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PubMed2006

Preparation of biodegradable polymeric hollow microspheres using O/O/W emulsion stabilized by Labrafil.

Biodegradable hollow microspheres were prepared by double oil and water emulsion using a lipophilic surfactant, Labrafil M 1944 CS. Olive oil was emulsified in biodegradable polymer-dissolved dichloromethane mixed with Labrafil by vigorous sonication. This oil-in-oil emulsion was directly re-emulsified in 0.1% poly(vinyl alcohol) solution, subsequently solidified by evaporating dichloromethane. Olive oil and Labrafil were extracted from the microspheres by using hexane. After vigorous washing with n-hexane, the hollow microsphere was freeze-dried and examined under scanning electron microscopy, confirming the morphology of hollow microspheres with thin walls and huge blank cores inside. The concentration of poly(l-lactide) in dichloromethane affected the size of hollow microspheres while the volume of olive oil or dichloromethane did not. This hollow microsphere is expected to be employed as an imaging contrast agent and a novel drug delivery vehicle.

Emulsions↗
PubMed2004

PLGA microspheres for the ocular delivery of a peptide drug, vancomycin using emulsification/spray-drying as the preparation method: in vitro/in vivo studies.

The aim of this study was an in vitro/in vivo investigation on poly(lactide-co-glycolide) (PLGA) microspheres as carriers for the topical ocular delivery of a peptide drug vancomycin (VA). The microspheres were prepared by an emulsification/spray-drying technique that can be proposed as an alternative to the double emulsion method for preparation of peptide-loaded microparticles. The drug encapsulation efficiencies were close to the theoretical values (84.2-99.5%); the average particle size, expressed as dvs, was about 11 microm. The microspheres were able to modulate the in vitro drug release of VA with a behavior dependent on their composition: the highest drug content corresponded to the highest release rate. In vivo studies were carried out by assessing the pharmacokinetic profile of VA in the aqueous humor of rabbits after topical administration of aqueous suspensions of microspheres. High and prolonged VA concentrations and increased AUC values (2-fold) with respect to an aqueous solution of the drug were observed. Increasing the viscosity of the microsphere suspension by addition of a suspending-viscosizing agent (hydroxypropylcellulose) did not produce an increase of the ocular bioavailability. PLGA microspheres can be proposed as a system for ocular delivery of peptide drugs.

Animals↗
PubMed2005

Mucoadhesive, triclosan-loaded polymer microspheres for application to the oral cavity: preparation and controlled release characteristics.

The aim of this study was to develop mucoadhesive microspheres that can be utilised for the controlled release of triclosan in oral-care formulations, specifically dental pastes. Using a double-emulsion solvent evaporation technique, triclosan was incorporated into microspheres that were prepared from Gantreztrade mark MS-955, Carbopol 974P, polycarbophil or chitosan and the profiles for its release were established under simulated 'in use' conditions. Triclosan was rapidly released into a sodium lauryl sulphate containing buffer from all but the chitosan microspheres. The release of triclosan from microspheres suspended in a non-aqueous paste, was found to be sustained over considerable time-periods, which were influenced strongly by the nature of the polymeric carrier. For microspheres that were fabricated from Gantrez, Carbopol or polycarbophil, the release appeared to obey zero-order kinetics whereas in the case of chitosan-derived vehicles, the release profile fitted the Baker and Lonsdale model. The work has demonstrated that these polymeric microspheres, particularly those of chitosan, are promising candidates for the sustained release of triclosan in the oral cavity.

Adhesives↗
PubMed2006

Preparation of superoxide dismutase loaded chitosan microspheres: characterization and release studies.

Superoxide dismutase (SOD) is the most potent antioxidant enzyme. In this study, SOD was encapsulated in chitosan microspheres to obtain suitable sustained protein delivery. Protein-loaded chitosan microspheres with various formulations were prepared based on complex coacervation process. Due to the inherent characteristic of SOD, high encapsulation efficiency could not be obtained with simple preparation method. The pH of chitosan solution is 3.0; when the chitosan microspheres were prepared with this solution, encapsulation was low. Therefore, several strategies have been tested to increase the encapsulation efficiency and good results have been obtained. 70-80% protein encapsulation efficiency was obtained. The addition of PEG to the protein solution enhanced the encapsulation efficiency also. Mean sizes of microspheres were between 1.38 and 1.94 microm. Factors affecting the release behaviour of SOD from microspheres have been studied. They included pH values of chitosan solution (the pH of chitosan solution is 3.0), addition of PEG to the protein solution and the use of adsorption technique. In general, biphasic release profiles were obtained with these formulations. The protein activity changed between 70 and 100% during the release. In general, the protein activity remained in acceptable limits. The SOD encapsulated chitosan microspheres can be prepared by changing the pH or addition of PEG, allowing the safe incorporation of protein for controlled release.

