Kinetics of a Model Nucleoside (Guanosine) Release from Biodegradable Poly(dl-lactide-co-glycolide) Microspheres: A Delivery System for Long-Term Intraocular Delivery

The objective of this study was to prepare poly(dl-lactide-co-glycolide)(PLGA) microspheres containing guanosine as a model drug for intraocular administration. Microspheres were prepared by solvent evaporation technique using o/w emulsion system. The influence of composition and molecular weight of PLGA, drug loading efficiency, microsphere size, and in vitro and in vivo release rates were determined. Differential scanning calorimetry (DSC) and FTIR studies were conducted to examine the guanosine–polymer interaction. In vitro release studies indicated that the permeant release from microspheres exhibits an initial burst followed by slow first-order kinetics. Ascending molecular weights of the polymers generated progressively slower release rates. Three different sizes of microspheres were prepared. The release continued for 7 days with a maximum of 70% of the content released within that time period. DSC and FTIR studies showed no polymer–guanosine interaction. A novel microdialysis technique was used to examine the initial release kinetics from microspheres in isolated vitreous humor. This technique was also employed to observe in vivo intravitreal release in albino rabbits. A good correlation exists between in vitro and in vivo release rates from both 75 and 140 kDa PLGA microspheres. Guanosine-loaded microspheres could be prepared for once-a-week intravitreal injection with minimum required concentration maintained throughout the dosing interval. Because the structural and solubility characteristics of guanosine are similar to those of acyclovir and ganciclovir (two acycloguanosine analogues effective against herpes simplex virus [HSV-1] and cytomegalovirus [CMV], respectively), similar biodegradable polymer-based microsphere technology can be employed for the long-term intraocular delivery of these two drugs.     

Polymer and microsphere blending to alter the release of a peptide from PLGA microspheres.

The objective of this study was to evaluate the effect of polymer and microsphere blending in achieving both a sufficient initial release and a desired continuous release of a peptide from poly(D, L-lactide-co-glycolide) microspheres. Leuprolide acetate loaded hydrophilic 50:50 PLGA microspheres were prepared by a solvent-extraction/evaporation process and were characterized for their drug load, bulk density, size distribution, surface area, surface morphology, in vitro drug release, and in vivo efficacy. Combining PLGA polymers that varied in their molecular weights in various ratios yielded microspheres with varied drug release profiles commensurate with the hydration tendencies of the polymers. Increasing the component of lower molecular weight 50:50 hydrophilic PLGA polymer, 8.6 kDa increased the initial drug release. A similar microsphere formulation prepared instead with blending microspheres from individual polymers showed a similar increase. In an animal model, microspheres obtained from polymer or microsphere blends attained a faster onset of testosterone suppression as compared to microspheres from higher molecular weight 50:50 hydrophilic PLGA polymer, 28.3 kDa, alone. These studies illustrated the feasibility of blending polymers or microspheres of varied characteristics in achieving modified drug release. In particular the increased initial release of the peptide could help avoid the therapeutic lag phase usually observed with microencapsulated macromolecules.     

Microspheres made by w/o/o emulsion method with reduced initial burst for long-term delivery of endostar, a novel recombinant human endostatin

The purpose of this work is to design biodegradable Poly(lactide-co-glycolide) (PLGA) microspheres with low initial burst for sustained delivery of Endostar (a novel recombinant human endostatin) and investigate effects of PLGA molecular weight and composition on the release behavior of Endostar microspheres. Endostar microspheres were prepared by using novel w/o/o multiple emulsification-evaporation technique. Effects of polymer molecular weight and copolymer composition on particle properties and release behavior (in vitro and in vivo) have been reported. Drug release in vitro decreased with increase in molecular weight and lactide content of PLGA. Zero order release and low initial burst were obtained with all microsphere formulations. The in vivo performance of Endostar microspheres were also found to be dependent on the polymer molecular weight and copolymer composition. Together, these results suggest that the initial burst release can be reduced by w/o/o emulsion method and the release of Endostar can be changed significantly by varying the polymer molecular weight and copolymer composition.     

