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PubMed1996

Antitumour activity of mitoxantrone-loaded chitosan microspheres against Ehrlich ascites carcinoma.

Glutaraldehyde cross-linked chitosan microspheres containing the antineoplastic agent mitoxantrone were prepared and the antitumour activity was evaluated against Ehrlich ascites carcinoma in mice by intraperitoneal injections. The tumour inhibitory effect was followed by monitoring animal survival time and change in body weight for a period of 60 days. While the mean survival time of animals which received 2 mg and 1 mg of free mitoxantrone intraperitoneally was 2.1 and 4.6 days, respectively, animals which received 2 mg mitoxantrone via microspheres showed a mean survival time of 50 days. Five out of 8 animals treated using microspheres lived beyond 60 days. The percentage ratio mean survival time of the treated group divided by the mean survival time of the untreated group for animals treated using mitoxantrone-loaded chitosan microspheres containing 2 mg of the drug was 290 compared with 12.2 for those which received 2 mg of the free drug. The antitumour effect of mitoxantrone-loaded microspheres against Ehrlich ascites carcinoma was much higher than that of doxorubicin-loaded microspheres reported by previous workers. Our data demonstrate the potential of mitoxantrone-loaded chitosan microspheres for sustained drug delivery to minimize drug toxicity and maximize therapeutic efficacy.

Animals↗
PubMed2002

Mucosal or parenteral administration of microsphere-associated Bacillus anthracis protective antigen protects against anthrax infection in mice.

Existing licensed anthrax vaccines are administered parenterally and require multiple doses to induce protective immunity. This requires trained personnel and is not the optimum route for stimulating a mucosal immune response. Microencapsulation of vaccine antigens offers a number of advantages over traditional vaccine formulations, including stability without refrigeration and the potential for utilizing less invasive routes of administration. Recombinant protective antigen (rPA), the dominant antigen for protection against anthrax infection, was encapsulated in poly-L-lactide 100-kDa microspheres. Alternatively, rPA was loosely attached to the surfaces of microspheres by lyophilization. All of the microspheric formulations were administered to A/J mice with a two-dose schedule by either the intramuscular route, the intranasal route, or a combination of these two routes, and immunogenicity and protective efficacy were assessed. An intramuscular priming immunization followed by either an intramuscular or intranasal boost gave optimum anti-rPA immunoglobulin G titers. Despite differences in rPA-specific antibody titers, all immunized mice survived an injected challenge consisting of 10(3) median lethal doses of Bacillus anthracis STI spores. Immunization with microencapsulated and microsphere-associated formulations of rPA also protected against aerosol challenge with 30 median lethal doses of STI spores. These results show that rPA can be encapsulated and surface bound to polymeric microspheres without impairing its immunogenicity and also that mucosal or parenteral administration of microspheric formulations of rPA efficiently protects mice against both injected and aerosol challenges with B. anthracis spores. Microspheric formulations of rPA could represent the next generation of anthrax vaccines, which could require fewer doses because they are more potent, are less reactogenic than currently available human anthrax vaccines, and could be self-administered without injection.

Administration, Intranasal↗
PubMed1978

Quantitation of collateral and ischemic flows with microspheres and diffusible indicator.

Flow to myocardium following coronary occlusion may not originate solely from collateral channels. Some flow might be derived from overlapping coronary arteries which also perfuse tissue within the territory of the obstructed vessel prior to occlusion. Left atrial microsphere injection during perfusion of the left anterior descending (LAD) artery from a special reservoir containing microsphere-free blood and again after LAD occlusion permitted measurement of noncollateral overlap and total ischemic LAD (TIF) flows, respectively, and mathematical derivation of true collateral flow (TCF). Whereas TIF averaged 0.25 +/- 0.03 ml/min per g, TCF was 0.14 +/- 0.03 ml/min per g, only 50.6% of TIF. The remainder of the TIF represented either inadvertant inclusion of normally perfused tissue with the ischemic LAD myocardium or actual overlap of LAD and left circumflex circulations. 86RbCl was injected simultaneously with the microspheres following coronary occlusion. 86Rb and microsphere densities in the whole heart and ischemic area were closely correlated, although microsphere distribution tended to be more heterogeneous. No segment of ischemic myocardium containing 86Rb was free of microspheres. Therefore, the geometry of undeveloped collateral channels is adequate to permit passage of 15-micron particles. Absolute 86Rb flows were consistently less than microsphere flows.

