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At least 19 recordsLinked to original sources
PubMedDate not supplied

Encapsulation of antihypertensive drugs in cellulose-based matrix microspheres: characterization and release kinetics of microspheres and tableted microspheres.

This study is an attempt to prepare microspheres loaded with two antihypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.

Antihypertensive Agents↗
PubMed1983

Selective targeting of magnetic albumin microspheres to the Yoshida sarcoma: ultrastructural evaluation of microsphere disposition.

Magnetic albumin microspheres (1 micron average diameter) were selectively targeted to subcutaneous solid Yoshida sarcoma tumors (average size 450 mm2) in Holtzman rats. This was accomplished by placing an external magnet adjacent to the tumor while the microspheres were infused. Microspheres contained ultra-fine particles of Fe3O4 and no drug (placebo). Placebo microspheres were used due to the previously demonstrated rapid tumoricidal effect of targeted low-dose doxorubicin microspheres. Animals were killed 10 min, 60 min, 30 min, 24 hr and 72 hr after microsphere administration and tumors were examined by transmission electron microscopy to determine the in vivo disposition of the magnetically targeted microspheres. Using placebo microspheres, we have demonstrated microspheres endocytosed in endothelial cells as early as 10 min after infusion. By 30 min microspheres can be seen in the extravascular compartment, sitting adjacent to tumor cells and occasionally in tumor cells. By 24 hr the majority of microspheres have been endocytosed by tumor cells. Microspheres were still observed within tumor cells as late as 72 hr after administration. The rapid extravasation and cellular uptake of magnetically focused microspheres explains the extremely rapid tumoricidal effect previously observed when doxorubicin-containing microspheres were targeted to the tumor.

Animals↗
PubMed2005

In vitro and in vivo studies of cyclosporin A-loaded microspheres based on copolymers of lactide and epsilon-caprolactone: comparison with conventional PLGA microspheres.

A hydrophobic peptide, cyclosporin A (CyA), was incorporated in microspheres based on poly(lactide-b-epsilon-caprolactone) (P(LA-b-CL), LA/CL (in molar ratio): 78.7/21.3 and 48.1/51.9) and poly(lactide-co-glycolide) (PLGA, LA/GA: 80/20) using oil-in-water (O/W) emulsion solvent evaporation method. The microspheres were characterized by SEM, DSC and X-ray diffraction, and CyA release rate was determined by HPLC. It was revealed that CyA can be efficiently loaded into all the microspheres (exceed 96%). Compared to PLGA microspheres, P(LA-b-CL) microspheres liberated CyA more rapidly. Within the first day, about 75, 50 and 12% of CyA released from P(LA-b-CL) (48.1/51.9), P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively, which can be attributed to the partial crystallization occurring in P(LA-b-CL) microspheres. CyA levels in whole blood were also tested. In comparison with PLGA microspheres, P(LA-b-CL) microspheres provided a higher blood level of CyA. The maximum CyA concentration in whole blood (approximately 520, 450 and 400 ng ml(-1) for P(LA-b-CL) (48.1/51.9) P(LA-b-CL) (78.7/21.3) and PLGA microspheres, respectively) was reached at the second day post administration. And then P(LA-b-CL) microspheres showed a constant CyA level (about 100-200 ng ml(-1)) for extended periods of time (several weeks). Such CyA-loaded P(LA-b-CL) microspheres displaying higher CyA concentration during the first few days and similar constant blood CyA level thereafter showed more advantages than those prepared with PLGA and could meet clinical needs more efficiently.

Animals↗
PubMed1997

Effect of microsphere size distribution on the ultrasonographic contrast efficacy of air-filled albumin microspheres in the left ventricle of dog hearts.

