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At least 973 records · Page 54Linked to original sources
PubMed1997

Development of a statistical model for the formation of poly [acryloyl hydroxyethyl starch] microspheres.

PURPOSE: To develop a mathematical model for predicting the molecular weight between crosslinks, Mc, of poly[Acryloyl Hydroxyethyl Starch] (Ac-HES) microspheres system and to identify and evaluate the key microsphere preparation parameters which affect the Mc of the formed microsphere structure based on the developed model. METHODS: Link probability generating functions (LPGFs) based on the classical branching theory were used to derive a model for the calculation of Mc for the Ac-HES system. Based on the developed model, simulation was made to study the effects of the microsphere preparation variables on Mc of the formed microspheres. The process variables were the degree of derivatization (DD) of the Ac-HES, the molar ratio (MR) of the Ac-HES to acrylamide monomer, the fractional conversion of the unsaturation (alpha), the initiator efficiency (f), the molar concentration of initiator (I), the fraction of intramolecular cyclization (c), and the total weight of the reactable monomer and polymer (s). RESULTS: A model to describe the crosslinking reaction of Ac-HES system and predict Mc was developed. Simulation based on the model showed that Mc decreased as alpha increased and reached a limiting value before total conversion. At constant alpha, Mc initially decreased with MR to a minimum and then increased with MR; while Mc decreased monotonically with DD. I and c affected Mc only at very low alpha and changes in s and f had no effect on Mc. CONCLUSIONS: Simulation based on the model suggested that the most important microsphere preparation parameters influencing Mc of the Ac-HES system are the number of functional groups on the Ac-HES (DD) and the stoichiometry (MR) of the crosslinking reaction.

Acrylic Resins↗
PubMed1997

Biological activity of lysozyme after entrapment in poly(d,l-lactide-co-glycolide)-microspheres.

PURPOSE: The purpose of this study was to investigate the process of preparing microspheres for maximising entrapment efficiently (EE) and retained biological activity (RBA) of peptides and proteins. METHODS: A controlled-release formulation based on poly(d,l-lactide-co-glycolide) was designed and produced using a small-scale double emulsion method. These PLG microspheres contained a model peptide, lysozyme. The retained bioactivity of the incorporated lysozyme was determined by bacterial assay. The size distributions and the morphology of the microspheres were characterized. RESULTS: The RBA and EE improved when the PLG concentration in the organic phase of the emulsion was increased. A high lysozyme concentration in the inner water phase of the emulsion resulted in decreased EE and an increase in the proportion of fragmented particles. The RBA of lysozyme in the microspheres varied between 30 and 80% with changes to the process. CONCLUSIONS: The study shows that the RBA of lysozyme in PLG microspheres is strongly dependent on the experimental conditions for preparing the microspheres. Measurement of the EE alone, without the RBA is insufficient to evaluate the efficacy of the designed delivery system.

Animals↗
PubMed1997

Utilization of an amorphous form of a water-soluble GPIIb/IIIa antagonist for controlled release from biodegradable microspheres.

PURPOSE: We prepared injectable microspheres for controlled release of TAK-029, a water-soluble GPIIb/IIIa antagonist and discussed the characteristics of controlled release from microspheres. METHODS: Copoly(dl-lactic/glycolic)acid (PLGA) microspheres were used for controlled release of TAK-029 [4-(4-amidinobenzoylglycyl)-3-methoxycarbonyl-2-oxopiperazine++ +-1-acetic acid]. They were prepared with a solid-in-oil-in-water (S/O/W) emulsion solvent evaporation technique using either a crystalline form or an amorphous form of the drug. RESULTS: An amorphous form of TAK-029 gave more homogeneous S/O dispersion and higher viscosity than its crystalline form when added to dichloromethane solution of PLGA, resulting in a high drug entrapment into microspheres and a well-controlled release of the drug. Additions of sodium chloride into an external aqueous phase and L-arginine into an oil phase also increased entrapment of the drug, and reduced initial burst of the drug from the microspheres. The microspheres demonstrated a desirable plasma level profile in therapeutic range (20-100 ng/ml) for 3 weeks in rats after single subcutaneous injection. CONCLUSIONS: A well-controlled release of TAK-029, a water-soluble neutral drug, with small initial burst was achieved by utilizing its amorphous form as a result of possible interaction with PLGA and L-arginine.

