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PubMedDate not supplied

Preparation of enteric-coated microspheres of Mycoplasma hyopneumoniae vaccine with cellulose acetate phthalate: (II). Effect of temperature and pH on the stability and release behaviour of microspheres.

The in vitro stability (temperature and pH) and dissolution study (pH 7.4 phosphate buffer solution and pH changed medium) of the enteric-coated microspheres containing Mycoplasma hyopneumoniae vaccine (MHV) were examined. The MHV microspheres were thermally more stable than the unencapsulated MHV. More than 90% of antigenicity was retained in the MHV microspheres for 3 weeks when stored at 4 degrees C. The MHV microspheres in pH 1.2 and pH 3.0 medium were more stable than the unencapsulated MHV. The MHV enteric-coated microspheres exhibited an excellent enteric function to prevent pH-related inactivation. The influence of particle size, CAP concentration and span 80 concentration on the MHV released from microspheres was also determined. The smaller the particle size, the higher the dissolution rate due to the larger surface area of the smaller particle. The higher the concentration of span 80 used, the more the greater the amount of MHV released. This was attributed to the more porous structure of microspheres prepared by the higher concentration of span 80. By increasing the CAP concentration, however, the release rate of MHV was decreased due to the larger amount of CAP and the more compact structure of microspheres.

Animals↗

PubMed2006

Cross-linked starch microspheres: effect of cross-linking condition on the microsphere characteristics.

Cross-linked starch microspheres were prepared using different kinds of cross-linking agents. The influence of several parameters on morphology, size, swelling ratio and drug release rate from these microspheres were evaluated. These parameters included cross-linker type, concentration and the duration of cross-linking reaction. Microspheres cross-linked with glutaraldehyde had smooth surface compared with those prepared with epichlorhydrine or formaldehyde. The particle size increased with increasing the cross-linking time and increasing the drug loading. Swelling ratio of the particles was a function of cross-linker type but not the concentration or time of cross-linking. Drug release from starch microspheres was measured in phosphate buffer and also in phosphate buffer containing alpha-amylase. Results showed that microspheres cross-linked with epichlorhydrine released all their drug content in the first 30 minutes. However, cross-linking of the starch microspheres with glutaraldehyde or formaldehyde decreased drug release rate. SEM and drug release studies showed that cross-linked starch microspheres were susceptible to the enzymatic degradation under the influence of alpha-amylase. Changing the enzyme concentration from 5000 to 10,000 IU/L, increased drug release rate but higher concentration of enzyme (20,000 IU/L) caused no more acceleration.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1995

Glutaraldehyde cross-linked chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle.

Chitosan microspheres were prepared from 74% deacetylated chitin by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of liquid paraffin and petroleum ether stabilized using sorbitan sesquioleate as the surfactant. Cross-linking and hardening of the spherical particles were achieved by the addition of glutaraldehyde-saturated toluene through the organic phase. A relatively novel antineoplastic agent, mitoxantrone, was incorporated into the microspheres and the drug release was studied in vitro into phosphate buffer for over 4 weeks at 27 degrees C. Drug release was found to be effectively controlled by the extent of cross-linking. Only about 25% of the incorporated drug was released over 36 days from microspheres of high cross-linking density. Implantation of placebo chitosan microspheres in the skeletal muscle of rats was carried out in order to assess the biocompatibility and biodegradability of the microspheres. Histological analysis showed that the microspheres were well tolerated by the living tissue. However, no significant biodegradation of the material was noticed over a period of 3 months in the skeletal muscle of rats. Data obtained indicate the possibility of using cross-linked chitosan microspheres as a drug carrier for sustained drug release for very long periods.

Animals↗

PubMed2006

Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres.