Alginates↗
PubMed2006

Effect of preparation conditions on the nutrient release properties of alginate-whey protein granular microspheres.

The effect of preparation conditions on nutrient release from alginate (AL)-whey protein isolate (WPI) granular microspheres obtained by an emulsification/internal cold gelation method was studied by varying WPI/AL ratio, microsphere diameter, total polymer concentration and riboflavin loading. Microsphere size distribution and nutrient encapsulation efficiency (EE) were examined. Riboflavin release profiles were investigated in simulated gastric and intestinal fluids. Values for EE above 80% were obtained for most microspheres, with the notable exceptions of high AL or pure AL. Variations in WPI/AL ratio, granule size and nutrient loading have major impact on nutrient release. Microspheres prepared with a WPI/AL ratio of 8:2, a riboflavin concentration of 1% in the initial aqueous phase and diameters near 94 microm retained the vitamin in SGF and released it in SIF. By careful process design, granular microspheres with potential as oral delivery vehicles for bioactive compounds may be developed.

Administration, Oral↗
PubMed2006

Insulin encapsulation in reinforced alginate microspheres prepared by internal gelation.

Insulin-loaded alginate microspheres prepared by emulsification/internal gelation were reinforced by blending with polyanionic additive polymers and/or chitosan-coating in order to increase the protection of insulin at simulated gastric pH and obtain a sustained release at simulated intestinal pH. Polyanionic additive polymers blended with alginate were cellulose acetate phtalate (CAP), Eudragit L100 (EL100), sodium carboxymethylcellulose (CMC), polyphosphate (PP), dextran sulfate (DS) and cellulose sulfate (CS). Chitosan-coating was applied by using a one-stage procedure. The influence of additive polymers and chitosan-coating on the size distribution of microspheres, encapsulation efficiency and release profile of insulin in simulated gastrointestinal pH conditions was studied. The mean diameter of blended microspheres ranged from 65 to 106 microm and encapsulation efficiency of insulin varied from 14 to 100%, reaching a maximum value when CS and DS were incorporated in the alginate matrix. Insulin release, at pH 1.2, was almost prevented by the incorporation of PP, DS and CS. When uncoated microspheres were transferred to pH 6.8, a fast dissolution occurred, independently of the additive polymer blended with alginate, and insulin was completely released. Increasing the additive polymer concentration in the alginate matrix and/or chitosan-coating the blended alginate microspheres did not promote a sustained release of insulin from microspheres at pH 6.8.

Alginates↗
PubMed2003

Preparation and characterization of injectable microspheres of contraceptive hormones.

Present study describes the development of a new formulation of levonorgestrel and ethinylestradiol based on double emulsion-solvent evaporation technique using poly(epsilon-caprolactone) (PCL) as biodegradable polymer. The effect of polymer concentration on microspheres and entrapment of drug into microspheres were studied. PCL was selected because of its hydrophobicity and advantages over other biodegradable polymers. Characterization of biodegradable polymer used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performances. The selected characterisation techniques established for PCL microspheres include its loading and entrapment efficiencies, DSC to analyse thermal behaviour, SEM to observe surface morphology, drug content of microspheres and in vitro release of drugs from microspheres. The SEM reports showed that microspheres were with smooth surface and DSC thermograms revealed no interaction between drug and polymer. The entrapment was found to be 58 and 47% for 1:10 and 1:5 batches and in vitro release studies showed that about 69.7% of LNG and 66.7% of EE from 1:10 batch and about 80% of LNG and 75.5% of EE from 1:5 batch for 150 days.

Contraceptives, Oral, Synthetic↗
PubMed2004

Intranasal administration of melatonin starch microspheres.

