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PubMed1990

Morphology of polyanhydride microsphere delivery systems.

Scanning electron microscopy (SEM) was used to elucidate the mechanism of polymer degradation and drug release in polyanhydride microspheres. Three different fabrication methods--solvent removal, solvent evaporation, and hot melt microencapsulation--were used to prepare polyanhydride microspheres containing a variety of drugs. The morphology of these microspheres releasing drug in vitro and in vivo was studied by SEM and compared with degradation and release data measured by conventional methods. Microspheres prepared by the three techniques were shown to have distinctive morphological characteristics induced by the nature of the fabrication method. In addition, SEM analysis could be used to explain the drug release profiles and polymer degradation behavior seen in vitro as well as the in vivo effects of insulin-loaded microspheres on diabetic rats. This study has shown SEM to be an important and powerful tool for analyzing the effects of microsphere fabrication method on drug release.

Anhydrides↗
PubMedDate not supplied

Enhanced drug retention in VX2 tumors by use of degradable starch microspheres.

Twenty-nine rabbits with 12- to 14-day-old VX2 tumors in the hind leg were injected intraarterially with technetium-99m (99mTc) DTPA and various combinations of biodegradable starch microspheres, Spherex (Pharmacia, Sweden), to evaluate the efficacy of the microspheres in enhancing tumor retention of 99mTc DTPA. A gamma camera and nuclear medicine computer were used to generate time activity curves of 99mTc DTPA concentration in the tumors. Blood flow to the tumor and various muscles was also measured at intervals by left ventricular injection of 15 micron radiolabeled plastic microspheres. Ninety minutes following the administration of 99mTc DTPA, specimens from the tumor, plasma and different muscles were counted in a NaI well counter connected to a multichannel analyzer. When biodegradable microspheres mixed with 99mTc DTPA were injected and followed by a slow infusion of plain starch microspheres, the 99mTc DTPA was retained in the tumor at concentrations up to 11 times that seen when 99mTc DTPA alone was injected; the corresponding biological half-time was 13 times longer than control values. Additionally, the degree of drug retention was inversely related to blood flow, with retention increasing as blood flow decreased. The results have possible applications to the use of biodegradable microspheres in the intraarterial delivery of chemotherapeutic agents to solid tumors.

Animals↗
PubMed1981

Albumin microspheres labeled with Ga-67 by chelation: concise communication.

Albumin microspheres have been synthesized eith EDTA and DTPA chelating groups covalently bound to their surface. The microspheres may be labeled with Ga-67 at high yield (97 +/- 2%) by transcomplexation from a 0.1 M Ga-67 acetate solution. With EDTA microspheres the resulting label dissociates only slightly after no detectable dissociation over this period. By contrast, microspheres without chelating groups lose their label virtually completely under these conditions. Following intravenous administration of sized Ga-67 DTPA microspheres in mice, about (84 +/- 16)% of the activity localizes in the lungs at 5 min, with (60 +/- 7)% remaining after 2 hr. Since labeling is by chelation, the microspheres may also be tagged with other metallic radionuclides

Albumins↗
PubMed1995

Fluorescent vs. radioactive microsphere measurement of regional myocardial blood flow.

OBJECTIVES: This study compared simultaneous regional myocardial blood flow (RMBF) measurements using fluorescent microspheres (FM) and radiolabeled microspheres (RM). The utility of an internal standard during processing was also examined. METHODS: Paired FM and RM were injected into the left atrium of 9 anaesthetised rabbits. RMBF was altered by use of either regional ischaemia or (-)-N6-(2-phenylisopropyl)-adenosine. Radioactivity of blood reference and tissue samples was quantitated using standard methods. Samples were then digested with potassium hydroxide and microspheres recovered by vacuum filtration, with an additional label of FM as the internal standard. FM labels were extracted using Carbitol acetate and quantitated using fluorescence spectroscopy. Agreement between the fluorescent and radioactive methods was assessed using both orthogonal regression and difference-against-mean analyses. RESULTS: Using recovery-uncorrected data, the slope of the orthogonal regression of RM and FM-determined RMBF was not statistically different from 1, but the intercept was statistically different from 0 [-0.03(0.01), P = 0.005] and the mean RMBF by each method differed from one another [1.24(0.08) vs. 1.17(0.08) ml.min-1.g-1, P = 0.0002]. The mean +/- 2 s.d. of the differences of RMBF (RM minus FM) was +0.07 +/- 0.30 ml.min-1.g-1. Although recovery of FM from tissue averaged 97.6(1.2)%, use of the internal standard to correct for losses substantially improved the agreement between RM and FM-determined RMBF: the orthogonal regression slope was not statistically different from 1, the intercept was not statistically different from 0, and the means of the flows were not different. The mean +/- 2 s.d. of the differences of RMBF was -0.01 +/- 0.22 ml.min-1.g-1. The internal standard also improved RMBF estimates from samples with simulated large spillage during processing. CONCLUSION: Fluorescent microspheres are an equivalent alternative to radiolabeled microspheres for the estimation of RMBF. Although the overall recovery of microspheres using this technique was high, use of an internal standard is recommended for correction of random losses.