The biodegradable chitosan microspheres containing vancomycin hydrochloride (VANCO) were prepared by spray drying method with different polymer:drug ratios (1:1, 2:1, 3:1 and 4:1). Thermal behaviour, particle size and distribution, morphological characteristics, drug content, encapsulation efficiency, in vitro release assessments of formulations have been carried out to obtain suitable formulation which shows sustained-release effect when implanted. Sterilized VANCO loaded microspheres were implanted to proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Intramuscular (IM) injection of VANCO for 21 days was applied to another group for comparison. After 3 weeks of treatment, bone samples were analysed with a microbiological assay. According to the results, encapsulation efficiency and yield of microspheres in all formulations were higher than 98% and 47%, respectively. Particle sizes of microspheres were smaller than 6 microm. All microsphere formulations have shown sustained-release effect. In vitro drug release rate decreased due to the increase in polymer:drug ratio but no significant difference was seen between these results (p>0.05). Based on our in vivo data, rats implanted VANCO-loaded chitosan microspheres and administered IM injection showed 3354+/-3366 and 52500+/-25635 colony forming unit of MRSA in 1g bone samples (CFU/g), respectively. As a result, implanted VANCO-loaded microspheres were found to be more effective than IM route for the treatment of experimental osteomyelitis.

Animals↗

PubMed2006

Microsphere-integrated collagen scaffolds for tissue engineering: effect of microsphere formulation and scaffold properties on protein release kinetics.

A promising approach to control the time and space distribution of signalling molecules inside tissue engineering scaffolds consists in entrapping biodegradable microspheres releasing the protein locally for long time frames. However, a rational design of microsphere-integrated scaffolds requires the knowledge of protein release profiles directly within the polymeric template. In this work, PLGA microspheres encapsulating rhodamine-labelled bovine serum albumin (BSA-Rhod) as a model protein were produced in different formulation conditions and tested for their release features in solution and in collagen and collagen/hyaluronic acid (HA) scaffolds. BSA-Rhod release profiles from single microspheres in solution and within the scaffold were assessed by using a confocal laser scanning microscopy (CLSM)-assisted method. Results suggest that the same diffusion-erosion process controls BSA-Rhod release from microspheres in solution and collagen. Nonetheless, two main factors contribute protein release within the scaffold, that is water activity in the release environment and transport properties of the protein in the gel. While microsphere formulation mainly controls the induction time necessary to activate protein release, polymer scaffold composition governs the release rate. Thus, the fine regulation of a tissue engineering construct may be obtained by an appropriate combination of microspheres and scaffolds, providing a spatial and temporal control over signalling molecule delivery.

Animals↗

PubMed1999

Porous chitosan microsphere for controlling the antigen release of Newcastle disease vaccine: preparation of antigen-adsorbed microsphere and in vitro release.

Porous chitosan microspheres suitable for the delivery of antigen were prepared using a wet phase-inversion method. The pore structure of the chitosan microsphere could be modified by the change of pH value of the coagulation medium, which is the aqueous tripolyphosphate (TPP) solution. High porosity of chitosan microsphere with an open porous structure on its surface was prepared by coagulation in TPP aq. solution of pH 8.9. The porous chitosan microspheres were modified chemically with reagents to introduce three types of functional groups; carboxyl, hydrophobic acyl and quaternary ammonium groups. Antigen of ND vaccine was immobilized into the pores of porous chitosan microspheres and the adsorbed antigen was assayed by the Hemoglobin Aggregation (HA) analytical method. Sustained-release of ND vaccine's antigen could be achieved through an adsorption-desorption release test. The chemical modifications of the porous chitosan microspheres have a strong large influence on the adsorption efficiency or release rates of the antigen investigated. The porous microspheres have a higher adsorption efficiency and the slower release rate of antigen when modified chemically with 3-chloro-2-hydroypropyltrimethylamonium chloride.

Adsorption↗

PubMed1998

Polyorganophosphazene microspheres for drug release: polymer synthesis, microsphere preparation, in vitro and in vivo naproxen release.