Using melatonin as model drug, starch microspheres for intranasal administration were prepared by an emulsification-crosslinking technique using a uniform design to optimize preparation conditions. The entrapment ratio of melatonin in the microspheres was 11.0% and particle sizes ranged from 30 to 60 microm. Melatonin was released from the microspheres in a sustained manner in vitro. Nasal clearance of 99mTC labeled starch microspheres was investigated using gamma scintigraphy. It was revealed that >80% of the starch microspheres could be detected in the nasal tissue 2h after administration, compared to 30% for a solution. The pharmacokinetics of melatonin starch microspheres was investigated after intranasal administration. The absorption rate was rapid (T(max) min), and the absolute bioavailability was high, 84.07%. A good correlation was found between in vitro release and in vivo absorption data.

Administration, Intranasal↗
PubMed2004

Optimisation of aciclovir poly(D,L-lactide-co-glycolide) microspheres for intravitreal administration using a factorial design study.

The purpose of this work was to obtain an optimised long-term aciclovir PLGA microspheres formulation for intravitreal administration to minimise, as much as possible, the dose of microspheres to be administered with a suitable particle size for its injection through a 27G needle in a single dose. Microspheres were prepared by the solvent evaporation method. To obtain the optimum formulation a two-factor five-level central rotatable composite 2(2) + star design was employed. The independent variables were aciclovir and gelatin (added to the external phase of the emulsion). The dependent variables were the yield of production (%), the encapsulation efficiency (%), the initial burst release (%), the cumulative amount released from 1 to 14 days and the amount of aciclovir at the end of the release assay (microg aciclovir/mg microspheres). The best formulation according to the studied variables was (0,0), prepared with 80 mg of aciclovir and 80 mg of gelatin. This formulation showed good yield of production (70.14 +/- 3.72 %) and encapsulation efficiency ( 70.77 +/- 2.62 %), and released the drug at a constant rate for 63 days with a mean release constant of 1.73 +/- 0.08 microg/day per mg microspheres. The selected formulation reduces a 40% the dose of microspheres to be administered through a 27G needle with respect to previous studies.

Acyclovir↗
PubMed2004

Mucoadhesive microspheres prepared by interpolymer complexation and solvent diffusion method.

Mucoadhesive microspheres were prepared to increase gastric residence time using an interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and a solvent diffusion method. The complexation between poly(acrylic acid) and poly(vinyl pyrrolidone) as a result of hydrogen bonding was confirmed by the shift in the carbonyl absorption bands of poly(acrylic acid) using FT-IR. A mixture of ethanol/water was used as the internal phase, corn oil was used as the external phase of emulsion, and span 80 was used as the surfactant. Spherical microspheres were prepared and the inside of the microspheres was completely filled. The optimum solvent ratio of the internal phase (ethanol/water) was 8/2 and 7/3, and the particle size increased as the content of water was increased. The mean particle size increased with the increase in polymer concentration. The adhesive force of microspheres was equivalent to that of Carbopol. The release rate of acetaminophen from the complex microspheres was slower than the PVP microspheres at pH 2.0 and 6.8.

Adhesives↗
PubMed2005

Biodisposition of PEG-coated lipid microspheres of indomethacin in arthritic rats.

Conventional lipid microspheres (LM) were prepared using soybean oil and lipid at a 5.5:1 weight ratio with lipid phase consisting of PC (phosphatidyl choline):CH (cholesterol) (1:0.5) by molar ratio. The average diameter of the particles was 150 nm. Long-circulating microspheres (S-LM) were also prepared similarly but the lipid phase consisted of PC:CH:DSPE-PEG (phosphatidyl choline:cholesterol:distearoyl phosphatidyl ethanolamine-polyethylene glycol) 1:0.5:0.16 by molar ratio. A comparative biodistribution study was conducted between free indomethacin and lipo-indomethacin (LM and S-LM) in the arthritic rats by administering the formulations at a dose equivalent to 12 mg of indomethacin/kg. It was observed that the free drug as well as the encapsulated drug followed biphasic clearance from the blood. Pharmacokinetic parameters, such as AUC(0-t), terminal half-life, MRT increased significantly when the drug was used in encapsulated form (p < 0.05). Clearance of the drug was reduced 1.4 times with the conventional lipid microspheres and was reduced three-fold when encapsulated in polyethylene glycol-coated lipid microspheres. The overall drug targeting efficiency (T(e)) with the PEG-coated lipid microspheres was 7.5-fold higher than the conventional lipid microspheres. The high accumulation of the drug in arthritic paw with S-LM system may be accounted for by the reduced uptake by RES cells, and thereby, availability for extravascularization in the inflammatory tissues.

