Preparation, characterization and performance evaluation of neomycin-HSA microspheres

Human serum albumin microspheres containing neomycin sulphate were prepared using emulsion polymerization and polymer dispersion techniques. The many variables which may affect the shape, size, stability, release of the drug from the microspheres such as internal phase to external phase volume ratio, human serum albumin content, stirring rate, polymer content and stabilizing agent concentration, were studied. Unlike the microspheres prepared by the emulsion polymerization technique, polymer dispersion stabilised microspheres were uniform in size and shape with a narrow range of size distribution. In vitro release of neomycin sulphate from albumin microspheres was studied using the dialysis cell method. The drug release from microspheres followed Q versus (t)-1/2 linear relationship. The in vivo distribution studies on prepared microspheres revealed that the localization takes place preferably in lung tissues, liver, spleen and kidney and is found to be dependent on the microsphere size. On administration of microspheres of 3-6 microns size, approximately 55 per cent of administered drug could be localized in the lungs.     

Formulation and in vitro characterization of inhalable rifampicin-loaded PLGA microspheres for sustained lung delivery

The solvent evaporation method with premix membrane homogenization was applied, with class-3 ethyl acetate as organic solvent, to produce narrowly size-distributed rifampicin (RIF)-loaded poly(lactide-co-glycolide) (PLGA) microspheres for sustained lung delivery as aerosol. Microsphere formulations (simple or multiple emulsions, different PLGA and RIF concentrations) and process parameters (transmembrane pressure, SPG membrane pore diameter) were investigated as their effects on RIF content, microsphere size, aerodynamic properties of the freeze-dried powder and in vitro release profiles. Narrowly size distributed microspheres with diameters from 2 to 8 μm, satisfactory RIF contents (from 4.9 to 16.5%), 80% RIF release from 12h to 4 days, and adequate aerodynamic properties were prepared from a multiple emulsion and using SPG membrane pore diameter of 19.9 μm. The premix membrane homogenization appeared to be a rapid and efficient method to prepare monodisperse drug-loaded microspheres suitable for lung delivery as sustained-release microsphere aerosol.     

Streptomycin sulphate microspheres: dissolution rate studies and release kinetics. I

Targeting of drugs by microspheres, nanoparticles and liposomes is intended to increase the selective targeting to specific organs and to reduce their side effects. Streptomycin sulphate, a tuberculostatic antibiotic, is used as the active principle in this study. The aim is to accumulate the loaded microspheres in the lungs. The release of drugs associated with microsphere carriers has been found to be dependent on a number of factors. The aim of the investigation was to study the influence of the extent and nature of cross-linking, the type and the amount of the matrix material on the release characteristics of streptomycin sulphate microspheres. Human serum albumin and gelatin (Type B) were used as two different matrix materials. The crosslinking agents used were 2,3-butanedione and formaldehyde at different concentrations, and variable duration times. The in vitro release of streptomycin sulphate from microspheres is characteristically biphasic, with an initial fast release (the 'burst effect'), followed by a much slower release. Alteration in the characteristics of drug-loaded microspheres result in significant changes in the second (slow) phase of release. The release profiles of the different formulations has been studied and evaluated kinetically.     

Preparation,characterization and performance evaluation of neomycin-HSA microspheres

Abstract

Human serum albumin microspheres containing neomycin sulphate were prepared using emulsion polymerization and polymer dispersion techniques. The many variables which may affect the shape, size, stability, release of the drug from the microspheres such as internal phase to external phase volume ratio, human serum albumin content, stirring rate, polymer content and stabilizing agent concentration, were studied. Unlike the microspheres prepared by the emulsion polymerization technique, polymer dispersion stabilised microspheres were uniform in size and shape with a narrow range of size distribution. In vitro release of neomycin sulphate from albumin microspheres was studied using the dialysis cell method. The drug release from microspheres followed Q versus (t)^?1/2 linear relationship. The in vivo distribution studies on prepared microspheres revealed that the localization takes place preferably in lung tissues, liver, spleen and kidney and is found to be dependent on the microsphere size. On administration of microspheres of 3-6 μm size, approximately 55 per cent of administered drug could be localized in the lungs.     

Study of processing parameters influencing the properties of diltiazem hydrochloride microspheres

Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 microm and entrapment efficiency of approximately 60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55 degreesC, for 12 weeks.     

Sophoridine-loaded PLGA microspheres for lung targeting: preparation,in vitro,and in vivo evaluation

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17?μm with 90% of the microspheres ranging from 12 to 24?μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4?h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10?μg/g for microspheres and 6.77?μg/g for solution after intraveneous injection for 30?min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.     