Microsphere preparation for naproxen slow release was investigated using two newly prepared biodegradable polyorganophosphazenes, derivatized at the phosphorus atoms with phenylalanine ethyl ester and imidazole at molar ratios of 71/29 and 80/20. The polymers were prepared by substitution of the chloride atoms of polydichlorophosphazene with a phenylalanine ethyl ester-imidazole mixture followed, after 7 or 48 h reaction, by the addition of excess imidazole. Three methods of microsphere preparation have been considered: spray-drying, emulsion/solvent evaporation and emulsion/solvent evaporation-extraction. Microparticles obtained by spray-drying were found to possess a narrow distribution size with a mean diameter of 2-5 microm. Their internal structure consisted of a porous or empty core depending upon the solvent used for the preparation. Furthermore the microspheres prepared with this technique rapidly released the entrapped naproxen independently of the used polymer, the drug loading or the preparation process. On the other hand microspheres prepared by solvent evaporation or solvent evaporation-extraction showed a distribution size ranging between 10 and 100 microm. By the appropriate choice of pH and solvent composition of the external phase, naproxen could be entrapped, in these microspheres, with a yield higher of 80%. The polymer composition dictates the in vitro release rate of naproxen from the particles, which was faster when the microspheres were prepared with the polymer at higher imidazole content. In vivo experiments, carried out by subcutaneous implantation in rats of microspheres prepared by solvent evaporation, demonstrated that a constant level of naproxen in plasma could be maintained up to 400 h at a suitable concentration for antinflammatory activity.

Animals↗

PubMed1991

In vitro release profile of mitomycin C from albumin microspheres: extrapolation from macrospheres to microspheres.

To analyze the in vitro release profiles of mitomycin C from albumin microspheres prepared by chemical denaturation in a multiparticulate system, a method to calculate the total cumulative amount of mitomycin C released from a batch of microspheres was developed. Mitomycin C-loaded albumin macrospheres (diameter in mm range) were prepared, and the in vitro release kinetics of mitomycin C from individual macrospheres were determined. Then the relationship between the kinetic parameters and the physical parameters (e.g., diameter, weight) was investigated under the assumption that macrospheres and microspheres behave identically. Further, the size distribution of microspheres was measured, and the total cumulative amount of mitomycin C released from albumin microspheres was calculated. The release profiles of mitomycin C from individual macrospheres fitted first-order release kinetics better than spherical matrix kinetics. The calculated initial mitomycin C contents and first-order release rate constants for individual macrospheres were correlated with the weight and reciprocal of surface area of the macrospheres, respectively. The observed in vitro release profile for the microspheres agreed with the calculated values. These results suggest that this method is valid for calculating drug release from albumin microspheres.

Albumins↗

PubMedDate not supplied

In vitro controlled release of bupivacaine from albumin microspheres and a co-matrix formed by microspheres in a poly(lactide-co-glycolide) film.

Albumin microspheres cross-linked with glutaraldehyde and loaded with bupivacaine, a local anaesthetic, were synthesized (138 +/- 59 microm diameter). A matrix formed by bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film was prepared in order to improve the controlled release of the drug. In vitro release of the drug was determined in phosphate buffer at 37 degrees C in the absence and in the presence of protease type VIII to mimic a biological system. The effect of temperature and protease on bupivacaine as a function of time was examined; both of them cause a degradative effect on the drug. A rapid release (60 +/- 8% of the drug) takes place at 1 h, and maximum release is found at 50 +/- 6 h from microspheres with swelling. In the presence of protease, maximum release of bupivacaine from microspheres is found at 28 +/- 2 h; the microspheres disappear at 8 days. Inclusion of bupivacaine-loaded microspheres in a poly(lactide-co-glycolide) film causes a slower release of the drug, up to 18 days, with swelling. In the presence of protease, the polymer protects bupivacaine-loaded microspheres from degradation, which takes place at 20 days.

