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At least 919 records · Page 51Linked to original sources
PubMed2004

Importance of single or blended polymer types for controlled in vitro release and plasma levels of a somatostatin analogue entrapped in PLA/PLGA microspheres.

The aim of the work was to develop biodegradable microspheres for controlled delivery of the somatostatin analogue vapreotide and maintenance of sustained plasma levels over 2-4 weeks after a single injection in rats. Vapreotide was microencapsulated into end-group capped and uncapped low molecular weight poly(lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) by spray-drying and coacervation. Microspheres were prepared from single and blended (1:1) polymer types. The microparticles were characterized for peptide loading, in vitro release and pharmocokinetics in rats. Spray-drying and coacervation produced microspheres in the size range of 1-15 and 10-70 microm, respectively, and with encapsulation efficiencies varying between 46% and 87%. In vitro release of vapreotide followed a regular pattern and lasted more than 4 weeks, time at which 40-80% of the total dose were released. Microspheres made of 14-kDa end-group uncapped PLGA50:50 or 1:1 blends of this polymer with 35 kDa end-group uncapped PLGA50:50 gave the best release profiles and yielded the most sustained plasma levels above a pre-defined 1 ng/ml over approximately 14 days. In vitro/in vivo correlation analyses showed for several microsphere formulations a linear correlation between the mean residence time in vivo and the mean dissolution time (r=0.958) and also between the amount released between 6 h and 14 days and the AUC(6h-14d) (r=0.932). For several other parameters or time periods, no in vitro/in vivo correlation was found. This study demonstrates that controlled release of the vapreotide is possible in vivo for a duration of a least 2 weeks when administered i.m. to rats. These results constitute a step forward towards a twice-a-month or once-a-month microsphere-formulation for the treatment of acromegaly and neuroendocrine tumors.

Animals↗
PubMed2005

Preparation and characterization of melittin-loaded poly (DL-lactic acid) or poly (DL-lactic-co-glycolic acid) microspheres made by the double emulsion method.

The water soluble peptide, melittin, isolated from bee venom and composed of twenty-six amino acids, was encapsulated in poly (DL-lactic acid, PLA) and poly (DL-lactic-co-glycolic acid, PLGA) microspheres prepared by a multiple emulsion [(W1/O)W2] solvent evaporation method. The aim of this work was to develop a controlled release injection that would deliver the melittin over a period of about one month. The influence of various preparation parameters, such as the type of polymer, its concentration, stabilizer PVA concentration, volume of internal water phase and level of drug loading on the characteristics of the microspheres and drug release was investigated. It was found that the microspheres of about 5 microm in size can be produced in high encapsulation (up to 90%), and the melittin content in the microspheres was up to 10% (w/w). The drug release profiles in vitro exhibited a significant burst release, followed by a lag phase of little or no release and then a phase of constant melittin release. The type of polymer used was a critical factor in controlling the release of melittin from the microspheres. In this study, the rate of peptide release from the microspheres correlated well with the rate of polymer degradation. Moreover, melittin was released completely during the study period of 30 days, which agreed well with the polymer degradation rate.

Drug Carriers↗
PubMed2000

Progesterone release from glutaraldehyde cross-linked casein microspheres: in vitro studies and in vivo response in rabbits.

Microspheres of bovine milk protein casein loaded with progesterone were fabricated by glutaraldehyde cross-linking of an aqueous alkaline solution of the protein dispersed in a hexane and dichloromethane non-aqueous dispersion medium with an aliphatic polyurethane as the stabilizer. Microspheres were characterized for their surface morphology and internal structure using scanning electron microscopy. In vitro release studies in phosphate buffer at 37 degrees C demonstrated that the rate of release of the steroid from the microsphere matrix was a function of cross-linking density, particle size, and drug payload. Microsphere formulations released 50% to 60% of the incorporated steroid in about 30 days and, thereafter, attained a steady state. In the presence of a protein-digesting enzyme such as protease, complete release of the steroid was observed in about 4 days in vitro into phosphate buffer. Intramuscular injection of progesterone-loaded microspheres into rabbits showed a plasma concentration of 1 to 2 ng/mL up to 5 months without any significant burst effect, whereas the powdered steroid administered in saline demonstrated a large burst effect peaking over 20 ng/mL, and the plasma concentration was not sustained beyond 4 days. Data obtained suggest that casein microspheres would be promising as a biodegradable drug carrier for sustained delivery of steroids.