Animals↗
PubMed1994

[The distribution and pharmacokinetics in lung of bovine serum albumin microspheres for pulmonary targeting in mice].

125I-labeled bovine serum albumin microspheres loaded cisplatinum (CDDP-125I-BSA-MS) with the size range of 7-25 microns were prepared and injected into the tail vein of mice. The results showed that the microspheres were accumulated almost entirely in the lung after i.v. injection (about 97.52% injected dose at the highest concentration). While in blood and other organs almost no accumulation was found. Photomicrographs showed that microspheres reached the lung and lodged in precapillary arteriols and capillaries of lung. The microspheres in lung were eliminated gradually. The pharmacokinetics of microspheres in lung of mice was also studied with "practical pharmacokinetic program-version 87", and was fitted by two-compartment model with i.v. injection or one-compartment model with 1st order absorption, but the meaning of some parameters changed. Based on the analysis of the models and parameters, it was concluded that the pharmacokinetics of microspheres in lungs can be described by the model of "one-compartment of first-order intake and first-order elimination".

Animals↗
PubMedDate not supplied

Protein release from poly(lactic-co-glycolic acid) microspheres: protein stability problems.

The enzyme, carbonic anhydrase, has been incorporated within poly(lactic-co-glycolic acid) microspheres using a double emulsion and solvent evaporation technique. The protein stability problems during the microsphere formulation procedure and during the release period were examined in relation to the protein release kinetics over a 2 month period. Different protein release profiles could be obtained depending on the polymers used. The protein release kinetics exhibited an initial fast release followed by a slow release, resulting in an incomplete protein release although the microspheres degraded significantly. The very slow release kinetics were attributed to the protein aggregation and non-specific adsorption within the microspheres. It was found that the protein was significantly denatured and aggregated during the double emulsion formulation step. Several excipients such as albumin, poly(ethylene oxide), Pluronic F-127, and gelatin, which were loaded along with the protein within microspheres, demonstrated better protein release kinetics partly due to an increase in the protein stability. The released protein from these fast degrading microspheres, however, was severely hydrolyzed and lost its catalytic activity, caused by the accumulation of degradation products in the medium.

Carbonic Anhydrases↗
PubMed1995

Measurement of organ blood flow with coloured microspheres in the rat.

OBJECTIVE: The aim was to establish a method for measuring organ blood flow in rats using commercially available, coloured, dye extraction microspheres. METHODS: A mixture of radiolabelled and dye extraction microspheres was infused into rats at rest (basal) and during intravenous administration of either angiotensin II (0.5 microgram.kg-1.min-1) or isoprenaline [12.5 ng.(g0.74)-1.min-1]. Tissues were removed and placed in test tubes, counted for radioactivity, then digested with 2N sodium hydroxide. Within the same tube, microspheres were isolated using centrifugation and the dye was extracted with dimethylformamide. The dye was quantified by spectrophotometry. RESULTS: Recovery of microspheres averaged greater than 95% for all tissues studied; larger reagent volumes were required to achieve this level of recovery from white adipose tissue. Statistical analyses showed excellent correlations between blood flow values obtained by the dye extraction and radiolabelled microsphere techniques. Blood flow values obtained with the radioactive technique tended to be slightly higher. There were no differences in the results obtained with the two techniques when they were simultaneously used to measure changes in organ blood flow induced by angiotensin II or isoprenaline. CONCLUSIONS: The coloured, dye extraction microsphere technique accurately measured organ blood flow in rats. This technique is potentially useful for estimating blood flow in any animal, even if tissue sample size is limited.

