Radiating resin microspheres in the treatment of cancer: the endoarterial administration of 32p- and 51cr-labeled microspheres.
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Animals↗
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[Studies on the applicability of 99m Tc-labelled human albumin microspheres ( 99m Tc-HAM) for perfusion scintigraphy of the lung. I. Physical properties and organ distribution of 99m Tc-labelled human albumin microspheres].
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Animals↗
[Experimental observations on the injection of microspheres of resin labeled with P32 in the medullary canal of the long bones. Changes in behavior in relation to the varying caliber of the microspheres].
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Animals↗
[Effects of lidocaine on impairment of learning and memory function and cholinergic system caused by cerebral microsphere embolism in rats].
OBJECTIVE: To investigate the effects of lidocaine on impairment of learning and memory function and cholinergic system caused by cerebral microsphere embolism in rats. METHODS: Healthy male Wister rats were randomly divided into the following groups. (1) Control group. (2) 600 microsphere group and 900 microsphere group, in which 600 or 900 microspheres were injected into the right internal carotid artery, respectively. (3) 600 treatment group and 900 treatment group, in which 600 or 900 microspheres were injected into the right internal carotid artery, respectively, and lidocaine was given. Water maze tasks were tested for 5 consecutive days from the 7th postoperative day. The rats were then decapitated and regions of cerebral cortex, hippocampus, and striatum were selected. The activities of choline acetyltransferase and cholinesterase and the binding activity of muscarinic receptor were determined. RESULTS: (1) The latency periods were significantly longer in the 900 microsphere group than in the control group and in the 600 microsphere group. (2) The percentages of effective search strategy were significantly lower in the 600 and 900 microsphere groups than in the control group. They were significantly higher in the 600 and 900 treatment groups than in the corresponding microsphere groups. (3) The activities of choline acetyltransferase of cerebral cortex were significantly lower in the 900 microsphere and two treatment groups than in the control group. They were also significantly lower in the 600 and 900 treatment groups than in the corresponding microsphere groups. Those of striatum were all significantly lower in the microsphere and treatment groups than in the control group. (4) The activities of cholinesterase of cerebral cortex were significantly lower in the 900 microsphere group than in the control and 600 microsphere groups. They were significantly higher in the 900 treatment group than in the 900 microsphere group. Those of hippocampus were all significantly lower in the microsphere and treatment groups than in the control group. (5) The binding activities of muscarinic receptor of cerebral cortex were significantly lower in the 900 microsphere and two treatment groups than in the control group. They were also significantly lower in the two treatment groups than in the corresponding microsphere groups. Those of hippocampus and striatum were all significantly lower in the microsphere and treatment groups then in the control group. They were also significantly lower in the 600 or 900 treatment group than in the corresponding microsphere group. CONCLUSION: Cerebral microsphere embolism caused significant and quantity-dependent impairment of learning and memory function and cholinergic system in rats. Lidocaine alleviated learning and memory dysfunction caused by cerebral microsphere embolism, but further inhibited the parameters of central cholinergic system.
Animals↗
Development and characterization of Ni-NTA-bearing microspheres.