Animals↗
PubMed2003

Mucoadhesive microspheres containing gentamicin sulfate for nasal administration: preparation and in vitro characterization.

In this study, suitable microsphere formulations were designed in order to provide the absorption of a high polar drug through nasal mucosa. For this purpose, gentamicin sulfate (GS) was chosen as a model drug and used at different drug/polymer ratios in the microsphere formulations. The microspheres were prepared by spray drying technique. Hydroxypropyl methylcellulose was used as a mucoadhesive polymer in the formulations to increase the residence time of the microspheres on the mucosa. Sodium cholate was added into the formulations for increasing the absorption of GS through nasal mucosa. The in vitro characteristics of the microspheres were determined. The microspheres were evaluated with respect to the particle size, production yield, encapsulation efficiency, shape and surface properties, drug-polymer interaction, mucoadhesive property, in vitro drug release and suitability for nasal drug delivery.

Adhesives↗
PubMed2000

Use of spray-dried zirconia microspheres in the separation of immunoglobulins from cell culture supernatant.

A method suitable for the isolation of monoclonal antibodies (MAbs) on novel zirconia microspheres (20-30 microm) is described. Zirconia microspheres were generated by spray drying colloidal zirconia. Spray-dried zirconia microspheres were further classified and characterized by X-ray diffraction, BET porosimetry and scanning electron microscopy. Spray-dried zirconia microspheres were modified with ethylenediamine-N,N'-tetra(methylenephosphonic) acid (EDTPA) to create a cation-exchange chromatographic support. The chromatographic behavior of a semi-preparative column packed with EDTPA-modified zirconia microspheres was evaluated and implications for scale-up are provided. EDTPA-modified zirconia microspheres were further used to purify MAbs from cell culture supernatant. Analysis by enzyme linked immunosorbent assay and gel electrophoresis demonstrate that MAbs can be recovered from a cell culture supernatant at high yield (92-98%) and high purity (>95%) in a single chromatographic step.

Animals↗
PubMed1989

Affinity separation with polyaldehyde microsphere beads.

Agarose polyaldehyde microsphere beads were prepared by encapsulating polyaldehyde microspheres of various diameters, e.g., polyacrolein or polyglutaraldehyde microspheres, within agarose beads. Amino ligands such as proteins or drugs can be bound covalently to the beads in a single step at physiological pH. The binding capacity of the beads towards various amino ligands is inversely related to the diameter of the microspheres encapsulated in the agarose matrix. Different reagents, e.g., bovine serum albumin, ethanolamine and hydroxylamine, were studied as blocking reagents of the free aldehyde groups. Blocking the remaining aldehyde groups after coupling the amino ligands to the beads is essential for increasing or retaining the reactivity of the ligands conjugated to the beads. Among the reagent studied, hydroxylamine was found to be the most suitable blocking reagent of the free aldehyde groups of beads conjugated with proteins. The extent of leakage of amino ligands bound to the agarose-polyaldehyde microsphere beads was studied as a function of the pH of aqueous solutions of the beads. At physiological pH the leakage was negligible. At acid pH, leakage of ligands containing several primary amine groups, e.g., proteins, was insignificant. However, significant leakage was detected for ligands containing a single amino group. The leakage of proteins bound to the agarose-polyaldehyde microsphere beads was found to be much less than the leakage of the same proteins bound to agarose beads through the cyanogen bromide activation method.