Animals↗
PubMed1991

Development and evaluation of sustained-release ibuprofen-wax microspheres. I. Effect of formulation variables on physical characteristics.

A congealable disperse phase encapsulation method was used to prepare sustained-release ibuprofen-wax microspheres. Microspheres prepared with paraffin wax, such as ceresine and microcrystalline waxes, using polyvinylpyrrolidone (PVP) as dispersant had a tendency to aggregate, but the addition of wax modifiers (stearyl alcohol and glyceryl monostearate) greatly reduced aggregation. Optimum modifier and dispersant concentrations were 20% (w/w) and 5% (w/v), respectively. The particle size distribution of the microspheres was log-normal. An increase in modifier, dispersant concentration, emulsification stirring speed, or temperature shifted the size distribution toward finer particles. Microcrystalline wax required a higher emulsification temperature and produced finer particles than ozokerite wax. The recovery of drug from the different microsphere formulations varied between 71 and 92%. Differential scanning calorimetry (DSC) of the single components and physical mixtures showed endothermic peaks at the respective melting-point ranges. The DSC of the ceresine and microcrystalline wax microspheres was similar to rescans of ternary mixtures of components of the microspheres with less prominent and lower melting temperatures than individual components or physical mixtures.

Delayed-Action Preparations↗
PubMed1990

Release of human serum albumin from poly(lactide-co-glycolide) microspheres.

Human serum albumin (HSA) was encapsulated in a 50:50 copolymer of DL-lactide/glycolide in the form of microspheres. These microspheres were used as a model formulation to study the feasibility of controlling the release of large proteins over a 20- to 30-day period. We show that HSA can be successfully incorporated into microspheres and released intact from these microspheres into various buffer systems at 37 degrees C. A continuous release of the protein could be achieved in physiological buffers at 37 degrees C over a 20- to 30-day period from microspheres with high protein loadings (11.6%). These results demonstrate the potential of poly(DL-lactide-co-glycolide) microspheres for continuous delivery of large proteins.

Buffers↗
PubMed1999

pH and osmotic pressure inside biodegradable microspheres during erosion.

PURPOSE: To measure changes in pH as well as osmotic pressure in aqueous pores and cavities inside biodegradable microspheres made from polymers such as poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA). METHODS: The internal osmotic pressure inside eroding PLA microspheres was analyzed with differential scanning calorimetry (DSC) in a temperature range of 10 to--25 degrees C. The osmotic pressure was calculated from the melting peaks of the aqueous phase using purity analysis. For pH determination, PLGA microspheres were loaded with a pH-sensitive spin probe which allowed the determination of pH by electron paramagnetic resonance (EPR). RESULTS: The osmotic pressure in PLA microspheres increased to 600 mOsm within four days and decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study was < or =4.7. Basic drugs such as gentamicin free base or buffering additives led to a pH increase. In no case, however, did the internal pH exceed a value of 6 within 13 hours. CONCLUSIONS: DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres. This data in combination with detailed information on peptide and protein stability could allow in the future to predict the stability of such compounds within degradable polymers.

Algorithms↗
PubMed1993

Albumin microspheres as a drug delivery system: relation among turbidity ratio, degree of cross-linking, and drug release.

The degree of cross-linking of albumin microspheres, with and without drug, was assessed using turbidity measurements carried out in the presence of water and the protein denaturant guanidine hydrochloride (GuHCl) at a concentration that disrupted noncovalent bonds while having no effect on covalent bonds. The measurements allowed calculation of a turbidity ratio (TG/TW), expressed as the ratio of the turbidity of albumin microspheres in 6 M GuHCl (TG) divided by that in water (TW). A linear relation existed between TG/TW and the (i) temperature at which the microspheres were prepared, (ii) concentration of the cross-linking agent glutaraldehyde, and (iii) time of exposure to a second cross-linking agent, formaldehyde vapor, three conditions that increase the degree of cross-linking. The turbidity ratio also increased as the concentration of the albumin solution used to prepare the microspheres increased from 25 to 50%. Drug release from the microspheres consisted of an initial, rapid, burst followed by a second, slower, phase. The rates in both release phases were inversely related to the turbidity ratio, suggesting that this parameter has utility as an indicator of the degree of cross-linking in albumin microspheres.