BACKGROUND: For ease of purification, proteins are often expressed with a short affinity sequence of five or six adjacent histidine residues (His-tag). This His-tag binds to the metal of metal chelator complexes such as Ni(2+)-nitrilotriacetic acid (Ni-NTA) or -iminodiacetic acid (Ni-IDA). Chromatography resins bearing covalently attached metal chelator complexes are used widely for the easy affinity purification of His-tagged proteins or peptides. Because Ni-NTA microspheres were not commercially available at the beginning of our studies, we prepared and characterized such microspheres to immobilize His-tagged proteins and study their interactions. Our microspheres are of three types: (a) metal chelator complexes bound covalently to polystyrene microspheres, (b) metal chelator complexes bound covalently to silica microspheres, and (c) lipid-linked metal chelator complexes adsorbed to silica microspheres forming self-assembled bilayer membranes where the metal chelators have lateral mobility. METHODS: The microspheres bearing covalently attached Ni-chelator were synthesized by reacting a primary amine-bearing Ni-NTA ligand with carboxy-functionalized microspheres and then loading with Ni(2+). Microspheres with laterally mobile metal chelator were made by incubating glass microspheres with liposomes containing phosphatidylcholine (PC) and the metal chelating lipid 1,2-dioleoyl-sn-glycero-3-[(N (5-amino-1-carboxypentyl)iminodiacetic acid)succinyl]. Binding of a His-tagged enhanced green fluorescent protein (EGFP) was used to characterize these microspheres by flow cytometry for their specificity, sensitivity, capacity and stability. RESULTS: While all micospheres specifically bind His-tagged proteins, the conditions to achieve this are different for the polystyrene- and silica-based spheres. All three types of microspheres bind His-EGFP with saturation occurring at 30-50 nM and an apparent avidity (concentration of half-maximal binding) of approximately 1 to 2 x 10(-8) M at pH 7.4. Binding of His-EGFP is inhibited by imidazole or ethylene-diaminetetraacetic acid (EDTA). Polystyrene Ni-NTA microspheres showed significant nonspecific binding as measured by binding in the presence of imidazole or EDTA or by binding of fluorescent proteins lacking a His-tag. This nonspecific binding of proteins to and aggregation of polystyrene spheres could only be prevented by the inclusion of low concentrations of Tween 20, but not by including bovine serum albumin (BSA), polyethylene glycols, or polyvinylpyrrolidones as blocking agents. In contrast, silica-based microspheres with covalently attached Ni-NTA or silica microspheres bearing adsorbed bilayers that contain Ni-NTA-lipid showed little nonspecific binding in the presence of BSA. Our results on the stability of immobilization indicate that washing destabilizes the binding of His-tagged proteins to Ni-NTA microspheres. This binding consists of two interactions of different affinities. We also demonstrate that limited multiplexed analysis with differently sized silica microspheres bearing the Ni-NTA-lipid is feasible. CONCLUSIONS: The microspheres described are well suited to selectively immobilize His-tagged proteins to analyze their interactions by flow cytometry. The affinity and kinetic stability of the interaction of His-tagged proteins with Ni-NTA are insufficient to use Ni-NTA microspheres in multiplexed analysis formats where different His-tagged proteins are bound to distinct microspheres. Improvements towards this end (improved chelators and/or improved affinity tags) are critical for extending the use of this method. We are currently working on novel chelators to strengthen the stability of immobilization of His-tagged proteins to surfaces. Such improvements would greatly enhance the analysis of interactions of immobilized His-tagged proteins and could make the development of microsphere-based arrays with His-tagged protein/antibody possible.
Binding Sites↗
Determination of protein loading in biodegradable polymer microspheres containing tetanus toxoid.