Adipose Tissue↗
PubMed1994

The use of field effects to generate calcium alginate microspheres and its application in cell transplantation.

The diameter and sphericity of alginate-poly-L-lysine-alginate microcapsules, which was determined by the size and shape of calcium alginate microspheres, affected durability and biocompatibility of microcapsules and the result of transplantation. The commonly used airjet spray method generated microspheres with wide variation in diameter and sphericity. In order to overcome these drawbacks, we designed a field effect microparticle generator which established a stable electric field. This generated calcium alginate microspheres with an adjustable diameter (range, 50-350 microns). Factors which influenced the diameter and sphericity of microspheres included the percentage of alginate, field strength, speed of extrusion of alginate, needle gauge, field distance, and cell density in sodium alginate. The conditions used for microencapsulation of rat, pig, and human islets were 5500-6500 volts, 22 gauge needle with blunt end, 1-cm field distance, 1.5% sodium alginate, and 0.57 mL/min extrusion speed. These combinations would give most of the islet-containing microcapsules a diameter of 300-450 microns when alginate microspheres were incubated with calcium chloride solution for a total of six minutes. If individual cells (eg, NS-1) were microencapsulated, a larger gauge needle resulted in smaller microcapsules. Field strength of 6500 volts at a distance of 1 cm did not change the doubling time of NS-1 myeloma cells. By using the electric field microparticle generator, encapsulated cells were distributed around the periphery of the microspheres and thus improved the oxygen and nutrient supply of these encapsulated cells.

Alginates↗
PubMed1993

Yttrium-90 glass microspheres injected via the portal vein. An experimental study.

Nondegradable glass microspheres (35 mu) were injected into the portal vein for toxicity test in 15 rabbits. In 10 animals the microspheres were loaded with 90Y, giving liver absorbed doses between 24.6 and 437.4 Gy, and in 5 with 89Y (control group). The total amount of microspheres injected in each animal varied between 35 and 140 mg. The rabbits in the experimental group tolerated the effect of radioembolization in a dose 4 times higher than the upper limit of the clinical dose (100 Gy). After injection of 90Y glass microspheres into the portal vein of rats with diethylnitrosamine (DEN)-induced hepatic carcinoma, the microspheres, in addition to the liver parenchyma, accumulated in central and peripheral parts of the cancer nodules, causing necrosis. The internal radiation therapy of 90Y glass microspheres delivered via the portal vein may be an effective nonsurgical method for the treatment of liver cancer, especially in small nodules.

Animals↗
PubMed1993

Sustained delivery of retinoic acid from microspheres of biodegradable polymer in PVR.

PURPOSE: The aims were to obtain a controlled intravitreous release of retinoic acid (RA) by injecting drug loaded microspheres of biodegradable polymers and to study the potential use of this RA delivery system in a rabbit model of proliferative vitreoretinopathy (PVR). METHODS: The release of RA in vitro from 15 mg of 50-50 poly(DL-lactide-co-glycolide) (PLGA) in 1 ml of water at room temperature was measured with a spectrophotometer. In a rabbit model of PVR, 11 eyes were injected with 5 mg of microspheres containing 22 micrograms of RA/mg of PLGA, and seven control eyes were injected with microspheres of the same polymer that did not contain RA. In a third group, six rabbits were injected with 5 mg (n = 3) and 10 mg (n = 3) of microspheres containing RA. RESULTS: The initial concentration of RA was 20.8 micrograms/mg of PLGA. The release curve showed a fairly constant daily release of 7 micrograms/d for about 30 days. At 40 days, the release rate decreased to about 6 micrograms/d. After 40 days, 82.8% of the RA was released. Four of 11 treated rabbits (36%) and 7/7 (100%) controls showed tractional retinal detachment (TRD) (P < 0.01) after 2 months. Histopathologically, a mild, localized, foreign body reaction was observed. CONCLUSIONS: The authors obtained a sustained release of RA from PLGA microspheres in vitro for 40 days. A single injection of RA-loaded microspheres in suspension in BSS was effective in reducing the incidence of TRD after 2 months in a rabbit model of PVR.

Animals↗
PubMed1993

Preparation and evaluation in vitro and vivo of copoly (lactic/glycolic) acid microspheres containing norethisterone.

