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PubMed2006

Biodegradable polymeric microspheres with "open/closed" pores for sustained release of human growth hormone.

A new approach for attaining sustained release of protein is introduced, involving a pore-closing process of preformed porous PLGA microspheres. Highly porous biodegradable poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres were fabricated by a single water-in-oil emulsion solvent evaporation technique using Pluronic F127 as an extractable porogen. Recombinant human growth hormone (rhGH) was incorporated into porous microspheres by a simple solution dipping method. For their controlled release, porous microspheres containing hGH were treated with water-miscible solvents in aqueous phase for production of pore-closed microspheres. These microspheres showed sustained release patterns over an extended period; however, the drug loading efficiency was extremely low. To overcome the drug loading problem, the pore-closing process was performed in an ethanol vapor phase using a fluidized bed reactor. The resultant pore-closed microspheres exhibited high protein loading amount as well as sustained rhGH release profiles. Also, the released rhGH exhibited structural integrity after the treatment.

Coated Materials, Biocompatible↗
PubMed2006

Aminated gelatin microspheres as a nasal delivery system for peptide drugs: evaluation of in vitro release and in vivo insulin absorption in rats.

Aminated gelatin microspheres (AGMS) was investigated as a nasal drug delivery system for peptide drugs. The in vitro drug release from microspheres was evaluated using a fluorescein-labeled insulin (RITC-insulin) and FITC-dextran with a molecular weight of 4.4 kDa (FD-4) as model drugs. RITC-insulin release from AGMS was significantly slower than from native gelatin microspheres (GMS), with a cumulate release of 18.4% and 32.4% within 30 min, and 56.9% and 75.1% within 8 h respectively. However, the release of FD-4 from both AGMS and GMS was quite rapid and no difference was observed for the two microspheres. The electrostatic interactions between the model drugs and the microspheres were supposed to be the main factor that controlled the release behavior. The absorption enhancing effect was estimated by measuring the changes of plasma glucose concentrations of healthy rats following intranasal administration of insulin-incorporated microspheres in both suspension and dry powder forms. AGMS could significantly increase the nasal absorption of insulin in rats when administered in a dry powder formulation, but no significant hypoglycemic effect was observed when given in suspensions. One of the mechanisms for the increased insulin absorption was attributed to the hydrogel nature of the microspheres that could absorb water from the nasal mucosa and thus resulted in a temporarily dehydration of the epithelium membrane and opening of the tight junctions. The positive charge of the AGMS has also evidently contributed to the absorption enhancing effect. In addition, the mucoadhesive properties of AGMS might also have played a role to the total effect. AGMS might be a new candidate carrier for the nasal delivery of peptide drugs.

Absorption↗
PubMed2006

Novel polymeric microspheres containing norcantharidin for chemoembolization.

Chemoembolization has been found to be a potentially effective method of treating certain types of cancer. It involves arterial embolization of a tumor, in combination with simultaneous or subsequent local delivery of chemotherapeutic agents. In this study, PLGA-alginate microspheres were evaluated for their potential application in chemoembolization. Norcantharidin, which possesses anti-tumor properties, was used to investigate the application of drug-containing microspheres for chemoembolization. The release profiles of alginate, PLGA and PLGA-alginate microspheres were markedly different in phosphate buffered saline, with the composite microspheres showing the most appropriate release rate for chemoembolization. Burst effect decreased while particle size increased with increasing proportion of alginate in the PLGA-alginate microspheres. PLGA-alginate microspheres containing norcantharidin were effective in destroying the cancer cells used in this study. The growth inhibitory effect was concentration and time dependent. These microspheres also exhibited excellent embolization and therapeutic effects on rats with transplanted tumors.

Alginates↗
PubMed2006

A novel chemistry for conjugating pneumococcal polysaccharides to Luminex microspheres.