Various methods to determine loading of vaccine in biodegradable polymer microspheres encapsulating tetanus toxoid were evaluated. The microspheres were composed of poly (D-lactic acid) (PLA) and poly (DL-lactic-co-glycolic acid) (PLGA). Dissolution of microspheres in organic solvents such as methylene chloride, chloroform, or dimethyl sulfoxide and extraction of vaccine antigen or total protein with phosphate buffered saline gave variable results which depended upon the characteristics of the microspheres, such as type of polymer, excipients used in the microspheres and formulation conditions. Microspheres made from low molecular weight PLGA polymer and showing a large burst release exhibited up to 25% extraction of antigen whereas microspheres made from PLA microspheres with low burst release showed < 1% extraction. Extraction of total protein with 0.1 N NaOH and 5% sodium dodecyl sulfate showed results similar to those obtained with organic solvent extraction method. Partial digestion of microspheres with 6 N HCl at 60 degrees C for 20 h resulted in approximately 30% loss in TT protein by micro-bicinchoninic acid (BCA) assay. The major problem with this method was strong reactions in the micro-BCA assay of stabilizers, particularly sugars (glucose, sucrose) used in the microsphere formulations. Complete digestion of microspheres with 6 N HCl at 110 degrees C for 20 h or with 13.5 N NaOH at 121 degrees C for 1 h and quantitation of amino acids by a modified ninhydrin assay showed reproducible results on the protein loading in the microspheres. However, this method was affected by the presence of stabilizers, such as gelatin, which contain amino acids. Further, sucrose concentrations higher than 10% caused interference in the ninhydrin assay on samples hydrolyzed with 6 N HCl. In contrast, hydrolysis with 13.5 N NaOH did not show any interference by sucrose. Stabilizers used outside the microspheres for lyophilization purposes may be removed by washing the microspheres before loading determination or by dialysis but stabilizers used inside the microspheres would still cause interference. For reliable determination of total protein in the microspheres containing vaccines, we suggest complete digestion of microspheres with acid or base followed by amino acid analysis by colorimeteric assays such as ninhydrin method or using amino acid analyzers. The method needs to be optimized for each type of formulation to eliminate interference by the excipients. Alternatively, total protein nitrogen in the microspheres may be determined by the Kjel-dahl method if no amino acids or other nitrogen containing stabilizer is used inside the microspheres.
Antigens, Bacterial↗
In vitro and in vivo evaluation of mucoadhesive microspheres prepared for the gastrointestinal tract using polyglycerol esters of fatty acids and a poly(acrylic acid) derivative.
Two types of polyglycerol ester of fatty acid (PGEF)-based microspheres were prepared: Carbopol 934P (CP)-coated microspheres (CPC-microspheres) and CP-dispersion microspheres (CPD-microspheres). Comparative studies on mucoadhesion were done with these microspheres and PGEF-based microspheres without CP (PGEF-microspheres). In an in vitro adhesion test, the CPD-microspheres adhered strongly to mucosa prepared from rat stomach and small intestine because each CP particle in the CPD-microsphere was hydrated and swelled with part of it remaining within the microsphere and part extending to the surface serving to anchor the microsphere to the mucus layer. The gastrointestinal transit patterns after administration of the CPD-microspheres and PGEF-microspheres to fasted rats were fitted to a model in which the microspheres are emptied from the stomach monoexponentially with a lag time and then transit through the small intestine at zero-order. Parameters obtained by curve fitting confirmed that the gastrointestinal transit time of the CPD-microspheres was prolonged compared with that of the PGEF-microspheres. MRT in the gastrointestinal tract was also prolonged after administration of the CPD-microspheres compared with that following the administration of the PGEF-microspheres.
Acrylates↗
A comparative biocompatibility study of microspheres based on crosslinked dextran or poly(lactic-co-glycolic)acid after subcutaneous injection in rats.
Microspheres based on methacrylated dextran (dex-MA), dextran derivatized with lactate-hydroxyethyl methacrylate (dex-lactate-HEMA) or derivatized with HEMA (dex-HEMA) were prepared. The microspheres were injected subcutaneously in rats and the effect of the particle size and network characteristics [initial water content and degree of methacrylate substitution (DS)] on the tissue reaction was investigated for 6 weeks. As a control, poly(lactic-co-glycolic)acid (PLGA) microspheres with varying sizes (unsized, smaller than 10 microm, smaller and larger than 20 microm) were injected as well. A mild tissue reaction to the PLGA microspheres was observed, characterized by infiltration of macrophages (MØs) and some granulocytes. Six weeks postinjection, the PLGA microspheres were still present. However, their size was decreased indicating degradation and many spheres had been phagocytosed. The tissue reaction was hardly affected by size differences, except for particles smaller than 10 microm, which induced an extensive tissue reaction. The initial tissue reaction to nondegradable dex-MA microspheres was stronger than towards the PLGA microspheres, but at day 10 the tissue reactions were comparable for both groups. Six weeks postinjection, the dex-MA microspheres were completely phagocytosed, and no signs of degradation were observed. The size and initial water content of dex-MA microspheres hardly affected the tissue response, although less granulocytes were observed for microspheres with higher DS. Slowly degrading dextran microspheres composed of dex-(lactate(1)-)HEMA induced a tissue reaction comparable to the PLGA microspheres. However, degradation of the dex-(lactate(1,3)-)HEMA microspheres was associated with an increased number of MØ's and giant cells, both phagocytosing the microspheres and their degradation products. Similar to PLGA, no adverse reactions were observed for the nondegradable dex-MA and degradable dextran microspheres. This study shows that both nondegradable and degradable dextran-based microspheres are well tolerated after subcutaneous injection in rats, which make them interesting candidates as controlled drug delivery systems.