Animals↗
PubMed2005

Impurity formation studies with peptide-loaded polymeric microspheres Part I. In vivo evaluation.

The purpose of the present investigation was to assess the peptide related substances or impurities formed during incubation of drug loaded poly-(D,L-lactide-co-glycolide) (PLGA) and poly-(D,L-lactide) (PLA) microspheres under in vivo conditions. Sprague-Dawley rats were injected with separate batches of octreotide microspheres prepared by either an oil/water or oil/oil dispersion technique. At specified time points (days 14, 22, 30, and 41), animals were sacrificed and microsphere particles were recovered from the subcutaneous injection sites. The recovered particles were further extracted with 1:1 mixture of dimethylsulfoxide:dichloromethane for subsequent impurity analysis by HPLC and mass spectrometry. During incubation, the percentage purity of parent compound depended on the PLGA co-monomer ratio (e.g. 50:50, 85:15, and 100:0 glycolide:lactide ratios). After 41 days of incubation, for instance, octreotide area percentage by HPLC was determined to be approximately 47% for PLGA 50:50 microspheres, approximately 75% for PLGA 85:15 microspheres, and approximately 87% for PLA microspheres. Spectral analysis of particle extracts revealed the presence of peptide related substances with 58 m/z and 72 m/z units higher than the parent peptide m/z value. This indicated the presence of glycoyl and lactoyl covalent substitutions on the drug compound, resulting from chemical interaction between peptide amine groups and PLGA or PLA ester groups.

Animals↗
PubMed2005

Controlled release of levonorgestrel from biodegradable poly(D,L-lactide-co-glycolide) microspheres: in vitro and in vivo studies.

Poly(D,L-lactide-co-glycolide) (PLG) biodegradable microspheres containing a contraceptive drug, levonorgestrel (LNG), were prepared using both the solvent evaporation method and a modified solvent extraction-evaporation method. The microspheres prepared with the solvent evaporation process had porous surfaces with low product yields and poor encapsulation efficiencies. On the other hand, the microspheres prepared using the modified solvent extraction-evaporation method were nonporous with encapsulation efficiencies close to 100%. In vitro drug release showed the nonporous microspheres had a lower initial burst and a slightly prolonged duration of release than those porous microspheres. In vivo release kinetics of the low burst microspheres were determined by measuring LNG plasma levels after a single intramuscular injection to female rats. At a LNG dose of 41.1 mg/kg, average plasma LNG levels were 6-10 ng/ml in the first 24 h and subsequently remained above 1 ng/ml until 126 days. The duration above the minimum effective LNG plasma level of 0.2 ng/ml was 168 days. By comparison, a similar dose of LNG microcrystals used as control produced a much higher plasma level of 15-21 ng/ml in the first day followed by a fast and continuous decline of LNG levels with a duration of only about 35 days.

Animals↗
PubMed2005

Release of a macromolecular drug from alginate-impregnated microspheres.

Macroporous microspheres were impregnated with calcium alginate to encapsulate fluorescein isothiocyanate-labeled dextran (FITC-dextran) and control its release. The detailed study of the impregnation process lead to its optimization: the quantity of alginate in the impregnated microspheres and the FITC-dextran encapsulation efficiency were increased. FITC-dextran diffused out of the impregnated microspheres in a slow rate in deionised water, while in presence of sodium ions, its release rate was increased as a consequence of the progressive swelling and erosion of calcium alginate. Release studies from different formulations of impregnated microspheres were performed in a continuous flow apparatus. The release profiles were composed of a slow release phase explained by the progressive erosion of calcium alginate and a faster release phase related to eroded impregnated microspheres. Therefore, the delayed release by microspheres induced by impregnation would permit the delivery of their payload at the vascular occlusion site, limit the amount of drug lost in the systemic circulation and improve the therapy.

Alginates↗
PubMed2006

Stabilization and encapsulation of a staphylokinase variant (K35R) into poly(lactic-co-glycolic acid) microspheres.

