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PubMedDate not supplied

Poly(hydroxybutyrate-hydroxyvalerate) microspheres containing progesterone: preparation, morphology and release properties.

The biodegradable polyesters, poly(hydroxybutyrate) (PHB) and poly(hydroxybutyrate-hydroxyvalerate) (PHBV) were investigated for use as sustained delivery carriers of a model drug, progesterone. Spherical microspheres containing the drug were prepared by an emulsion solvent-evaporation method with gelatin as an emulsifier. Methylene chloride as the polymer solvent yielded smoother microspheres than chloroform. The surface texture was also dependent upon the temperature of the preparation and polymer used. Surface crystals were observed when the drug loading was increased beyond 5 per cent w/w. Thermograms of the microspheres did not show an endotherm corresponding to the melting of the drug because the drug dissolved in the melted polymer while heating. The amount of residual solvent in the microspheres (gas chromatographic assay) ranged from 3.4 to 58.4 ppm and was dependent on the processing temperature, concentration of the polymer in the solvent and the polymer composition. In vitro release of the drug was slowest from microspheres made from copolymer containing 9 per cent hydroxyvalerate. A less porous microsphere matrix was formed by this copolymer.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Formulation and evaluation of vinylpyrrolidone/vinylacetate copolymer microspheres with griseofulvin.

Regular spherical microspheres of 220-260 microns average size have been prepared from vinylpyrrolidone/vinylacetate copolymer using a solvent evaporation method. Griseofulvin has been incorporated into these microspheres and its physical characterization has been carried out by differential scanning calorimetry (DSC), X-ray diffractometry and X-ray photoelectron spectroscopy. An increase of solubility was observed only with the 1:3 drug/polymer microspheres and the comparison of the dissolution profiles of microspheres with pure griseofulvin resulted in an enhancing effect. Furthermore the release rate of griseofulvin, incorporated into the microspheres, was shown to be biphasic and dependent upon the penetration of water into the microspheres, hydration and dissolution of the polymer and finally dissolution of the drug.

Chemical Phenomena↗
PubMedDate not supplied

Evaluation of spray drying as a method for polylactide and polylactide-co-glycolide microsphere preparation.

Polylactide and polylactide-co-glycolide microspheres containing a lipophilic model drug (vitamin D3) were prepared by spray drying. The purpose of this work is to evaluate the efficacy of spray drying as a method for microsphere preparation. The study was carried out on five different polymers of lactide class: poly-L-lactide 57000 MW, poly-D,L-lactide 209,000 MW, 109,000 MW, 16,000 MW, and polylactide-co-glycolide 22,000 MW. The process conditions were experimentally assessed for each polymer used. The microspheres obtained were characterized for their shape, size and drug content, and the influence of the polymer on microsphere characteristics was evaluated. Results show that polymer type, polymer molecular weight and its concentration in the spraying solution greatly affect microsphere characteristics. In vitro dissolution tests performed with the rotating bottle method resulted in different release profiles depending on type of polymer and on microsphere morphology.

Biocompatible Materials↗
PubMedDate not supplied

Formulation, preparation and dissolution characteristics of propranolol hydrochloride microspheres.

Propranolol HCl was encapsulated with cellulose acetate butyrate (CAB) by an emulsion-solvent evaporation method to obtain discrete, spherical microspheres. The effects of drug to polymer ratio and microsphere size on dissolution characteristics were studied. Drug release was faster in simulated intestinal fluid than in simulated gastric fluid. Unencapsulated propranolol HCl powder had very rapid dissolution, as expected. Release rate from CAB microspheres increased with higher drug to polymer ratios and decreased with increasing diameter. Drug release from microspheres sizes larger than 180 microns was reasonably well described by the spherical matrix model. For microsphere size fractions between 127 and 359 microns the relationship between the 50 per cent release time and the square of the microsphere diameter was linear (r = 0.9999).

Cellulose↗
PubMedDate not supplied

Formulation and release kinetics of cephalexin monohydrate from biodegradable polymeric microspheres.

Sustained release cephalexin microspheres have been formulated with poly(L-lactic acid) for intraperitoneal administration. Microspheres were prepared with spray-dried cephalexin by phase separation in organic solvent containing a fixed concentration of polymer, then sieve-sized. Batch-to-batch reproducibility of microsphere size distribution and encapsulation efficiency ( > 95%) were demonstrated. The quality of the microspheres was dependent on the rate of stirring during preparation and was highest as 400 rpm. Scanning electron micrographs revealed approximately spherical shapes and porous surfaces. The release of cephalexin followed second order dissolution model kinetics for multiparticulate systems. The apparent second order rate constant, k2, was lowest for the highest sieve-size fraction (250-425 microns) and varied with drug loading reaching a minimum at 33% w/w. A lower molecular weight PLA of 50 000 produced a faster release of cephalexin from microspheres. Cephalexin was released from microspheres for at least 4 h compared to only 10 min for complete dissolution of an equivalent weight of cephalexin powder, indicating sustained release which may be appropriate in treating localized infections.

Cephalexin↗
PubMedDate not supplied

Sustained-release of oxytetracycline from chitosan microspheres prepared by interfacial acylation and spray hardening methods.

Chitosan microspheres containing oxytetracycline (OTC), an antibiotic agent, were prepared by spray hardening and interfacial acylation methods. The object of this study was to prepare oxytetracycline-containing microspheres for oral administration and injection using different molecular weight (Mw 70,000 approximately 2,000,000) of chitosan. By the spray hardening method, microspheres with particle sizes between 5 and 30 microns could be obtained and might be suitable for intramuscular injection. On the other hand, chitosan microspheres with the ability to extend the dissolution period of oxytetracycline in low pH medium were also prepared by the interfacial acylation method. The result indicated that the releasing of oxytetracycline from various acylated chitosan microspheres was decreased with increasing the molecular weight of chitosan and would show well sustained-release property. Besides, the morphology of various microspheres and crystalline form transition of oxytetracycline were also studied using electron scanning microscope and X-ray analysis.

Acetylation↗
PubMedDate not supplied

Preparation and characterization of sustained-release microspheres of chlorpromazine.

Sustained release microspheres of chlorpromazine were prepared from Eudragit RS 100 by an emulsion-solvent evaporation method using a six-baffled vessel. The morphology of microspheres was characterized by scanning electron microscopy (SEM). In the presence of aluminium tristearate (5%), microspheres were spherical in shape and uniform. The release of chlorpromazine from microspheres was pH-independent. With increasing amount of aluminium tristearate and increasing ratio of Eudragit RS 100/drug from 1:1 to 9:1, the particle size of chlorpromazine microspheres was reduced and the release rate decreased. The microspheres prepared with the polymer/drug ratio of 9:1 produced a 12-h sustained release pattern.

Antipsychotic Agents↗
PubMedDate not supplied

Iodo-2'-deoxyuridine (IUdR) and 125IUdR loaded biodegradable microspheres for controlled delivery to the brain.

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2'-deoxyuridine (125IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of 125IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable microspheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter 125I, as 125IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external aqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30-40% followed by a sustained release over 35 days.

Antimetabolites↗
PubMed1995

Biodegradation and tissue reaction to intravitreous biodegradable poly(D,L-lactic-co-glycolic)acid microspheres.

We studied the biodegradation of and the tissue reaction to microspheres of 50:50 poly(D,L-lactic-co-glycolic)acid (PLGA) (viscosity-average MW: 3000 d), injected intravitreous in rabbits. These microspheres are under investigation as injectable devices for intravitreous sustained drug delivery. The rate of intravitreous degradation of PLGA microspheres has not been well documented in the literature. Twenty two pigmented rabbits underwent gas vitrectomy in one eye: 19 eyes received 2.5 mg of PLGA microspheres in 1 ml of balanced salt solution (BSS) and 3 control eyes received 1 ml of BSS only. Slit lamp exam and indirect ophthalmoscopy were performed periodically from day 1 to 6 months after surgery. The eyes were enucleated and studied by light microscopy and immunohistochemistry at various time points. The electroretinogram (ERG) was recorded in a subgroup of rabbits before injection and after 1 and 6 months. The amount of microspheres in the vitreous cavity progressively decreased. At 6 months microspheres were found in 1/4 rabbits at indirect ophthalmoscopy and in 4/4 rabbits histopathologically. A mild localized, non progressive foreign body reaction was observed. The cell reaction was composed mostly of vimentin and glial fibrillary acidic protein positive cells which probably represent glial cells and fibroblasts. The choroid and retina were normal. The ERG showed no abnormalities. No clinical inflammatory signs were observed 4 days postoperatively and thereafter.