Aldehydes↗
PubMed2003

Change in secondary structure of silk fibroin during preparation of its microspheres by spray-drying and exposure to humid atmosphere.

Silk microspheres prepared by spray-drying were exposed to humid atmosphere (89% relative humidity, RH). Change in the secondary structure of silk fibroin during preparation of silk microspheres and exposure to high humidity was studied. Scoured silk fiber was dissolved in an aqueous solution of calcium chloride mixed with ethanol. After dialysis against purified water, theophylline was added to the solution as a model drug. Silk microspheres were obtained by spray-drying. Silk fibroin and theophylline were found to be amorphous in the microsphere by means of powder X-ray diffractometry. Fibroin assumed a beta-sheet conformation in the scoured silk fiber while it has an irregular structure in the microsphere, according to FTIR and Raman spectra. Fibroin recrystallized and its secondary structure changed to beta-sheet conformation by exposure of the microspheres to an atmosphere of 89% RH.

Fibroins↗
PubMed1997

Effects of fructose-1,6-biphosphate on microsphere-induced cerebral ischemia in the rat.

Fructose-1,6-bisphosphate has been shown to exert beneficial effects in different experimental models of cerebral ischemia. In view of this evidence, we have determined whether the compound protects the brain during microsphere-induced ischemia. One thousand two hundred microspheres were injected into female rats through a catheter inserted into the right common carotid artery and, 15 minutes and again 24 hours later, we intravenously treated the animals with 333 mg Kg(-1) of fructose-1,6-bisphosphate. The injection of microspheres produced significant changes in the rats' gross behavior, in their performance in the beam walking test, and in their brain lactate concentrations. The treatment with fructose-1,6-bisphosphate significantly attenuated the behavioral alterations induced by microsphere ischemia, but not in reducing brain accumulation of lactate. Moreover, the compound was shown to ameliorate the blood-brain barrier dysfunction, produced 2 and 4 hours after microsphere injection, evaluated by the Evans blue method. These results suggest that fructose-1,6-bisphosphate possesses salutary properties against the damages induced by microsphere ischemia.

Animals↗
PubMed2000

Intraseptal implantation of NGF-releasing microspheres promote the survival of axotomized cholinergic neurons.

Neurotrophic factors therapy requires their precise delivery to the targeted neuronal population. For this purpose, a wide range of strategies have been developed, and among them the stereotaxic implantation of biodegradable microparticles. To assess the in vivo activity of NGF-releasing PLGA microspheres, unloaded and NGF-loaded microparticles were implanted in the rat brain, near the septal cholinergic neurons, axotomized by an unilateral transection of the fornix-fimbria. Histological analysis at two and six weeks after implantation revealed a non-specific astro- and micro-glial reaction around the microspheres, identical for both unloaded and NGF-loaded microspheres. No neuronal toxicity was noticed, and healthy looking neurons were observed in contact with the microspheres. In the non-treated animals, the percentage of axotomized surviving neurons, when compared to the contralateral intact side, was 31 +/- 2 and 27 +/- 1% at two and six weeks, respectively. Unloaded microspheres caused no protective nor neurotoxic effects (40 +/- 9 and 39 +/- 6% of surviving cholinergic neurons at two and six weeks, respectively). In contrast, NGF-loaded microspheres showed a significant effect on the survival of axotomized cholinergic neurons at two and six weeks after implantation (66 +/- 9 and 61 +/- 5% when compared to the contralateral intact side, respectively). These results show that PLGA microparticles present no neurotoxicity and release sufficient amounts of bioactive NGF to significantly limit the lesion-induced disappearance of cholinergic neurons in the septum during at least six weeks. PLGA microparticles can be used in the future to administer neurotrophic factors in central nervous system disorders.

Animals↗
PubMed2002

Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices.