Albumins↗
PubMed2004

In vitro/in vivo correlation for 14C-methylated lysozyme release from poly(ether-ester) microspheres.

PURPOSE: The purpose of this study was to obtain an in vitro/in vivo correlation for the sustained release of a protein from poly(ethylene glycol) terephthalate (PEGT)/poly(butylene terephthalate) (PBT) microspheres. METHODS: Radiolabeled lysozyme was encapsulated in PEGT/PBT microspheres via a water-in-oil-in-water emulsion. Three microsphere formulations varying in copolymer composition were administered subcutaneously to rats. The blood plasma was analyzed for radioactivity content representing released lysozyme at various time points post-dose. The in vitro release was studied in phosphate-buffered saline. RESULTS: The encapsulation efficiency, calculated from the radioactivity in the outer water phase of the emulsion, varied from 60-87%. Depending on the PEG segment length and wt% PEGT, the lysozyme was released completely in vitro within 14 to 28 days without initial burst. 14C-methylated lysozyme could be detected in the plasma over the same time courses. The in vitro/in vivo correlation coefficients obtained from point-to-point analysis were greater than 0.96 for all microsphere formulations. In addition, less then 10% of administered radioactivity remained at dose site at 28 days for the microsphere formulations, indicating no notable retention of the protein at the injection site. CONCLUSION: The in vitro release in phosphate-buffered saline and the in vivo release in rats showed an excellent congruence independent of the release rate of 14C-methylated lysozyme from PEGT/PBT microspheres.

Animals↗
PubMed2003

Tramadol encapsulated into polyhydroxybutyrate microspheres: in vitro release and epidural analgesic effect in rats.

BACKGROUND: Controlled release techniques are used to increase the duration of action and decrease the toxicity of drugs. Any controlled release form of tramadol in spinal or epidural blocks has not been studied previously. Tramadol was encapsulated into polyhydroxybutyrate (PHB) microspheres and release kinetics was studied. The epidural analgesic effect of this solution in rats was also compared with free tramadol. METHODS: Controlled release of tramadol from PHB microspheres into 10 ml of phosphate buffer solution at pH 7.4 and 37 degrees C was studied in vitro. In vivo studies were performed in 40 rats. Epidural catheters were placed during general anaesthesia. Rats were randomly allocated into one of the four study groups to receive normal saline, 4 mg of tramadol, PHB microspheres without tramadol, or 4 mg of tramadol encapsulated into PHB microspheres. Analgesia was evaluated with tail flick tests performed at 52.5 +/- 0.5 degrees C before injection and at intervals up to 30 h after injection. Catalepsy and loss of corneal reflexes were considered as signs of supraspinal toxicity. RESULTS: In vitro drug release was observed for more than 6 days. Epidural analgesic effects of tramadol released from PHB microspheres were observed for 21 h, whereas an equal dose of free tramadol was effective for less than 5 h. No signs of toxicity were observed. CONCLUSION: Controlled release of tramadol from PHB microspheres is possible, and pain relief during epidural analgesia is prolonged by this drug formulation compared with free tramadol.

Analgesia, Epidural↗
PubMed2003

Locally delivered minocycline microspheres for the treatment of periodontitis in smokers.