Ondansetron-loaded biodegradable microspheres as a nasal sustained delivery system: In vitro/in vivo studies

The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mixture of DCM and ethyl acetate) on the microsphere characteristics was also examined. The prepared microspheres were evaluated with respect to the morphological properties, particle size, zeta potential, drug loading efficiency, and in vitro drug release. The mean particle size (d₅₀) of microsphere formulations was ranged from 11.67–25.54 μm, indicating suitable particle size for nasal administration. All microspheres had low drug loading efficiency in the range of 12.28–21.04%. The results indicated that particle size of microspheres were affected by both type of polymer and organic solvent, however drug loading efficiency of microspheres were affected by only the type of organic solvent used. All microspheres were negatively charged due to the polymers (PLA or PLGA) used. A prolonged in vitro drug release profile was observed for 96?h. Based on in vitro data, the selected microsphere formulation has been applied via nasal route to rats in vivo. Following nasal administration of ondansetron-loaded microsphere to rats, ondansetron plasma levels were within a range of 30–48?ng/mL during 96?h, indicating a sustained drug delivery pattern and relatively a constant plasma drug concentration level. The results suggested that biodegradable microspheres prepared with emulsification/spray-drying technique could be considered to deliver ondansetron via nasal route to obtain a prolonged release.     

Ondansetron-loaded biodegradable microspheres as a nasal sustained delivery system: In vitro/in vivo studies

The aim of this study was to prepare ondansetron-loaded biodegradable microspheres as a nasal delivery system. Microspheres were prepared with emulsification/spray-drying technique using poly(d,l-lactide) (PLA) and two different types of poly(d,l-lactide-co-glycolide) (PLGA). The effect of the type of organic solvent (dichloromethane (DCM) or a mixture of DCM and ethyl acetate) on the microsphere characteristics was also examined. The prepared microspheres were evaluated with respect to the morphological properties, particle size, zeta potential, drug loading efficiency, and in vitro drug release. The mean particle size (d(50)) of microsphere formulations was ranged from 11.67-25.54 μm, indicating suitable particle size for nasal administration. All microspheres had low drug loading efficiency in the range of 12.28-21.04%. The results indicated that particle size of microspheres were affected by both type of polymer and organic solvent, however drug loading efficiency of microspheres were affected by only the type of organic solvent used. All microspheres were negatively charged due to the polymers (PLA or PLGA) used. A prolonged in vitro drug release profile was observed for 96?h. Based on in vitro data, the selected microsphere formulation has been applied via nasal route to rats in vivo. Following nasal administration of ondansetron-loaded microsphere to rats, ondansetron plasma levels were within a range of 30-48?ng/mL during 96?h, indicating a sustained drug delivery pattern and relatively a constant plasma drug concentration level. The results suggested that biodegradable microspheres prepared with emulsification/spray-drying technique could be considered to deliver ondansetron via nasal route to obtain a prolonged release.     

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.     

Dissolution,Stability, and Morphological Properties of Conventional and Multiphase Poly(DL-Lactic-Co-Glycolic Acid) Microspheres Containing Water-Soluble Compounds

Multiphase microspheres of poly(DL-lactic-co-glycolic acid) (PLGA) containing water-soluble compounds were prepared by a multiple-emulsion solvent evaporation technique. These compounds were dissolved in the aqueous phase of a W/O emulsion with soybean oil as the oil phase. This emulsion was dispersed throughout the matrix of the microsphere. The morphological properties of the multiphase microspheres during in vitro dissolution studies were compared to those of conventional microspheres prepared from the same polymer. Drug release from the multiphase microspheres was characterized by an initial uniform release for the first 20 days followed by a more rapid phase of drug release. Chlorpheniramine maleate (CPM) and brilliant blue (BB) were the soluble model compounds investigated. The release rates of these agents from the multiphase microspheres were independent of the drug content in the microspheres. The release profiles from the conventional microspheres showed a lag time of 10 and 16 days for the CPM and BB, respectively. The dissolution rate of the model soluble compounds from the conventional microspheres increased as the loading in the microspheres increased. No differences in the degradation rate of the PLGA from the multiphase and the conventional microspheres were seen during the dissolution studies.     