Here we describe a novel method to conjugate pneumococcal polysaccharides (PnPS) to Luminex microspheres for use in serological assays. 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methyl-morpholinium (DMTMM) modification of PnPS and conjugation to carboxyl functional groups on Luminex microspheres (COOH-DMTMM method) was shown to be a reproducible chemistry that efficiently conjugated PnPS to Luminex microspheres without affecting the antigenicity of a broad set of PnPS. The COOH-DMTMM method was compared to three other methods for robustness, reproducibility and effect on PnPS antigenicity in a multiplexed assay format. The other methods examined included adsorption of the unmodified PnPS to Luminex microspheres, oxidation of the PnPS to conjugate them to amino-modified microspheres using carbodiimide chemistry and poly-l-lysine modification of the PnPS before conjugating to carboxy Luminex microspheres using carbodiimide chemistry. Of the four methods, the COOH-DMTMM chemistry was shown to be a robust methodology, producing stable PnPS coupled microspheres with a 4-log dynamic range and low cross-reactivity when used in a PnPS-specific IgG serology assay. This novel chemistry should be useful for developing serological assays to measure antibodies to polysaccharides for use in vaccine and epidemiology studies.

Antibodies, Bacterial↗
PubMed2005

Hepatocytes cultured in alginate microspheres: an optimized technique to study enzyme induction.

An important application of hepatocyte cultures is identification of drugs acting as inducers of biotransformation enzymes that alter metabolic clearance of other therapeutic agents. In the present study we optimized an in vitro system with hepatocytes cultured in alginate microspheres that allow studies of enzyme induction with excellent sensitivity. Induction factors obtained with standard inducers, such as 3-methylcholanthrene or phenobarbital, were higher compared to those with conventional hepatocyte co-cultures on collagen coated dishes. This is illustrated by activities of 7-ethoxyresorufin-O-deethylase (EROD) after incubation with 5 microM 3-methylcholanthrene (3-MC), a standard inducer for cytochrome P4501A1 and 1A2. Mean activities for solvent controls and 3-MC exposed cells were 2.99 and 449 pmol/min/mg protein (induction factor: 150) for hepatocytes cultured in microspheres compared to 2.72 and 80.6 pmol/min/mg (induction factor: 29.6) for hepatocytes on collagen coated dishes. To compare these in vitro data to the in vivo situation male Sprague Dawley rats, the same strain that was used also for the in vitro studies, were exposed to 3-MC in vivo using a protocol that guarantees maximal induction. Activities were 29.2 and 1656 pmol/min/mg in liver homogenate of solvent and 3-MC treated animals (induction factor: 56.7). Thus, the absolute activities of 3-MC exposed hepatocytes in microspheres are lower compared to the in vivo situation. However, the induction factor in vitro was even higher compared to the in vivo situation (150-fold versus 56.7-fold). A similar scenario was observed using phenobarbital (0.75 mM) for induction of CYP2B and 3A isoenzymes: induction factors for testosterone hydroxylation in position 16beta were 127.5- and 50.4-fold for hepatocytes in microspheres and conventionally cultured hepatocytes, respectively. The new in vitro system with hepatocytes embedded in solid alginate microspheres offers several technical advantages: (i) the solid alginate microspheres can be liquefied within 60s, allowing a fast and complete harvest of hepatocytes; (ii) alginate capsules are stable allowing transport and mechanical stress; (iii) high numbers of hepatocytes can be encapsulated in short periods; (iv) defined cell numbers between 600 hepatocytes, the approximate number of cells in one capsule, and 18 x 10(6) hepatocytes, the number of hepatocytes in 6 ml alginate, can be transferred to a culture dish or flask. Thus, encapsulated hepatocytes allow a flexible organization of experiments with respect to cell number. In conclusion, we optimized a technique for encapsulation of hepatocytes in alginate microspheres that allows identification of enzyme induction with an improved sensitivity compared to existing systems.

Alginates↗
PubMed2005

Intranasal immunization of BALB/c mice with enterotoxigenic Escherichia coli colonization factor CS6 encapsulated in biodegradable poly(DL-lactide-co-glycolide) microspheres.