AIM: The aim of the present analysis of a larger phase 3 clinical trial was to evaluate the efficacy of 1 mg minocycline hydrochloride microencapsulated in 3 mg of resorbable polymer, subgingivally administered as an adjunct to scaling and root planing (SRP) in smokers with chronic periodontitis. MATERIAL AND METHODS: Two hundred and seventy-one patients who smoked were randomized to one of three treatment groups: (1) SRP alone, (2) SRP plus vehicle (polymer without minocycline) or (3) SRP plus minocycline microspheres. Full mouth SRP was performed for all groups at baseline, and vehicle or minocycline microspheres were administered to the appropriate patients at all periodontal pockets > or =5 mm at baseline, 3 and 6 months. Efficacy was evaluated over 9 months. RESULTS: Significantly greater pocket depth reductions with SRP plus adjunctive minocycline microsphere treatment were observed at 1, 6 and 9 months (p<0.05) versus control treatments. At 9 months, smokers treated with SRP plus minocycline microspheres exhibited a pocket depth reduction of 1.19 mm from baseline, as compared to 0.90 mm for smokers treated with SRP alone. The efficacy of adjunctive minocycline microspheres was consistent among all tested smoking subcohorts, including those based on gender, age and smoking exposures. CONCLUSION: These data indicate that treatment with SRP plus locally delivered minocycline microspheres is more effective than SRP alone in reducing pocket depths in smokers with periodontitis.

Administration, Topical↗
PubMed1992

Is there a relationship between regional microsphere distribution and hepatic arterial blood flow?

The relationship between hepatic arterial albumin microsphere distribution and hepatic arterial blood flow and the effects of regional angiotensin II were studied in a rat liver metastases model. Hooded-Lister rats were inoculated subcapsularly with 2 x 10(6) HSN sarcoma cells. At 20 days, hepatic arterial blood flow was measured using the reference microsphere technique. Animals then randomly received 50 microliters hepatic arterial saline or albumin microspheres (40 microns, 20 mg ml-1). Hepatic arterial blood flow measurements were then repeated at 5 min. After 5 min, animals were killed and tissues were weighed and counted in a gamma well counter. There were no significant differences between the hepatic blood flow measurements recorded before and after the control hepatic arterial saline infusion. However, regional albumin microspheres produced a significant reduction in tumour and normal liver blood flow and an 80% reduction in mean T/N blood flow ratio. Regional albumin microspheres were delivered to tumour in greater proportions (mean T/N ratio 3.89, SE 0.49) than would be expected from baseline hepatic arterial blood flow (mean T/N ratio 1.28, SE 0.22. P = 0.006). There was no correlation between T/N for baseline blood flow and albumin microsphere distribution.

Animals↗
PubMedDate not supplied

Coacervate microspheres as carriers of recombinant adenoviruses.

The therapeutic utility of recombinant adenoviruses (rAds) is limited in part by difficulties in directing the viruses to specific sites and by the requirement for bolus administration, both of which limit the efficiency of target tissue infection. As a first step toward overcoming these limitations, rAds were encapsulated in coacervate microspheres comprised of gelatin and alginate followed by stabilization with calcium ions. Ultrastructural evaluation showed that the microspheres formed in this manner were 0.8-10 microM in diameter, with viruses evenly distributed. The microspheres achieved a sustained release of adenovirus with a nominal loss of bioactivity. The pattern of release and the total amount of virus released was modified by changes in microsphere formulation. Administration of the adenovirus-containing microspheres to human tumor nodules engrafted in mice showed that the viral transgene was transferred to the tumor cells. It is concluded that coacervate microspheres can be used to encapsulate bioactive rAd and release it in a time-dependent manner.

Adenoviridae↗
PubMed1998

Microsphere infusion reverses vasoconstrictor-mediated change in hindlimb oxygen uptake and energy status.