Poly (lactic/glycolic) acid (PLGA) microspheres containing 20% norethisterone (NET) were prepared and the preparation methodology was optimised. The microspheres showed a slow and steady release pattern up to more than 96 hours in 27.5 wt% ethanol solution. In vivo performance of the microspheres indicated that a single intramuscular injection of 80 mg of microspheres could significantly prolong the duration of estrus suppression up to 45 days in rats. In addition, the studies on the stability of microspheres showed that there was no significant change both in the NET content of microspheres and the NET release rate in vitro after storage for one year.

Animals↗
PubMed1998

[New approaches for encapsulation of peptides into poly(lactic/glycolic acid) microspheres].

The aim of the work was to develop small microspheres made from a biodegradable polymer, poly(lactide-co-glycolide), in order to entrap small peptides. Microspheres prepared by a water-in-oil-in-water emulsion solvent evaporation technique displayed a mean diameter below than 10 microns and showed high encapsulation efficiency of a 33 amino acid peptide (V3 BRU). In vitro release kinetics studies showed that such microparticles could be employed for both oral immunization and controlled release. The encapsulation of a seven aminoacid peptide in the same conditions, led to a very low encapsulation efficiency. In order to increase the entrapment efficiency, two strategies were adopted: taking into account the solubility of pBC 264 at different pH, a pH gradient was created to prevent the leakage of the encapsulated peptide into the outer aqueous phase. The inner aqueous phase was maintained at basic pH where the peptide was soluble, while the external aqueous phase was acidic: ovalbumin was added during preparation to stabilize the inner emulsion. These two strategies allowed to increase significantly the encapsulation rate of pBC 264. Nevertheless, the in vitro release kinetics of the peptide were strongly influenced by the presence of ovalbumin which seems to form pores in the microsphere structure (80% of the total peptide content was released after 30 minutes). By contrast, when ovalbumin was replaced by Pluronic F 68 microspheres did not have pores, thus the release profile and the extent of the burst were much smaller. When microspheres were stereotactically implanted in the rat brain, in vivo release profiles were in good agreement with the release observed in vitro. In conclusion, these microspheres are well suited for the slow delivery of neuropeptides in the brain, a feature expected to facilitate the study of long term effects of these compounds.

Animals↗
PubMed1994

Biodegradable microspheres as controlled-release tetanus toxoid delivery systems.

Purified tetanus toxoid, a high-molecular-weight protein, was entrapped within poly(L-lactic acid) (PLA) and poly(D,L-lactic/glycolic acid) (PLGA) microspheres prepared by either a solvent extraction or a solvent evaporation method carried out in a multiple emulsion system (water-in-oil-in-water). The physical integrity and antigenicity of the protein treated under different processing conditions were investigated. A reduction of antigenicity that was related to the percentage of aggregated protein was noticed under some experimental conditions. This partial loss of antigenicity was associated with the lyophilization process and affected by the nature of the organic solvent. All types of microspheres prepared with different molecular weight PLA and PLGA displayed a high protein-loading efficiency (> 80%) but their size was strongly influenced by polymer molecular weight (3000 versus 100,000). Protein release pattern was influenced by both polymer molecular weight and composition (PLA versus PLGA). A constant release pattern after an induction period of 10 days was observed for microspheres composed of high-molecular-weight polymers (PLA and PLGA). The release rate was lower from PLA microspheres than from PLGA microspheres. In contrast, a continuously increasing release rate preceded by a burst was observed for low-molecular-weight (3000) PLGA microspheres. Microencapsulated tetanus toxoid was significantly more immunogenic in mice than fluid toxoid as determined by IgG anti-tetanus antibody levels and neutralizing antibodies. However, the magnitude and duration of the antibody response did not differ significantly from a similar dose of aluminium phosphate-adsorbed toxoid. We conclude that microencapsulated tetanus toxoid shows significant adjuvant activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Preparation of AgCl-polyacrylamide composite microspheres via combination of a polymer microgel template method and a reverse micelle technique.

A new route was created for the preparation of AgCl-polyacrylamide (AgCl-PAM) composite microspheres with patterned surface structures. The route is a combination of a polymer microgel template method and a reverse micelle technique. The size of the AgCl nanoparticles existing on the surfaces of the composite microspheres and the clearness of the surface patterns of the composite microspheres can be altered by simply adjusting the amount of precipitated AgCl and the rate of the deposition reaction. The route can be also used for the preparation of other water-insoluble salt-polymer composite microspheres, such as BaSO(4)-PAM. It is expected that the composite microspheres with patterned surface structures may not only combine the advantages of polymers and those of inorganic compounds, but also combine the advantages of microspheres in the micrometer size range and those in the nanometer size range.