Mice were intranasally administered enterotoxigenic Escherichia coli colonization factor CS6 encapsulated in poly(DL-lactide-co-glycolide) microspheres (CS6-PLG), with immune response measured and compared to that of similarly administered native CS6 and CS6 plus mutant heat-labile enterotoxin mucosal adjuvant (CS6+mLT). Native CS6 and the CS6-PLG microspheres administered intranasally to mice induced serum IgG responses, with the CS6-PLG microspheres inducing a significantly greater (P<0.001) response than native CS6. Following intranasal administration of native CS6, no fecal IgG and IgA responses were measured; however, the CS6-PLG microspheres induced significantly greater (P<0.001) fecal IgG and IgA responses than native CS6. The coadministration of the mLT mucosal adjuvant with CS6 induced significantly greater serum (P<0.001) and fecal (P<0.01) responses than the CS6-PLG microspheres. However, following intranasal administration of the mLT adjuvant, the mice showed definite signs of distress, indicating an adverse reaction to the mLT. Thus, this brings into question the safety of the mLT and its use as an intranasal adjuvant. In contrast, the PLG-microspheres administered intranasally caused no noticeable distress to the mice. The results obtained in this study indicate that the encapsulation of CS6 in PLG-microspheres administered intranasally to mice acted in an adjuvant capacity to enhance the CS6 immune response.

Adjuvants, Immunologic↗
PubMed2000

Clarithromycin targeting to lung: characterization, size distribution and in vivo evaluation of the human serum albumin microspheres.

Microspheres of clarithromycin have been prepared from human serum albumin using the emulsion polymerization technique. Albumin microspheres containing the active substance were injected into the tail vein of mice. Mice were sacrificed at intervals and microspheres collected from lungs and livers. The clarithromycin amount in microspheres was determined by reversed phase high performance liquid chromatographic (HPLC) method from the mice organs. Morphological and histopathological observations were also reported. The microsphere accumulation began at 10 min, and increased gradually until 6 h, then a decrease was observed. The microspheres were still present after 24 h. In the liver sample, no microsphere accumulation was observed at any time.

Albumins↗
PubMed2002

Gamma irradiation effects and EPR investigation on poly(lactide-co-glycolide) microspheres containing bupivacaine.

The effects of gamma radiation on the stability of microspheres made of a polylactide-co-glycolide 50:50 copolymer (PLGA) and loaded with 40% bupivacaine (BU) were studied. The radiolysis mechanisms of BU and BU-loaded microspheres were investigated by using electronic paramagnetic resonance (EPR) analysis. Microspheres were prepared by means of a spray drying method. Gamma Irradiation was carried out in the open, at the dose of 25 kGy, by using a 60Co source. The stability of BU-loaded microspheres was evaluated over a 1-year period on the basis of drug content and dissolution profile. Non-irradiated microspheres were stable over the whole period under consideration. Immediately after irradiation the amount of BU released after 24 h from irradiated microspheres increased from 17 to 25%; in the following 3 months of storage it increased to about 35%, and then it kept constant for 1 year. Radicals generated by BU irradiation were identified by EPR analysis; the sensitivity to gamma radiation of BU was about four times lower than that of PLGA. Furthermore, the EPR spectra of loaded microspheres showed that the relative abundance of BU radicals plus PLGA radicals was proportionate to the electronic fractions of the components; this implies that no spin transfer BU/PLGA had occurred during gamma irradiation.

Alanine↗
PubMed2003

Histologic features of uterine leiomyomata treated with microsphere embolization.

BACKGROUND: Therapeutic embolization is a new treatment for symptomatic leiomyomata. Material available in the United States for uterine embolization includes precisely calibrated hydrophilic microporous microspheres made of a cross-linked acrylic copolymer. CASE: A 42-year-old woman with a longstanding history of symptomatic leiomyomatous uterus underwent uterine artery embolization with microspheres. Because of continuous intractable pelvic pain, an abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. The gross and histologic findings included large amounts of microspheres and pus within the uterine cavity, infarcted leiomyomata with microspheres, and intravascular microspheres within hyalinized leiomyomas. CONCLUSION: Microsphere embolization leads to hyalinizing and ischemic necrosis with residual microsphere material in the myometrium, uterine cavity, fallopian tubes, and ovaries.

Adult↗
PubMed2001

Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method.