RATIONALE AND OBJECTIVES: The in vitro ultrasonographic contrast efficacy of air-filled albumin microspheres has been found to depend on the size distribution of microspheres. The objective of the current study was to empirically describe the relationship between the size distribution of injected air-filled albumin microspheres and the in vivo contrast efficacy after lung capillary filtration in a dog model. METHODS: Twenty different air-filled microspheres with large and well-defined differences in size distribution were prepared from nine different batches of Albunex (Molecular Biosystems Inc.) and subsequently characterized by Coulter counting. The in vivo ultrasonographic contrast enhancement of these preparations was investigated with a VingMed CFM750 in closed chest model in six mongrel dogs. The observed contrast efficacy, measured as gray-level enhancement in the left ventricle (LV), was correlated to the microsphere size distribution, using both univariate and multivariate approaches. RESULTS: The results demonstrated a significant contribution to LV contrast efficacy from microspheres larger than approximately 7 microm, and a lack of contribution from microspheres smaller than approximately 7 microm. Linear relationships were found between LV contrast efficacy, and both the number concentration of microspheres between 8 to 12 microm and the total microsphere volume concentration. No significant covariance between in vivo contrast efficacy and the number concentration between 1 to 38 microm or 4 to 10 microm was observed. The multivariate model showed a significant contribution to the in vivo gray-level enhancement from microspheres in the size range 7 to 15 microm, with optimal efficacy per microsphere at approximately 13 microm. CONCLUSIONS: Large microspheres (> 7 microm), which had been expected to be trapped in the lung capillary bed, contribute most of the observed ultrasound contrast in the LV of the heart.

Albumins↗
PubMedDate not supplied

Development and evaluation of controlled-release diclofenac microspheres and tabletted microspheres.

Diclofenac wax microspheres were prepared using the congealable dispersephase encapsulation method. Emulsifiers, glyceryl monostearate (GMS) and stearic acid, were added to improve the efficiency of emulsification. Microspheres containing either of the emulsifiers or both showed a high drug content (80-90%) and the particle size distribution was log-normal compared with microspheres without the emulsifiers. Increase in GMS concentration decreased the drug release and, in contrast, stearic acid appeared to channel the drug from the wax matrix. The addition of both emulsifiers at different concentrations modified drug release. Increase in dispersant (PVP) concentration, and decrease in microsphere size accelerated the rate of drug release. Higuchi/Baker Londsdale spherical matrix dissolution kinetics was followed. Disintegrating tableted microspheres were prepared with Avicel and Explotab. With the increase in compression pressure the crushing force and disintegrating time increased, but the thickness decreased, and the dissolution profile did not appear to be affected. Slightly faster release was noticed with tableted microspheres compared with that of uncompressed microspheres. Tablets containing 40 and 60% microsphere loadings had disintegration times of 5.12 +/- 0.63 and 57.73 +/- 3.53 min, respectively. In contrast, tablet formulation containing 80% microsphere load had a significant increase in disintegration time (130.83 +/- 4.26 min). The dissolution from this formulation also showed a lag time of 30 min in contrast with the other two formulations, which showed no lag time. Increased microsphere size from 215 to 630 microns had no effect on tableting properties (such as hardness and thickness); and only very little effect on dissolution. The microspheres appeared deformed but intact irrespective of compression pressures on scanning electron micrographs.

Delayed-Action Preparations↗
PubMed2004

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.

Anhydrides↗
PubMed1999

Modification of release rates of cyclosporin A from polyl(L-lactic acid) microspheres by fatty acid esters and in-vivo evaluation of the microspheres.

Biodegradable microspheres containing cyclosporin A (CyA, cyclosporine) were prepared using poly(L-lactic acid) (PLA) and poly(lactide-co-glycolide)(PLGA) by a solvent evaporation method. CyA was efficiently entrapped in PLA, PLGA(50/50) and PLGA(75/25) microspheres in a range of 81-85%. CyA released constantly from PLA microspheres without any lag time, whereas the drug from PLGA(50/50) and PLGA(75/25) microspheres was released after lag time of about 1 and 3 weeks, respectively. Addition of fatty acid esters enhanced the release rates of CyA from PLA microspheres. In-vivo study was performed using rats with adjuvant-induced arthritis. PLA microspheres with ethyl myristate sustained high blood levels of CyA compared with the microspheres with no additives over 4 weeks. In addition, the PLA microspheres improved the symptoms such as the decrease in body weight and the increase in paw swelling occurred by adjuvant-induced arthritis in rats. Consequently, the release rate of CyA from PLA microspheres can be improved by adding fatty acid esters and PLA microspheres with fatty acid esters seem to be a useful dosage form for autoimmune disease therapy.

Animals↗
PubMed2000

Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres.