Animals↗
PubMed1981

Effect of microsphere size on apparent intramural distribution of intestinal blood flow.

Microspheres were used in earlier studies to determine the distribution of blood flow within the intestinal wall, but the selection of microsphere size was not systematic. In one study, a 5-micrometers difference in mean diameter markedly altered the submucosal vs. mucosal distribution of microspheres. Therefore, we examined the effect of size on microsphere distribution within the gut wall. Loops of canine small bowel were perfused at constant pressure, and microspheres were injected in the following order: 9 +/- 1, 15 +/- 1, and 26 +/- 2 micrometers. Gut segments were separated into mucosal, submucosal, and muscularis tissues. The microspheres were recovered from digested tissues and venous blood. The number and diameter of spheres in an aliquot of resuspended spheres were determined by digital image analysis. The ratio of mucosal to submucosal accumulation varied 60-fold for sphere diameters from 8 to 20 micrometers. The muscularis' share did not vary systematically with sphere size. Approximately 20% of spheres less than 11 micrometers reached venous blood, whereas few (less than 1%) of larger sizes did. We conclude: 1) sphere distribution within the gut wall is size dependent, 2) correction for microsphere shunting will be difficult, because the route taken by untrapped spheres is unknown, and 3) fractionating intramural flow among the three layers is not practical with commercially available spheres. However, under control conditions 15-micrometers spheres seem to distribute independently of size between muscularis and a lumped mucosal-submucosal compartment.

Animals↗
PubMed1985

Microsphere passage through intestinal circulation: via shunts or capillaries?

Significant quantities of 9-micron microspheres (20-30%) are not trapped in the intestine following intracardiac or intra-arterial injection, but reach venous blood. Some investigators propose that the passage of 9-micron spheres measures blood flow through noncapillary connections. Because frequency distributions of intestinal capillary diameters and 9-micron spheres overlap, microspheres could simply pass through capillaries. Therefore, we developed simple probabilistic models to predict both the size distribution and the percentage of injected spheres [9 +/- 1 (SD) micron] that should appear in venous blood. Chief assumptions in models are that microsphere delivery and sphere diameter are independent and that microspheres pass through capillaries of equal or larger size. The passage predicted by the models was consistent with values in canine intestinal circulation, demonstrating that passage through capillaries [7.38 +/- 1.4 (SD) micron] adequately accounts for spheres in venous blood. Because the diameters of nominal 9-micron spheres were distributed too narrowly to show a marked sieving effect on passage through the intestinal circulation, we also injected microspheres varying from 5 to 20 micron in diameter. This mixture demonstrated a marked sieving effect. The predicted frequency distribution for microsphere diameters in venous blood agreed with the observed distribution. Our models demonstrate that the passage of 9-micron spheres through capillaries, rather than through "shunts," adequately accounts for the appearance of spheres in venous blood and suggests that the frequency distribution of venous microspheres can provide an in vivo method for estimating the frequency distribution of intestinal capillary diameters.

Animals↗
PubMed1987

Validity of microsphere depositions for regional myocardial flows.

Due to the particulate nature of microspheres, their deposition in small-tissue regions may not be strictly flow dependent. To evaluate the importance of rheological and geometric factors and random error, their deposition densities in small regions of rabbit hearts were examined in comparison with those of a new "molecular microsphere," 2-iododesmethylimipramine (IDMI), whose high lipid solubility allows it to be delivered into tissue in proportion to flow, and whose binding in tissue prevents rapid washout. 141Ce- and 103Ru-labeled 16.5-micron spheres in one syringe and [125I]- and [131I]DMI in another syringe were injected simultaneously into the left atrium of open-chest rabbits, while obtaining reference blood samples from the femoral artery. Hearts were removed 1 min after injection, cut into approximately 100 pieces averaging 54 mg, and the regional deposition densities calculated for each tracer from the isotopic counts. Correlations between the differently labeled microspheres were r greater than 0.95 and for the two IDMIs were greater than 0.98. Scatter plots of sphere densities vs. IDMI densities showed that differences between microspheres and IDMI had substantial scatter, 0.87 less than r less than 0.96 and were not random. Microsphere depositions tended to be lower than IDMI depositions at low flows and higher at high flows. The tendency for spheres to be deposited preferentially in high-flow regions may be explained by a bias at bifurcations toward entering the branch with higher flow and secondarily toward entering those branches that are straighter. We conclude that microspheres are generally adequate for estimating regional flows but suffer systematic error when the regions of interest are supplied via arteries of diameters only a few times those of the microspheres.