The surface and internal morphology, drug distribution and release kinetics at 22 degrees C of polyesters such as PCL (polycaprolactone) and PLGA (poly(DL-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM (confocal laser scanning microscope) micrographs reveal that the polyvinylalcohol (PVA as an emulsifier) concentration in the external water phase strongly influences drug distribution within microspheres and release profiles. The presence of PVA in the internal water phase enhances the stabilization of inner water droplets against coalescence. This results in a more uniform drug distribution and a slower BSA release. Different oil-phase volumes and polymer concentrations yield different solvent exchange and precipitation mechanisms, which lead to different morphologies. A low oil-phase volume yields microspheres with a porous matrix and defective skin surface, which gives a high initial BSA burst as well as a fast release profile. Microspheres fabricated from a low polymer concentration have less defective skin surface, but with a less tortuous inner matrix which results in a more rapid BSA release. A higher BSA loading yields a larger concentration gradient between the emulsion droplet and the continuous water phase as well as between the microspheres and the in vitro medium. The former results in a lower encapsulation efficiency, whereas the latter yields a faster initial burst and a more rapid release profile. High stirring speed can reduce microsphere size, but decreases the yield of microspheres.

Biodegradation, Environmental↗
PubMed2003

Adipose tissue engineering based on human preadipocytes combined with gelatin microspheres containing basic fibroblast growth factor.

Gelatin microspheres containing basic fibroblast growth factor (bFGF) were prepared for the controlled release of bFGF. Co-implantation with the gelatin microspheres enabled preadipocytes to induce adipose tissue formation at the implanted site. Preadipocytes isolated from human fat tissue were suspended with the gelatin microspheres containing bFGF and incorporated into a collagen sponge of cell scaffold. Following subcutaneous implantation of the collagen sponge incorporating human preadipocytes, and gelatin microspheres containing 1 microg of bFGF into the back of nude mice, adipose tissue was formed at the implanted site of collagen sponge within 6 weeks postoperatively although the extent depended on the number of preadipocytes transplanted and the bFGF dose. The formation of adipose tissue was significant compared with the implantation of collagen sponge incorporating human preadipocytes and 1 microg of free bFGF. The area of adipose tissue newly formed was increased with the number of preadipocytes transplanted until to 1.0 x 10(5) cells/site and thereafter leveled off. The maximum area was observed at the bFGF dose of 1 microg/site. The area was significantly smaller at the bFGF dose of 0.5 microg/site or larger than 1 microg/site. Immunohistochemical examination indicated that the adipose tissue newly formed was composed of human matured adipocytes. No adipogenesis was observed at the implanted site of collagen sponge incorporating either gelatin microspheres containing bFGF or human preadipocytes and the mixed gelatin microspheres containing bFGF and human preadipocytes. We conclude that combination of gelatin microspheres containing bFGF and preadipocytes with the collagen sponge is essential to achieve tissue engineering of fat tissue.

Adipocytes↗
PubMed2004

The release profiles and bioactivity of parathyroid hormone from poly(lactic-co-glycolic acid) microspheres.

Poly(lactic-co-glycolic acid) (PLGA) microspheres containing bovine serum albumin (BSA) or human parathyroid hormone (PTH)(1-34) were prepared using a double emulsion method with high encapsulation efficiency and controlled particle sizes. The microspheres were characterized with regard to their surface morphology, size, protein loading, degradation and release kinetics, and in vitro and in vivo assessments of biological activity of released PTH. PLGA5050 microspheres degraded rapidly after a 3-week lag time and were degraded completely within 4 months. In vitro BSA release kinetics from PLGA5050 microspheres were characterized by a burst effect followed by a slow release phase within 1-7 weeks and a second burst release at 8 weeks, which was consistent with the degradation study. The PTH incorporated PLGA5050 microspheres released detectable PTH in the initial 24h, and the released PTH was biologically active as evidenced by the stimulated release of cAMP from ROS 17/2.8 osteosarcoma cells as well as increased serum calcium levels when injected subcutaneously into mice. Both in vitro and in vivo assays demonstrated that the bioactivity of PTH was maintained largely during the fabrication of PLGA microspheres and upon release. These studies illustrate the feasibility of achieving local delivery of PTH to induce a biologically active response in bone by a microsphere encapsulation technique.

