging zones (5–10 μm) may have been present in the 0–1 μm particle size composites, but elastic shielding alone can explain the observed toughening. The specimen geometry used here permitted toughness measurements using small specimens (< 5 mm) but is limited to materials having bridging zones that are less than about 250 μm.     

Stabilization of 10-hydroxycamptothecin in poly(lactide-co-glycolide) microsphere delivery vehicles

PURPOSE: The purpose of this study was to investigate the potential of poly(lactide-co-glycolide) (PLGA) microspheres to stabilize and deliver the analogue of camptothecin, 10-hydroxycamptothecin (10-HCPT). METHODS: 10-HCPT was encapsulated in PLGA 50:50 microspheres by using an oil-in-water emulsion-solvent evaporation method. The influence of encapsulation conditions (i.e., polymer molecular weight (Mw), polymer concentration, and carrier solvent composition) on the release of 10-HCPT from microspheres at 37 degrees C under perfect sink conditions was examined. Analysis of the drug stability in the microspheres was performed by two methods: i) by extraction of 10-HCPT from microspheres and ii) by sampling release media before lactone--carboxylate conversion could take place. RESULTS: Microspheres made of low Mw polymer (inherent viscosity 0.15 dl/g) exhibited more continuous drug release than those prepared from polymers of higher Mw (i.v. = 0.58 and 1.07 dl/g). In addition, a high polymer concentration and the presence of cosolvent in the carrier solution to dissolve 10-HCPT were both necessary in the microsphere preparation in order to eliminate a large initial burst of the released 10-HCPT. An optimal microsphere formulation released 10-HCPT slowly and continuously for over two months with a relatively small initial burst of the released drug. Both analytical methods used to assess the stability of 10-HCPT revealed that the unreleased camptothecin analogue in the microspheres remained in its active lactone form (> 95%) over the entire 2-month duration of study. CONCLUSIONS: PLGA carriers such as those described here may be clinically useful to stabilize and deliver camptothecins for the treatment of cancer.     

Effect of size, concentration, surface area, and volume of polymethylmethacrylate particles on human macrophages in vitro

This study investigated effects of different sizes, concentrations, volumes, and surface areas of polymethylmethacrylate (PMMA) particles on human macrophages. Adherent peripheral blood monocytes isolated from five healthy individuals were exposed for 48 h to phagocytosable (0.325 micron and 5.5 microns) and nonphagocytosable (200 microns) spherical particles. Each particle size was tested over a range of concentrations (10(4)-10(11) particles per milliliter [0.325 micron], 10(2)-10(7) particles per milliliter [5.5 microns], 10(1)-10(4) particles per milliliter [200 microns]) to provide overlap in number, volume, and surface area. Primary human monocyte/macrophages were cultured in macrophage serum-free medium and 5% fetal calf serum. Macrophage viability was assessed by 3H-thymidine uptake and activation was quantified by release of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, prostaglandin E2 (PGE2), and the lysosomal enzyme hexosaminidase. Medium alone served as a negative control; lipopolysaccharide (10 micrograms/mL) was also tested. PMMA particles were not toxic to human macrophages at any concentration tested. The smallest phagocytosable particles (0.325 micron) stimulated the release of interleukin-1 beta, interleukin-6, prostaglandin E2, and hexosaminidase at concentrations of 10(10)-10(11) particles/mL. The release of cytokines, PGE2, and hexosaminidase depended on the size, concentration, surface area, and volume of the phagocytosable particles. This study demonstrates that PMMA particle load Mi.e., the concentration of phagocytosable particles per tissue volume, characterized by size, surface area, and volume, rather than simply particle number-determines the degree of macrophage activation.     

The cytochrome P-450 inhibitor cobalt chloride prevents inhibition of renal Na,K-ATPase and redistribution of apical NHE-3 during acute hypertension

PURPOSE: Many tumors express elevated levels of LDL receptors (apoB, E receptors) on their membranes. Selective delivery of anti-neoplastic drugs to tumors by incorporation of these drugs into LDL or LDL-resembling particles should improve the efficacy of tumor therapy and minimize the severe side-effects. Since the apolipoproteins on the particles are essential for the LDL receptor recognition, drugs should preferably be incorporated into the lipid moiety. Most anti-tumor agents are too hydrophilic for incorporation into these carriers. METHODS: We synthesized LAD, a lipophilic prodrug of daunorubicin, by coupling the drug via a lysosomally degradable peptide spacer to a cholesteryl oleate analog. RESULTS: The overall yield of the synthesis was 50% with a purity of > 90%. Radioactively ([3H]) labeled LAD was obtained via a slightly modified procedure (yield 40%). The octanol/water partition coefficient of LAD is 30-fold higher than that of daunorubicin. LAD could be incorporated into triglyceride-rich lipid emulsions and small liposomes, which, if provided with apoE, have been demonstrated earlier to be cleared in vivo via the LDL receptor. The liposomes contained approximately 10 molecules of LAD per liposomal particle. Analysis of differently sized LAD-containing emulsions suggests that LAD associates with the surface of lipidic particles. In the presence of human serum, LAD did not dissociate from the emulsion particles, indicating a firm association of LAD with the carrier. CONCLUSIONS: The coupling of a cholesterol ester analog to daunorubicin results in a lipophilic prodrug that can be firmly anchored into lipidic carries. LAD-loaded emulsions and liposomes provided with recombinant apoE will be tested in the near future for their ability to deliver LAD to tumor tissue in vivo via the LDL receptor.     