The aim of this study is to prepare poly(lactic-co-glycolic acid) (PLGA) microspheres containing a staphylokinase variant K35R (DGR) with purpose of preserving the protein stability during both encapsulation and drug release. DGR-loaded microspheres are fabricated using a double-emulsion solvent extraction technique. Prior to encapsulation, the effect of ultrasonication emulsification of DGR solutions with methylene chloride on protein recovery was investigated. Moderate ultrasonic treatment of aqueous DGR/dichloromethane mixtures caused approximately 84% DGR aggregation. Polyvinyl alcohol (PVA) added into aqueous DGR solutions significantly improved DGR recovery to >90%. The effects of co-encapsulated PVA and NaCl in the external aqueous phase on the characteristics of the microspheres were investigated. When 2% PVA was co-encapsulated and 2.5% NaCl was added to the external water phase, DGR encapsulation efficiency was significantly increased from 7.1% to 78.1% and DGR was distributed uniformly throughout the microspheres. In vitro release test showed that DGR was released from PLGA microspheres in a sustained manner over 15 days. A large amount of released DGR was inactive in the absence of co-encapsulated PVA. On the contrary, when 2% PVA was co-encapsulated, the released DGR was almost completely intact within 9 days. In conclusion, PLGA microspheres can be an effective carrier for DGR and form a promising depot system.

Chemistry, Pharmaceutical↗
PubMed2006

Production of GMP-grade radioactive holmium loaded poly(L-lactic acid) microspheres for clinical application.

Radioactive holmium-166 loaded poly(L-lactic acid) microspheres are promising systems for the treatment of liver malignancies. The microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method. After preparation, the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. In this paper, the aspects of the production of a (relatively) large-scale GMP batch (4 g, suitable for treatment of 5-10 patients) of Ho-PLLA-MS are described. The critical steps of the Ho-PLLA-MS production process (sieving procedure, temperature control during evaporation and raw materials) were considered and the pharmaceutical quality of the microspheres was evaluated. The pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) of the produced Ho-PLLA-MS batches were in compliance with the requirements of the European Pharmacopoeia. Moreover, neutron irradiated Ho-PLLA-MS retained their morphological integrity and the holmium remained stably associated with the microspheres; it was observed that after 270h (10 times the half-life of Ho-166) only 0.3+/-0.1% of the loading was released from the microspheres in an aqueous solution. In conclusion, Ho-PLLA-MS which are produced as described in this paper, can be clinically applied, with respect to their pharmaceutical quality.

Brachytherapy↗
PubMed2006

Pharmacokinetics and in vitro and in vivo correlation of huperzine A loaded poly(lactic-co-glycolic acid) microspheres in dogs.

The purpose of this study was to investigate the pharmacokinetics and in vitro/in vivo correlation (IVIVC) of huperzine A loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in dogs. Several huperzine A loaded PLGA microspheres were prepared by an O/W method and three of them (single dose) were injected intramuscularly (i.m.) or subcutaneously (s.c.) to five beagle dogs, respectively. With the increase of the molecular weight of PLGA and the particle size of microspheres, the in vitro and in vivo release periods of huperzine A were prolonged. After s.c. injection, the release of huperzine A from microspheres was faster than that after i.m. injection. The IVIVC models of huperzine A loaded PLGA microspheres were established successfully and after i.m. administration the linear relationship between the in vitro and the in vivo releases was better than that after s.c. administration. It was also found when the particle size of the microspheres was smaller; the values of correlation coefficient were higher.

Alkaloids↗
PubMed2004

Uniform double-walled polymer microspheres of controllable shell thickness.

A method for fabricating uniform double-walled microspheres with controllable size and shell thickness has been developed. The method, based on previous work to fabricate uniform microspheres, employs multiple concentric nozzles to produce a smooth coaxial jet comprising an annular shell and core material, which is acoustically excited to break up into uniform core-shell droplets. The orientation of the jets, material flow rates, and rate of solvent extraction are controlled to create uniform and well-centered "double-walled" microspheres exhibiting a controllable shell thickness. Double-walled microspheres were fabricated with different arrangements of bulk-eroding poly(D,L-lactide-co-glycolide) (PLG) and surface-eroding poly[(1,6-bis-carboxyphenoxy) hexane] (PCPH). Variation of the fabrication parameters allowed complete encapsulation by the shell phase, including the efficient formation of a PCPH shell encapsulating a PLG core. Utilizing this technology, double-walled microsphere shell thickness can be varied from <2 microm to tens of microns while maintaining complete and well-centered core encapsulation for double-walled microspheres near 50 microm in overall diameter.

Microspheres↗