The vasoconstrictors, angiotensin II (AII) and serotonin (5-HT) produce opposing metabolic effects and appear to control different flow routes in the constant-flow perfused rat hindlimb. In the present study the association between vascular flow route recruitment and metabolism was assessed by selective microsphere embolism of either route. Microspheres (MS, 11.9 +/- 0.1 microns, mean +/- SE diameter) were injected during AII, 5-HT or vehicle infusions (basal conditions) and the effects on hindlimb (4.7 +/- 0.1 g muscle) oxygen uptake (VO2) and indices of energy status CrP/Cr, CrP/ATP and energy charge (EC) of the calf muscle group assessed. MS (1.5 x 10(6)) injected during vehicle, or 5-HT infusion increased VO2 (P < 0.05) but did not affect energy status. During AII, MS decreased VO2. Change in VO2 correlated positively with CrP/Cr (r = 0.68, P < 0.0001) and CrP/ATP (r = 0.51, P < 0.001) but not EC (r = 0.08, P = 0.59). MS (1.5 x 10(6)) increased pressure but did not affect the flow rate. The metabolic changes resulting from 1.5 x 10(6) microspheres were intensified by a second injection of 1.5 x 10(6) microspheres but further injection (> 3.0 x 10(6) microspheres) began to inhibit flow. It is concluded that a finite number (< or = 3.0 x 10(6)) of microspheres of 11.9 microns diameter has opposite effects on VO2 depending on the vasoconstrictor present and that these effects result from the occlusion of the different vascular route accessed by each vasoconstrictor. The data support the proposal that hindlimb metabolism can be controlled by vasoconstrictors as a result of selective vascular recruitment.

Angiotensin II↗
PubMed1996

Slow delivery of the selective cholecystokinin agonist pBC 264 into the rat nucleus accumbens using microspheres.

Neuropeptides have been shown to play a critical role in adaptational processes, probably by long-term modulation of neuronal pathways. It could therefore be interesting to study behavioral changes induced by chronic local stimulation of neuropeptide receptors. With this aim poly(lactide-co-glycolide) microspheres loaded with a highly potent, peptidase-resistant, cholecystokinin (CCK)-B-selective CCK peptidomimetic agonist (pBC 264) were prepared by a water in oil in water emulsion solvent evaporation method and stereotaxically implanted into the anterior part of the rat nucleus accumbens. Two different kinds of loaded polymeric microspheres differing only by the stabilizing agent [ovalbumin (OVA) or Pluronic F 68] added to the inner emulsion were used. The histological and behavioral studies done 24 h and 8 days after implantation of nonloaded microspheres in the nucleus accumbens indicated that the microspheres were well tolerated. The in vivo release of the selective CCK-B agonist pBC 264 (associated with a tracer dose of [3H]pBC 264) from microspheres prepared with OVA was very fast (92% after 6 h), whereas only 26% (88 pmol) of pBC 264 was released from the formulation with Pluronic F 68 after 24 h. Eight days after implantation 36% of pBC 264 had diffused from the microspheres, and 8% (approximately 30 pmol) was still present in the brain concentrated around the site of administration. In all cases the released material was found to correspond to intact pBC 264, thus demonstrating the possibility of obtaining a slow controlled release of peptide in vivo. This method opens up interesting perspectives to study the long-term effects of neuropeptides.

Animals↗
PubMed2000

Microsphere-adenoviral complexes target and transduce the glomerulus in vivo.

BACKGROUND: Developing new treatments for glomerulonephritis makes the glomerulus a logical target for gene therapy. Microspheres may lodge in the glomerulus, and replication-deficient recombinant adenoviruses are potent mediators of gene transfer. We postulated that adenoviral-microsphere complexes could result in DNA transfer (transduction) into glomerular cells in vivo. METHODS: Two adenoviruses, each one containing a luciferase or beta-galactosidase (beta-gal) transgene expression cassette, were complexed to polystyrene microspheres. To assess in vivo glomerular transduction with this tool, male Sprague-Dawley rats underwent aortic injections with adenovirus linked to 11 or 16 microm diameter microspheres. RESULTS: After 48 hours, adenoviral-microsphere complexes resulted in transduction of up to 19% of glomeruli per kidney section. Endothelial and mesangial cells were transduced with this approach, and transprotein expression persisted for 21 days. Transduction efficiency was greater in the 16 microm group. For all rats, there was a strong correlation between kidney luciferase levels and the number of beta-gal-positive glomeruli (r = 0.87), indicating that transgene expression was primarily glomerular in location. This was supported by reverse transcriptase in situ polymerase chain reaction, which demonstrated glomerular localization of the beta-gal transgene. CONCLUSIONS: The aortic injection of adenoviral-microsphere complexes transduces the glomerulus in vivo and may be a useful tool in developing approaches to gene therapy of glomerular disease.