Journal Article↗
PubMed1997

Biodegradation and biocompatibility of PLA and PLGA microspheres.

A fundamental understanding of the in vivo biodegradation phenomenon as well as an appreciation of cellular and tissue responses which determine the biocompatibility of biodegradable PLA and PLGA microspheres are important components in the design and development of biodegradable microspheres containing bioactive agents for therapeutic application. This chapter is a critical review of biodegradation, biocompatibility and tissue/material interactions, and selected examples of PLA and PLGA microsphere controlled release systems. Emphasis is placed on polymer and microsphere characteristics which modulate the degradation behaviour and the foreign body reaction to the microspheres. Selected examples presented in the chapter include microspheres incorporating bone morphogenetic protein (BMP) and leuprorelin acetate as well as applications or interactions with the eye, central nervous system, and lymphoid tissue and their relevance to vaccine development. A subsection on nanoparticles and nanospheres is also included. The chapter emphasizes biodegradation and biocompatibility; bioactive agent release characteristics of various systems have not been included except where significant biodegradation and biocompatibility information have been provided.

Journal Article↗
PubMed1998

Microspheres as nasal drug delivery systems.

All types of microspheres that have been used as nasal drug delivery systems are water-insoluble but absorb water into the sphere's matrix, resulting in swelling of the spheres and the formation of a gel. The building materials in the microspheres have been starch, dextran, albumin and hyaluronic acid, and the bioavailability of several peptides and proteins has been improved in different animal models. Also, some low-molecular weight drugs have been successfully delivered in microsphere preparations. The residence time in the cavity is considerably increased for microspheres compared to solutions. However, this is not the only factor to increase the absorption of large hydrophilic drugs. Microspheres also exert a direct effect on the mucosa, resulting in the opening of tight junctions between the epithelial cells. Starch and dextran microspheres have been administered repeatedly and can be classified as safe dosage forms.

Journal Article↗
PubMed2006

Room temperature synthesis of hollow CdMoO(4) microspheres by a surfactant-free aqueous solution route.

Hollow cadmium molybdate microspheres have been successfully prepared via a template-free aqueous solution method with the assistance of NaCl at room temperature. The structure and morphology of the CdMoO(4) hollow microspheres were characterized by X-ray diffraction, field-emission scanning electron microscopy, and transmission electron microscopy. The microspheres have diameters of 3-6 microm and hollow interiors of 2-3 microm. The shell is composed of numerous single-crystalline nanorods with diameters of 30-120 nm and lengths of 1-2 microm which are radially oriented to the center. A certain concentration of NaCl plays a key important role in the formation process of hollow microspheres, which might provide a suitable chemical environment to favor the formation of hollow CdMoO(4) microspheres. A possible NaCl-induced Ostwald ripening process is proposed for the formation of hollow CdMoO(4) microspheres on the basis of scanning electron microscopy observation of intermediate products at different precipitation stages.

Journal Article↗
PubMed1999

Preparation of phosphorus-containing silica glass microspheres for radiotherapy of cancer by ion implantation.

A chemically durable glass microsphere containing a large amount of phosphorus is useful for in situ irradiation of cancers, since they can be activated to be a beta-emitter with a half-life of 14.3 d by neutron bombardment. When the activated microspheres are injected to the tumors, they can irradiate the tumors directly with beta-rays without irradiating neighboring normal tissues. In the present study, P+ ion was implanted into silica glass microspheres of 25 microm in average diameter at 50 keV with nominal doses of 2.5 x 10(16) and 3.35 x 10(1)6 cm(-2). The glass microspheres were put into a stainless container and the container was continuously shaken during the ion implantation so that P+ ion was implanted into them uniformly. The implanted phosphorus was localized in deep regions of the glass microsphere with the maximum concentration at about 50 nm depth without distributing up to the surface even for a nominal dose of 3.35 x 10(16) cm(-2). Both samples released phosphorus and silicon into water at 95 degrees C for 7 d. On the basis of the previous study on P+-implanted silica glass plates, the silica glass microspheres containing more phosphorus which is desired for actual treatment could be obtained, without losing high chemical durability, if P+ ion would be implanted at higher energy than 50 keV to be localized in deeper region.

Journal Article↗