Animals↗
PubMed1987

[14C]iodoantipyrine and microsphere blood flow estimates in cat brain.

A comparison of local cerebral blood flow estimates with the microsphere and the 4-[N-methyl-14C]iodoantipyrine ([14C]IAP) techniques has been performed in cats. Good correlation of [14C]IAP with microsphere flow estimates in the gray matter was found. In the white matter, however, [14C]IAP flow estimates were consistently lower than microsphere flow estimates. Error analysis of both techniques and comparison with previous studies suggest that peculiarities of white matter arterial vasculature with preferential microsphere accumulation may lead to this discrepancy. Microspheres did not interfere with flow as shown by the normal appearance of subsequent [14C]IAP autoradiograms. The number of microspheres seen on autoradiograms was used for an estimate of microvessels blocked by spheres and found to be negligible. The study also demonstrates that [14C]IAP is not diffusion limited up to the observed flow values of 2 ml.g-1.min-1. Both techniques might be used together for a combination of their respective advantages, which are temporal and spatial resolution for microsphere and [14C]IAP, respectively.

Animals↗
PubMed1998

Microsphere-induced bronchial artery vasodilation: role of adenosine, prostacyclin, and nitric oxide.

We previously found that injection of 15-micron microspheres into the bronchial artery of sheep decreased bronchial artery resistance. This effect was inhibited partially by indomethacin or 8-phenyltheophylline, suggesting that microspheres caused release of a dilating prostaglandin and adenosine. To identify the prostaglandin and confirm adenosine release, we perfused the bronchial artery in anesthetized sheep. In 12 sheep, bronchial artery blood samples were obtained before and after the infusion of 1 x 10(6) microspheres or microsphere diluent into the bronchial artery. Microspheres, but not diluent, decreased bronchial artery resistance by 40% and increased bronchial artery plasma 6-ketoprostaglandin F1 alpha (194.7 +/- 45.0 to 496.5 +/- 101.3 pg/ml), the stable metabolite of prostacyclin, and prostaglandin (PG) F2 alpha (28.1 +/- 4.4 to 46.2 +/- 9.7 pg/ml). There were no changes in PGD2, PGE2, thromboxane B2, adenosine, inosine, or hypoxanthine. Pretreatment with dipyridamole, an adenosine uptake inhibitor, did not affect bronchial artery nucleoside concentrations (n = 7). Microsphere-induced vasodilation was not enhanced by dipyridamole (n = 9) and was not inhibited by either the adenosine receptor antagonist xanthine amine congener (n = 4) or the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (n = 8). These results do not support a role for either adenosine or NO and suggest that microspheres caused bronchial artery vasodilation through release of prostacylin and an unidentified vasodilator.

Adenine Nucleotides↗
PubMed2000

The 400 microsphere per piece "rule" does not apply to all blood flow studies.

Microsphere experiments are useful in measuring regional organ perfusion as well as heterogeneity of blood flow within organs and correlation of perfusion between organ pieces at different time points. A 400 microspheres/piece "rule" is often used in planning experiments or to determine whether experiments are valid. This rule is based on the statement that 400 microspheres must lodge in a region for 95% confidence that the observed flow in the region is within 10% of the true flow. The 400 microspheres precision rule, however, only applies to measurements of perfusion to a single region or organ piece. Examples, simulations, and an animal experiment were carried out to show that good precision for measurements of heterogeneity and correlation can be obtained from many experiments with <400 microspheres/piece. Furthermore, methods were developed and tested for correcting the observed heterogeneity and correlation to remove the Poisson "noise" due to discrete microsphere measurements. The animal experiment shows adjusted values of heterogeneity and correlation that are in close agreement for measurements made with many or few microspheres/piece. Simulations demonstrate that the adjusted values are accurate for a variety of experiments with far fewer than 400 microspheres/piece. Thus the 400 microspheres rule does not apply to many experiments. A "rule of thumb" is that experiments with a total of at least 15,000 microspheres, for all pieces combined, are very likely to yield accurate estimates of heterogeneity. Experiments with a total of at least 25,000 microspheres are very likely to yield accurate estimates of correlation coefficients.