Study of processing parameters influencing the properties of Diltiazem hydrochloride microspheres

Diltiazem hydrochloride-ethylcellulose microspheres were prepared by the water-in-oil emulsion-solvent evaporation technique. Small and spherical microspheres having a mean microsphere diameter in the range of 40-300 µm and entrapment efficiency of ~60-90% were obtained. Scanning electron micrographs of drug-loaded microspheres showed the presence of uniformly distributed small pores and absence of drug crystals on their surface, indicating simultaneous precipitation of drug and the polymer from the solvent during solvent evaporation. Differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the microspheres. The stability studies of the drug-loaded microspheres showed that the drug was stable at storage temperatures, 5-55°C, for 12 weeks.     

Prenatal effect of pyrantel pamoate on several hematological parameter of offsprings in mice

In attempt to develop a drug delivery system using serum albumin microspheres, bovine serum albumin microspheres containing antitumar agent, cytarabine, were prepared. The shape, surface characteristics, size distribution, behavior of in vivo distribution, drug release behavior, and degradation of albumin microspheres in animal liver tissue homogenate and proteolytic enzyme were investigated. The shape of albumin microspheres was spherical and the surface was smooth and compact. The size distribution of the albumin microspheres was effected by dispertion forces during emulsification and albumin concentration. Distribution of albumin microspheres after imtravenous administration in rabbit was achieved immediately.In vitro, albumin microsphere matrix was so hard that it retained most of cytarabine except initial burst during the first 10 minutes, and the level of drug release during the initial burst was affected by heating temperature, drug/albumin concentration ratio and size distribution. After drug release test, the morphology of albumin microspheres was not changed. Albumin microsphere matrix was degraded by the animal liver tissue homogenate and proteolytic enzyme. The degree of degradation was affected by heating temperature.     

Development of specific organ-targeting drug delivery system I: Physico-pharmaceutical characteristics of thermally denatured albumin microspheres containing cytarabine

In attempt to develop a drug delivery system using serum albumin microspheres, bovine serum albumin microspheres containing antitumor agent, cytarabine, were prepared. The shape, surface characteristics, size distribution, behavior ofin vitro distribution, drug release behavior, and degradation of albumin microspheres in animal liver tissue homogenate and proteolytic enzyme were investigated. The shape of albumin microspheres was spherical and the surface was smooth and compact. The size distribution of the albumin microspheres was affected by dispersion forces during emulsification and albumin concentration. Distribution of albumin microspheres after intravenous administration in rabbit was achieved immediately.In vitro, albumin microsphere matrix was so hard that it retained most of cytarabine except initial burst during the first 10 minutes, and the level of drug release during the initial burst was affected by heating temperature, drug/albumin concentration ratio and size distribution. After drug release test, the morphology of albumin microspheres was not changed. Albumin microsphere matrix was degraded by the rabbit liver tissue homogenate and proteolytic enzyme. The degree of degradation was affected by heating temperature.     

In-vitro/in-vivo studies of the biodegradable poly-(D,L-lactide-co-glycolide) microspheres of a novel luteinizing hormone-releasing hormone antagonist for prostate cancer treatment

The introduction of luteinizing hormone-releasing hormone (LHRH) analogs and their antagonists is revolutionizing the treatment of prostate cancer. In this study, poly(D,L-lactideco-glycolide) (PLGA) microspheres containing a highly potent LHRH antagonist (LXT-101) of interest in the indication of prostate cancer were evaluated on release mechanisms in vitro and biological performance in vivo. LXT-101 microspheres were prepared by the water/oil/water double emulsion method and the solid/oil/oil method. The results showed that the mechanism of LXT-101 releasing from PLGA 14,000 microspheres was the cooperation of drug diffusion and polymer degradation. This clarified the relationship between the microsphere characterization and hormone level in vivo. The larger microspheres (33 μm) could inhibit the testosterone level to castration for a longer time (35 days) than the smaller microspheres (15 μm, 14 days). The formulation containing the hydrophilic additive (polyethylene glycol 6000) could suppress the testosterone level to castration for a longer time (> 35 days) than the formulation without polyethylene glycol (14 days). The appearance of testis, vesicular seminalis, and prostates changed after treatment. The weights of sexual organs decreased significantly. The in-vivo release of the LXT-101 PLGA 14,000 microspheres curve showed that in-vivo release started immediately after day 1 (22.7%) and was rapid during the first 5 days (40.2% release). The LXT-101 microspheres could be a promising drug delivery system candidate to treat sex hormone-dependent tumors and other related disorders.     