The objective of this study was to evaluate the effect of polymer and microsphere blending in achieving both a sufficient initial release and a desired continuous release of a peptide from poly(D, L-lactide-co-glycolide) microspheres. Leuprolide acetate loaded hydrophilic 50:50 PLGA microspheres were prepared by a solvent-extraction/evaporation process and were characterized for their drug load, bulk density, size distribution, surface area, surface morphology, in vitro drug release, and in vivo efficacy. Combining PLGA polymers that varied in their molecular weights in various ratios yielded microspheres with varied drug release profiles commensurate with the hydration tendencies of the polymers. Increasing the component of lower molecular weight 50:50 hydrophilic PLGA polymer, 8.6 kDa increased the initial drug release. A similar microsphere formulation prepared instead with blending microspheres from individual polymers showed a similar increase. In an animal model, microspheres obtained from polymer or microsphere blends attained a faster onset of testosterone suppression as compared to microspheres from higher molecular weight 50:50 hydrophilic PLGA polymer, 28.3 kDa, alone. These studies illustrated the feasibility of blending polymers or microspheres of varied characteristics in achieving modified drug release. In particular the increased initial release of the peptide could help avoid the therapeutic lag phase usually observed with microencapsulated macromolecules.

Animals↗
PubMed2004

Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. II. Controlled drug release and microsphere degradation.

This article describes the effects of six processing parameters on the release kinetics of a model drug Texas red dextran (TRD) from poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres as well as the degradation of these microspheres. The microspheres were fabricated using a double emulsion-solvent extraction technique in which the following six parameters were varied: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) in the internal aqueous phase, and poly(vinyl alcohol) concentration in the external aqueous phase. We have previously characterized these microspheres in terms of microsphere morphology, size distribution, and TRD entrapment efficiency. In this work, the TRD release profiles in phosphate-buffered saline were determined and all formulations showed an initial burst release in the first 2 days followed by a decreased sustained release over a 38-day period. The initial burst release varied from 5.1 (+/-1.1) to 67.7 (+/-3.4)% of the entrapped TRD, and was affected most by the viscosity of the polymer solution used for microsphere fabrication. The sustained release between day 2 and day 38 ranged from 7.9 (+/-0.8) to 27.2 (+/-3.1)% of the entrapped TRD. During 11 weeks of in vitro degradation, the mass of the microspheres remained relatively constant for the first 3 weeks after which it decreased dramatically, whereas the molecular weight of the polymers decreased immediately upon placement in phosphate-buffered saline. Increasing the PPF content in the PPF/PLGA blend resulted in slower microsphere degradation. Overall, this study provides further understanding of the effects of various processing parameters on the release kinetics from PPF/PLGA blend microspheres thus allowing modulation of drug release to achieve a wide spectrum of release profiles.

Biocompatible Materials↗
PubMed2007

The effect of microsphere degradation rate on the efficacy of polymeric microspheres as bulking agents: an 18-month follow-up study.

The injection of bulking substances has been proposed as a new therapy to treat urinary incontinence and vesicoureteral reflux. Our previous study demonstrated that poly(lactic-co-glycolic acid) (PLGA) microspheres have the potential to serve as a bulking agent for urological injection therapies. Hybrid tissues exhibiting a bulking effect were formed in vivo by PLGA microsphere injection, but long-term volume stability was not proven. In this study, we hypothesized that the biodegradation rate of the bulking substance (polymer microspheres) would affect the duration of volume conservation of the induced hybrid tissue. To test this hypothesis, rapidly degrading 75:25 PLGA microspheres and slowly degrading poly(L-lactic acid) (PLLA) microspheres were used as injectable bulking agents for the injection therapy. In vitro degradation tests showed that the mass losses of PLLA and PLGA were 16 and 96% of the initial masses, respectively, at 30 weeks. PLLA and PLGA microspheres were injected into the subcutaneous dorsum of mice. Both types of microspheres were easily injectable through 24-gauge needles. Histological examinations at various time points indicated that host cells from the surrounding tissues migrated to the spaces between both types of injected microspheres and formed new hybrid tissue structures. Lymphocyte migration was noted around the implanted PLGA and PLLA microspheres, but the inflammatory reaction diminished with time. Importantly, the volume of the PLLA hybrid tissues slowly decreased to 52% of the initial volume at 12 months and maintained that volume until 18 months, whereas the volume of the PLGA hybrid tissues rapidly decreased to 22% at 6 months, and the PLGA hybrid tissues disappeared at 11 months. These results show that the biodegradation rate of the bulking substance may be useful for controlling the duration of volume conservation of the induced hybrid tissue.

Animals↗
PubMed2006

Intramuscular delivery of DNA releasing microspheres: microsphere properties and transgene expression.

