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PubMedDate not supplied

Ibuprofen-loaded ethylcellulose/polystyrene microspheres: an approach to get prolonged drug release with reduced burst effect and low ethylcellulose content.

The aim of this study was to develop ethylcellulose microspheres for prolonged drug delivery with reduced burst effect. Ethylcellulose microspheres loaded with ibuprofen were prepared with and without polystyrene, which was used to retard drug release from ethylcellulose microspheres. Ibuprofen-loaded ethylcellulose microspheres with a polystyrene content of 0-25% were prepared by the solvent evaporation technique and characterized by drug loading, infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy. The in vitro release studies were performed to study the influence of polystyrene on ibuprofen release from ethylcellulose microspheres. The microspheres showed 28-46% of drug loading and 80-92% of entrapment, depending on polymer/drug ratio. The infrared spectrum and thermogram showed stable character of ibuprofen in the microspheres and revealed an absence of drug polymer interaction. The prepared microspheres were spherical in shape and had a size range of 0.1-4 microm. Ethylcellulose/polystyrene microspheres showed prolonged drug release and less burst effect when compared to microspheres prepared with ethylcellulose alone. Microspheres prepared with an ethylcellulose/polystyrene ratio of 80:20 gave a required release pattern for oral drug delivery. The presence of polystyrene above this ratio gave release over 24 h. To find out the mechanism of drug release from ethylcellulose/polystyrene microspheres, the data obtained from in vitro release were fitted in various kinetic models. High correlation was obtained in Higuchi and Korsmeyer-Peppas models. The drug release from ethylcellulose/polystyrene microspheres was found to be diffusion controlled.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

In vitro and in vivo release properties of brilliant blue and tumour necrosis factor-alpha (TNF-alpha) from poly(D,L-lactic-co-glycolic acid) multiphase microspheres.

The dissolution properties of two model compounds, brilliant blue and tumour necrosis factor (TNF-alpha), from poly(D,L-lactic-co-glycolic acid) (PLGA) multiphase microspheres were investigated. In addition, the in vivo release of TNF-alpha from the microspheres, in mice, was studied. The microspheres were prepared by an anhydrous multiple emulsion solvent evaporation method. Multiphase microspheres containing brilliant blue exhibited a three phase release profile in vitro, and displayed a significantly lower level of dye released during the initial phase compared to conventional matrix-type microspheres. Slow release of the dye was observed during the second phase, which was followed by a disintegration of the polymer wall during the third phase of the release process. In vitro dissolution profiles of TNF-alpha were calculated by compensation for the simultaneous degradation of the protein in the dissolution medium. The initial burst release of TNF-alpha was significantly reduced with the multiphase microspheres. The three phase release profile, as seen with the dye, was not observed for the microspheres containing the TNF-alpha. The rate of release of the protein from the microspheres was determined in vivo by analysing the residual level of TNF-alpha remaining in the particles following intraperitoneal administration of the microspheres to mice. The release of the protein from the microspheres in vivo was significantly faster than predicted from the results of the in vitro studies. The absence of an initial burst release of TNF-alpha from the multiphase microspheres was reflected in a significant reduction in the plasma level of TNF-alpha when compared to the matrix-type microspheres and a solution of the protein. The controlled release property of the multiphase microspheres is expected to overcome the adverse reactions due to dose dumping that occurs following the local administration of TNF-alpha.

Animals↗
PubMed1999

Stabilization of pH-induced degradation of porcine insulin in biodegradable polyester microspheres.