Animals↗

PubMed2005

Preparation of cross-linked chitosan microspheres by spray drying: effect of cross-linking agent on the properties of spray dried microspheres.

Chitosan microspheres cross-linked with three different cross-linking agents viz, tripolyphosphate (TPP), formaldehyde (FA) and gluteraldehyde (GA) have been prepared by spray drying technique. The influence of these cross-linking agents on the properties of spray dried chitosan microspheres was extensively investigated. The particle size and encapsulation efficiencies of thus prepared chitosan microspheres ranged mainly between 4.1-4.7 microm and 95.12-99.17%, respectively. Surface morphology, % erosion, % water uptake and drug release properties of the spray dried chitosan microspheres was remarkably influenced by the type (chemical or ionic) and extent (1 or 2% w/w) of cross-linking agents. Spray dried chitosan microspheres cross-linked with TPP exhibited higher swelling capacity, % water uptake, % erosion and drug release rate at both the cross-linking extent (1 and 2% w/w) when compared to those cross-linked with FA and GA. The sphericity and surface smoothness of the spray dried chitosan microspheres was lost when the cross-linking extent was increased from 1 to 2% w/w. Release rate of the drug from spray dried chitosan microspheres decreased when the cross-linking extent was increased from 1 to 2% w/w. The physical state of the drug in chitosan-TPP, chitosan-FA and chitosan-GA matrices was confirmed by the X-ray diffraction (XRD) study and found that the drug remains in a crystalline state even after its encapsulation. Release of the drug from chitosan-TPP, chitosan-FA and chitosan-GA matrices followed Fick's law of diffusion.

Acetaminophen↗

PubMed2000

Comparison of various injectable protein-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices: in-situ-formed implant versus in-situ-formed microspheres versus isolated microspheres.

The purpose of this research was to prepare various injectable, protein (cytochrome c)-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices by a novel microencapsulation method and to compare their characteristics. Syringeable mixtures of polymer and protein solidified upon injection when coming in contact with water, and formed a solid matrix-type implant or microspheres (in-situ-formed implant or in-situ-formed microspheres, respectively) with cytochrome c entrapped. These devices exhibited different characteristics in terms of in vitro cytochrome c release profile, percentage cytochrome c encapsulation efficiency, and particle size. The burst effect from these devices exhibited the following trend: in-situ-formed implant > in-situ-formed microspheres > isolated microspheres. The in-situ-formed microspheres were larger in size than the isolated microspheres. Also, the isolated microspheres exhibited the slowest release of cytochrome c, whereas the in-situ-formed implant exhibited the fastest release. The microencapsulation process can produce various drug-loaded injectable biodegradable PLGA devices having different characteristics.

Cytochrome c Group↗

PubMed1994

Casein as a carrier matrix for 5-fluorouracil: drug release from microspheres, drug-protein conjugates and in-vivo degradation of microspheres in rat muscle.

Glutaraldehyde cross-linked casein microspheres were loaded with 5-fluorouracil (5-FU) from concentrated aqueous solutions of the drug after the microspheres were synthesized and cleaned. In-vitro release of the drug was examined in phosphate buffer in the absence and in the presence of protease at 37 degrees C. Drug release data showed that only about 20% of the drug is released in the absence of protease even after 5 days, while digestion of the matrix with protease released the entrapped drug completely in about 24 h. A protein-drug conjugate was synthesized via carbamoyl linkage using 6-(5-FU-1-yl)hexyl isocyanate and the drug release was examined in phosphate buffer at 37 degrees C. Release from the protein-5-FU conjugate was slower compared with the release from microspheres in the presence of protease. Implantation of placebo microspheres of different cross-linking densities in the gluteal muscle of rats showed no adverse tissue reactions over a one-year period. Histopathological examination of the tissues containing injected microspheres suggested that the biological life of casein microspheres in muscle is about 6 months, which is three times that of cross-linked albumin microspheres.

