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PubMedDate not supplied

Preparation and evaluation of sustained release cross-linked chitosan microspheres containing phenobarbitone.

Chitosan microspheres containing phenobarbitone were successfully prepared by glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in light liquid paraffin containing sorbitan mono-oleate as a stabilizing agent. Uniform and spherical microspheres, with a loading efficiency up to 57.2%, could be prepared depending on the preparation conditions. The main parameters affecting the preparation and the performance of the prepared microspheres were the molecular weight and concentration of chitosan as well as the concentration of the used stabilizing agent. The incorporation of citric acid into the microspheres was found to increase the formation of a water-soluble gel when the microspheres come in contact with the dissolution medium increasing the rate of drug release. The particle size was shifted towards smaller diameters with increased concentration of sorbitan mono-oleate, up to 4.0% v/v, by use of a lower concentration of chitosan (1.0% w/v) and chitosan with low molecular weight. Rapid initial drug release (20-30% of the incorporated drug) was exhibited in all the prepared microspheres followed by slow release of the remaining amount of the drug. The release rate of the drug from the microspheres prepared from high molecular weight chitosan was slow in comparison with that prepared from medium and low molecular weight chitosan. High concentrations of sorbitan mono-oleate increased the rate of drug release.

Animals↗
PubMedDate not supplied

Bovine serum albumin loaded poly(lactide-co-glycolide) microspheres: the influence of polymer purity on particle characteristics.

To study the influence of polymer purity on microsphere characteristics, bovine serum albumin (BSA) loaded biodegradable microspheres were prepared by spray drying using two samples of poly(lactide-co-glycolide), PLG, (50:50, mwt = 35 and 69 kDa). Polymer properties were varied by DL-lactide and glycolide addition or by ultrafiltration. While the effective drug loading was not affected by polymer purity, Tg was decreased with increasing monomer and oligomer content. The removal of these low molecular weight substances by ultrafiltration led to a narrower molecular weight distribution compared to the untreated PLG. Concerning the polymer with the higher molecular weight, microsphere morphology was also strongly affected by polymer composition. In contrast to the non-modified PLG, monomer addition yielded particles with a much smoother surface structure. Moreover, in vitro cytotoxicity of the microspheres prepared from the polymer pretreated by ultrafiltration was significantly reduced, whereas monomer addition caused a dramatic decrease of cells surviving contact with the microsphere extract. The in vivo degradation rate of the ultrafiltered microspheres was decreased and as a result, protein release at later times was slowed down. Furthermore, depending on the effective drug loading level, monomer addition resulted in a decrease in the initial protein burst. It can be concluded that the effect of low molecular weight impurities in a polymer on microsphere characteristics and on cytotoxicity cannot be ignored. Their elimination is possible by ultrafiltration.

Animals↗
PubMedDate not supplied

Influence of additives on the release profile of nifedipine from poly(DL-lactide-co-glycolide) microspheres.

Nifedipine-containing poly(DL-lactide-co-glycolide) (PLGA) microspheres of various sizes and drug contents were prepared by the solvent evaporation method. The in vitro release profiles of nifedipine from PLGA microspheres and the degradation pattern of the polymer were evaluated. Four additives were incorporated in the microspheres: two non-fatty plasticizers: diethylphthalate and triacetin, and two fatty substances: isopropyl myristate and Myvacet. Diethylphthalate and Myvacet increased the nifedipine release rate while isopropyl myristate and triacetin had no influence on it. Triacetin seems to be very poorly incorporated into the microspheres. These additives did not modify the degradation rate of the polymer. Differential scanning calorimetry detected a decrease of the glass transition temperature of diethylphthalate-containing microspheres, a small variation with Myvacet, and very little change when triacetin or isopropyl myristate were incorporated. This variation of the glass transition temperature (Tg) tends to imply that nifedipine is released by a diffusion process through the polymer matrix which is enhanced when additives decrease the Tg. Scanning electron microscopy allowed the vizualization of the highly porous structure of microspheres containing the oily substances, and the unchanged smooth surface of diethylphthalate-containing microspheres.

Biocompatible Materials↗
PubMedDate not supplied

In vitro and in vivo responses of doxorubicin ion exchange microspheres to hyperthermia.

The utility of microspheres as targeted drug delivery agents is addressed with reference to using heat during formulation and to administration in combination with hyperthermia. It was demonstrated that rate of loading of the drug doxorubicin onto resin microspheres is enhanced under conditions of elevated temperature but this was shown to increase the incidence of microsphere aggregation. Total amount of drug loaded was related to time rather than temperature such that low temperature loading for up to 24 h produced optimum quality injectates. However, release of doxorubicin from microspheres was significantly increased during elevations of temperature to 43 degrees C. Thus, during hyperthermia doxorubicin release can be increased to provide periods of high drug availability targeted to tumour tissue for concomitant thermochemotherapy with microspheres. The therapeutic benefit derived from this combined therapy was assessed in 20 rabbits with VX2 carcinoma implanted in the liver. Hyperthermia was delivered by 2450 MHz microwave applicator to the exteriorized liver at 43 degrees C for 30 min, while chemotherapy was administered by intratumoural injection of doxorubicin microspheres (2.3 mg) into each tumour. Both hyperthermia and chemotherapy alone significantly reduced the size of tumours 10 days following treatment (p less than 0.01). However, in animals treated with both modalities, the size of tumours was significantly less than either treatment alone (p less than 0.05). These results provide a strong rationale for combining hyperthermia with targeted chemotherapy using microspheres.

Animals↗
PubMed1993

Comparison of poly(DL-lactide-co-glycolide) and polystyrene microsphere targeting to intestinal M cells.

The interaction of poly(DL-lactide-co-glycolide) (PLG) and polystyrene microspheres with the follicle-associated epithelium (FAE) of rabbit Peyer's patches was compared. Binding by PLG microspheres to the FAE was an order of magnitude lower than that of polystyrene microspheres of equivalent size (0.5-0.6 microns diameter). Although PLG microspheres are not selectively targeted to the M cell surface, as is the case with polystyrene microspheres, a high proportion of those that bind to M cells are transcytosed, resulting in the transepithelial delivery of 1.5 x 10(4) PLG microspheres/mm2 FAE. This represents the first direct demonstration of transepithelial delivery of PLG microspheres by M cells, which is crucial to the potential use of such vehicles for the oral delivery of drugs and vaccines. As native PLG microspheres are not optimally targeted to the M cell surface, there is scope for the further improvement of their efficacy by surface modifications.

Animals↗
PubMed1994

Stability study of drug-loaded proteinoid microsphere formulations during freeze-drying.

Drug-loaded proteinoid microspheres were freeze-dried to facilitate shipping and handling and to enable long term storage. Heparin was chosen as the model drug in developing the optimum lyophilization process. The factors influencing the integrity of either heparin-loaded or unloaded ('empty') proteinoid microspheres during freeze-drying were determined, with emphasis on: selecting an optimum freezing and resuspending temperature; choosing an appropriate cryoprotectant and its optimum concentration in the formulation; and, designing a suitable method for formulating the microspheres. Freezing at/below -70 degrees C was found to minimize damage to the microspheres. Addition of sugars, such as trehalose and lactose, as cryoprotectants, further increased the stability of the heparin-loaded microspheres during freeze-drying. The optimum trehalose or lactose concentrations were determined to be 5% (w/v). Using the optimumized lyophilization process described in this manuscript, microspheres remained intact during freeze-drying. The freeze-dried microspheres were stable for at least three months post-lyophilization.

Cryoprotective Agents↗
PubMed1996

Biliary excretion of polystyrene microspheres with covalently linked FITC fluorescence after oral and parenteral administration to male Wistar rats.

To further our understanding of microspheres as a drug delivery system, the biliary excretion of covalently linked FITC fluorescence polystyrene microspheres of various diameters was investigated after oral and parenteral administration to male Wistar rats. About 36%, 16% 3% and 1% of the dose was excreted into the bile after parenteral injection of 50 nm, 500 nm, 1 micron and 3 microns diameter microspheres, respectively, over 24 h. In addition, about 30%, 11%, 1%, and 1% of the dose, respectively, was found in the blood at 24 h. After oral administration of 50 nm, 500 nm, and 1 micron microspheres, the recovery was about 18%, 8% and 1% of the dose in the bile and about 9%, 1%, and 0% in the blood, respectively. No 3 microns microspheres were detected in the bile or blood after oral administration. Particles were not detected in the urine of any group tested. Thus, the present study demonstrated that biliary excretion plays an important role in the disposition of microspheres administered by the oral or parenteral routes, and there is a size-related excretion of microspheres into the bile.

Administration, Oral↗
PubMed1997

Preparation and evaluation of chitosan microspheres containing bisphosphonates.

Local implantation or injection of microspheres containing bisphosphonates for site-specific therapy may aid in treating several pathological conditions associated with bone destruction. Chitosan microspheres containing two antiresorption and anticalcification agents, pamidronate and suberoylbisphosphonate (SuBP), were prepared from a w/o emulsion. Various formulation variables were studied for their effect on the release rate profile of these bone-seeking agents. Polymer coating of micromatrices yielded microspheres with the most retarded release rate, and the drug delivery system was found biocompatible in endothelial cell culture. The microspheres were examined in vitro and in vivo for release kinetics and drug disposition. The release of bisphosphonate from the microspheres was faster in vitro than in vivo. Drug disposition following implantation of microspheres in the tibialis muscle resulted in a relatively increased disposition in the adjacent tibia while injection of drug solution in the tibialis muscle resulted in uniform disposition of the drug in the femorae and tibiae. Bisphosphonate released from chitosan microspheres effectively inhibited bioprosthetic tissue calcification in the rat subdermal model.

Animals↗
PubMed1996

Interaction of recombinant human bone morphogenetic protein-2 with poly(d,l lactide-co-glycolide) microspheres.

The combination of recombinant human bone morphogenetic protein-2 (rhBMP-2) with poly(d,l lactide-co-glycolide) (PLGA) porous microspheres provided for "sustained release" of the protein from the microspheres. Soaking 50:50 PLGA microspheres in a buffered rhBMP-2 solution for a sufficient period of time to permit equilibrium binding enabled quantification of "free" and "bound" protein. "Free" protein is defined as protein present within the porous matrix of the microspheres, whereas "bound" refers to protein adsorbed to PLGA surfaces. Kinetics of the rhBMP-2-microsphere association revealed that equilibrium was attained within 8 hr for two buffer systems (arginine/histidine, pH 6.50; and glutamic acid/sodium glutamate, pH 4.50). Increasing the concentration of the rhBMP-2 stock solution used for the interaction studies from 0.025 to 1.0 mg/ml increased the amount of rhBMP-2 adsorbed and the concentration of free rhBMP-2. Beyond a 1.0 mg/mL concentration, only free rhBMP-2 levels increased. Linearized Langmuir treatment of the adsorption data yielded values corresponding to monolayer coverage of the microspheres (Cm) and the equilibrium adsorption constant (K) of 0.17 microgram/cm2 and 7.57 ml/mg, respectively. Studies performed to determine the effect of ionic strength revealed that increasing NaCl and buffer concentration decreased the amount of protein adsorbed. rhBMP-2 release studies, conducted in an isotonic phosphate buffered saline, pH 7.4 vehicle, revealed that free rhBMP-2 was released during an initial period of 72-96 hr. Following this period, there was no discernible release of rhBMP-2 from the microspheres for up to 7 days, suggesting that the bound protein would remain at a defect site and release slowly upon erosion of the polymer. Mass balances performed by using an extraction buffer of high ionic strength confirmed this prediction.

Adsorption↗
PubMed1997

Solid tumor chemotherapy and in vivo distribution of fluorouracil following administration in poly(L-lactic acid) microspheres.