The purpose of this research project was to stabilize the pH-induced degradation of porcine insulin encapsulated within biodegradable polyester microspheres through the incorporation of a basic additive. Insulin microspheres fabricated using Poly(L-lactide) (L-PLA) and Poly(DL-lactide-co-glycolide) (50:50 DL-PLGA) were subjected to in vitro release studies and the stability of unreleased insulin encapsulated within microspheres was investigated. The intramicrosphere pH was estimated by encapsulating acid-base indicators covering a wide pH transition range within 50:50 DL-PLGA microspheres. Finally, a basic excipient sodium bicarbonate was incorporated in 50:50 DL-PLGA microspheres to minimize acid-induced insulin degradation. The in vitro release was slow and incomplete (< 30% in 30 days). Extraction and analyses of the unreleased insulin within the microspheres revealed that an average of approximately 11% remained intact. The degradation products observed consisted of approximately 15% of three distinct deamidated hydrolysis products including A-21 Desamido insulin, approximately 22% Covalent Insulin Dimer and trace amounts of High Molecular Weight Transformation Products. Comparison of the degradation profile of unreleased insulin contained in various microsphere formulations with the in vitro release kinetics indicated that an increase in covalent dimer formation within the microspheres prior to release is associated with a decrease in the cumulative percent insulin released during a 30-day incubation period. In an attempt to correlate insulin degradation with the drop in intra-microsphere pH due to polymer hydrolysis, it was determined that the pH within a degrading microsphere reaches a value of approximately 1.8 after 4 weeks. The incorporation of a basic excipient, sodium bicarbonate, in 50:50 DL-PLGA microspheres resulted in an improved in vitro release profile (cumulative release approximately 47.3% in 30 days) as well as a significant reduction in covalent dimerization of the unreleased insulin to barely detectable levels. The low pH microenvironment within a degrading microsphere is one of the major factors leading to protein instability, and the degradation of proteins encapsulated within polyester microspheres can be minimized by the incorporation of a basic excipient.

Animals↗
PubMed1995

Motor and blood pressure effects of epidural sustained-release bupivacaine from polymer microspheres: a dose-response study in rabbits.

The incorporation of local anesthetics into injectable polymer microspheres can be useful in providing prolonged regional effects. This randomized study was designed to compare the effects of bupivacaine and bupivacaine-loaded microspheres on the time course of motor block in rabbits injected epidurally. Bupivacaine-loaded microspheres and drug-free microspheres 1-10 microns in size were devised from poly-d,l-lactic acid by using a solvent evaporation/extraction method. The effects of bupivacaine and of similar amounts of bupivacaine-loaded microspheres were studied in 26 rabbits as follows: 0.9% sodium chloride, followed by drug-free microspheres, then 1.25 mg of bupivacaine and 1.25 mg of bupivacaine-loaded microspheres (Group I; n = 8); 2.5 mg of bupivacaine, then 2.5 mg of bupivacaine-loaded microspheres (Group II; n = 8); and 5 mg of bupivacaine and 5 mg of bupivacaine-loaded microspheres (Group III; n = 10). Motor block was evaluated blindly by observation of walking disturbances, using a scale from 0 (free movements) to 3 (total limb paralysis). A period of 3 days elapsed between each injection. No limitation on movements was observed after 0.9% sodium chloride and drug-free microsphere injection. With 5 mg, both bupivacaine solutions provided complete motor block which was significantly more prolonged (+244% +/- 129%, mean +/- SD) with bupivacaine-loaded microspheres than bupivacaine. With 2.5 and 1.25 mg, block intensity was less marked, and block duration was shorter after administration of bupivacaine-loaded microspheres than after bupivacaine. We concluded that blocks resulting from bupivacaine-loaded microspheres are highly influenced by the amount of drug initially released by the polymer.

Animals↗
PubMed2000

Immunogenicity of antigens in boiled alginate microspheres.