Animals↗
Preparation, characterization, and in vitro evaluation of physostigmine-loaded poly(ortho ester) and poly(ortho ester)/poly(D,L-lactide-co-glycolide) blend microspheres fabricated by spray drying.
The physostigmine-loaded poly(ortho ester) (POE), poly(dl-lactide-co-glycolide) (PLGA) and POE/PLGA blend microspheres were fabricated by a spray drying technique. The in vitro degradation of, and physostigmine release from, the microspheres were investigated. SEM analysis showed that the POE and POE/PLGA blend particles were spherical. They were better dispersed when compared to the pure PLGA microspheres. Two glass transition temperature ( Tg ) values of the POE/PLGA blend microspheres were observed due to the phase separation of POE and PLGA in the blend system. XPS analysis proved that POE dominated the surfaces of POE/PLGA blend microspheres, indicating that the blend microspheres were coated with POE. The encapsulation efficiencies of all the microspheres were more than 95%. The incorporation of physostigmine reduced the Tg value of microspheres. The Tg value of the degrading microspheres increased with the release of physostigmine. For instance, POE blank microspheres and physostigmine-loaded POE microspheres had a Tg value of 67 degrees C and 48 degrees C, respectively. After 19 days in vitro incubation, Tg of the degrading POE microspheres increased to 55 degrees C. Weight loss studies showed that the degradation of the blend microspheres was accelerated with the presence of PLGA because its degradation products catalyzed the degradation of both POE and PLGA. The release rate of physostigmine increased with increase of PLGA content in the blend microspheres. The initial burst release of physostigmine was effectively suppressed by introducing POE to the blend microspheres. However, there was an optimized weight ratio of POE to PLGA (85:15 in weight), below which a high initial burst was induced. The POE/PLGA blend microspheres may make a good drug delivery system.
Body Fluids↗
Effects of lung surfactants on rifampicin release rate from monodisperse rifampicin-loaded PLGA microspheres.
We have prepared inhalable and monodisperse poly(lactide-co-glycolide) (PLGA) microspheres targeting tubercle bacilli residing in alveolar macrophages. The effects of pulmonary surfactant on the rifampicin (RFP) release rate from RFP-loaded poly (lactide-co-glycolide) microspheres were studied. Also, those of their surface properties of RFP-loaded PLGA microspheres were studied. The RFP release from RFP/PLGA microspheres was accelerated by adsorption of pulmonary surfactant on the particle surface. The fastest RFP release rate was observed from pulmonary surfactant-adsorbed PLGA particles in pH 7.4 buffer solution compared with those in pH 4.0 buffer solution and saline solution. The slowest release rate was observed in the case when saline solution was used as dispersion phase of RFP/PLGA microspheres, although RFP release rate increased by the addition of pulmonary surfactant. From these results it is suggested that when RFP/PLGA microspheres are administrated by inhalation, the RFP release rates from the particles which are not taken up by alveolar macrophages and remain in the alveoli will be small. On the other hand, the RFP release rates and release amounts will be high after RFP/PLGA microspheres are taken up by alveolar macrophages existing in phagosomes, but they become relatively small after RFP/PLGA microspheres move into phagosome-lysosomes by the fusion of phagosomes with lysosomes. The absolute values of the electrophoretic mobility of PLGA microspheres increased by the adsorption of pulmonary surfactants on the surfaces of PLGA microspheres. By analyzing the experimental data using the soft-particle theory, it was indicated that the microspheres became 'softer' and the surface charge density of microspheres increases by the degradation. On the other hand, the surface of PLGA microspheres became harder and the electric charge density increased by the adsorption of pulmonary surfactant on the surfaces of PLGA microspheres. The changes in the surface charge density with degradation became larger by the adsorption of the lung surfactant on PLGA microsphere surfaces. It is considered that the changes in surface properties of PLGA microspheres affect their uptake efficiency by alveolar macrophage.