Animals↗
PubMed1993

Validation of fluorescent-labeled microspheres for measurement of regional organ perfusion.

Estimations of dog lung, pig heart, and pig kidney regional perfusion by use of fluorescent-labeled microspheres were compared with measurements obtained with standard radiolabeled microspheres. Pairs of radio- and fluorescent-labeled microspheres (15 microns diam, 6 colors) were injected into a central vein of a supine anesthetized dog and the left ventricle of three supine anesthetized pigs while reference blood samples were simultaneously withdrawn from a femoral artery in the pigs. The lungs were cubed into approximately 2 cm3 pieces (n = 1,510). Each pig heart and kidney was cubed into approximately 1-g pieces (total n = 192 and 120, respectively). The radioactivity of each organ piece and reference blood sample was determined using a scintillation counter with count rates corrected for decay, background, and spillover. Tissue samples and reference blood samples were digested with KOH and filtered and the fluorescent dye was extracted with a solvent, or the dye was extracted from lung tissue without filtering. The fluorescence of each sample was determined for each color by use of an automated spectrophotometer. Perfusion was calculated for each organ piece from both the radioactivity and fluorescence. Correlation between flow determined by radio- and fluorescent-labeled microspheres was as follows: r = 0.96 +/- 0.01 (SD) (lung, filtered, n = 588), r = 0.99 +/- 0.00 (lung, nonfiltered, n = 710), r = 0.95 +/- 0.02 (heart, filtered), and r = 0.96 +/- 0.02 (kidney, filtered). Compared with colored microspheres, methods for quantitating fluorescent-labeled microspheres are more sensitive, less labor intensive, and less expensive. Fluorescent-labeled microspheres provide a new nonradioactive method for single and repeated measurement of regional organ perfusion.

Animals↗
PubMed1994

Biodegradable microspheres containing a colchicine analogue inhibit DNA synthesis in vascular smooth muscle cells.

BACKGROUND: Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local application of agents capable of modulating vascular responses, including smooth muscle cell proliferation, has been achieved, but difficulty in maintaining active levels locally has been a factor limiting the efficacy of such approaches. One strategy to maintain adequate levels is the local delivery of microspheres that release active agents over sustained time periods. METHODS AND RESULTS: We incorporated a colchicine analogue into biodegradable microspheres composed of a lactic acid/glycolic acid copolymer and characterized their drug release behavior as well as their effects on bovine aortic smooth muscle cells (BASMCs) in culture. Drug release was evaluated by spectrophotometric assay. Drug effects on DNA synthesis were measured by thymidine incorporation after addition of serum to subconfluent cells synchronized by serum withdrawal as well as in asynchronous cell populations. Polymeric microspheres incorporating 10% to 17% drug by weight and averaging 6 microns in size were found to release the colchicine analog in buffered saline solutions over more than several weeks. Drug-loaded particles inhibited DNA synthesis completely, with EC50 values ranging from 0.001 to 0.005 g% (wt/wt). Morphological changes suggesting microtubule depolymerization were observed after drug particle treatment, with similar EC50 values. Microspheres allowed to contact the cell surface demonstrated effects similar to those seen with microspheres suspended in the nutrient medium by porous polycarbonate filters, at EC50 values approximately fivefold lower. In contrast, control microspheres composed only of polymer with no incorporated active drug demonstrated no observable toxicity to BASMCs and < 40% inhibition of thymidine incorporation even in suspensions containing up to 0.5 g% particles. CONCLUSIONS: Biodegradable microspheres were fashioned that release a colchicine analogue and inhibit DNA synthesis in smooth muscle cells. Drug-loaded polymeric particles are candidates for local delivery at sites of arterial injury to decrease restenosis.

Animals↗
PubMed1992

Sustained damage to energy metabolism of brain regions after microsphere embolism in rats.