The effect of different grades of PLGA on characteristics of microspheres encapsulated with cyclosporine A

The aim of this study was to evaluate the effect of different grades of poly D, L lactide-co-glycolide (PLGA) on the properties of microspheres encapsulated with Cyclosporine A (CyA). Microspheres were prepared by solvent evaporation method using three grades of PLGA. Various characteristics of microspheres such as morphology, size distribution, encapsulation efficiency and release profile were evaluated. Complementary studies were also carried out by Infrared (IR) spectroscopy and Differential scanning calorimetry (DSC) to evaluate possible drug-polymer interactions. Scanning electron microscopy (SEM) studies showed microspheres as spherical particles with CyA deposited as islands on the surface of spheres. Particle size range was 1-25 microm for microspheres made of PLGA (50:50) which showed the minimum size. Encapsulation efficiency was found to vary from 75% to 92% in various formulations. The profile of release was biphasic, showing an initial rapid phase followed by a continuous and slower rate thereafter. Microspheres made of grades 50:50 and 85:15 showed the highest and lowest amount of drug release, respectively. IR spectra for drug, polymer and microspheres did not indicate any chemical interaction between the components of microsphere and DSC thermograms revealed that CyA was present in its amorphous state within microspheres. In conclusion, the effect of polymer characteristics should be considered in microsphere formulations. In this study, suitable microspheres especially with PLGA (50:50) were prepared which allow the controlled release of CyA over a prolonged period of time.     

Chitosan-based mucoadhesive microspheres of clarithromycin as a delivery system for antibiotic to stomach

The objective of the present study was to develop chitosan-based mucoadhesive microspheres of clarithromycin to provide prolonged contact time for drug delivery of antibiotics to treat stomach ulcers. Microspheres based mucoadhesive formulation were extensively evaluated and characterized for in vitro performance followed by investigation of in vivo pharmacokinetics in rats. Microspheres were prepared by emulsification technique using glutaraldehyde as a crosslinking agent. Formulation conditions were optimized for percent drug entrapment and mucoadhesion, by varying different formulation and process parameters like drug to polymer ratio, concentration of crosslinking agent and time of crosslinking. Prepared microspheres were evaluated extensively for particle size, percent drug entrapment, swelling kinetics, in vitro mucoadhesion using rat stomach membrane and in vitro drug release studies. In vitro permeation studies across rat stomach membrane were carried out to determine diffusion parameters and drug retention in the stomach membrane of the formulation and the plain drug. Finally in vivo performance of microsphere formulation in comparison to plain drug was evaluated by pharmacokinetic studies in albino rats. Drug entrapment upto 74% was obtained. Swelling studies indicated that with an increase in cross-linking, the swelling ability decreased. The in vitro drug release and in vitro mucoadhesion studies showed a dependence on the extent of cross-linking and concentration of chitosan. Extent of cross-linking exhibited an inverse relation to drug release rate as well as mucoadhesion, whereas polymer concentration exhibited an inverse correlation with drug release while linear relationship with mucoadhesion (up to 86%). In vitro permeation studies across stomach tissue showed higher accumulation of drug in the stomach tissue with microspheres formulation as compared to that of free drug. This is evident from higher value of K (partition coefficient) and Qm/Csf values for microspheres (68.34 and 106.42X10(3), respectively) as compared to that of free drug (1.86 and 173.00, respectively). These findings when analyzed showed an increase in the bioavailability of clarithromycin from microsphere formulation as compared to plain drug suspension in vivo, with AUC 0-->alpha being 91.7 (microg h/ml)and 24.9 (microg h/ml) respectively. Results of the study demonstrated good mucoadhesion of the microspheres with the stomach mucosa as well as higher accumulation of drug in the stomach membrane. Microspheres also exhibited sustained release of drug. Thus chitosan microspheres appear, technically, promising mucoadhesive drug delivery systems for delivering clarithromycin to treat stomach ulcers.     

Biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres for sustained release of risperidone: Zero-order release formulation

The preparation and investigation of sustained-release risperidone-encapsulated microspheres using erodible poly(D, L-lactide-co-glycolide) (PLGA) of lower molecular weight were performed and compared to that of commercial Risperdal Consta^? for the treatment of schizophrenia. The research included screening and optimizing of suitable commercial polymers of lower molecular weight PLGA50/50 or the blends of these PLGA polymers to prepare microspheres with zero-order release kinetics properties. Solvent evaporation method was applied here while studies of the risperidone loaded microsphere were carried out on its drug encapsulation capacity, morphology, particle size, as well as in vitro release profiles. Results showed that microspheres prepared using 50504A PLGA or blends of 5050-type PLGAs exerted spherical and smooth morphology, with a higher encapsulation efficiency and nearly zero-order release kinetics. These optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta^?, which could further improve the patient compliance.     

Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac

The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments.     

Indomethacin-Dipalmitoylphosphatidylcholine Interaction. A Calorimetric Study of Drug Release from Poly(Lactide-co-glycolide) Microspheres into Multilamellar Vesicles

A comparative study of indomethacin controlled release from poly(lactide-co-glycolide) (50:50, molecular weight 3000) (PLGA) microspheres loaded with two different amounts of drug (10.9 ± 1%, and 34.1 ± 1% w/w) and pure free indomethacin, considering the effects exerted by the drug on the thermotropic behavior of dipalmitoylphosphatidylcholine multilamellar vesicles, was carried out by differential scanning calorimetry (DSC). The release was monitored by comparing the effect exerted by the free indomethacin on lipid thermotropic behavior with that of the drug released by the microspheres and relating these effects to a lipid aqueous dispersion containing the molar ratio of drug able to cause it. By DSC measurements, the pure free indomethacin was found to be able to have a fluidifying effect on the model membrane, causing a shift toward lower values of the transitional temperature (T_m), characteristic of phospholipid liposomes, without variations in the enthalpic changes (ΔH). This shift was found to be modulated by the drug molar fraction with respect to the lipid concentration in the aqueous dispersion. Successively, calorimetric measurements were performed on suspensions of blank liposomes added to weighed amounts of unloaded and indometha-cin-loaded microspheres as well as free powdered indomethacin, and the T_m shifts of the lipid bilayer caused by the drug released from the polymeric system, as well as by the free drug, were compared with that caused by free drug increasing molar fractions dispersed directly on the membrane, employed as a calibration curve to obtain the fraction of drug released. This drug release model could be employed to determine the different kinetics involved in the drug transfer from the microspheres to a membrane. This in vitro study suggests that the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres. This calorimetric study shows that the PLGA microspheres are a good delivery system able to sustain drug release. Moreover, the DSC technique applied to the drug interaction with biomembranes constitutes a good tool for determining the drug release representing an innovative alternative in vitro model.     

Enhancing initial release of peptide from poly(d,l-lactide-co-glycolide) (PLGA) microspheres by addition of a porosigen and increasing drug load

The objective of this study was to evaluate formulation variables such as drug load and addition of a porosigen in achieving an increased initial release of peptide from poly(d,l-lactide-co-glycolide) (PLGA) microspheres by altering carrier characteristics. Leuprolide acetate-loaded PLGA microspheres were prepared by a solvent-extraction-evaporation process and were characterized for their drug load (HPLC assay), bulk density (tapping method), size distribution (dynamic light scattering), specific surface area (Brunauer-Emmett-Teller [BET] analysis), surface morphology (scanning electron microscopy), in vitro drug release (at 37 degrees C), and in vivo efficacy (suppression of rat serum testosterone). Increasing the drug load, and adding various amounts of calcium chloride to organic and aqueous phases of the emulsion during processing yielded particles with increased porosity, lower bulk density, higher specific surface area, and accordingly higher initial release. In an animal model, these formulations showed a faster onset of testosterone suppression compared to microspheres without higher drug load or calcium chloride. The approaches employed in this study were found to be effective in avoiding the therapeutic lag phase usually observed with microencapsulated macromolecular drugs.     

Chitosan microspheres of aceclofenac: In vitro and in vivo evaluation

The objective of this investigation was to achieve controlled drug release of Aceclofenac (ACE) microspheres and to minimize local side-effects in the gastrointestinal tract (GIT). Sustained release chitosan microspheres containing ACE were prepared using double-emulsion solvent evaporation method (O/W/O). Chitosan microspheres were prepared by varying drug to polymer ratio (1:3, 1:4, 1:5 and 1:6). Microspheres were characterized for morphology, swelling behavior, mucoadhesive properties, FTIR and DSC study, drug loading efficiency, in vitro release, release kinetics, and in vivo study was performed on rat model. ACE-loaded microspheres were successfully prepared having production yield, 57–70% w/w. Drug encapsulation efficiency was ranging from 53–72% w/w, Scanning electron microscopy (SEM) revealed particle size of microspheres was between 39 and 55 μm. FTIR spectra and DSC thermograms demonstrated no interaction between drug and polymer. The in vitro release profiles of drug from chitosan microspheres showed sustained-release pattern of the drug in phosphate buffer, pH 6.8. In vitro release data showed correlation (r² > 0.98), good fit with Higuchi/Korsmeyer-Peppas models, and exhibited Fickian diffusion. ACE microspheres demonstrated controlled delivery of aceclofenac and apparently, no G.I.T. erosion was noticed.     