Adenoviridae↗
PubMed2001

Intra-arterial embolization of head-and-neck cancer with radioactive holmium-166 poly(L-lactic acid) microspheres: an experimental study in rabbits.

A total of 22 NZW rabbits with VX2 squamous cell carcinomas transplanted into the auricles were intra-arterially (i.a.) embolized with radioactive or inactive holmium-labelled poly(L-lactic acid) (HoPLA) microspheres with a mean diameter of 38-80 microm. The effects on tumour growth, the efficiency of i.a. infusion, the efficacy of retention of microspheres in the primary tumour and the excretion of free holmium-166 were analyzed. Complete tumour remissions were obtained in 79% and 86% following embolization with radioactive and inactive microspheres, respectively. Over 95% of the microspheres were retained in the tumour and the leaching of holmium-166 in urine and faeces was less than 0.1% in 2 days. The injection efficiency was not optimal, as 40% of the microspheres were retained in the cannulation system. Arterio-arteriolar connections should be detected and closed prior to embolization to prevent stray emboli from entering the brain. It is concluded that 166HoPLA microspheres are promising candidates for further studies on radio-embolization of unresectable head-and-neck cancer.

Animals↗
PubMed2003

Biologic activity of nerve growth factor slowly released from microspheres.

Efficient and sustained delivery of neurotrophic factors to the regenerating nerve in biologically active form presents a challenge. Protein delivery in biodegradable microsphere vehicles has been difficult, based on destabilization and breakdown during both the loading and release phases. This study examines the extravasation and stability of Nerve Growth Factor (NGF) in polylactic-co-glycolic acid (PLGA) microspheres, via both ELISA and PC-12 bioassays. PLGA microspheres co-loaded with bovine serum albumin (BSA) and NGF were prepared by a water-in-oil-in-water (W/O/W) technique, using chloroform for the organic phase and 1 percent polyvinyl alcohol (PVA) for the emulsion step. Aliquots of lyophilized microspheres were incubated in double distilled water (dd H2O) at 37 degrees C, and the supernatants assayed over time for NGF activity. ELISA was utilized for quantitative determination of NGF concentration, and a PC-12 cell neurite outgrowth assay assessed biologic activity. Both ELISA and PC-12 assays demonstrated the extravasation of NGF from microspheres. Over time, the predicted concentration of NGF via the two assays differed, suggesting possible preservation of recognizable epitopes for ELISA, but loss of biologic activity. NGF can be stored and released from microspheres. Extravasation studies should include biologically relevant assays for activity.

Animals↗
PubMed2001

Neoadjuvant therapy with interleukin-12-loaded polylactic acid microspheres reduces local recurrence and distant metastases.

BACKGROUND: We previously demonstrated that the intratumoral injection of biodegradable polylactic acid microspheres that were loaded with interleukin (IL)-12 can induce a systemic antitumor immunity. We sought to investigate the clinical potential as neoadjuvant therapy. METHODS: Mice were inoculated with 5 x 10(7) Line-1 cells subcutaneously. Six days later, a single intratumoral injection of IL-12- or BSA-loaded microspheres were given; 14 days later, autopsy was performed to document metastases. Mice were inoculated with 5 x 10(7) Line-1 cells and 10 days later either treated with IL-12- or BSA-loaded microspheres or resected. Treated tumors were resected 6 days after treatment. Mice were observed 45 days for local recurrence before autopsy. RESULTS: Intratumoral injection of IL-12 microspheres resulted in significant suppression of tumor growth compared with controls (599 +/- 255 mm(3) vs 1591 +/- 372 mm(3); P =.001) and pulmonary metastases (0.4 vs 3.8 nodules per mouse; P =.003). Given before the operation, IL-12-loaded microspheres both decreased the local recurrence rate (100% to 40%) and pulmonary metastases (5.2 vs 0.6 nodules per mouse; P =.06). Earlier resection did not improve local recurrence or distant metastases. CONCLUSIONS: Intratumoral injection of IL-12-loaded polylactic acid microspheres promotes the development of systemic antitumor immunity that can eradicate micrometastases. As a neoadjuvant therapy, this can result in decreased local and distant recurrence.

Adenocarcinoma↗