Humans↗
Evaluation of gelatin microspheres for nasal and intramuscular administrations of salmon calcitonin.
The suitability of gelatin microspheres for nasal and intramuscular delivery of salmon calcitonin (sCT) was examined. Negatively and positively charged gelatin microspheres were prepared using acidic gelatin [isoelectric point (IEP) value of 5.0] and basic gelatin (IEP=9.0), respectively. The average diameters of positively charged gelatin microspheres in their dried state were 3.4, 11.2, 22.5 and 71.5 microm, while that of negatively charged gelatin microspheres was 10.9 microm. Both types of gelatin microspheres were capable of adhering to the nasal mucosa. The mucoadhesion of positively charged gelatin microspheres was significantly higher than that of their negatively charged counterparts. The absorption of sCT after intranasal and intramuscular administration was evaluated by calculating the area above the hypocalcemic-time curve (AAC) in rats. The AAC values after nasal administration of sCT in positively and negatively charged gelatin microspheres were significantly greater than that in pH 7.0 PBS. Therefore, the nasal absorption of sCT was enhanced by both types of gelatin microspheres. The hypocalcemic effect after administration of sCT in positively charged gelatin microspheres of 11.2 microm was significantly greater than that of negatively charged gelatin microspheres of the same size. On the other hand, AAC values were not affected by their particle sizes. The AAC values after the intramuscular administration of sCT in positively and negatively charged gelatin microspheres were significantly increased compared to that in PBS. Furthermore, the time-courses of the plasma calcium levels differed between positively and negatively charged gelatin microspheres. The hypocalcemic effect of the negatively charged gelatin microspheres tended to appear more slowly and last longer compared to that of positively charged gelatin microspheres. The hypocalcemic effects after intramuscular administration of sCT in gelatin microspheres were not affected by their particle sizes as well as those after intranasal administration. In conclusion, the gelatin microspheres have been shown to be a useful vehicle for nasal or intramuscular delivery of sCT.
Administration, Inhalation↗
In vitro release of ibuprofen and gentamicin from PMMA functional microspheres.
Drug-containing microspheres based on synthetic polymers such as poly(methyl methacrylate) (PMMA) and PMMA derivatives are known for their medical applications, particularly for hard tissue repair and regeneration. In our earlier work, we have reported that the synthesis of PMMA and carboxyl group-containing PMMA functional (PMMA-F) microspheres and these microspheres were fully characterized by various techniques. In the present investigation, an attempt was made to prepare drug-containing PMMA (without carboxylic functional groups) and PMMA-F (with carboxylic functional groups) microspheres by solvent evaporation technique. The presence of characteristic groups in the drug-containing PMMA and PMMA-F microspheres was confirmed using 1H-FT-NMR spectroscopy. Equilibrium swelling experiments of both microspheres was carried out in pH 7.4 phosphate buffer and pH 1.2 gastric medium. PMMA-F microspheres were able to float in the pH 1.2 and 7.4 media, whereas PMMA microspheres settled in both. Optical and scanning electron micrographs indicated that the microspheres are spherical and porous in nature. The carboxylic groups of PMMA-F microspheres were coupled with amino groups of gentamicin using 1-ethyl-3(3-dimethylpropyl) carbodiamide as coupling agent, whereas in the case of PMMA microspheres, the gentamicin was incorporated in the porous site of the microspheres. The ibuprofen drug was incorporated in the porous site of PMMA and PMMA-F microspheres. The cumulative in vitro release profiles of gentamicin and ibuprofen from PMMA and PMMA-F microspheres were performed in PBS pH 7.4 at 37 degrees C. It shows that gentamicin containing PMMA-F microspheres releases the drug ones a longer period compared to PMMA microspheres.