Vaccine efficacy can be enhanced by delivery of antigens in synthetic microspheres. The process of antigen incorporation into microspheres can expose fragile antigens to damaging conditions, such as high temperatures, and to bacterial contamination. Maintenance of immunogenicity of several antigens and reduction of bacterial load in alginate microspheres following boiling was evaluated. Mice were immunized subcutaneously, initially and again 21 days later, with either non-boiled or boiled microspheres containing ovalbumin (OVA), a culture supernatant vaccine of Pasteurella haemolytica (PHV), or a potassium thiocyanate extract of P. multocida (PTE). Serum samples were obtained prior to immunization and at the time of euthanasia 28 days later. Culture of microspheres showed that boiling completely eliminated aerobic bacterial growth for OVA-containing microspheres, and reduced growth by a factor of 10(4) for PTE microspheres. More bacteria were cultured after boiling than before for PHV microspheres. ELISA performed on serum and intestinal lamina propria explant supernatants showed that immunogenicity of PHV microspheres was not altered by boiling. Boiled OVA microspheres were still able to stimulate a significant serum IgG anti-OVA titer in mice, but boiled PTE microspheres completely lacked immunogenicity. Elispot assays of spleens showed that only PHV microspheres were able to retain immunogenicity after boiling. Results indicate that boiling is not an effective means for reducing the bacterial load of alginate microspheres and that the process is associated with a diminution of vaccine immunogenicity.

Alginates↗
PubMed2002

In vivo biocompatibility studies of poly(D,L-lactide)/poly(ethylene glycol)-poly(L-lactide) microspheres containing all-trans-retinoic acid.

Biocompatibility studies of all-trans-retinoic acid (RA)-loaded microspheres were carried out after they were subcutaneously injected into rats. To characterize the inflammatory response to these microspheres, tissue reactions at the implantation site and cell types in the interstices of the microspheres were evaluated for 180 days. On the 15th day, the cross-sectional area of the fibrous capsules surrounding the implantation site of the RA-loaded microspheres was four times larger than that of the control microspheres. The size of the fibrous capsules surrounding the implantation site of the RA-loaded microspheres decreased significantly over a period of 75 days, while the size of the fibrous capsules surrounding the implantation site of the control microspheres remained almost constant throughout the entire course of 180 days. The tissue response to the RA-loaded microspheres was more intensified by the increased extensive cellular infiltration of macrophages, granulation tissue, and fibrosis than that to the control microspheres. The difference in the inflammatory response between the RA-loaded microspheres and the control microspheres was significant for 75 days after implantation. It was suggested that the released RA from the microspheres stimulated inflammatory responses. However, no further enhanced inflammation reactions were detected after RA had been completely released from the microspheres.

Animals↗
PubMed1999

Neovascularization effect of biodegradable gelatin microspheres incorporating basic fibroblast growth factor.

Biodegradable microspheres were prepared through glutaraldehyde cross-linking of gelatin without using any surfactants as a carrier matrix of basic fibroblast growth factor (bFGF). In the in vitro system, bFGF was sorbed to microspheres of acidic gelatin with an isoelectric point (IEP) of 5.0, but not to those of basic gelatin with an IEP of 9.0. The rate of bFGF sorption to the acidic gelatin microsphere in phosphate-buffered saline solution (pH 7.4) was smaller than that in water. Following incorporation of bFGF into the microspheres at 4 degrees C for 12 h, bFGF release from the bFGF-incorporating microspheres was studied. Approximately 30% of incorporated bFGF was released from the acidic gelatin microsphere within the initial 3 h, followed by no substantial release, whereas the basic gelatin microsphere released almost completely the incorporated bFGF within 1 day. It is likely that when basic bFGF molecules were immobilized to the acidic gelatin constituting microspheres through polyion complexation, they were not readily released under the in vitro nondegradation condition of gelatin. Incorporation of anionic carboxylmethyl cellulose (CMC) into the acidic gelatin microspheres reduced the amount of bFGF desorbed initially. This indicates that the initial burst is ascribed to free bFGF which is not ionically interacted with the acidic gelatin. CMC will function as a bFGF sorbent to suppress the initial leakage from the microspheres. When injected subcutaneously into the mouse back, bFGF-incorporating acidic gelatin microspheres were degraded over time and induced neovascularization around the injection site, in marked contrast to bFGF in the solution form. CMC incorporation slowed down the biodegradation and vascularization effect of bFGF-incorporating gelatin microspheres. It was concluded that the gelatin microsphere was a promising carrier matrix of bFGF to enhance the vascularization effect.

Animals↗
PubMed2006

Microencapsulation of hemoglobin in chitosan-coated alginate microspheres prepared by emulsification/internal gelation.

Chitosan-coated alginate microspheres prepared by emulsification/internal gelation were chosen as carriers for a model protein, hemoglobin (Hb), owing to nontoxicity of the polymers and mild conditions of the method. The influence of process variables related to the emulsification step and microsphere recovering and formulation variables, such as alginate gelation and chitosan coating, on the size distribution and encapsulation efficiency was studied. The effect of microsphere coating as well its drying procedure on the Hb release profile was also evaluated. Chitosan coating was applied by either a continuous microencapsulation procedure or a 2-stage coating process. Microspheres with a mean diameter of less than 30 microm and an encapsulation efficiency above 90% were obtained. Calcium alginate cross-linking was optimized by using an acid/CaCO(3) molar ratio of 2.5, and microsphere-recovery with acetate buffer led to higher encapsulation efficiency. Hb release in gastric fluid was minimal for air-dried microspheres. Coating effect revealed a total release of 27% for 2-stage coated wet microspheres, while other formulations showed an Hb release above 50%. Lyophilized microspheres behaved similar to wet microspheres, although a higher total protein release was obtained with 2-stage coating. At pH 6.8, uncoated microspheres dissolved in less than 1 hour; however, Hb release from air-dried microspheres was incomplete. Chitosan coating decreased the release rate of Hb, but an incomplete release was obtained. The 2-stage coated microspheres showed no burst effect, whereas the 1-stage coated microspheres permitted a higher protein release.

Alginates↗
PubMed1998

Preparation and testing of cyclosporine microsphere and solution formulations in the treatment of polyarthritis in rats.

We prepared a microencapsulated sustained-release formulation of cyclosporine A (CsA) and compared its efficacy to the solution formulation of cyclosporine A (Sandimmune, Sandoz) in an attempt to improve the treatment of rheumatoid arthritis. Microspheres containing cyclosporine were prepared with poly(lactic co-glycolic acid) (PLGA), a polymer in the submicron particle range of 0.22-0.8 micron. Studies were carried out to determine uptake rates and mechanisms of lymphocyte inhibition mediated by macrophages containing CsA microspheres in vitro. The results of these studies were used to establish whether lower doses of the microencapsulated cyclosporine could be used in in vivo studies in the polyarthritic rat model for rheumatoid arthritis. In vitro dissolution testing revealed that CsA was released extremely slowly from microspheres for up to 48 hr (0.002%). Radiolabeled 3H CsA was incorporated into some PLGA microspheres or the microspheres were labeled using a 99mTc radioligand when needed, and radiolabeling efficiency was consistently above 50%. Uptake studies at various microsphere-to-macrophage ratios (1:1, 1:5, 1:10) were carried out using 99mTc radiolabeled microspheres and macrophages obtained from normal and polyarthritic rats. Normal macrophages behaved significantly differently from arthritic macrophages throughout the study. Arthritic macrophages cause increased amounts of CsA to be released (68% of the dose) into the culture medium past 24 hr compared to normal macrophages (48% of the dose). This factor may account for the significantly increased inhibition (68.2%) of mixed lymphocyte culture proliferation in the presence of arthritic macrophages containing CsA-loaded PLGA microspheres over normal macrophages (48.2%) that were pre-exposed to the same microsphere dose. The equivalent quantity of CsA as that contained in the microspheres when placed in solution or the same quantity of blank PLGA microspheres caused decreased levels of lymphocyte inhibition when compared to the effects of CsA microspheres in macrophages of normal cells, but significantly decreased levels of inhibition in arthritic cells. From the in vivo studies, it is evident that CsA microspheres, even at low dose levels, were highly effective in inhibiting polyarthritis in rats.

Animals↗
PubMed2002

Minocycline microspheres: a complementary medical-mechanical model for the treatment of chronic periodontitis.

Locally delivered antimicrobials represent an expanding class of therapeutics that may complement conventional mechanical treatments for chronic periodontitis. Currently available locally delivered antimicrobials include a tetracycline fiber, chlorhexidine chip, doxycycline gel, and newly approved minocycline microspheres. This last therapeutic is formulated to contain 3 mg polyglycolide-co-dl lactide (PGLA) copolymer and 1 mg of minocycline per unit (pocket) dose. As the polymer microspheres resorb, minocycline is released locally within the periodontal pocket at effective concentrations for at least 14 days. Recently, three phase 3 human clinical trials were conducted to assess the efficacy and safety of minocycline microspheres in patients with moderate-to-advanced chronic periodontitis. Data from an open-label trial involving 173 subjects indicated that minocycline microspheres plus scaling and root planing (SRP) at baseline produced significant improvements in pocket depth (PD) (> or = 1.5 mm) at 1 and 3 months. Retreatment with minocycline microspheres at 3 and 6 months maintained these improvements for 12 months. Two concurrent, blinded studies cumulatively recruited 748 periodontitis subjects who were randomized to SRP plus minocycline microspheres, SRP plus vehicle (placebo), or SRP alone at baseline. Minocycline microspheres or the vehicle were readministered per the randomization at 3 and 6 months. Patients receiving minocycline microspheres plus SRP exhibited significantly greater PD reduction at 1, 3, 6, and 9 months compared to patients receiving SRP plus vehicle or SRP alone. Overall, mean PD reduction with adjunctive minocycline-microsphere treatment increased when patients with more advanced periodontitis (mean PD > or = 6 mm or 7 mm) were considered. Similarly, significant improvements in clinical attachment level and percent bleeding on probing were observed among advanced periodontitis patients treated with SRP plus minocycline microspheres relative to controls. Patients treated with minocycline microspheres plus SRP were 50% more likely to shift to an overall mean PD < 5 mm or to a more maintainable case definition. No increased incidence of adverse events or tetracycline resistance were observed with minocycline-microsphere treatment. The data from these clinical trials indicate that minocycline microspheres plus SRP are safe in patients and more effective than SRP alone in reducting the signs of chronic periodontitis.

Analysis of Variance↗
PubMed2005

Immune responses in mice of beta-galactosidase adsorbed or encapsulated in poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres.

The immune response induced in mice by beta-galactosidase (beta-gal) adsorbed or encapsulated on poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres was investigated. The encapsulated protein elicited higher antibody response than the protein adsorbed on the microspheres in the case of the PLA microspheres. However, the encapsulated protein elicited weaker antibody response than the adsorbed protein in the case of the PLGA (50:50) microspheres, probably because, in this case, the encapsulation process adversely affected protein immunogenicity. In the case of adsorbed beta-gal, higher antibody response was obtained with the PLA microspheres than with the PLGA (50:50) microspheres. This may be related to the lower rate of beta-gal desorption from the PLA microspheres. Based on the immunoglobulin G1/immunoglobulin G2a ratios and the stimulation indices for interferon-gamma and interleukin-4, beta-gal encapsulated or adsorbed on PLA microspheres induced a Th(1)-biased immune response whereas beta-gal encapsulated or adsorbed on PLGA (50:50) microspheres induced a Th(2)-biased immune response. The results obtained indicate that more potent immune responses are obtained when the protein is encapsulated than adsorbed on the microspheres, providing that the encapsulation process does not adversely affect protein immunogenicity. Also, the type of polymer used to prepare the microspheres, but not the method of protein association with the microspheres, may affect the type of immune response.

Adsorption↗
PubMed1993

Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats.

The blood clearance and organ deposition of sterically stabilized (poloxamine-908 coated) polystyrene microspheres of two different sizes (60 and 220 nm in diameter) were compared in control and zymosan-stimulated rats 3 h after intravenous administration. Poloxamine coating dramatically decreased the uptake of 60-nm microspheres by organs of the reticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remained in the blood, but eventually a large fraction of these microspheres was filtered by the spleen. Daily administration of zymosan produced a marked increase in the intravascular clearance of the large, but not the small, poloxamine-coated microspheres. The enhanced intravascular clearance of large poloxamine-coated microspheres in zymosan-treated rats was the result of hepatic sequestration. On the other hand, the splenic filtration of these microspheres was depressed by 225% below the control values, despite the dramatic increase in spleen size of zymosan-treated rats. Preincubation of large poloxamine-coated microspheres in serum derived from both the control and zymosan-treated animals suggested that the enhanced hepatic uptake of large sterically stabilized microspheres following zymosan stimulation was not the result of "specific opsonization" processes. Instead, the changes in the proliferative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake of large poloxamine-coated microspheres, as opposed to smaller particles, is suggested to be due to differences in surface characteristics and the properties of microspheres. These may include differences in polymer density and the surface conformation of the polyoxyethylene segments of the polymer in the biological environment and the way they interact with both plasma components and the macrophage surface. These observations could be of importance in the use of sterically stabilized drug carriers for delivery of therapeutic agents to sites other than the reticuloendothelial system in clinical conditions associated with globally or regionally enhanced reticuloendothelial activity.

Animals↗
PubMed1996

Measurement of optic nerve blood flow with nonradioactive colored microspheres in rabbits.

The objective of this study was to establish a nonradioactive technique to accurately assess blood flow in a small tissue such as the anterior optic nerve. Colored microspheres, 10.2 +/- 0.23 microns in diameter, were injected into the left atrium in each of 17 anesthetized rabbits. The rabbits were divided into four groups injected, respectively, with 5, 10, 50, or 100 million microspheres. Microsphere quantification in the tissue was performed after postmortem dissection and alkaline corrosion of the anterior optic nerve. Blood flow was evaluated by means of reference sample comparison method. While the relative interocular difference (range, 15.3-162.8%) was not significantly different between the rabbits injected with 5, 10, or 50 million microspheres (Kruskal-Wallis test, P = 0.11), injection with 100 million microspheres yielded a significantly lower relative interocular differences (range 2.3-12.8%) compared to the other three groups (Kruskal-Wallis test, P = 0.0048). In addition, reproducibility of microsphere counts was evaluated by ranking the difference between right and left optic nerve in percentage of the average number of microspheres per milligram of tissue in both optic nerves. The correlation between the relative interocular difference (range, 2.3-162.8%) and the average number of microspheres per milligram of tissue (1.2-78.7 microspheres/mg optic nerve tissue) was statistically significant (Spearman R, -0.90; P < 0.0001). The interocular variability in microsphere counts and interocular difference in intraocular pressure did not correlate (Spearman R, 0.33; P = 0.20). The rabbits injected with 100 million microspheres showed the highest average number of microspheres (range, 31.8-78.7 microspheres/mg optic nerve tissue). The optic nerve blood flow ranged between 0.14 and 0.24 microliters/mg/min among the rabbits injected with 100 million microspheres. The present experimental technique of optic nerve blood flow measurement is relatively inexpensive, highly reproducible, and obviates disposal of radioactive materials.

Animals↗
PubMed1984

Disposition of 3-, 7-, and 13-microns microspheres instilled into lungs of dogs.

This study examined the lung retention and clearance of particles which differed only in their size. Radiolabeled polystyrene microspheres 3, 7, and 13 microns in real size, were instilled into the lungs of beagle dogs. A fiberoptic bronchoscope was used to distribute a 10-ml saline suspension of the microspheres among lung lobes of 24 dogs. The retention and clearance patterns of the microspheres were observed for 128 days after instillation. Tissue and excreta content of the radiolabel provided the basis for defining the fate of the microspheres or radiolabel dissolved from the microspheres. Approximately 2 to 3% of each size of the microspheres cleared the lung within a few days after the instillation procedure, primarily via the mucociliary escalator. Thereafter, the 3-microns microspheres cleared the lung with a biological retention half-time of 820 +/- 54 days; 7- and 13-microns microspheres were retained with biological retention half-times in excess of several thousand days and too long to be determined in this study. Approximately 1.7% of the instilled burden of 3-microns microspheres translocated to tracheobronchial lymph nodes during this 128-day study. Approximately 0.2% of the 7-microns microspheres and none of the 13-microns microspheres accumulated in tracheobronchial lymph nodes. From these data, it was concluded that microspheres or particles 7 microns or more real diameter may be retained indefinitely in the lungs of dogs after deposition by instillation. Similar results are predicted for humans for large particles deposited in the lung by inhalation.