Tableting of coated particles. I. Small particle size chitosan as an agent protecting coating membrane from mechanical damage of compression force

Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulose or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.     

In Situ Partial Exfiltration of Rainfall Runoff. II: Particle Separation

Metal elements or other constituents transported in urban and transportation land use rainfall runoff are often adsorbed on or incorporated with entrained particles that are ubiquitous in such runoff. Infiltration–exfiltration can be an effective in situ particle separation and quantity control structural best management practices or low impact development practices allowing runoff to return to soil after passive physical-chemical treatment. The in situ partial exfiltration reactor (PER), which combined the surface straining of the cementitious porous pavement (CPP) layer with filtration of oxide coated sand media beneath, provided control of water quantity and quality. Particle analyses were carried out for both influent and effluent to examine filter efficiency as a function of particle size and hydrology. Influent dm/dp ratios suggest that the dominant PER particle separation mechanisms were unsaturated physical–chemical filtration with the CPP layer functioning as a straining surface. Particle size distributions were modeled based on a two-parameter cumulative power-law function. The performance of the PER as a filter is shown to be a function of the unsteady site hydrology. Temporal variation in the filter coefficient and the volumetric particle fraction remaining were directly related to the unsteady influent loading rate. Particle removal efficiency by the PER based on concentration ranged from 71 to 96% on a mass-based concentration and 92–99% on a number based concentration. Results suggest that a properly designed PER can provide effective in situ control for particles and could be combined with or function separately from source control (i.e., pavement cleaning or a mass trading framework).     

SBA-15脱除超细颗粒的机制研究

利用扫描电迁移率颗粒物粒径谱仪（SMPS),针对不同孔径的介孔材料SBA-15,探索对UFPs（2.5～25 nm）的去除效率及脱除机理,以期为介孔材料过滤脱除UFPs在钢铁工业颗粒物超低排放控制的应用提供理论基础。基于实验结果及表征分析得知:UFPs入孔效应使大孔径介孔过滤介质效率更佳;介孔材料孔径端部内外表面存在大量UFPs亲和位点,提高端部复杂程度有利于提升材料过滤性能;氮气的有无对UFPs去除结果基本没有影响;介孔的存在使UFPs扩散效应更强,颗粒入孔使扩散系数增加,故UFPs在介孔材料实际扩散结果与传统扩散模式理论值（m=?2/3）不同。      

High-dose intravenous steroid pulse therapy in thyroid-associated ophthalmopathy

MIcrospheres containing diclofenac sodium (DS) were prepared using carboxymethylcellulose (CMC) as the main support material (1.0, 2.0, 3.0% (w/v)) and aluminum chloride as the crosslinker. Drug to polymer ratios of 1:1, 1:2 and 1:4 were used to obtain a range of microspheres. The microspheres were then coated with an enteric coating material, Eudragit S-100, efficiency, % yield value, particle sizes an in-vitro dissolution behaviour were investigated. The surface of the enteric coated microspheres seemed to be all covered with Eudragit S-100 from scanning electron microscopy observation. It was also observed that increasing the CMC concentration led to an increase in the encapsulation efficiency, % yield value and particle size and decreased the release rate. Eudragit S-100 coating did not significantly alter the size but the release rate was significantly lower even when the lower concentration solution was used.     

Drug targeting using low density lipoprotein (LDL): physicochemical factors affecting drug loading into LDL particles

Low density lipoprotein (LDL) has been found suitable as a targeting carrier for cytotoxic drugs. However, higher drug loading into LDL particles without disrupting their native integrity remains a major obstacle. The purpose of this study is to investigate the different physicochemical factors that may affect drug loading and to characterize LDL-drug conjugates. Doxorubicin (Dox) and 3', 5'-O-dipalmitoyl-5-iodo-2'-deoxyuridine (dpIUdR) were used as reference cytotoxic drugs. Drugs were loaded into LDL particles using the dry film method with or without surfactants, liposomal and the direct addition method. The effects of incubation temperature, time and stoichiometry of LDL-drug conjugates on drug loading were investigated. The LDL-drug conjugates were evaluated for their stability and characterized by differential scanning calorimetry (DSC), denatured gel (SDS-PAGE), and electron microscopy (EM). We have suitably incorporated 45+/-10 Dox and 150+/-25 dpIUdR molecules/LDL particle. A seven-fold increase in Dox incorporation was achieved with the liposomal preparation compared to the dry film method. A 4- to 6-h incubation at 37 degreesC was suitable to restore the native structure of LDL particles. No apo B fragmentation of LDL particles was noted on denatured gel. DSC studies showed no change in the Tm of the LDL and the LDL-drug conjugates. An increase in particle size of LDL-dpIUdR, not LDL-Dox was observed in EM compared to the native LDL which may be related to higher incorporation of dpIUdR. The results indicate that physicochemical factors significantly affect drug loading efficiency and may need to be considered to optimize drug incorporation into LDL particles.     