The physicochemical properties and in vivo distribution of poly(L-lactide) (L-PLA) microspheres containing 5-fluorouracil (5-FU) prepared by a solvent evaporation method were evaluated for potential use in the treatment of liver cancers. Two different molecular weight polymers of L-PLA [L-PLA1 (152,500 Da) and L-PLA2 (52,000 Da)] were used to prepare 5-FU-loaded microspheres. The mean particle size of the microspheres was 3-6 microns, and there was a direct relationship between the mean particle size and the molecular weight of the polymers. The drug release behavior from microspheres exhibited a diffusion mechanism in different dissolution media, with the molecular weight of the polymer being a major factor in controlling the drug release and degradation rates. Following intravenous injection of 99mTc-labeled L-PLA microspheres, with or without 5-FU, or free 5-FU into mice, L-PLA2 microspheres localized mainly in the liver. The disappearance rate of radioactivity from the tissue was very slow in comparison to that of free 5-FU. The results were confirmed by histological examination of liver tissue following administration of fluorescein particles. In addition, growth of a human liver tumor as first transplant generation under the renal capsule of immunocompetent rats and antitumor activity of L-PLA2 microspheres were investigated. Histological examination by optical microscopy showed that there was no neoplastic tissue of the kidney or in other tissues examined after treatment.

Animals↗
PubMed1998

Influence of swelling degree on release of nicardipine hydrochloride from acrylic microspheres prepared by solvent evaporation method.

The purpose of this study was to prepare and evaluate an enteric coated dosage form of nicardipine hydrochloride (NCH)-loaded microspheres for delivery over a 12-hr period. Microspheres containing Eudragit RS and L with different ratios were prepared by solvent evaporation method and the effect of swelling on the release rate and characteristics was investigated. The change in the diameters of microspheres with time in simulated intestinal fluid (pH 7.5) at 37 degrees C has been studied. Drug release was determined using the flow-through cell method, and related to the degree of swelling (Q) of the microspheres. Q values in turn depended on the ratio of Eudragit RS-L used. Release of NCH from microspheres increased with Eudragit L amount, but no controlled-release pattern was observed. Q values > or = 18.88 caused a slow initial release followed by an accelerated release. Microspheres with an Eudragit RS-L ratio of 1:5.7, Q value of 38.71, and drug release rate of 0.155% min-1 exhibited a remarkable delayed time for erosion to begin (120 min). Thus, microspheres prepared from this formulation may provide an effective enteric dosage form, releasing NCH at a predetermined rate.

Acrylic Resins↗
PubMed2002

PELA microspheres loaded H. pylori lysates and their mucosal immune response.

AIM: To prepare poly (D,L-lactide)-polyethylene glycol copolymer (PELA) microspheres loaded H.pylori lysates or Cystografin and observe their targeting in gastrointestinal mucous membrane or analyze the mucosal immune responses by oral administration. METHODS: PELA microspheres loaded H.pylori lysates or Cystografin were prepared by double emulsion evaporation method. Their distribution in gastrointestinal mucous membrane was observed by CT. Balb/c mice orally immunized in mucosal immune responses, whose antibody production in salivary and gut washing and antibody secreting cells in Peyer's patches (PP) were estimated by ELISA and ELISPOT, respectively. The microspheres physical properties, such as particle size, protein level and morphology were investigated. RESULTS: All prepared microspheres were found to have a smooth surface morphology from 3.20-4.05 microm in diameter and high encapsulation efficiency from 74.9-82.2 %. No significant correlation in their physical properties was shown, depending on their molecular weight at the similar composition ratio. Immunization with all types of PELA-Hp microspheres elevated the saliva sIgA level at week 3 by approximately 3-4 times that with soluble antigen, which was greatly enhanced after boosting. At one week after last immunization with all types of PELA-Hp microspheres (week 8), the specific sIgA-ASCs, IgG-ASCs and sIgA in salivary rose obviously. In intestinal Peyer's patches, the specific sIgA-ASCs were 5.92-6.98X10(4)/ml cell and IgG-ASCs were 3.47-4.02X10(4)/ml cell, about 5-9 times higher than those with soluble antigen (P<0.01). ASCs in intestine were more than those in stomach and the majority of the ASCs were sIgA-ASCs. The sIgA in gut washing fluid was 1.62-1.85 OD, about 3-6 times tthat of those with soluble antigen. There were significant differences of the ASCs and sIgA in gut washing fluid as compared with those of PBS and MS-0 (P<0.05). There appeared to be good correlation between sIgA level in gut washing fluid and sIgA-ASCs in intestinal Peyer's patches. CONCLUSION: PELA microspheres may be used as vehicle to delivery antigen and adjuvant in designing oral vaccination.

Administration, Oral↗
PubMedDate not supplied

Effects of 10-hydroxycamptothecin, delivered from locally injectable poly(lactide-co-glycolide) microspheres, in a murine human oral squamous cell carcinoma regression model.

This study investigated whether local delivery of 10-hydroxycamptothecin provides effective inductive chemotherapy as assessed by significant tumor reduction. Established tumorigenic human oral squamous cell carcinoma cells were used for these experiments. The experimental groups were comprised of: control (blank (no drug) poly(lactide-co-glycolide) (PLGA) microspheres), intraperitoneal 10-hydroxycamptothecin delivery + blank microspheres, local bolus 10-hydroxycamptothecin + blank microspheres, and PLGA controlled-release microspheres. The 10-hydroxycamptothecin dose administered was 12 mg/kg (bolus-intraperitoneal, local) or controlled-release over 10 days. Regardless of delivery route, 10-hydroxycamptothecin significantly reduces tumor volume. However, PLGA microspheres provide significantly higher intratumor-drug concentrations (approximately 10 and 100 fold higher) relative to local bolus and intraperitoneal routes, respectively. Also, only the PLGA microspheres significantly reduced tumor weights. Camptothecin clinical applications are limited by drug inactivation at physiological pH and the need for sustained infusions. However, due to their acidic, camptothecin-stabilizing microclimate, PLGA microspheres could provide a novel delivery system for camptothecin-based induction chemotherapy.

Animals↗
PubMed2001

Nifedipine loaded chitosan microspheres: characterization of internal structure.

In the present investigation, a simple technique was employed to obtain cross-sections of unloaded and nifedipine loaded chitosan microspheres. Microspheres, adhering to a polymerized resin block, were cut with an ultramicrotome and viewed with a scanning electron microscope. Unloaded microspheres exhibited a uniform dense matrix structure while crystals of nifedipine were clearly visible in the drug-loaded microspheres. At 2% drug loading, however, no crystals could be seen in the microspheres indicating that either the drug was molecularly dispersed or dissolved in the matrix at this concentration. This was confirmed by powder X-ray diffractometry studies where no peak due to crystalline nifedipine was observed. At high Span 85 concentration (1.5% w/v), the external surface of the microspheres collapsed, but the internal structure remained dense. When the drug was dispersed in the chitosan solution with stirring during preparation, the entrapment was good and the shape of the crystals was changed. The internal structure of the microspheres following dissolution exhibited the presence of pores.

Chitin↗
PubMed2000

[The acute effect of tetrandrine pulmonary targeting microspheres on hypoxic pulmonary hypertension in rats].

OBJECTIVE: To investigate the effect of tetrandrine (Tet) pulmonary targeting microspheres on hypoxic pulmonary hypertension and its selective role on pulmonary circulation. METHODS: Tet pulmonary targeting microspheres were synthesized by spraying desiccation, the content of tetrandrine in pulmonary targeting microspheres is 32%. Twenty Wistar rats were exposed to hypoxia for three weeks, the rats were given Tet pulmonary targeting microspheres and Tet aqueous solution respectively and another 10 rats were as normal control. The mean pulmonary arterial pressure (mPAP) was measured by a right cardiac catheterization, mean systemic blood pressure (mSBP) was measured by left femoral catheterization. RESULTS: At the end of hypoxic treatment, rats developed pulmonary hypertension. mPAP in the rats receiving Tet pulmonary targeting microspheres decreased more obviously than the rats receiving Tet aqueous solution (P < 0.05), and the effects maintained for 60 min after administration. However, the mSBP remained normal in rats receiving Tet pulmonary targeting microspheres. CONCLUSION: Tet pulmonary targeting microspheres can improve the effect of Tet on the hypoxic pulmonary hypertension and Tet has the selective role on the pulmonary circulation.

Alkaloids↗
PubMed2002

Therapeutic effect of in vivo sustained estradiol release from poly (lactide-co-glycolide) microspheres on bone mineral density of osteoporosis rats.