Animals↗
PubMed2004

Plasmid-DNA loaded chitosan microspheres for in vitro IL-2 expression.

Interleukin-2 (IL-2) expression plasmid (pCXWN-hIL-2) loaded chitosan microspheres were evaluated for using in gene-based immunotherapy. Chitosan microspheres containing pCXWN-hIL-2 were prepared by using a precipitation technique. In addition, the effects of different factors such as the concentration (0.35-0.70%) and the molecular weight of chitosan (low and medium molecular weights), the plasmid amount (5-10 microg/ml) and the presence of glutaraldehyde during the encapsulation process, on microsphere characteristics were investigated. The size of microspheres changed between 1.45 and 2.00 microm. All the formulation factors affected the size of microspheres. The structure of plasmid remained unchanged during the encapsulation process and the release studies. Plasmid encapsulation efficiency of chitosan microspheres was high (82-92%). The zeta potential values of microspheres was approximately +5.2 to +12.4 mV. In vitro release properties of microspheres changed with formulation variables. In vitro release of DNA changed with the concentration and molecular weight of chitosan and initial plasmid amount. Addition of glutaraldehyde is not necessary for a formulation. MAT-LyLu, the rat prostate adenocarcinoma cell line, was used for the determination of the in vitro transfectional activity of IL-2 encoding plasmid DNA loaded chitosan microspheres and the level of IL-2 expressed into the cells was assayed using a ELISA kit. High level of IL-2 expression was obtained with plasmid-loaded chitosan microspheres. Microspheres showed similar IL-2 production as lipofectin. The molecular weight of chitosan used and the amount of plasmid influenced the in vitro IL-2 production in the cells. Encapsulation of IL-2 encoding gene into chitosan microspheres might be a useful strategy to increase the expression and to control the delivery of cytokine gene to cells.

Animals↗
PubMed2005

Activated leukocytes and endothelial cells enhance retention of ultrasound contrast microspheres containing perfluoropropane in inflamed venules.

PURPOSE: To characterize the flow dynamics of albumin ultrasound contrast microspheres containing perfluoropropane (PFP) in normal and inflamed microvasculature. MATERIALS AND METHODS: Mesenteric microvessels of rats were examined after an intravenous injection of fluorocein-labeled erythrocytes or PFP microspheres by fluorescence intravital microscopy with and without local application of 10(-8) M platelet activating factor (PAF) as an experimental form of inflammation. RESULTS: All the microspheres passed freely through arterioles and capillaries. Mean velocities of the microspheres in each vessel were closely correlated with those of erythrocytes. Only a minor fraction of the microspheres was retained in the venules (> or =0.1 s stoppage) by attachment to endothelial cells. The frequency of microsphere retention in venules was significantly enhanced by PAF (2.6+/-2.1%, P<0.01 vs. control), especially in regions with leukocyte adhesion. Treatment with a monoclonal antibody to intercellular adhesion molecule-1, P-selectin or the common leukocyte antigen inhibited PAF-induced microsphere retention in venules (P<0.05). In the inflamed microcirculation, a small subgroup of microspheres becomes attached to venular endothelial cells in regions with leukocyte adhesion via interaction among microspheres, activated leukocytes and endothelial cells via adhesion molecules. CONCLUSION: In inflamed microcirculation, a small subgroup of microspheres becomes attached to venular endothelial cells in regions with leukocyte adhesion via interaction among microspheres, activated leukocytes and endothelial cells via adhesion molecules. These results suggest that ultrasonography with microspheres has the potential to evaluate inflammatory site distribution as well as tissue perfusion.

Animals↗
PubMed2004

Stomach-specific anti-H. pylori therapy; part III: effect of chitosan microspheres crosslinking on the gastric residence and local tetracycline concentrations in fasted gerbils.