BACKGROUND AND PURPOSE: Information on sustained damage to cerebral function and metabolism after cerebral ischemia is useful for prophylaxis and therapeutics of cerebral infarction. The purpose of the present study was to induce sustained damage to brain regions after cerebral ischemia in experimental animals. For this purpose, we examined animal behavior and cerebral energy metabolism following microsphere embolism in rats. METHODS: We injected 900 microspheres (48 microns in diameter) into the right internal carotid artery of 110 rats and determined the time course of changes in the rats' behavior and the energy metabolism of the cortex, striatum, and hippocampus of both hemispheres. We injected the same volume of vehicle, without microspheres, into 28 sham-operated rats; there were 14 nonoperated control rats. RESULTS: Peak increase in lactate content and decrease in adenosine triphosphate and creatine phosphate of these brain regions of the right hemisphere were seen on the first day after microsphere embolism, whereas peak increases in glucose and glycogen contents of these regions were observed on the third day. Most of the metabolic alterations in all these regions continued for up to 28 days after operation, although they recovered toward control levels with time after the operation. The extent and trend of metabolite changes of the right hemisphere after microsphere embolism were similar in the three brain regions. In the left hemisphere, similar metabolic changes were observed, but to a lesser degree. The time course of changes in behavioral scores following microsphere embolism revealed marked stroke-like symptoms on the first day and relatively rapid disappearance of the symptoms with time after embolism. CONCLUSIONS: Microsphere embolism is capable of inducing widespread, sustained damage to energy metabolism of brain regions.

Adenosine Triphosphate↗
PubMed2002

Surface studies of coated polymer microspheres and protein release from tissue-engineered scaffolds.

The controlled release of growth factors from porous, polymer scaffolds is being studied for potential use as tissue-engineered scaffolds. Biodegradable polymer microspheres were coated with a biocompatible polymer membrane to permit the incorporation of the microspheres into tissue-engineered scaffolds. Surface studies with poly(D,L-lactic-co-glycolic acid) [PLGA], and poly(vinyl alcohol) [PVA] were conducted. Polymer films were dip-coated onto glass slides and water contact angles were measured. The contact angles revealed an initially hydrophobic PLGA film, which became hydrophilic after PVA coating. After immersion in water, the PVA coating was removed and a hydrophobic PLGA film remained. Following optimization using these 2D contact angle studies, biodegradable PLGA microspheres were prepared, characterized, and coated with PVA. X-ray photoelectron spectroscopy was used to further characterize coated slides and microspheres. The release of the model protein bovine serum albumin from PVA-coated PLGA microspheres was studied over 8 days. The release of BSA from PVA-coated PLGA microspheres embedded in porous PLGA scaffolds over 24 days was also examined. Coating of the PLGA microspheres with PVA permitted their incorporation into tissue-engineered scaffolds and resulted in a controlled release of BSA.

Coated Materials, Biocompatible↗
PubMed2001

Adsorption studies of human serum albumin, human gamma-globulins, and human fibrinogen on the surface of p(S/PGL) microspheres.

Adsorption of human serum albumin (HSA), human gamma-globulins (gammaG), and human fibrinogen (Fb) onto the surface of poly(styrene/alpha-t-butoxy-omega-vinylbenzyl-polyglycidol) microspheres (P(S/PGL)) with controlled fraction of polyglycidol in the interfacial layer was investigated. The microspheres were synthesized by the emulsifier-free radical copolymerization of styrene and alpha-t-butoxy-omega-vinylbenzyl-polyglycidol macromonomer (PGL). Macromonomers with number average molecular weights Mn = 950 and 2,700 were used in the syntheses. Fraction of polyglycidol in the microsphere surface layer was varied from 0.22 to 0.44, depending on the composition of the monomer feed. It was found that the maximal surface concentration of adsorbed proteins and the equilibrium constant of protein adsorption decreased with increased fraction of polyglycidol in the microsphere surface layer. For microspheres with the highest fraction of polyglycidol at the surface the maximal surface protein concentration was c. ten times lower and the adsorption equilibrium constant was c. one hundred times lower than for the reference polystyrene microspheres. The dependence of maximal surface concentration of adsorbed proteins on the fraction of polyglycidol in the particle interfacial layer indicated random distribution of polyglycidol chains without formation of polyglycidol and polystyrene patches at the microspheres surface.

Adsorption↗
PubMed2003

Hydrogel-microsphere-enhanced surface plasmon resonance for the detection of a K-ras point mutation employing peptide nucleic acid.

Highly-sensitive detection of a K-ras point mutation in codon 12, frequently found in pancreatic cancer, based on DNA-carrying hydrogel microspheres as a response enhancer for surface plasmon resonance (SPR), is described. Acrylamide-based microspheres with carboxyl groups were conjugated with DNA probes. Use of the DNA-carrying microsphere in the sandwich method, that is, binding of the microspheres with target DNAs at the sensor surface, enhanced the SPR response as a combined result of increased dielectric constant by the DNA-carrying microspheres. Microspheres lead to response enhancement, as shown by a 100-fold increase in sensitivity compared to that of non-amplified DNA target hybridization. In addition, the advantage of peptide nucleic acid (PNA) in the detection of a K-ras point mutation at the sensor surface by increasing temperature and flow rate is discussed. Results illustrate that the sandwich method through DNA-carrying microspheres for a SPR sensor is a promising approach for ultrasensitive DNA detection.

DNA Probes↗
PubMed1997

Fabrication of microspheres using blends of poly(ethylene adipate) and poly(ethylene adipate)/poly(hydroxybutyrate-hydroxyvalerate) with poly(caprolactone): incorporation and release of bovine serum albumin.

Spherical microspheres composed of polymer blends 80:20 PEAD/PCL II and 40:40:20 PEAD/P(HB-HV)/PCL II containing a range of BSA loadings have been fabricated using a single emulsion technique with solvent evaporation. 80:20 PEAD/PCL II microspheres had smooth surfaces while 40:40:20 PEAD/P(HB-HV)/PCL II microspheres consisted of a mixture of smooth surfaced, microporous and macroporous microsphere fractions. Irrespective of fabrication polymer, microspheres were produced in high yield (> 75%) and BSA incorporation had no significant effect on microsphere size distribution which ranged from 0.6 to 5 microns and from 2.1 to 50 microns for 80:20 PEAD/PCL II and 40:40:20 PEAD/P(HB-HV)/PCL II microspheres, respectively. The loss of BSA by partitioning into the aqueous phase resulted in low encapsulation efficiencies (< 14.5%). BSA release increased significantly with the-oretical percentage loading but the relationship could not be confirmed when the total cumulative release of BSA was expressed as a percentage of the actual total BSA incorporated. Significant BSA release could be detected for up to 26 days.

Animals↗
PubMed1981

A rapid method for immunofluorescent staining of paraffin sections using iron-containing protein A microspheres.

A method to rapidly perform immunofluorescence or light microscopic staining on formalin-fixed paraffin sections has been devised utilizing magnetic albumin microspheres containing Staphylococcal protein A. Because the protein A constituent of the microspheres has the property of binding the Fc portion of immunoglobulin G (IgG) class antibodies, the microspheres can be used to rapidly bind antigen-antibody complexes by the Fc portion of the antibody. Deparaffinized sections were stained with fluorescein isothiocyanate-conjugated antibody (IgG fractions) by standard techniques, after which the protein A microspheres were layered over the sections. Distinct fluorescence of sections was noted with the addition of the microspheres, whereas only autofluorescence was present with direct staining alone. The microspheres were also visualized by light microscopy by a subsequent Prussian blue reaction, staining the Fe3O4 within the microsphere matrix. This method represents a more rapid method for identifying antigens in tissues embedded in paraffin than has previously been reported.

Fluorescent Antibody Technique↗
PubMed2001

Long-term release of clodronate from biodegradable microspheres.

This paper describes the formulation of a biodegradable microparticulate drug delivery system containing clodronate, a bisphosphonate intended for the treatment of bone diseases. Microspheres were prepared with several poly(D,L-lactide-co-glycolide) (PLGA) copolymers of various molecular weights and molar compositions and 1 poly(D,L-lactide) (PDLLA) homopolymer by a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation procedure. Critical process parameters and formulation variables (ie, addition of stabilizing agents) were evaluated for their effect on drug encapsulation efficiency and clodronate release rate from microparticles. Well-formed clodronate-loaded microspheres were obtained for all polymers by selecting suitable process parameters (inner water/oil volume ratio 1:16, temperature-raising rate in the solvent evaporation step 1 degree C/min, 2% wt/vol NaCl in the external aqueous phase). Good yields were obtained in all batches of clodronate microspheres (above 60%); drug encapsulation efficiencies ranged between 49% and 75% depending on the polymer used. Clodronate release from all copolymer microspheres was completed in about 48 hours, while those from PDLLA microspheres required about 20 days. The change of microsphere composition by adding a surfactant such as Span 20 or a viscosing agent such as carboxymethylcellulose extended the long-term release up to 3 months. Clodronate was successfully entrapped in PLGA and PDLLA microspheres, and drug release could be modulated from 48 hours up to 3 months by suitable selection of polymer, composition, additives, and manufacturing conditions.

Biodegradation, Environmental↗