Encoding, repetition, and the mirror effect in recognition memory: symmetry in motion

The entrapment of loperamide hydrochloride (LPM) in biodegradable polymeric drug carriers such as nanoparticles might enable its passage across the blood-brain barrier. The optimization of the preparation of the LPM-loaded PLA nanoparticles was performed employing high pressure emulsification-solvent evaporation. The resulting nanoparticles were characterized by particle size, distribution, thermal analysis, and drug release profiles. The partition of LPM into the organic phase increased with an increase in pH of the aqueous phase and with addition of lipophilic surfactants such as sorbitan fatty acid esters, resulting in an increase in the drug entrapment in the nanoparticles. Evaporation of the organic phase under reduced pressure and the addition of ethanol in the organic phase yielded a high drug entrapment due to the rapid polymer precipitation. The addition of the sorbitan fatty acid esters further increased the drug entrapment even at higher LPM concentrations. The results of thermal analysis suggest that LPM was homogeneously dispersed in the amorphous polymer matrix. The in vitro release of the drug from nanoparticles was biphasic, with a fast initial phase, followed by a second slower phase. Different drug release profiles from nanoparticles can be achieved by addition of sorbitan fatty acid esters, or the employment of different solvents as the organic phase.     

Mechanisms of retardation of rigid spherical particles with 3 to 1,085 nm radius in capillary electrophoresis, using buffered polyacrylamide (molecular weight 5 x 10(6)) solutions

Subjecting particles in the size range of 3 to 1085 nm radius (R) to capillary electrophoresis in buffered solution of entangled uncrosslinked polyacrylamide (M(r) 5 x 10(6)), it was found that particle size-dependent retardation ("molecular sieving") becomes electric field- and particle size range-dependent once the particle size exceeds 15-20 nm in radius. The field strength dependence of the retardation coefficient [KR = d(log mobility)/ d(polymer concentration] and the positive or negative sign of dKR/dR suggest the existence of two different mechanisms of molecular sieving depending on the particle size range: particles with diameters less than the screening length (or blob size) of the polymer network are thought to penetrate into the available spaces within a discontinuous polymer network; particles with diameters larger than the screening length (or blob size) of the polymer network are thought to undergo size-dependent retardation by exerting shear stress against polymer chains, and displacing them, so as to cause local deformations in a continuous polymer network. A limit in the separating capacity of molecular sieving, due to a sharp increase in the rate of band widening with polymer concentration, was found when the value of the retardation coefficient exceeded 60 (mL/g).     

Iodo-2'-deoxyuridine (IUdR) and 125IUdR loaded biodegradable microspheres for controlled delivery to the brain

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2'-deoxyuridine (125IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of 125IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable microspheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter 125I, as 125IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external aqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30-40% followed by a sustained release over 35 days.     

Bean Dwarf mosaic geminivirus movement proteins recognize DNA in a form- and size-specific manner

Various ratios of succinic acid to fenoldopam mesylate, ranging from 0:1 to 18:1 were incorporated in pellets and coated with 1.5-12% w/w Surelease. Even though the coating level did influence the rate and amount of fenoldopam release, the influence of the succinic acid to drug ratio was much more important and evident at all coating levels. Being a weakly basic drug, fenoldopam release ceased when testing in SIF for succinic acid to drug ratios of 0:1-4:1, with the end of release being more abrupt for the 0:1 than for the 4:1 ratio. Only for a succinic acid to drug ratio of > or =5 was fenoldopam release constant for 6-8 h and independent of the pH-value of dissolution media. For a thin coat of about 2.5% w/w Surelease, those pellets showed an ideal controlled release behaviour with release rates of about 5-10%/h and a total release of almost 80% in 8 h. The dissolution profiles of Surelease coated pellets with high succinic acid to drug ratios (> or =5) and different coating levels, were evaluated for best fits to commonly used kinetic models. Sustained release mechanisms are discussed according to best fit models. The quantification of the pH-adjuster succinic acid, released from pellets with an acid to drug ratio of < or =1 showed, that despite their failure as a controlled release system for fenoldopam, the investigated coats could control the release of succinic acid effectively at optimized coating levels. For increasing succinic acid to drug ratios (< or =4) succinic acid was released at an ever more constant rate and release rates, though still faster than the release rates of fenoldopam, decreased steadily for increasing ratios. At a 5:1 ratio finally release rates of succinic acid and fenoldopam were almost identical. Therefore those pellet cores were almost completely emptied during dissolution testing, with both fenoldopam and succinic acid leaving at a constant rate and a total release of about 80% each for a 2.5% Surelease coat, while lower succinic acid to drug ratios had failed to show any sustained release for such thin Surelease coats. A similar formulation with fumaric acid instead of succinic acid failed to show the desired release pattern, indicating that it is the presence of a sufficiently high amount of succinic acid rather than the presence of an acidic compound in general, that ensures fenoldopam solubility at higher pH-values.