Anti-Bacterial Agents↗
Gelatin microspheres as a pulmonary delivery system: evaluation of salmon calcitonin absorption.
The use of negatively and positively charged gelatin microspheres for pulmonary delivery of salmon calcitonin was examined in rats. The microspheres were prepared using acidic gelatin (isoelectric point (IEP):, 5.0) and basic gelatin (IEP, 9.0) for the negatively and positively charged microspheres, respectively. The average diameters of positively charged gelatin microspheres in the dry state were 3.4, 11.2, 22.5 and 71.5 microm, and that of negatively charged gelatin microspheres was 10.9 microm. Neither positively nor negatively charged gelatin microspheres underwent any degradation in pH 7.0 PBS and there was less than 8% degradation in bronchoalveolar lavage fluid (BALF) after 8 h. In in-vitro release studies in pH 7.0 PBS, salmon calcitonin was rapidly released from positively charged gelatin microspheres within 2 h, and its cumulative release was approximately 85%. In addition, the release profiles were not influenced by particle sizes. The release rates of salmon calcitonin from negatively charged gelatin microspheres were lower than that from positively charged gelatin microspheres. The cumulative release was approximately 40% after 2 h, but there was no evidence of any sustained release. The pulmonary absorption of salmon calcitonin from gelatin microspheres was estimated by measuring its hypocalcaemic effect in rats. The pharmacological availability after administration of salmon calcitonin in positively and negatively charged gelatin microspheres was significantly higher than that in pH 7.0 PBS. The pharmacological availability after administration of salmon calcitonin in positively charged gelatin microspheres was significantly higher than that in negatively charged gelatin microspheres. Administration of salmon calcitonin in positively charged gelatin microspheres with smaller particle sizes led to a higher pharmacological availability. The pharmacological availability after pulmonary administration of salmon calcitonin in positively charged gelatin microspheres with particle sizes of 3.4 and 11.2 microm was approximately 50%. In conclusion, the gelatin microspheres have been shown to be a useful vehicle for pulmonary delivery of salmon calcitonin.
Analgesics↗
Biodegradable microspheres targeting mucosal immune-regulating cells: new approach for treatment of inflammatory bowel disease.