The main objective of the present study was to examine the effect of chemical crosslinking of chitosan microspheres on the gastric residence and local tetracycline concentrations following oral administration in fasted gerbils. Radioiodinated [125I] glyoxal-crosslinked chitosan microsphere suspension in deionized distilled water was administered for the gastric residence studies. At different time points, the animals were sacrificed and the radioactivity in tissues and fluids was measured. Stomach tetracycline concentrations were determined using tritiated-[3H]-tetracycline-loaded crosslinked chitosan microspheres. The radioactivity, measured with a liquid scintillation analyzer, was used to determine the microgram of drug per gram of tissues or fluids. After 2 h in the fasted stomach, approximately 10% of the non-crosslinked chitosan microspheres remained. On the other hand, 17% of the crosslinked chitosan microspheres remained in the fasted stomach after the same time period. The microspheres were predominantly found in the colon after 6 h of administration. There was no detectable radioactivity in the plasma, urine, small intestine, liver, and kidneys. Tetracycline concentration profile in the stomach from the crosslinked microsphere formulation was higher than that of the aqueous solution and the non-crosslinked microsphere formulation. While the area-under-the-curve (AUC(0.5-->10 h)) for tetracycline solution and non-crosslinked chitosan microspheres was 447.3 and 358.2 microg h/g of tissue, respectively, the AUC(0.5-->10 h) for the crosslinked chitosan microspheres was 868.9 microg h/g of tissue. The drug was predominantly found in the colon and urine after 6 h of administration. Results of this study show that chitosan microspheres prepared by chemical crosslinking provide a longer residence time in the fasted gerbil stomach than either tetracycline solution or microspheres prepared by ionic precipitation.

Administration, Oral↗
PubMed2004

Evaluation of the clearance characteristics of various microspheres in the human nose by gamma-scintigraphy.

The nasal cavity possesses many advantages as a site for drug delivery, such as; ease of administration, applicability for long-term treatments and a large surface area for absorption. One important limiting factor for nasal drug delivery is the limited time available for absorption within the nasal cavity due to mucociliary clearance. Several drug delivery systems including different kinds of microspheres have been tried for encapsulation of drugs and increasing the residence time in nasal cavity. In this study the clearance rate of three kinds of microspheres (Alginate, PLGA, and Sephadex) was determined by gamma-scintigraphy with lactose powder being used as negative control. (99m)Tc labeled microspheres were prepared using technetium pertechnetate in the presence of a potent reducing agent, stannus chloride. The labeling procedure was set in a manner that each 3-5 mg of microspheres contained 2 MBq of radioactivity. Labeling efficiency was calculated by paper chromatography using acetone as a mobile phase. Each delivery system containing 2 MBq of activity was administered into right nostril of four healthy volunteers and 1 min static views were repeated each half an hour until 4 h. Clearance rates were compared using two regions of interest (ROIs); the initial site of deposition of particles, and all of the nasopharynx region. The clearance rate of each one of microspheres was calculated after applying the physical decay corrections. The mean labeling efficiencies for Alginate, PLGA, and Sephadex microspheres were calculated as 60%, 59%, and 74%, respectively. The cleared percent of formulations from nasopharynx region after 4 h was determined as follows: PLGA microspheres 48.5 +/- 8.2%; Alginate microspheres 45.0 +/- 0.8%; Sephadex microspheres 63.1 +/- 3.4%; lactose powder 74.5 +/- 4.9%. Alginate and PLGA microspheres showed the lowest clearance rate compared to lactose powder (P < 0.0001 and P < 0.001, respectively), followed by Sephadex microspheres (P < 0.01). The clearance profiles of formulations from deposition ROI and nasopharynx ROI were identical. This study shows that Alginate and PLGA microspheres have the highest mucoadhesion properties and are suitable nasal delivery systems. Futhermore, this study proves that limiting step for the nasal clearance of nasally administered particulate systems is their dislocation from the initial site of deposition, and their following interactions with mucus layer in the rest of the nasal passage does not significantly affect the clearance time.

Adult↗