Animals↗
PubMed2004

Studies on the microspheres comprised of reconstituted collagen and hydroxyapatite.

Microspheres comprised of hydroxyapatite particles, dispersed in reconstituted fibrous collagen, were prepared and characterized. The hydroxyapatite particles distributed evenly throughout the collagen matrix of the microsphere. Diameters of the reconstituted collagen fibers ranged from 30 to 90 nm, and exhibited a regular banding pattern with cross-striation of 50-60 nm under transmission electron microscope, suggesting that the reconstitution of collagen was not hindered by the hydroxyapatite particulates. When osteoblast cells isolated from newborn rat calvaria were seeded and cultured on the microspheres, the cell density increased from 2x10(4) to 3.2x10(4)cells/cm(2) in 8 days. Von Kossa staining exhibited spotty accumulation of mineral deposits on microspheres indicating matrix mineralization of the cultured cells. Analyses by electron microscopy and confocal microscopy showed that the osteoblast cells spread and attached to the microsphere via focal adhesion, while F-actin and DNA staining demonstrated the presence of stress fibers; moreover, mitotic cells could be observed. Together, these results indicate that osteoblast cells are capable of proliferating, differentiating and mineralizing in the matrix of the microspheres, and suggest that the microspheric composite is a potential grafting material for future clinical applications.

Animals↗
PubMed1997

Surface characterization of poly(alpha-hydroxy acid) microspheres prepared by a solvent evaporation/extraction process.

This work constitutes the first attempt to characterize the wettability of poly(alpha-hydroxy acid) (PAHA) microspheres in situ, prepared according to a complex process involving emulsification, solvent evaporation, washing and freeze-drying. The analysis of the flotation profile of the microspheres has allowed us to determine both advancing and receding contact angles at the microsphere/air/water interface and furnished information on the organization of poly(vinyl alcohol) (PVA) and bovine serum albumin (BSA) at the surface of the PAHA coating. By the comparison of contact angles measured from model surfaces obtained by sampling pure PAHA, PVA, BSA and mixed PVA/PAHA monolayers on glass and poly(methyl methacrylate) (PMMA) substrates, it was concluded that the emulsifier (PVA or BSA) was strongly anchored to the surfaces of the microspheres. The use of BSA to formulate the microspheres from a single oil-in-water emulsion led to dry particles having a hydrophobic surface. The unfolding of the hydrophilic segments of the BSA embedded at the surface of the microspheres, following immersion in water, increased the wettability of the microspheres by water. The same qualitative results were obtained when PVA was used to stabilize single emulsions. On the other hand, microspheres formulated from a double water-in-oil-in-water emulsion displayed no modifications of their wettability when immersed in water. This can be explained by the absence of mobility of the hydrophilic segments of the emulsifier which are blocked in the surface or at the subsurface of the polymer matrix.

Biocompatible Materials↗
PubMedDate not supplied

Preparation and characterization of pH-sensitive proteinoid microspheres for the oral delivery of methotrexate.

Prot A7, a polypeptidic proteinoid composed of seven different amino acids, was synthesized and microspheres of 1-5 microm size were prepared by the self-assembly process. The morphological characterization of the microspheres was carried out using optical microscopy and SEM (scanning electron microscopy). Emphasis also has been made on studying the mechanism behind the microsphere formation and to relate it with the conformation of the polypeptide. These self-assembled microspheres were found to be pH-sensitive in aqueous medium. The suitability of the Prot A7 microspheres as a carrier for gastric irritant drugs was verified by choosing methotrexate (MTX) as a model drug. MTX was entrapped in proteinoid microspheres and its utility for the oral delivery system was verified by carrying out the drug dissolution studies in simulated gastric medium (pH 1.2) and neutral medium of the blood (pH 7) under physiological conditions. The pH responsive dissolution behaviour of the microspheres was clarified.