The purpose of this research was to develop polylactic-co-glycolic acid (PLGA) microspheres for continuous delivery of dexamethasone for over a 1-month period, in an effort to suppress the acute and chronic inflammatory reactions to implants such as biosensors, which interfere with their functionality. The microspheres were prepared using an oil-in-water emulsion technique. The oil phase was composed of 9:1 dichloromethane to methanol with dissolved PLGA and dexamethasone. Some microspheres were predegraded for 1 or 2 weeks. Ten percent of polyethylene glycol was added to the oil phase in alternative formulations to delay drug release. The in vitro release studies were performed in a constant temperature (37 C) warm room, in phosphate-buffered saline at sink conditions. Drug loading and release rates were determined by HPLC-UV analysis. The standard microsphere systems did not provide the desired release profile since, following an initial burst release, a delay of 2 weeks occurred prior to continuous drug release. Predegraded microspheres started to release dexamethasone immediately but the rate of release decreased after only 2 weeks. A mixed standard and predegraded microsphere system was used to avoid this delay and to provide continuous release of dexamethasone for 1 month.

Anti-Inflammatory Agents↗
PubMed2002

Influence of neutron irradiation on holmium acetylacetonate loaded poly(L-lactic acid) microspheres.

Holmium-loaded microspheres are useful systems in radio-embolization therapy of liver metastases. For administration to a patient, the holmium-loaded microspheres have to be irradiated in a nuclear reactor to become radioactive. In this paper. the influence of neutron irradiation on poly(L-lactic acid) (PLLA) microspheres and films, with or without holmium acetylacetonate (HoAcAc), is investigated, in particular using differential scanning calorimetry (MDSC), scanning electron microscopy, gel permeation chromatography (GPC), infrared spectroscopy, and X-ray diffraction. After irradiation of the microspheres, only minor surface changes were seen using scanning electron microscopy, and the holmium complex remained immobilized in the polymer matrix as reflected by a relatively small release of this complex. GPC and MDSC measurements showed a decrease in molecular weight and crystallinity of the PLLA, respectively, which can be ascribed to radiation induced chain scission. Irradiation of the HoAcAc loaded PLLA matrices resulted in evaporation of the non-coordinated and one coordinated water molecule of the HoAcAc complex, as evidenced by MDSC and X-ray diffraction analysis. Infrared spectroscopy indicated that some degradation of the acetylacetonate anion occurred after irradiation. Although some radiation induced damage of both the PLLA matrix and the embedded HoAcAc-complex occurs, the microspheres retain their favourable properties (no marginal release of Ho, preservation of the microsphere size), which make these systems interesting candidates for the treatment of tumours by radio-embolization.

Calorimetry, Differential Scanning↗
PubMed2002

Design of an injectable system based on bioerodible polyanhydride microspheres for sustained drug delivery.

The fabrication, morphological characterization, and drug release kinetics from microspheres of three bioerodible polyanhydrides, poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)), poly(sebacic anhydride) (poly(SA)), and the copolymer poly(CPH-co-SA) 50:50 (CPH:SA 50:50) is reported. The fabrication technique yields microspheres with different morphologies for each of the three polymers studied, ranging from very smooth exterior surfaces for poly(CPH) to coarse surface roughness with large pores for poly(SA). Release profiles for the model drug, p-nitroaniline are also different for each polymer. The release profile from poly(CPH) has a large initial burst and shows little additional release after 2 days. The release from poly(SA) is nearly zero-order and lasts for about 8 days. The release profile from CPH:SA 50:50 shows a relatively small burst and then exhibits zero-order release for about I month. The different release profiles are attributed to both polymer erosion rates and drug distribution characteristics of the microspheres. Tailored release profiles of a burst followed by zero-order release are obtained by appropriately combining the microspheres. This technique enables independent modulation of both the burst and the zero-order release rate by varying the number of poly(CPH) and poly(SA) microspheres respectively. Additionally, the zero-order release can be extended from about a week to a month by including CPH:SA 50:50 microspheres.

Anhydrides↗
PubMed2002

A novel polyethylene depot device for the study of PLGA and P(FASA) microspheres in vitro and in vivo.