Site-Specific Drug Targeting with Fluorouracil Microspheres

The disposition of 5-fluorouracil following intra-arterial administration in albino rats, as a free drug suspension (control) or via magnetic albumin microspheres (treatment group) in normal saline, has been investigated. The rat tail was used as the target model wherein fluorouracil microspheres were injected into the ventral caudal artery. A magnetic field of 6000 G was directed toward a predetermined site on the tail. On analysis, it was observed that the magnetically responsive albumin microspheres of fluorouracil showed an increase in drug retention at the target site and liver. However, drug retention in the heart, kidney, and tissues in close proximity to the target site was considerably less. It was also observed that the amount of drug retained in nontarget sites (heart, kidney, and lungs) was less when fluorouracil was administered in the microsphere form rather than as a suspension. This results in low drug exposure of nontarget organs with the microsphere form, which would otherwise have exhibited toxicity effects.     

Site-Specific Drug Targeting with Fluorouracil Microspheres

Abstract

The disposition of 5-fluorouracil following intra-arterial administration in albino rats, as a free drug suspension (control) or via magnetic albumin microspheres (treatment group) in normal saline, has been investigated. The rat tail was used as the target model wherein fluorouracil microspheres were injected into the ventral caudal artery. A magnetic field of 6000 G was directed toward a predetermined site on the tail. On analysis, it was observed that the magnetically responsive albumin microspheres of fluorouracil showed an increase in drug retention at the target site and liver. However, drug retention in the heart, kidney, and tissues in close proximity to the target site was considerably less. It was also observed that the amount of drug retained in nontarget sites (heart, kidney, and lungs) was less when fluorouracil was administered in the microsphere form rather than as a suspension. This results in low drug exposure of nontarget organs with the microsphere form, which would otherwise have exhibited toxicity effects.     

Targeted delivery of low dose doxorubicin hydrochloride administered via magnetic albumin microspheres in rats

The efficacy of magnetic albumin microspheres in the targeted delivery of an anti-cancer agent, doxorubicin hydrochloride, has been investigated in rats. Using the tail as a target organ, the animals were intra-arterially administered with either 0.12 mg/kg of free drug, or 0.04 mg/kg of microsphere entrapped drug in the presence of a 8000 Gauss magnet applied for 30 min at the target-site. In each group, the animals were sacrificed over a 48 h period and their various tissues analysed for drug concentration using HPLC. It was found that compared to the free drug, a one-third dose of microsphere entrapped drug resulted in almost eight times higher drug exposure (AUC0-infinity) at the target site. In addition, the drug delivery to all the non-target tissues, including liver and heart, was substantially reduced. The study confirms the efficacy of magnetic albumin microspheres in the targeted delivery of chemotherapeutic agents.     

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

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

Comparison of albumin and casein microspheres as a carrier for doxorubicin

Doxorubicin (Adriamycin)-loaded casein and albumin microspheres, with diameters between 14 and 38 micron (50% weight average) were prepared by glutaraldehyde stabilization of the aqueous phase (containing protein and drug) of a water in oil emulsion. Physical properties, drug loading characteristics and release rates from microspheres in-vitro have been compared and correlated with effects on tumour growth when injected intratumourally in rats. Compared with albumin, the surface charge of the casein system was more negative and the microspheres exhibited a slower release of drug in-vitro. Both observations could be explained by the lower drug content of the casein system. There was evidence for the formation of a doxorubicin complex in the microspheres, the significance of which is not yet known. Casein microspheres containing 11 micrograms of doxorubicin had a similar inhibitory effect on tumour growth (growth delay = 20.7 days) to 85 micrograms of drug incorporated into albumin microspheres (growth delay = 18.6 days). The absence of a simple dose-response relationship shows that carrier matrix can influence potency of incorporated drug. The results are consistent with release rate of the drug from microspheres (obversely, rate of drug delivery to the tumour), being a determinant of potency in these systems.     

Albumin microspheres as vehicles for the sustained and controlled release of doxorubicin

Biodegradable albumin microspheres have been prepared with the intention of targeting doxorubicin preferentially to tumour tissue. A high-yielding microsphere manufacturing process has been developed that involved the denaturation of an aqueous protein emulsion by chemical and/or thermal crosslinking methods. Microspheres can be closely sized to a diameter of 25.3 +/- 2.6 microns with the aid of micro-sieves. The in-vitro release of doxorubicin from albumin microspheres was measured using a continuous flow system. Doxorubicin release can be sustained for up to 10 days and the rate of release could be controlled by manipulating protein denaturation conditions between the temperatures 110-135 degrees C in the presence of 0-2% glutaraldehyde. Release of doxorubicin was significantly faster in human plasma compared with isotonic saline.     