Albumins↗

PubMed2003

Etanidazole-loaded microspheres fabricated by spray-drying different poly(lactide/glycolide) polymers: effects on microsphere properties.

In this work, a spraying technique was used to encapsulate etanidazole (a hypoxic radiosensitizer) into different poly(lactide/glycolide) polymers. The properties of the obtained microspheres, especially the particle size and distribution, morphology and release rate were investigated. Unexpectedly, poly(L-lactide) (PLLA) shows a fast release rate, comparable to PLGA 50: 50, due to the dissociation of the microspheres although the release rate of the spray-dried microspheres of other polymers decreases with increasing lactide ratio. It is also interesting to note that, contrary to the viscosity sequence of the polymer solutions, the particle size of the microspheres decreases in the order PLGA 50: 50, PLGA 65: 35, PLGA 85: 15 and PDLA. The morphology of microspheres can be affected by polymer properties (e.g. lactide/glycolide ratio, molecular weight, crystallinity and Tg) and fabrication conditions (e.g. solvent and polymer concentration to be sprayed). Although most of the microspheres fabricated by EA have a donghnut-like shape with smooth surface, it is possible to obtain spherical particles by choosing proper polymer type and polymer concentration. A further examination of the mechanisms of the atomization process and the solvent evaporation process reveals their respective effect on droplet formation and particle formation, both of which are essential for the spray-drying technique. It is found that polymer phase transition (affected by the polymer solubility) and its subsequent solvent evaporation processes can finally determine the morphology and the particle size of the spray-dried particles made from different polymers. In essence, the lactide/glycolide ratio of the polymers plays a more important role in affecting the properties of the spray-dried microspheres.

Biocompatible Materials↗

PubMedDate not supplied

Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation technique. II. Some process parameters influencing the preparation and properties of microspheres.

D,L-polylactic acid (PLA) microspheres containing quinidine base and quinidine sulphate were prepared by the solvent evaporation method. The present study was carried out to examine how various process parameters in the aqueous phase influenced the preparation and properties of PLA-microspheres. The amount of drug that could be incorporated into the microspheres depended primarily on the solubility of the drug in the aqueous phase and the precipitation of PLA at the droplet surface. The drug content was found to be influenced by the organic solvent: aqueous phase ratio, the temperature of the aqueous phase, and the amount of emulsifying agent. Time-dependent pH-change studies in the aqueous phase showed that polymer precipitation at the outer surface of the microspheres, and drug loss due to partitioning, occurred rapidly. A partition method for increasing the payload of drug in the microspheres was developed by incorporating drug in both the aqueous and the organic phases. Using this method, drug could be loaded into the microspheres independent of the pH of the aqueous media. The partition method circumvented the surface degradation observed with PLA microspheres prepared at high pH values of the aqueous phase. This method may prove useful for the entrapment of water-soluble drugs.

Hydrogen-Ion Concentration↗

PubMedDate not supplied

Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation method. III. Morphology of the microspheres during dissolution studies.

Poly(dl-lactide) (PLA) microspheres containing quinidine or quinidine sulphate were prepared by the emulsification-solvent evaporation technique. The in vitro release profile of quinidine or quinidine sulphate from the microspheres was characterized by three phases: a lag time, a rapid release phase (burst), and a slow release phase. Drug release was studied as a function of the ionic strength of the dissolution medium, to demonstrate the importance of the water imbition into the microspheres which induced the drug release. The lag time increased with increasing ionic strength. The microspheres stayed intact during the dissolution study as shown by scanning electron microscopy (SEM). Disintegration of microspheres which was initially observed was an artifact introduced during the SEM procedure. The high vacuum applied either during the coating of the microspheres with gold-palladium or during the actual observation in the scanning electron microscope caused the microspheres to collapse or rupture.

Chemical Phenomena↗

PubMed2004

Paclitaxel loaded poly(L-lactic acid) (PLLA) microspheres. II. The effect of processing parameters on microsphere morphology and drug release kinetics.

The kinetics of solvent removal in microsphere preparation and their effect on the morphology and release characteristics of paclitaxel-loaded PLLA microspheres were determined. Microspheres were analyzed by SEM and DSC and in vitro paclitaxel release was monitored by HPLC. During manufacture, dichloromethane evaporated at a constant rate, which increased with dispersion stirring speed and decreased with increasing paclitaxel content. Paclitaxel-loaded microspheres had a dimpled surface, due to surface deposition of the drug, while controls were smooth. In the formation of larger microspheres, the deposition of drug in the surface slowed the solidification process resulting in drug-loading dependent thermal properties. Paclitaxel release did not follow diffusion kinetics, rather it was characterized by a large burst followed by a linear phase. We speculate that non-uniform (surface-rich) drug distribution in the microspheres may contribute to the deviation from the theoretical pattern of kinetics for diffusion from a sphere.

Calorimetry, Differential Scanning↗

PubMed2005

Development of a single dose tetanus toxoid formulation based on polymeric microspheres: a comparative study of poly(D,L-lactic-co-glycolic acid) versus chitosan microspheres.

Stable polymeric microspheres capable of controlled release of tetanus toxoid (TT) for periods ranging from days to over months were developed. TT was stabilized, encapsulated in microspheres prepared from poly(D,L)-lactide-co-glycolide (PLGA) and chitosan by using protein stabilizer (trehalose) and its immune response was compared. The influence of co-encapsulated protein stabilizer on tetanus toxoid's stability and release from the microspheres was studied. The protein stabilizer (trehalose) prevented structural losses and aggregation of microencapsulated TT. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polymer, we also co-incorporated into the polymer an antacid, (Mg(OH)2), which neutralized the acidity during degradation of the polymer and also prevented TT structural losses and aggregation. The in vitro release experiments with PLGA and chitosan microspheres were performed and the release of TT was increased up to 80-90%. The antigen integrity was investigated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by coomassie brilliant blue staining. The SDS-PAGE analysis confirmed that antigen integrity was not affected by the encapsulation procedure. In addition, the immunogenicity of PLGA and chitosan microspheres based single dose vaccine was evaluated in guinea pigs and compared with multiple doses of alum adsorbed TT. Results indicated that a single injection of PLGA and chitosan microspheres containing TT could maintain the antibody response at a level comparable to the booster injections of conventional alum adsorbed vaccines. The both PLGA and chitosan based stable vaccine formulations produced an equal immune response. Hence chitosan can be used to replace the expensive polymer PLGA. This approach should have potential application in the field of vaccine delivery.

Animals↗

PubMedDate not supplied

Sustained release properties of alginate microspheres and tabletted microspheres of diclofenac sodium.

This study focused on the properties of diclofenac sodium (DNa) alginate (alg) microspheres and tabletted DNa alg microspheres using different polymers as additives. DNa alginate microspheres were prepared by the emulsification method and different polymers such as Eudragit (Eud) NE 30 D, Eudragit (Eud) RS 30 D and Aquacoat, which were incorporated into alg gel to control the release rate of drug. The release properties of DNa alg microspheres (1:1) were affected by the size, drug load of microspheres and also by the incorporated polymers, pH and ionic strength of dissolution medium. Tabletting of alg microspheres using carrageenan (carr), alg, pectin, NaCMC, tragacanth (trgh) and HPMC as additives in a (50:50) ratio produced tablets with good physical properties and also better controlled release of DNa. Dissolution studies were carried out in pH 7.2 phosphate buffer and phosphate buffers whose pH values were gradually changed from pH 3 to 7.4. The rank order of DNa release from tablets was carr < alg < pectin < NaCMC < trgh < HPMC which relates to the viscosity and swelling properties of polymers. The drug release was very slow from trgh and HPMC based tablets, but addition of carr or alg in different ratios could adjust the release rate of drug.

Capsules↗