In vitro study of lysozyme in poly(lactide-co-glycolide) microspheres with sucrose acetate isobutyrate

This study investigated the suitability of microsphere formulations for extended protein delivery and complete protein release. These microspheres were prepared by a multi-emulsion method and prepared using a mixture of poly(lactide-co-glycolide) (PLGA), RG 502H (lactide:glycolide=50:50, M(W) 9300) and sucrose acetate isobutyrate (SAIB). SAIB embedded into the microspheres and mixed with PLGA, improved the efficiency of enzyme encapsulation. The in vitro release rate of lysozyme (Lys) from the microspheres was reduced due to the high viscosity of the added SAIB and less degradation of PLGA by SAIB. These properties enabled prolonged release of Lys for up to 2 months, characterized by a minimal initial burst of Lys and nearly zero-order protein release kinetics result from co-administration of sorbitan monooleate 80. When it is considered that degradation products of SAIB are inactive for labile proteins, SAIB may be regarded as a promising candidate for long-acting protein delivery.     

The initial release of cisplatin from poly(lactide-co-glycolide) microspheres

PLGA microspheres loaded with cisplatin were produced using a single emulsion method. A semi-empirical model, with bi-exponential terms, was found to give a better fit to the drug release profiles compared to a mono-exponential model. This model suggests that there are two separate fractions of drug present in the depot. A fraction of the drug is located near/at the surface of the depot, and is readily released during immersion in buffer. A second fraction of drug is entrapped deeper within the depot and is subsequently released. It was also found that the initial release of cisplatin from PLGA microsphere is highly diffusion-controlled and the classical Higuchi model provides a good fit. From studies of water diffusion using PFG-NMR, results suggested that 50:50 PLGA microsphere was most susceptible to swelling and this might have promoted the faster initial drug release. Results from NMR cryoporometry also indicated that the developed PLGA microspheres could have “ink-bottle” pores.     

Biodegradable polymeric microspheres for nalbuphine prodrug controlled delivery: in vitro characterization and in vivo pharmacokinetic studies

The objective of this work was to study the in vitro characteristics as well as in vivo pharmacokinetic performance of a series nalbuphine (NA) prodrug-loaded microspheres. An oil-in-water solvent evaporation method was used to incorporate the various NA prodrugs into poly(D,L-lactide-co-glycolide) (PLGA)-based microspheres. The morphology of microspheres under the scanning electron microscopy (SEM) revealed a spherical shape with smooth surface. Drug release rates for the microspheres were found to be a function of prodrug hydrophilicity, with higher drug release rates for microspheres loaded with more hydrophilic prodrugs. The release profiles fit well to the Baker and Lonsdale's spherical matrix model, suggesting the drug release from microspheres was consistent with a diffusion mechanism. The in vivo pharmacokinetic studies after s.c. injection of microspheres into rabbits showed sustained plasma NA-time profiles, with approximately 104.7, 67.2, and 41.0% relative bioavailability for microspheres loaded with nalbuphine propionate (NAP), nalbuphine pivalate (NPI), and nalbuphine decanoate (NDE), respectively. The in vitro release characteristics correlated well with the in vivo pharmacokinetic profiles. The results indicated that the prodrug hydrophilicity had significant effects on the in vitro as well as in vivo drug release kinetics. The present study demonstrates the feasibility of using biodegradable polymeric microspheres for controlled delivery of NA prodrugs.     