Polymer microspheres (0.5-5.0 microm) are difficult to characterize in vivo because they degrade, migrate, and are endocytosed. A novel polyethylene mesh pouch containing microspheres allowed for retrieval of degraded polymeric products from rats without affecting the rate of degradation. Pouches containing poly(lactic-co-glycolic acid) (PLGA) or poly(fumaric-co-sebacic acid) (P(FASA)) microspheres were implanted intramuscularly, subcutaneously, and intraperitoneally and analyzed after 3, 7, 14, and 28 days. In vivo, subcutaneous or intraperitoneal implants experienced an immediate mass loss and a delayed decrease in molecular weight (Mw). Intramuscular implants behaved similarly to in vitro samples, decreasing in Mw immediately and lagging in mass loss. These results suggest that mass loss, which is usually dependent on Mw loss in vitro, may be directly due to enzymatic, rather than hydrolytic, degradation subcutaneously and intraperitoneally, while intramuscular implants appear to be mostly dependent on hydrolytic cleavage. This observation is further supported by histology. Additional experiments on pouches loaded with PLGA microspheres encapsulating osteoprotegerin, a protein drug used to prevent bone resorption, revealed that use of the device prevented the artifactual polymer compression inherent to microsphere centrifugation during release studies and allowed for the extraction of active protein from microspheres implanted for 3 days in vivo.

Absorbable Implants↗
PubMed2004

Hyaluronan microspheres for sustained gene delivery and site-specific targeting.

Hyaluronan is a naturally occurring polymer that has enjoyed wide successes in biomedical and cosmetic applications as coatings, matrices, and hydrogels. For controlled delivery applications, formulating native hyaluronan into microspheres could be advantageous but has been difficult to process unless organic solvents are used or hyaluronan has been modified by etherification. Therefore, we present a novel method of preparing hyaluronan microspheres using adipic dihydrazide mediated crosslinking chemistry. To evaluate their potential for medical applications, hyaluronan microspheres are incorporated with DNA for gene delivery or conjugated with an antigen for cell-specific targeting. The results show that our method, originally developed for preparing hyaluronan hydrogels, generates robust microspheres with a size distribution of 5-20mum. The release of the encapsulated plasmid DNA can be sustained for months and is capable of transfection in vitro and in vivo. Hyaluronan microspheres, conjugated with monoclonal antibodies to E- and P-selectin, demonstrate selective binding to cells expressing these receptors. In conclusion, we have developed a novel microsphere preparation using native hyaluronan that delivers DNA at a controlled rate and adaptable for site-specific targeting.

Animals↗
PubMedDate not supplied

Degradation of porous poly(anhydride-co-imide) microspheres and implications for controlled macromolecule delivery.

The degradation properties of porous microspheres made using a new family of polyanhydride copolymers, the poly(anhydride-co-imides), were studied. Poly[trimellitylimido-L-tyrosine-co-sebacic acid-co-1,3-bis(carboxyphenoxy)propane] microspheres, with and without entrapped bovine serum albumin (BSA) as a model protein, were made using the double emulsion solvent evaporation process. Water penetration and anhydride bond cleavage (polymer degradation) occurred rapidly (< 5 days) compared to the time scale of overall microsphere erosion (weeks to months) with most polymer compositions. Subsequent to bond cleavage, the ultimate erosion of the microsphere and release of entrapped BSA was due mainly to the slow dissolution of the individual hydrophobic monomers (TMA-Tyr, SA and CPP) from the microsphere surface. BSA was released at approximately the same rate as the polymer eroded. Due to the fast degradation of anhydride bonds relative to microsphere erosion, initial polymer molecular weight did not have a significant effect on macromolecule release rates. Instead, monomer solubility correlated well with polymer erosion and BSA release rates. This erosion mechanism leads to predictable drug release rates which may be appropriate for the delivery of many protein therapeutics, including vaccine antigens. The anhydride-imide copolymers were well tolerated in acute toxicity studies in rats and therefore show promise as biomaterials.