Poly (lactide-co-glycolide or PLGA) microspheres containing 0.3% (w/w) of estradiol were prepared by a solvent evaporation method. These PLGA microspheres had a wide particle distribution between 0.5 and more than 100 microm. The average size was 76 microm. Physicochemical properties of the microspheres were characterized by X-ray diffraction patterns, FT-IR spectra and DSC. In vitro estradiol release was maintained at a constant rate from these PLGA microspheres for 1 month. The loaded drug was totally recovered in the collection buffer within this time period. In vivo experiments were performed on Wistar rats that had received ovariectomy. These rats were fed with a vitamin D-deficient and Ca-deficient diet. The combination of ovariectomy and diet induced osteoporosis. PLGA microspheres containing either 50, 100, or 200 microg estradiol were injected into these rats. The plasma estradiol in each rat was monitored for 50 days. These in vivo drug release patterns were found to be different from the one obtained from in vitro release. The Ca-AUC was not significant different among various dosages administered. However, bone mineral density for rats after the injection of estradiol loaded microspheres was higher than that obtained for the control. This suggested that all estradiol microspheres administration induced bone generation in osteoporosis rats.

Animals↗
PubMedDate not supplied

In vitro--in vivo evaluation of tableted caseinchitosan microspheres containing diltiazem hydrochloride.

Casein-chitosan microspheres containing diltiazem hydrochloride (DTZ.HCL) were prepared using aqueous coacervation technique. The formed microspheres were not suitable for tableting by direct compression due to their poor binding properties. The effect of hydroxypropylmethylcellulose (HPMC), ethylcellulose (EC), carbopol 940 and egg albumin as dry binders at different concentrations on the properties of the tablets was studied. Each blend of microspheres with dry binder and 2% w/w magnesium stearate as glidant was hand-filled into the die cavity of a single punch tablet machine to ensure constant amount of drug (90 mg) in each tablet. The compression force was adjusted to produce tablets with hardness value about 7.73 +/- 0.79 Kp. The prepared tablets showed good appearance and low friability. The tested binders HPMC (10 and 30% w/w) and EC (20 and 30% w/w) gave fast tablet disintegration with high initial drug release (burst effect) while, carbopol 940 (5 and 10% w/w) and egg albumin (30% w/w) gave non-disintegrating tablets with low initial drug release. Tableted microspheres prepared with 30% egg albumin showed drug release profile similar to one of the commercial tablets (Dilzem retard, 90 mg) and was chosen for in-vivo study. Tableted microspheres and commercial tablets were administered orally in different occasions to six beagle dogs and diltiazem was assayed in dog plasma. The pharmacokinetic parameters including maximum drug concentration (Cmax) and time to reach that maximum (Tmax) were 106.24 +/- 17.96 ng.ml-1 and 5.8 +/- 2.04 hours, respectively, for the commercial sustained release DTZ tablets while, those were 107.9 +/- 12.89 ng.ml-1 and 3.6 +/- 1.36 hours, respectively for tableted microspheres. The elimination half-lives were nearly the same for the commercial and the formulated tablets (8.22 +/- 4.19 and 7.95 +/- 4.28 hours, respectively). No statistical differences (P > 0.05) were found between the two treatments for area under the plasma concentration curve (AUC0 infinity), mean residence time (MRT) and rate of drug absorption (Cmax/AUC0 infinity) indicating comparable extent and rate of drug absorption for both formulations. It was concluded that the formulated tableted microspheres provide an acceptable delivery for DTZ over an extended period of time.

Animals↗
PubMed2005

Preparation of gelatin microspheres containing lactic acid--effect of cross-linking on drug release.

In this study, gelatin microspheres containing lactic acid were prepared by the polymerization technique using glutaraldehyde as the cross-linking agent. Dried microspheres were loaded by immersing them in an aqueous solution of lactic acid. In order to prepare microspheres with an appropriate drug release profile, the effect of time of cross-linking and the amount of cross-linking agent on the swelling properties of microspheres and their release profile were investigated. The microencapsulation efficiency, microspheres appearance, particle size, swelling ratio and drug release profile were also studied. Microspheres prepared with a larger amount of cross-linking agent, or after longer cross-linking time, showed a reduced swelling ratio in aqueous media. In vitro release pattern of lactic acid from gelatin microspheres showed a biphasic profile and the release rates were reduced upon increasing the amount of cross-liking agent and prolonging the cross-linking time.

Aging↗