Plasmid-loaded microspheres can provide localized and sustained release into the target tissue, and thus have the potential to enhance the efficiency of naked DNA at promoting transgene expression. In this report, microsphere design parameters are investigated by correlating the extent and duration of transgene expression intramuscularly to the polymer molecular weight and the mass of DNA delivered. Plasmid DNA was incorporated into poly (lactide-co-glycolide) microspheres using a cryogenic double emulsion process, and microspheres were injected intramuscularly. Bolus injection of naked plasmid was used for control, which exhibited transfection of muscle cells with transgene expression that gradually decreased over time. Microspheres fabricated from low molecular weight polymer had expression levels that increased from day 1 to day 92, which subsequently decreased through day 174. Decreasing the microsphere mass delivered resulted in steady expression during the same time. However, microspheres fabricated with high molecular weight polymer had expression for only 14 days. Intramuscular injection resulted in a foreign body response to the microspheres, and these infiltrating cells adjacent were primarily transfected. This understanding of microsphere properties that determine transgene expression and the distribution of transfected cells may facilitate their application to fields such as tissue engineering or DNA vaccines.

Animals↗
PubMedDate not supplied

Bioadhesive fluorescent microspheres as visible carriers for local delivery of drugs. I: preparation and characterization of insulin-loaded PCEFB/PLGA microspheres.

Inherently fluorescent microspheres composed of a fluorescent polyanhydride, poly(p-(carboxyethylformamido) benzoic anhydride) (PCEFB), and poly(lactide-co-glycolide) (PLGA) were prepared using the water-in-oil-in-water (w/o/w) emulsion solvent evaporation technique. The effect of the PCEFB/PLGA feed ratio and composition of the oil phase on insulin entrapment and microsphere diameter was evaluated. It was found that the insulin entrapment efficiency increased with PCEFB content and acetone per cent in the oil phase. Microsphere diameter decreased as acetone was added into the oil phase. The blend of microspheres were further characterized by GPC, IR, fluorometry and SEM. Although slight degradation of PCEFB during the fabrication process was revealed by GPC and IR, PCEFB/PLGA microspheres could still be clearly visualized by either CLSM or fluorescent microscopy, which makes it possible to directly detect the microspheres by fluorometry in vivo without the need of labelling with fluorescent dyes. The surface of PCEFB/PLGA (1:2) microspheres was smooth, while PCEFB/PLGA (2:1) microspheres were observed with rough and uneven surfaces. Sustained release of insulin from the microspheres could be achieved for approximately 4 days.

Adhesiveness↗
PubMed2002

Multiple injections of coloured microspheres for islet blood flow measurements in anaesthetised rats: influence of microsphere size.

We investigated if coloured microspheres could be used for repeated measurements of pancreatic islet blood flow in rats. An initial injection of 1.0-1.5 x 10(5) microspheres (black colour), with a size of 10 or 15 microm, was made into the ascending aorta, while an arterial reference sample was collected from the femoral artery. Twelve min later, 1 ml of saline or 30% D-glucose was injected intravenously. Three min after this injection a second injection of 10- or 15-microm microspheres (green colour) was given. The animals were then killed, and the pancreas and adrenals were removed and samples (150-200 mg) were secured from the duodenum, ileum, colon, right kidney and liver. The microsphere contents were determined with the aid of a freeze-thawing technique and blood flow values were calculated. Our results suggest that 10-microm microspheres, but not 15-microm microspheres, provide reproducible islet and total pancreatic blood flow measurements when repeatedly injected. Values for the blood flow to the intestines, kidney and liver were less sensitive to the size of the microspheres. We conclude that repeated administration of 15-microm microspheres induces a high risk for erroneous islet and total pancreatic blood flow measurements, whereas two such measurements can be performed if 10-microm microspheres are used.

Animals↗
PubMed2006

Biodegradable heparin-loaded microspheres: carrier molecular composition and microsphere structure.

Microspheres of amphiphilic triblock polymers PLLA-PEG-PLLA were investigated as carriers for heparin delivery. Two series of PLLA-PEG-PLLA triblock were synthesized and prepared into microspheres with heparin loaded. The microspheres were hollow and the surface morphology varied from smooth to porous. The pore size increased with increasing PEG content. The microsphere size distribution showed that higher PEG content increased the average microsphere size. The release rate of heparin was closely related to the surface morphology of the microspheres. DSC spectra showed that both cold crystalline temperature (Tc) and crystalline melting temperature (Tm) of heparin-loaded microspheres were related to the copolymer composition and the Tc was lower than those of corresponding pure microspheres. [IMAGES: SEE TEXT]

Anticoagulants↗
PubMed2003

POE/PLGA composite microspheres: formation and in vitro behavior of double walled microspheres.

