Biodegradable microspherical implants containing teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis.

BACKGROUND: The aim of this study was to prepare poly(d,l-lactide-co-glycolide) (PLGA) microspherical implants containing teicoplanin (TCP) using a double emulsion solvent evaporation method and to evaluate its efficacy 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 were carried out. Sterile TCP­PLGA 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 and evaluated histopathologically. RESULTS: Microspheres between the size ranges of 2.01 and 3.91 µm were obtained. Production yield of all formulations was found to be higher than 82% and encapsulation efficiencies of 33.6­69.8% were obtained. DSC thermogram showed that the TCP was in an amorphous state in microspheres. In vitro drug release studies had indicated that the drug release rate of microspheres was decreased upon increasing the polymer:drug ratio. Based on the in vivo data, rats treated with implants and intramuscular injection showed 1.7 × 10(3) ± 1.3 × 10(3) and 5.8 × 10(4) ± 5.3 × 10(4) colony forming unit of MRSA in 1 g bone samples (CFU/g), respectively (P < 0.01). CONCLUSIONS: The in vitro and in vivo studies had shown that the TCP­PLGA microspheres were effective for the treatment of chronic osteomyelitis in an animal experimental model. Hence, these microspheres may be potentially useful in the clinical setting with the need for further investigation for optimal dosing of TCP­PLGA microspheres.

Bioadhesive sulfacetamide sodium microspheres: evaluation of their effectiveness in the treatment of bacterial keratitis caused by Staphylococcus aureus and Pseudomonas aeruginosa in a rabbit model.

The aim of this study was to prepare bioadhesive sulfacetamide sodium (SA) microspheres to increase their residence time on the ocular surface and to enhance their treatment efficacy on ocular keratitis. Microspheres were fabricated by spray drying method using mixture of polymers such as pectin, polycarbophil and hydroxypropylmethyl cellulose (HPMC) at different ratios. The particle size and distribution, morphological characteristics, thermal behavior, encapsulation efficiency, mucoadhesion and in vitro drug release studies on formulations have been investigated. After optimisation studies, SA-loaded polycarbophil microsphere formulation with polymer:drug ratio of 2:1 was found to be the most suitable for ocular application and used in in vivo studies. In vivo studies were carried out on New Zealand male rabbit eyes with keratitis caused by Pseudomonas aeruginosa and Staphylococcus aureus. Sterile microsphere suspension in light mineral oil was applied to infected eyes twice a day. Plain SA suspension was used as a positive control. On 3rd and 6th days of the antimicrobial therapy, the eyes were examined in respect to clinical signs of infection (blepharitis, conjunctivitis, iritis, corneal oedema and corneal infiltrates) which are the main symptoms of bacterial keratitis and then cornea samples were counted microbiologically. The rabbit eyes treated with microspheres demonstrated significantly lower clinical scores than those treated with SA alone. A significant decrease in the number of viable bacteria in eyes treated with microspheres was observed in both infection models when compared to those treated with SA alone. In conclusion, in vitro and in vivo studies showed that SA-loaded microspheres were proven to be highly effective in the treatment of ocular keratitis.

Effect of thiolated polymers to textural and mucoadhesive properties of vaginal gel formulations prepared with polycarbophil and chitosan.

The aim of this study was to design and evaluate of mucoadhesive gel formulations for the vaginal application of clomiphene citrate (CLM) for local treatment of human papilloma virus (HPV) infections. Chitosan (CHI) and polycarbophil (PC) were covalently modified using the thioglycolic acid and L-cysteine, respectively. The formation of thiol conjugates of chitosan (CHI-TG) and polycarbophil (PC-CYS) were confirmed by FT-IR analysis and PC-CYS and CHI-TG were found to have 148.42 +/- 4.16 and 41.17 +/- 2.34 micromol of thiol groups per gram of polymer, respectively. One percent CLM gels were prepared by combination of various concentrations of PC and CHI with thiolated conjugates of these polymers. Hardness, compressibility, elasticity, adhesiveness and cohesiveness of the gels were measured by Texture profile analysis and the vaginal mucoadhesion was investigated by mucoadhesion test. The increasing in the amount of the thiol conjugates was found to enhance the elasticity, cohesiveness, adhesiveness and mucoadhesion of the gel formulations but not their hardness and compressibility when compared to gels prepared using their respective parent formulations. Slower release rate of CLM from gels was achieved when the polymer concentrations were increased in the gel formulations. PC and its thiol conjugate were found to prolong the release of CLM longer than 70 h unlike gel formulations prepared using CHI and its thiol conjugate which were able to release CLM up to 12 h. Stability of CLM was preserved during the 3 month stability analysis under controlled room temperature and accelerated conditions.

Preparation and characterisation of natamycin: gamma-cyclodextrin inclusion complex and its evaluation in vaginal mucoadhesive formulations.

Novel formulations of vaginal bioadhesive tablets were prepared where the natamycin was complexed with gamma-cyclodextrin (NT-gamma CyD) to increase the solubility and stability of NT in aqueous solutions and reduce the side effects of the drug without decreasing antimycotic activity. Favourable interactions between the NT and gamma CyD and formation of the 1:1 inclusion complex were observed. The MIC(90) of both NT alone and NT-gamma CyD complexes were below 0.0313 microg mL(-1), suggesting that complexation with gamma CyD has effectively increased the antimycotic activity of NT, thus indicating the clinical usefulness of NT-gamma CyD complexes. The sustained drug release of NT was achieved to over 8 h periods by altering the polymer component of formulations which was responsible for differences in water absorption and erosion behaviour of the tablets. Bioadhesion studies have clearly indicated that enhancement of mucoadhesion was achieved by inclusion of Carbopol 934P and by tailoring the ratio of Carbopol 934P in the formulation, a high mucoadhesion to vaginal mucosa can be achieved. Hence, the formation of complex between NT and gamma CyD and effective combination with polymers attain a bioadhesive and sustained release formulation of NT suitable for vaginal delivery and the effective treatment of Candida infections.

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.

Characterization of biodegradable chitosan microspheres containing vancomycin and treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus with prepared microspheres.

The biodegradable chitosan microspheres containing vancomycin hydrochloride (VANCO) were prepared by spray drying method with different polymer:drug ratios (1:1, 2:1, 3:1 and 4:1). Thermal behaviour, particle size and distribution, morphological characteristics, drug content, encapsulation efficiency, in vitro release assessments of formulations have been carried out to obtain suitable formulation which shows sustained-release effect when implanted. Sterilized VANCO loaded microspheres were implanted to proximal tibia of rats with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Intramuscular (IM) injection of VANCO for 21 days was applied to another group for comparison. After 3 weeks of treatment, bone samples were analysed with a microbiological assay. According to the results, encapsulation efficiency and yield of microspheres in all formulations were higher than 98% and 47%, respectively. Particle sizes of microspheres were smaller than 6 microm. All microsphere formulations have shown sustained-release effect. In vitro drug release rate decreased due to the increase in polymer:drug ratio but no significant difference was seen between these results (p>0.05). Based on our in vivo data, rats implanted VANCO-loaded chitosan microspheres and administered IM injection showed 3354+/-3366 and 52500+/-25635 colony forming unit of MRSA in 1g bone samples (CFU/g), respectively. As a result, implanted VANCO-loaded microspheres were found to be more effective than IM route for the treatment of experimental osteomyelitis.