Animals↗
PubMedDate not supplied

Preparation of hydrogel microspheres by coacervation of aqueous polyphosphazene solutions.

A new method of preparing ionically cross-linked polyphosphazene hydrogel microspheres which enables effective control over microsphere size distribution has been developed. The synthesized microspheres can be used in protein delivery and, especially, as vaccine delivery vehicles. A new technique utilizes the ability of aqueous solutions of poly[di(carboxylatophenoxy)phosphazene] (PCPP) to form coacervate microdroplets upon addition of sodium chloride. These microdroplets are then stabilized via polymer cross-linking with calcium ions. It was demonstrated that the method enables efficient microencapsulation of proteins. It was also shown that microsphere size can be controlled through the manipulation of microencapsulation conditions. The process is simple, highly reproducible and generates microspheres with a narrower microsphere size distribution, compared to the previous technologies.

Biocompatible Materials↗
PubMed1999

Fabrication, characterization and evaluation of bioceramic hollow microspheres used as microcarriers for 3-D bone tissue formation in rotating bioreactors.

Novel bioactive ceramic hollow microspheres with an apparent density in the range 0.8-1.0 g cm(-3) have been developed as microcarriers for 3-D bone tissue formation in rotating-wall vessels (RWV). Hollow ceramic microspheres with a composition of 58-72% SiO2, 28-42% Al2O3 (wt%) and an apparent density 0.8-1.0 g cm(-3) were pretreated in 1.0 N NaOH for 2 h before being coated with synthesized calcium hydroxyapatite (HA) particulate sol. The HA-coated hollow microspheres were sintered for 1 h at 600, 800 and 1000 degrees C. SEM analysis revealed that the grain size and pore size of the calcium phosphate coating increased with the sintering temperature. FTIR analysis showed that crystalline calcium hydroxyapatite was present in the coatings sintered at 600 and 800 degrees C. When sintered at 1000 degrees C, the coating consisted of alpha-tricalcium phosphate. All the coatings adhered well, independent of sintering temperature. The trajectory analysis revealed that the hollow microsphere remained suspended in a rotating-wall vessel (RWV), and experienced a low shear stress (approximately 0.6 dyn cm(-2)). Cell culture studies using rat bone marrow stromal cells and osteosarcoma cells (ROS 17/2.8) showed that the cells attached to and formed 3-D aggregates with the hollow microspheres in a RWV. Extracellular matrix was observed in the aggregates. These data suggest that these hollow bioactive ceramic microspheres can be used as microcarriers for 3-D bone tissue formation in vitro, as well as for the study of the effects of microgravity on bone cell functions.

Animals↗
PubMed1999

Microspheres of hydroxyapatite/reconstituted collagen as supports for osteoblast cell growth.

Microspheres comprised of particulate hydroxyapatites dispersed in fibrous collagen matrices were prepared. The procedure involved the droplet formation of hydroxyapatite/collagen mixture emulsified in olive oil, followed by the reconstitution of collagen in the presence of hydroxyapatite particles at 37 degrees C. Various sizes of microspheres could be obtained by controlling the stirring speed of the emulsified mixture. By increasing the stirring speed from 200 to 350 and 500 rpm, the average diameter of the microspheres decreased from 1038 to 513 and 226 microm, respectively. The sizes of the microspheres reduced substantially to a range of 141 microm when 2%. Span 85 was present in the emulsion mixture stirring at 200 rpm. The microspheres thus obtained can be used as carriers to support the growth of osteoblast cells. Osteoblast cells derived from calvaria proliferated from 1.5 x 10(5) to 4.5 x 10(5) cells/ml in 7 days. Correspondingly, the alkaline phosphatase activity increased 6 fold during this period. These results suggested that the hydroxyapatite/collagen microspheres could be used as the filling materials for bone defect.

Animals↗