Several studies have indicated that active monocytes, such as macrophages and T cells, play an important role in the pathogenesis of chronic human inflammatory bowel disease (IBD), although the etiology remains unclear. Manipulation of these cells appears essential for the treatment of patients with IBD. Recently, considerable attention has been paid to the use of polymer microspheres for the sustained release of various drugs and the targeting of therapeutic agents to their site of action. It was reported that biodegradable poly-D,L-lactic acid (PDLLA) microspheres can be efficiently taken up by macrophages and M cells. We evaluated the effect of a new drug delivery system targeting microfold cells and macrophages with PDLLA microspheres and gelatin microspheres (GM) on colitis models. In the first experiment, colitis was induced in Balb/c mice by 5% dextran sodium sulfate, and microspheres containing dexamethsone (Decadrone, Dx; Dx microspheres) were orally administered to these mice. Serum levels of Dx did not reach a detectable level after administration of Dx microspheres. The tissue distribution of microspheres containing 125I-Dx in inflamed colon was significantly higher than that in other organs. The histological score, myeloperoxidase activity, and nitric oxide production of mice treated with Dx microspheres were significantly lower than in those treated with Dx alone. Gene expression of proinflammatory cytokines was remarkably downregulated in mice treated with Dx microspheres compared to Dx alone. Next, we investigated the effect of elimination of resident macrophages using microspheres containing dichloromethylene diphosphonate (DMDP) on IL-10 knockout mice. We administered DMDP microspheres to IL-10 KO mice rectally and assessed whether this reagent could reduce the number of local Mac-1-positive cells in the intestine and suppress the development of colitis in IL-10 KO mice. DMDP microspheres reduced the numbers of resident macrophages in the colon of IL-10 KO mice but did not reduce the percentage of Mac-1-positive cells in the spleen, peritoneal cavity, or mesenteric lymph nodes. Depletion of intestinal macrophages significantly suppressed development of chronic colitis in IL-10 KO mice, however. Third, we developed gelatin microspheres containing IL-10, which can be released sustainedly to a local site without losing bioactivity. We administered these microspheres to IL-10 KO mice rectally to investigate whether this treatment can ameliorate colitis. Colonic inflammation in mice treated with GM-IL-10 is remarkably reduced compared to those treated with IL-10 alone. Moreover, expression of CD 40 on Mac-1-positive cells treated with GM-IL-10 is decreased more notably than in mice treated with IL-10 alone. These data suggest that a drug delivery system using these microspheres containing immunomodulatory agents may be a therapeutic approach to human IBD.
Absorbable Implants↗
Effect of preparation temperature on the characteristics and release profiles of PLGA microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method.
This study describes the influence of preparation temperature on the various characteristics and release profiles of poly(DL-lactide-co-glycolide) (PLGA) microspheres. The bovine serum albumin (BSA)-loaded microspheres were prepared using the water-in-oil-in-water (w/o/w) technique with poly(vinyl alcohol) as surfactant in the external aqueous phase. We have varied the preparation temperature to observe its effect on microsphere characteristics such as the microsphere shrinking rate during formation, particle size, density, surface and internal morphology, BSA encapsulation efficiency, BSA initial release, microsphere degradation and BSA in vitro release behaviour. During fabrication, a low preparation temperature of 5 degrees C gives the fastest initial but the slowest overall shrinking rate. Microspheres formed at high temperatures of 38 degrees C and 42 degrees C on the other hand have the lowest initial yet the highest overall shrinking rate. Subsequently, microsphere mean size increases and the particle size distribution widens with increase in the preparation temperature. Although all the microspheres have a porous surface as well as internal structure, microspheres fabricated at high temperatures have a uniform internal pore distribution and a very thin dense skin layer, while microspheres fabricated at lower temperatures have a thicker but porous skin layer and bigger pores in the middle of the sphere. Microspheres formed at 33 degrees C are found to give the highest initial burst release. In terms of in vitro release, microspheres fabricated at low temperatures (5 degrees C, 15 degrees C and 22 degrees C) exhibit similar, steady rates. Microspheres formed at higher temperatures however give very low release rates after their initial release. The results obtained suggest that preparation temperature significantly affects microsphere formation, resulting in their structural and protein release profile differences. These differences ultimately work together to affect the initial release and overall release patterns of the microspheres.
Algorithms↗
Effect of isopropyl myristic acid ester on the physical characteristics and in vitro release of etoposide from PLGA microspheres.