The poly(ortho ester) (POE) and poly(D,L-lactide-co-glycolide) 50:50 (PLGA) composite microspheres were fabricated by a water-in-oil-in-water (w/o/w) double emulsion process. The morphology of the composite microspheres varied depending on POE content. When the POE content was 50, 60 or 70% in weight, the double walled microspheres with a dense core of POE and a porous shell of PLGA were formed. The formation of the double walled POE/PLGA microspheres was analysed. Their in vitro degradation behavior was characterized by scanning electron microscopy, gel permeation chromatography, Fourier-transform infrared microscopy and nuclear magnetic resonance spectroscopy (NMR). It was found that compared to the neat POE or PLGA microspheres, distinct degradation mechanism was achieved in the double walled POE/PLGA microspheres system. The degradation of the POE core was accelerated due to the acidic microenvironment produced by the hydrolysis of the outer PLGA layer. The formation of hollow microspheres became pronounced after the first week in vitro. 1H NMR spectra showed that the POE core was completely degraded after 4 weeks. On the other hand, the outer PLGA layer experienced slightly retarded degradation after the POE core disappeared. PLGA in the double walled microspheres kept more than 32% of its initial molecular weight over a period of 7 weeks.

Chemical Phenomena↗
PubMed1998

Recombinant human erythropoietin (rhEPO) loaded poly(lactide-co-glycolide) microspheres: influence of the encapsulation technique and polymer purity on microsphere characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate-labelled dextran (FITC-dextran) loaded biodegradable microspheres were prepared from poly(lactide-co-glycolide) (PLG) by a modified spray-drying technique. This microencapsulation method was compared with the water-in-oil-in-water (w/o/w) double-emulsion method. As expected, microsphere morphology, particle size and particle size distribution strongly depended on the production process. The spray-drying method was found to have a number of advantages compared to the w/o/w double-emulsion technique. The content of residual dichloromethane (DCM) in the final product was significantly lower in case of the microspheres prepared by spray-drying. Concerning EPO loaded microspheres, spray-drying yielded higher encapsulation efficiencies. Although the microspheres obtained by spray-drying are subjected to intensive mechanical and thermal stress during the preparation, the amount of aggregates of EPO in PLG microspheres were not increased compared to the w/o/w technique. Depending on the manufacturing method, addition of cyclic DL-lactide dimers (referred to as monomers in the following) affected the in vitro release profiles of EPO and FITC-dextran from PLG microspheres. Using differential scanning calorimetry it was shown that these low molecular weight substances only seem to be present inside the microspheres produced by spray-drying. DL-Lactide significantly reduced the initial burst release of both EPO and FITC-dextran. While the following release period of EPO was not affected by the DL-lactide content, a more linear FITC-dextran release pattern could be achieved. It can be concluded that the spray-drying technique provides a number of advantages compared to the w/o/w method. The modulation of protein release using low molecular weight additives is of particular interest for parenteral depot systems.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I: Evaluation of formulation variables on microspheres characteristics for brain delivery.

The aim of this study was to formulate biodegradable microspheres containing an anti-parkinsonian agent, bromocryptine mesylate, for brain delivery. The effect of formulation parameters (e.g. polymer, emulsifying agent type and concentration) on the characteristics of the microspheres produced, the efficiency of drug encapsulation, the particle size distribution and in vitro drug release rates from the bromocryptine mesylate microspheres were investigated using a 3(2) factorial design. Bromocryptine mesylate was encapsulated into biodegradable polymers using the following three different polymers; poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). The SEM photomicrographs showed that the morphology of the microspheres greatly depended on the polymer and emulsifying agent. The results indicate that, regardless of the polymer type, increase in emulsifying agent concentration from 0.25-0.75% w/v markedly decreases the particle size of the microspheres. Determination of particle size revealed that the use of 0.75% w/v of emulsifying agent concentration and a polymer solution concentration of 10% w/v resulted in optimum particle size. In order to prepare biodegradable microspheres with high drug content and small particle size, selection of polymer concentration as well as emulsifying agent concentration is critical. Polymer type has a less pronounced effect on the percentage encapsulation efficiency and particle size of microspheres than on the t(50%). The microspheres prepared by all three polymers, at a polymer concentration of 10% w/v and an emulsifying agent concentration of 0.75% w/v with NaCMC:SO (4:1, w/v) mixture was as the optimum formulation.

Biodegradation, Environmental↗