Administration, Oral↗
PubMed2000

Microspheres for protein delivery prepared from amphiphilic multiblock copolymers. 1. Influence of preparation techniques on particle characteristics and protein delivery.

The entrapment of lysozyme in amphiphilic multiblock copolymer microspheres by emulsification and subsequent solvent removal processes was studied. The copolymers are composed of hydrophilic poly(ethylene glycol) (PEG) blocks and hydrophobic poly(butylene terephthalate) (PBT) blocks. Direct solvent extraction from a water-in-oil (w/o) emulsion in ethanol or methanol did not result in the formation of microspheres, due to massive polymer precipitation caused by rapid solvent extraction in these non-solvents. In a second process, microspheres were first prepared by a water-in-oil-in-water (w/o/w) emulsion system with 4% poly(vinyl alcohol) (PVA) as stabilizer in the external phase, followed by extraction of the remaining solvent. As non-solvents ethanol, methanol and mixtures of methanol and water were employed. However, the use of alcohols in the extraction medium resulted in microspheres which gave an incomplete lysozyme release at a non-constant rate. Complete lysozyme release was obtained from microspheres prepared by an emulsification-solvent evaporation method in PBS containing poly(vinyl pyrrolidone) (PVP) or PVA as stabilizer. PVA was most effective in stabilizing the w/o/w emulsion. Perfectly spherical microspheres were produced, with high protein entrapment efficiencies. These microspheres released lysozyme at an almost constant rate for approximately 28 days. The reproducibility of the w/o/w emulsion process was demonstrated by comparing particle characteristics and release profiles of three batches, prepared under similar conditions.

Drug Compounding↗
PubMed2001

In vitro uptake of polystyrene microspheres: effect of particle size, cell line and cell density.

Uptake of polycation-DNA particles is the first step in achieving gene delivery with non-viral vehicles. One of the important characteristics determining uptake of DNA particles is their size. Here we have characterized the ability of several cell lines to internalise labelled polystyrene microspheres of different sizes. All the cell lines tested ingested 20-nm microspheres avidly. With larger microspheres (93, 220, 560 and 1010 nm) cell type as well as growth related differences were observed. Whereas some cell lines (HUVEC, ECV 304 and HNX 14C) took up microspheres up to 1010 nm even when the cells were confluent, others did not take up many microspheres larger than 93 nm (Hepa 1-6 and HepG2). In one cell line (KLN 205), uptake of 93-, 220- and 560-nm microspheres was avid in growing cells, but not detectable when they were confluent. In KLN 205 cells, a good correlation was found between the uptake of 560-nm microspheres and the uptake of a peptide-DNA polyplex formulation, when it was prepared under conditions leading to small particle sizes. Little correlation was found when the polyplex formulation was allowed to aggregate.

Amino Acid Sequence↗
PubMed2001

Auto-catalyzed poly(ortho ester) microspheres: a study of their erosion and drug release mechanism.

A study has been carried out to investigate the degradation and protein release mechanisms of BSA-loaded microspheres made with auto-catalyzed poly(ortho esters) (POEs) of varying diol composition and molecular weights. Due to the instability of the POE/dichloromethane primary emulsion, microspheres made using the W/O/W double emulsion solvent extraction/evaporation method showed a multivesicular internal structure. An O/W single emulsion process yielded dense POE microspheres. Using electron scanning microscopy, the microspheres were observed to erode throughout their matrices with increasing internal pore sizes and a steady loss of mass. However, despite a substantial weight loss of almost 80% after an in vitro period of 129 days, the molecular weight of the polymer remained relatively unchanged with loss averaging about 18 and 32% for low- and high-molecular-weight POEs, respectively. Such constancy in molecular weight was similarly reflected in the glass transition temperature of the degrading microspheres. The differences in both the molecular weight loss and polydispersity index changes depended largely on the molecular weight of the polymer. For protein release of POE microspheres, an induction period followed by BSA release for a period of 3 to 10 days was observed. The lag time depended on the hydrophilicity and the molecular weight of the polymer as well as the morphology of the microspheres. Protein release was incomplete, possibly due to the slow degradation of the POE polymers, protein aggregation and protein degradation.

Acetates↗