Animals↗
PubMed1998

pH-sensitive release of indomethacin using lactan-acetate microspheres.

Hydrophobic lactan acetate was prepared from hydrophilic lactan gum by chemical modification and it was used for a pH-sensitive drug delivery system. Lactan acetate microspheres were prepared by the solvent evaporation method. The size of the microspheres prepared from lactan acetate was below 5 microns. The drug loading efficiencies of microspheres were approximately 70 and 80% at the initial amount of drug 40 and 80 mg, respectively. The microsphere showed pH-sensitive swelling behavior. The swelling capacity of microspheres at pH 7.4 was much greater than that at pH 1.2. The pH of the medium significantly influenced the in vitro release rate; the rate at pH 7.2 was approximately 10 times faster than that at pH 1.2. A pH-sensitive drug release pattern was due to the escape of drug from the microsphere that disintegrated after swelling.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Histological methods to determine blood flow distribution with fluorescent microspheres.

We evaluated several histological methods and determined their advantages and disadvantages for histological studies of tissues and organs perfused with fluorescent microspheres. Microspheres retained their fluorescence in 7-10 microm serial sections with a change in the antimedium from toluene when samples were fixed in formalin and embedded in paraffin. Several antimedia allowed both wax infiltration of tissue and preservation of microsphere fluorescence. Histoclear II was the best substitute for toluene. When samples were fixed in formalin and embedded in glycol methacrylate, thinner (3-5 microm) sections provided greater histological detail but had fewer microspheres per section. Air dried lung tissue followed by Vibratome sectioning provided thick sections (100 microm) that facilitated rapid survey of large volumes of tissue for microspheres but limited histological detail, and the air drying procedure was restricted to lung tissue. Samples fixed in formalin followed by Vibratome sectioning of unembedded tissue provided better histological detail of lung tissue and was also useful for other organs. These sections were more difficult to handle and to mount on slides compared to air dried tissue, whereas fixed tissue embedded in gelatin provided better tissue support for Vibratome sectioning. Rapid freezing followed by cryo-microtome sectioning resulted in frozen sections that were relatively difficult to handle compared to embedded or unembedded tissue; they also deteriorated relatively rapidly with time. Paraffin sections were stained with hematoxylin and eosin or with aqueous methyl green, although tissue autofluorescence by itself was usually sufficient to identify histological features. Methacrylate sections quenched tissue autofluorescence, and Lee's stain or Richardson's stain were used for staining sections. Toluene based mountants such as Cytoseal quenched fluorescence, particularly the red fluorescent microspheres. Aqueous based mountants such as Aquamount, Crystal/Mount, Fluoromount-G were substituted, although such preparations were not as permanent as Cytoseal mounted coverglasses and tended to cause fading of stained sections.

Animals↗
PubMed1993

Incorporation and release of chemically intact mitomycin C from albumin microspheres: a high performance liquid chromatography evaluation.

Preparation of mitomycin C-loaded human serum albumin (HSA) microspheres using a new technique that avoids the use of heat denaturation, which is known chemically to degrade incorporated drug, is described. This method is based on cross-linking of protein by glutaraldehyde (2.2%) during emulsification (W/O) at room temperature. The resultant particles have a mean (s.d.) diameter of 16.9 (0.34) microns (50% weight average), contain mean (s.d.) 1.15 (0.05%) mitomycin C (MMC) (w/w, n = 17) and maintain sustained release of drug over 20 h. High performance liquid chromatography (HPLC) with diode array detection was used to study the chemical integrity of the drug. Two classes of decomposition products were evaluated: chemical degradation products and drug/nucleophile covalent adducts. The HPLC separation was validated by a number of standards of proposed degradation products. To examine incorporated drug, a complete microsphere system was solubilized with 0.4% trypsin for 24 h, while to examine released drug, microspheres were immobilized on a flow-through glass wool column and fractions were collected. No evidence of significant chemical degradation or covalent coupling to protein was detected in microsphere digests. Two candidate decomposition products, representing approximately 10% of drug released from microspheres (assuming similar molar extinction coefficients to MMC), were identified in column fractions. One of these products appeared to be a covalent adduct, the other possibly an isomeric form of intact MMC. Thus, MMC is predominantly incorporated into and released (90%) chemically intact from HSA microspheres prepared by the technique described.

Chromatography, High Pressure Liquid↗
PubMed2000

Preparation of biodegradable microspheres of testosterone with poly(D,L-lactide-co-glycolide) and test of drug release in vitro.

Biodegradable microspheres formulation of testosterone (T) can be used as a new physiological approach for androgen replacement in hypogonadal men. In this study, poly(D,L-lactide-co-glycolide) (PLGA) microspheres containing T were prepared by a solvent-evaporation/solvent-diffusion process and the drug release tests of the microspheres were carried out in vitro. T/PLGA microspheres with good yield, desired size and satisfied drug loading were obtained. A significant testosterone sustained release was shown in the drug release tests in vitro. Since PLGA microspheres preparations are normally sterilized by colbat-60 irradiation, the effects of 25 kGy colbat-60 irradiation on physicochemical properties and in vitro drug release profile of T/PLGA microsphere were investigated. The results showed that the irradiation didn't have any effects on the physicochemical properties of T. Though about one-third decrease in molecular weight of PLGA was caused by the irradiation, no significant changes were observed on the drug release profile in vitro.

Biodegradation, Environmental↗
PubMed1994

Preparation and characterisation of poly(lactic acid) hemoglobin microspheres.

For many years, a lot of research effort has been carried out with a view to preparing blood substitutes. Our group has developed a process of encapsulation of hemoglobin in polylactid microspheres. An aqueous solution of hemoglobin was emulsified into a solution of polymer in methylene chloride to form a W/O emulsion. This primary emulsion was then added to a external aqueous phase under stirring until the evaporation of methylene chloride. The microspheres were separated by filtration and washed with distilled water. Microspheres were spherical and their sizes vary between 10 and 500 microns. More than 80% of the hemoglobin was encapsulated. From the absorption spectra of hemoglobin from microspheres, we did not notice any alteration of the oxygen carrier. The dissociation curve of the hemoglobin demonstrated the permeability of the polymeric wall of these microspheres to oxygen. This curve was relatively sigmoidal and presented a P50 similar to that of free hemoglobin in the same experimental conditions. A cellulose's acetate gel electrophoresis of hemoglobin extracted from the microspheres showed one band that correlates with intact hemoglobin. These results suggest that hemoglobin does not interact chemically with the polymer matrix and that the process of microencapsulation does not alter the hemoglobin molecule.

Blood Substitutes↗
PubMed1998

Effect of gastrointestinal protein adsorption on the in vitro release of AZT from ethylcellulose microspheres.

The purpose of this study was to assess the effect of gastrointestinal proteins on the in vitro release of zidovudine (AZT) from ethylcellulose microspheres, and to investigate protein adsorption as a possible mechanism that mediates this effect. AZT release from ethylcellulose microspheres was tested in the presence of different gastrointestinal proteins, both dietary (casein and albumin) and endogenous (pepsin, pancreatin, and mucin) in simulated gastric fluid and/or simulated intestinal fluid. The resulting release profiles were compared with those produced in the corresponding release media without the presence of proteins. Protein adsorption on AZT-loaded ethylcellulose microspheres was studied for the five proteins under investigation. The amounts of adsorbed proteins were determined by fluorescent spectrometry after the protein solution was reacted with fluoraldehyde reagent. All of the investigated proteins were found to slow the release of AZT from ethylcellulose microspheres. At gastric pH, ovalbumin and casein had the maximum effect on AZT release. Mucin exerted a more pronounced effect at gastric pH compared with that at intestinal pH. The negative effect of pancreatin on AZT release increased when its concentration was increased. The five proteins were found to adsorb on AZT-loaded ethylcellulose microspheres with varying quantities. The observed protein adsorption is believed to cause blockage of the small pores and channels in the microsphere structure, and consequently slow the release of AZT.

Adsorption↗
PubMed2001

Immunization with Staphylococcus aureus lysate incorporated into microspheres.

Antibiotics are of limited value against Staphylococcus aureus due to development of resistant strains, scar tissue formation, and blockage of ducts due to inflammation. Though macrophages are the predominant cell type in the mammary gland, they are primarily scavenger cells and are not effective against bacteria entering the gland. Neutrophil phagocytosis is the bovine's primary defense against S. aureus mastitis. Attempts to develop vaccines that enhance neutrophil phagocytosis by stimulating production of opsonizing antibodies to S. aureus have met with limited success because of the low immunogenicity of the exopolysaccharide capsule surrounding S. aureus. Staphylococcus aureus can also adhere to and penetrate epithelial tissue. This study was conducted to determine whether lysates of S. aureus encapsulated in biodegradable microspheres would increase the production of opsonizing antibodies to capsule and block adherence. Four groups of four cows each were injected with 1 ml of the respective treatment in the area of the supramammary lymph node and 1 ml in the hip muscle. The treatments were: lysate in NaCl, lysate in Freund's incomplete adjuvant (FICA), lysate in microspheres in NaCl, and lysate in microspheres in FICA. Antigen in microspheres produced a similar antibody response to antigen emulsified in FICA, but to a lesser magnitude. Antigen in microspheres produced antibodies that were more opsonic for neutrophils at 20 and 52 wk postimmunization and inhibited S. aureus adherence to mammary epithelium. Ability to control antigen release and presentation, and the benefit of a single injection for long-term immunity using microspheres warrants additional studies.

Animals↗
PubMed2001

Analysis of brain biocompatibility of drug-releasing biodegradable microspheres by scanning and transmission electron microscopy.

OBJECT: Stereotactically guided implantation of biodegradable microspheres is a promising strategy for delivery of neurotrophic factors in a precise and spatially defined brain area. The goal in this study was to show the biocompatibility of poly(D,L,lactide-co-glycolide) microspheres with brain tissue at the ultrastructural level and to analyze the three-dimensional (3D) ultrastructure after intrastriatal implantation of these microparticles. METHODS: Scanning and transmission electron microscopy were used to study the microspheres and their environment after implantation in an inert material (gelatin) and in the rat striatum. Observations were made at different time periods, ranging from 24 hours to 2 months postimplantation. CONCLUSIONS: The progressive degradation of the microspheres, with vacuolization, deformation, and shrinkage, was well visualized. This degradation was identical in microspheres implanted in the inert material and in the rat brain tissue, independent of the presence of macrophages. The studies preformed in the striatum permitted the authors to demonstrate the structural integrity of axons in contact with microspheres, confirming the biocompatibility of the polymer. Furthermore, scanning electron microscopy showed the preservation of the 3D ultrastructure of the striatum around the microparticles. These microparticles, which can be stereotactically implanted in functional areas of the brain and can release neurotrophic factors, could represent, for some indications, an alternative to gene therapy.

Animals↗
PubMed1992

Blood flow measurements by the reference sample method with microsphere injection in to the aorta: an accurate and easy approach.

The validity of hemodynamic measurements by the reference sample method with microspheres injection into the aorta, via a carotid artery catheter, was evaluated in rats and compared with the results obtained after left ventricle injection. In the aorta injection group, a good mix of microspheres was observed in 83% of the animals. Moreover, a symmetrical distribution of microspheres was observed in 10 out of 12 rats (83%). An excellent correlation between right and left kidney-testes blood flows was observed (r = 0.93 and 0.96, respectively; P less than 0.01). Mean arterial pressure was not modified during microspheres injection into the aorta. Cardiac output (104 +/- 26 vs 101 +/- 23 ml/min, NS) and portal blood flow (14.2 +/- 3.3 vs 13.5 +/- 2.2 ml/min, NS) were similar after aorta and left ventricle injections series, respectively. Our results indicate that the injection of microspheres into the aorta is an adequate and easy approach to systemic and splanchnic hemodynamic measurements. This approach could be a good alternative to left ventricle injection of microspheres in experimental studies in rats.

Animals↗