The purpose of this paper was to study the effect of the isopropyl myristic acid ester (IPM) on the physicochemical characteristics of etoposide-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres-specifically, the effects on the size and drug loading of the microspheres, the polymer matrix and surface morphology, and the release of etoposide from the microspheres. The experiment was structured to examine 2 IPM concentrations (25% and 50%) and 1 control (no IPM) at 2 different etoposide-loading percentages (10% and 5%). The microspheres were prepared using a single-emulsion solvent-extraction procedure. Samples from each batch of microspheres were then analyzed for size distribution, drug-loading efficiency, surface characteristics, in vitro release, and in vitro microsphere degradation. The incorporation of 50% IPM significantly increased (P <.05) the size of the microspheres when compared with the control and 25% IPM microspheres. However, incorporation of 25% or 50% IPM did not change (P >.05) the drug-loading efficiency in comparison with the microspheres prepared without IPM. The microspheres containing 50% IPM were shown to significantly increase (P <.05) the release of etoposide from the microspheres at both etoposide concentrations. The microspheres prepared incorporating 25% IPM and 5% etoposide increased the in vitro release (P <.05) in comparison with the microspheres prepared without IPM. The 5% etoposide-PLGA microspheres showed a smooth, nonporous surface that changed to a dimpled, nonporous surface after addition of 25% IPM. During the in vitro degradation study, the IPM-containing microspheres slowly became porous but retained their structural integrity throughout the experiment.
Delayed-Action Preparations↗
Preparation of biodegradable microspheres and matrix devices containing naltrexone.
In this study, the use of biodegradable polymers for microencapsulation of naltrexone using solvent evaporation technique is investigated. The use of naltrexone microspheres for the preparation of matrix devices is also studied. For this purpose, poly(L-lactide) (PLA) microspheres containing naltrexone prepared by solvent evaporation technique were compressed at temperatures above the Tg of the polymer. The effect of different process parameters, such as drug/polymer ratio and stirring rate during preparation of microspheres, on the morphology, size distribution, and in vitro drug release of microspheres was studied. As expected, stirring rate influenced particle size distribution of microspheres and hence drug release profiles. By increasing the stirring speed from 400 to 1200 rpm, the mean diameter of microspheres decreased from 251 microm to 104 microm. The drug release rate from smaller microspheres was faster than from larger microspheres. However, drug release from microspheres with low drug content (20% wt/wt) was not affected by the particle size of microspheres. Increasing the drug content of microspheres from 20% to 50% wt/wt led to significantly faster drug release from microspheres. It was also shown that drug release from matrix devices prepared by compression of naltrexone microspheres is much slower than that of microspheres. No burst release was observed with matrix devices. Applying higher compression force, when compressing microspheres to produce tablets, resulted in lower drug release from matrix devices. The results suggest that by regulating different variables, desired release profiles of naltrexone can be achieved using a PLA microparticulate system or matrix devices.
Biodegradation, Environmental↗
Controlled release of interleukin-2 from chitosan microspheres.
Chitosan microspheres were evaluated for sustained-release of recombinant human interleukin-2 (rIL-2) in this study. In addition, the effects of different formulation factors, such as chitosan and protein concentrations, the volume of sodium sulfate solution, addition technique of rIL-2, and presence of glutaraldehyde during the encapsulation process, on microsphere characteristics were investigated. Chitosan microspheres containing rIL-2 were prepared by using the precipitation technique. The average diameter of microspheres was between 1.11-1.59 microm. Recombinant IL-2 encapsulation efficiency in these microspheres was high (75-98%). Formulation factors had no effect on the microsphere size. Recombinant IL-2 had been released from chitosan microspheres over a period of 3 months. The encapsulated rIL-2 remained biologically active and could be completely recovered from the release medium. Briefly, rIL-2 was released from chitosan microspheres in a sustained manner. The efficacy of rIL-2 loaded chitosan microspheres was studied using two model cells, HeLa and L-strain cell lines. Chitosan microspheres were added to the cells at different concentrations, and the amount of rIL-2 was assayed using the ELISA kit. Cell culture studies indicated that microspheres were uptaken by cells, and rIL-2 was released from the microspheres. Cellular uptake of rIL-2-loaded microspheres was dose dependent. It can be said that chitosan microsphere is a suitable carrier for rIL-2 delivery.
Cell Culture Techniques↗