Localized rifampicin albumin microspheres

Rifampicin bearing albumin microspheres were prepared. The process variables which could affect the physical characteristics and in vitro release of the drug from the microspheres were optimized. Changes in the original size of the microspheres, namely swelling on exposure to buffer solution pH 7.2 and serum, were monitored. In vivo distribution studies on prepared microspheres revealed that 62 per cent of the drug could be localized in the lungs by controlling microsphere size. Hence, rifampicin bearing albumin microspheres can behave as a reservoir to build up higher local drug concentrations.     

Targeted delivery of low dose doxorubicin hydrochloride administered via magnetic albumin microspheres in rats

Abstract

The efficacy of magnetic albumin microspheres in the targeted delivery of an anti-cancer agent, doxorubicin hydrochloride, has been investigated in rats. Using the tail as a target organ, the animals were intra-arterially administered with either 0.12mg/kg of free drug, or 0.04mg/kg of microsphere entrapped drug in the presence of a 8000 Gauss magnet applied for 30 min at the target-site. In each group, the animals were sacrificed over a 48 h period and their various tissues analysed for drug concentration using HPLC. It was found that compared to the free drug, a one-third dose of microsphere entrapped drug resulted in almost eight times higher drug exposure (AUC_o-) at the target site. In addition, the drug delivery to all the non-target tissues, including liver and heart, was substantially reduced. The study confirms the efficacy of magnetic albumin microspheres in the targeted delivery of chemotherapeutic agents.     

Formulation and testing of vancomycin loaded albumin microspheres prepared by spray-drying

Microparticles are widely employed as carriers of biologically active compounds with many possible applications. For targeted drug delivery and sustained release purposes, biopolymers (i.e. polysaccharides and proteins) have been proposed. In this study, microsphere formulations of vancomycin were prepared by the spray-drying method. Bovine serum albumin (BSA) was used as a polymer matrix and was cross-linked with glutaraldehyde after microsphere preparation. The product yield obtained from the spray-drying method was approximately 75%. The mean particle size was 5 +/- 1.6 microm, with the majority of particles between 4 and 8 microm. The extent of cross-linking affected the release of vancomycin from microspheres. Moreover, both rate and extent of vancomycin release from microspheres decreased with increasing glutaraldehyde concentration. Encapsulation of vancomycin did not alter the bioactivity of the drug and it was more effective in killing Staphylococcus aureus than the solution form.     

Controlled Delivery Systems for Proteins Using Polyanhydride Microspheres

A method to provide near-constant sustained release of high molecular weight, water-soluble proteins from polyanhydride microspheres is described. The polyanhydrides used were poly (fatty acid dimer) (PFAD), poly(sebacic acid) (PSA), and their copolymers [P(FAD-SA)]. P(FAD-SA) microspheres containing proteins of different molecular sizes—lysozyme, trypsin, heparinase, ovalbumin, albumin, and immunoglobulin—were prepared by a solvent evaporation method using a double emulsion. The microspheres containing proteins were spherical, with diameters of 50–125 µm, and encapsulated more than 80% of the protein, irrespective of the protein used. Enzymatic activity studies showed that encapsulation of enzymes inside polyanhydride microspheres can protect them from activity loss. When not placed inside polyanhydride microspheres, trypsin lost 80% of its activity in solution at 37°C at pH 7.4 in 12 hr, whereas inside the polyanhydride microspheres the activity loss was less than 10% under these conditions. About 47% of the enzymatic activity of heparinase encapsulated in the microspheres was lost at 37°C in 24 hr, while in solution it lost over 90% of its activity. The protein-loaded microspheres displayed near-zero-order erosion kinetics over 5 days as judged by the release of sebacic acid (SA) from the microspheres. The microspheres degraded to form SA and FAD monomers. All proteins were released at a near-constant rate without any large initial burst, irrespective of polymer molecular weight and protein loading. The period of protein release was longer than that of SA and continued protein release was observed even after the microsphere matrix had completely degraded. Differential scanning calorimetric studies demonstrated an interaction between protein and the FAD monomers produced with microsphere degradation. It is likely that the protein interaction with FAD monomers permits formation of water-insoluble protein aggregates which slowly dissolve and diffuse out of the matrix, leading to delayed protein release. For trypsin-loaded microspheres, trypsin lost 40% of its activity during microsphere preparation. Activity studies demonstrated that the sonication process was primarily responsible for activity loss. A reduction in the period of ultrasound exposure decreased the loss of protein activity to around 20%.