微球的制备和表征

目的制备葡激酶突变体(K35R，DGR)的聚乳酸-羟基乙酸(PLGA)微球，使其在包封和释放过程中都能保持活性。方法使用复乳溶剂挥发法制备DGR的PLGA微球，研究了搅拌速度、PLGA浓度、内水相和外水相中的添加剂对蛋白包封率以及微球性质的影响，并进行了DGR微球的体外和体内释放试验。结果2%聚乙烯醇可以有效抑制超声乳化时DGR在水/二氯甲烷界面上的变性，将DGR的活性回收率从16%提高到几乎100%。在外水相中加入NaCl可以显著提高蛋白包封率，同时对微球的粒径分布和表面形态也产生了重要影响。DGR微球的体外释放呈现两个时相，15 d释放大约DGR总活性的50%。DGR微球在体内持续释放5 d。结论制备的PLGA微球，DGR包封率高，稳定性较好，是DGR的良好载药系统。     

Poly (D,L-lactide-co-glycolide) microspheres for long-term intravitreal delivery of aciclovir: influence of fatty and non-fatty additives

Aciclovir (acicloguanosine) has been demonstrated to be effective in the treatment of intraocular pathologies such as herpes simplex virus retinitis and acute retinal necrosis. Although intravitreal injections have been used with fewer side-effects than intravenous administration, the risk of complications increases with the frequency of intravitreous injections. For this reason, a biodegradable drug-delivery system, such as microspheres, able to promote prolonged release of the drug, offers a good alternative to multiple intraocular administrations. In this work, aciclovir-containing poly (D,L-lactide-co-glycolide) microspheres were prepared by the solvent evaporation method. Seven additives were incorporated in the microspheres to modulate the in vitro release rate of the drug: four non-fatty substances (polyethylene glycol 300, polyethylene glycol 1500, hydroxypropyl methylcellulose and gelatin) and three fatty substances (isopropyl myristate, vitamin E and Labrafil M 1944 CS). Morphology of microspheres was evaluated by scanning electron microscopy. Granulometric analysis showed that particle size distribution was significantly influenced by the incorporation of additives. Loading efficiency decreased when fatty substances were added, whereas non-fatty additives promoted higher incorporation of the drug. Infrared and differential scanning calorimetry analyses indicated that microspheres prepared by the solvent evaporation process were not influenced by the type of additive used. In all cases, the initial burst resulted less than 5%. Additive-free microspheres showed a slow release within the first days, but when additives were incorporated, in general, the release rates of the drug were increased. Best release results were obtained for gelatin-containing microspheres. The release of aciclovir from these microspheres was adjusted to a zero-order kinetic from 1 to 49 days with a release constant of 1.13 microg/day/mg microspheres. A dose of 0.74 mg microspheres would be therapeutic for the herpes simplex and Epstein-Barr viruses (MIC 0.1 microg/ml) and 7.4 mg for varicella zoster virus (MIC 1 microg/ml) treatment in an animal model.     

Sodium fusidate-poly(D,L-lactide-co-glycolide) microspheres: preparation, characterisation and in vivo evaluation of their effectiveness in the treatment of chronic osteomyelitis

PURPOSE: The aim of this study was to prepare poly(D,L-lactide-co-glycolide) (PLGA) microspheres containing sodium fusidate (SF) using a double emulsion solvent evaporation method with varying polymer:drug ratios (1:1, 2.5:1, 5:1) and to evaluate its efficiency for the local treatment of chronic osteomyelitis. METHODS: The particle size and distribution, morphological characteristics, thermal behaviour, drug content, encapsulation efficiency and in vitro release assessments of the formulations had been carried out. Sterilized SF-PLGA microspheres were implanted in the proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. After 3 weeks of treatment, bone samples were analysed with a microbiological assay. RESULTS: PLGA microspheres between the size ranges of 2.16-4.12 microm were obtained. Production yield of all formulations was found to be higher than 79% and encapsulation efficiencies of 19.8-34.3% were obtained. DSC thermogram showed that the SF was in an amorphous state in the microspheres and the glass transition temperature (T(g)) of PLGA was not influenced by the preparation procedure. In vitro drug release studies had indicated that these microspheres had significant burst release and their drug release rates were decreased upon increasing the polymer:drug ratio (p < 0.05). Based on the in vivo data, rats implanted with SF-PLGA microspheres and empty microspheres showed 1987 +/- 1196 and 55526 +/- 49086 colony forming unit of MRSA in 1 g bone samples (CFU/g), respectively (p < 0.01). CONCLUSION: The in vitro and in vivo studies had shown that the implanted SF loaded microspheres were found to be effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting.