Colon targeted curcumin microspheres laden with ascorbic acid for bioavailability enhancement

An objective of the present study was to prepare colon-specific microspheres of curcumin (CUR) containing ascorbic acid (AA) for improved oral bioavailability. 3² factorial design was used to optimise chitosan microspheres (CSMS) containing CUR and AA. Subsequently, optimised CSMS were coated with Eudragit S-100, for delivery to colon. In vitro drug release, in vivo pharmacokinetics, and organ distribution studies were performed in Albino Wistar rats. Stabilisation of CUR in alkaline pH was successfully guarded by AA to the extent 98.5–100%. Results revealed complete amorphisation/molecular dispersion of CUR. Bioavailability enhancement of CUR and 90% of MS in colon at the end of 8?h in animals, deciphered successful design of colon-specific CUR MS. It can be concluded that AA in MS shielded the degradation of CUR. The developed double coat MS could be considered as a promising colon-targeted system for CUR aiming bioavailability enhancements.     

Co-delivery of etoposide and curcumin by lipid nanoparticulate drug delivery system for the treatment of gastric tumors

Context: Gastric carcinoma (GC) is one of the most common cancers and the second most frequent cause of cancer-related deaths. Chemotherapy is an important therapeutic modality for GC. However, chemoresistance limited its success rate. Combination chemotherapy is often applied to prevent drug-induced resistance in cancers.

Objective: The aim of this study is to evaluate whether the co-delivery of etoposide (ETP) and curcumin (CUR) with one nanoparticle can result in synergistic effects of both drugs.

Methods: ETP- and CUR-loaded nanostructured lipid carriers (ETP-CUR-NLC) were prepared by the solvent injection technique. Their average size, zeta potential and drug loading were evaluated. Human gastric cancer cell lines (SGC7901 cells) were used for the testing of in vitro cytotoxicity studies, and in vivo anti-tumor efficacies of the carriers were evaluated on mice bearing SGC7901 cells xenografts.

Results: ETP-CUR-NLC has a particle size of 114?nm, EPT-loading quantity of 83% and CUR-loading quantity of 82%. ETP-CUR-NLC displayed high cytotoxicity and enhanced antitumor activity in vitro and in vivo. Meanwhile, ETP-CUR-NLC displayed low cytotoxicity in normal tissues in vivo.

Discussion and conclusion: The results demonstrate that ETP-CUR-NLC can achieve impressive anti-tumor activity. By combining CUR, an effective NF-κB inhibitor, with ETP, a powerful anticancer drug, in NLC, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies.     

口服用硝苯地平缓释微球的研究

用丙酮/液状石蜡乳剂一溶剂挥发法制备硝苯地平一EudragitRL缓释微球。微球中药物以非晶态分散于EudragitRL载体中。微球体外释药过程符合Higuchi方程。在不同条件下存贮6个月内微球的药物含量、药物分散状态和释药速率均无明显变化。经8名健康志愿者单剂量口服实验,缓释微球相对于进口缓释片的生物利用度为102.5%,两者具有生物等价性。缓释微球的体内外相关性显著(P<0.01)。     

Development and characterization of colon specific drug delivery system bearing 5-ASA and camylofine dihydrochloride for the treatment of ulcerative colitis

The treatment of ulcerative colitis (inflammatory bowel disease, IBD) has been achieved by using colon specific drug delivery system bearing 5-ASA and Camylofine dihydrochloride. Chitosan microspheres were prepared separately for both the drugs using emulsion method followed by enteric coating with Eudragit^®S-100. The in vitro drug release was investigated in different simulated GIT medium. The drug release in PBS (pH7.4) and simulated gastric fluid has shown almost similar pattern and rate, whereas a significant increase in drug release (70.3?±?1.36 and 72.5?±?1.33% of 5-ASA and Camylofine, respectively) was observed in medium containing 3% rat caecal matter, after 24?h. In control study, 57.1?±?1.13% of 5-ASA and 59.2?±?1.2% of Camylofine release was observed in 24?h. For enzyme induction, rats were orally administered with 1?mL of 1% w/v dispersion of chitosan for 5 days and release rate studies were conducted in SCF with 3% w/v of caecal matter. An enhanced drug release (i.e., 92.3?±?3.81 and 95.5?±?3.52% 5-ASA and Camylofine, respectively) was observed after 24?h in dissolution medium containing 3% caecal content obtained from enzyme induced animals. In vivo data showed that microspheres delivered most of its drug load (76.55?±?2.13%) to the colon after 9?h, which reflects its targeting potential to the colon. It is concluded that orally administered microspheres of both drugs can be used together for the specific delivery of drug to the colon and reduce symptoms of ulcerative colitis.     

Formulation and evaluation of chitosan microspheres of aceclofenac for colon‐targeted drug delivery

The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span‐85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41–80 µm. The swelling index was in the range 0.37–0.82 and the entrapment efficiency range was 51–75% for all the formulations. The optimised batch ACM₁₃ released 83.6% at 8 h and 104% at 24 h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9±0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non‐Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti‐inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. Copyright © 2010 John Wiley & Sons, Ltd.     

Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis

Objective: The study aims at formulation and optimization of macrophage-targeted curcumin-loaded mannosylated chitosan nanoparticles (Cur-MCNPs) of curcumin (CUR) to improve its therapeutic potential in the treatment of visceral leishmaniasis (VL).

Methods: Response surface methodology (RSM) using central composite design was employed to study the effect of formulation factors on physicochemical-dependent characteristics. Chitosan was coupled with d-mannose, by reductive amination, to prepare a mannosylated chitosan, a conjugate polymer and a subsequent formulation of Cur-MCNPs. Optimized formulation prepared using RSM was evaluated for in vitro release kinetics at physiological pH 7.4 and endosomal macrophage pH 4.5; in vivo pharmacokinetic profile and targeting potential were evaluated by fluorescence microscopy.

Results: Optimized Cur-MCNPs exhibited spherical and smooth surface with a mean particle size of 215 nm, polydispersity index of 0.381, zeta potential of + 24.37 mV and % entrapment efficiency of 82.12%. The pharmacokinetic study of optimized Cur-MCNPs showed significant improvement in the value of mean resident time (39.38 h) compared to free CUR solution (0.30 h) (p < 0.05). In vivo uptake study indicated that endocytosis took place effectively within the macrophages of reticuloendothelial system.

Conclusions: Thus, Cur-MCNPs could be considered as a promising delivery strategy towards active targeting of CUR to macrophages for the effective treatment of VL.     

Eudragit RL100 based microspheres for ocular administration of azelastine hydrochloride

In the present study, potential of polymeric microspheres for treatment of allergic conjunctivitis was investigated. Azelastine hydrochloride loaded Eudragit RL100 microspheres were prepared by solvent evaporation technique. The change in drug–polymer ratio on the particle size, zeta potential, entrapment efficiency and in vitro drug release was investigated. As Eudragit concentration ranged from 40 to 80?mg/ml the size range obtained was 4.18–7.36?µm with positive zeta potential. With the increase in drug polymer ratio, the entrapment efficiency was increased with maximum 14.56%. In vitro release studies demonstrated prolonged release of the drug over the period of 6?hr. Scanning electron micrographs showed that microspheres were spherical with distinct solid dense structure. Fourier transform infrared and differential scanning calorimetry studies concluded slight change in peak intensities of drug in microspheres. In vivo studies in rat model indicated that reduction in eosinophil count number was more pronounced in azelastine hydrochloride microspheres than marketed formulation, Azelast®.     

Multiparticulate System for Colon Targeted Delivery of Ondansetron

Targeted delivery of drugs to colon has the potential for local treatment of a variety of colonic diseases. The main objective of the study was to develop a multiparticulate system containing chitosan microspheres for the colon targeted delivery of ondansetron for the treatment of irritable bowel syndrome. This work combines pH-dependent solubility of eudragit S-100 polymers and microbial degradability of chitosan polymers. Chitosan microspheres containing ondansetron were prepared by emulsion cross linking method. The effect of process variables like chitosan concentration, drug-polymer ratio, emulsifier concentration and stirring speed were studied on particle size and entrapment efficiency of chitosan microspheres. In vitro drug release studies in simulated gastro intestinal fluids showed a burst drug release pattern in the initial hour necessitating microencapsulation around the chitosan microspheres. The optimized formulation was then subjected to microencapsulation with eudragit S-100 by solvent evaporation technique. The effect of different coat/core ratio on particle size, drug entrapment efficiency and in vitro drug release were studied. Formulation which contain 1:10 core/coat ratio released lesser amount of drug in the upper gastro intestinal conditions and so selected as best formulation and then subjected to in vitro drug release studies in presence of rat ceacal contents to assess biodegradability of chitosan microspheres in colon. In order to study the drug release mechanism in vitro drug release data was fitted into various kinetic models. Analysis of regression values suggested that the possible drug release mechanism was Peppas model.     

Metronidazole loaded pectin microspheres for colon targeting

A multiparticulate system having pH-sensitive property and specific enzyme biodegradability for colon-targeted delivery of metronidazole was developed. Pectin microspheres were prepared using emulsion-dehydration technique. These microspheres were coated with Eudragit® S-100 using oil-in-oil solvent evaporation method. The SEM was used to characterize the surface of these microspheres and a distinct coating over microspheres could be seen. The in vitro drug release studies exhibited no drug release at gastric pH, however continuous release of drug was observed from the formulation at colonic pH. Further, the release of drug from formulation was found to be higher in the presence of rat caecal contents, indicating the effect of colonic enzymes on the pectin microspheres. The in vivo studies were also performed by assessing the drug concentration in various parts of the GIT at different time intervals which exhibited the potentiality of formulation for colon targeting. Hence, it can be concluded that Eudragit coated pectin microspheres can be used for the colon specific delivery of drug. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4229–4236, 2009     

Glucagon-like peptide-2-loaded microspheres as treatment for ulcerative colitis in the murine model

Abstract

Glucagon-like peptide-2 (GLP-2) is an intestinal hormone that promotes intestinal growth, but the rapid degradation by dipeptidyl peptidase-IV limits its applications. PLGA microsphere is a well-developed drug delivery system, while seldom been studied as a solution for prolonging in vivo effects of GLP-2. In this study, we encapsulated porcine GLP-2 (pGLP-2) into microspheres and investigated its therapeutic effects in dextran sulfate sodium (DSS)-treated mice. pGLP-2 microspheres showed 20.36% in initial burst and constant release for at least 9?d. In the DSS-treated mice, a single injection of GLP-2 microspheres significantly increased the body weight, colonic length, small intestinal weight and mRNA expression of Occludin, decreased the colonic damage score, mRNA expression of IL-6, IL-10, TNF-α and IFN-γ. In conclusion, pGLP-2 microspheres were resistant to degradation and decreased the severity of DSS-induced ulcerative colitis which suggested that GLP-2-loaded microspheres could be a proper candidate for the treatment of ulcerative colitis.     

Anti-cancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin

Abstract

Background: Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the solution.

Purpose: The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo.

Methods: HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4?mg/kg CUR and 0.4?mg/kg DOX every 2?d for a total of 7 injections.

Results: CUR?+?DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR?+?DOX micelles did not exhibit any significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR?+?DOX micelles showed a significant tumor inhibition effect with an improvement in survival.

Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR?+?DOX micelles are effective and deserve further investigation.     

Curcumin-loaded mixed micelles: preparation,optimization, physicochemical properties and cytotoxicity in vitro

Abstract

Although curcumin (CUR) can inhibit proliferation and induce apoptosis of tumors, the poor water solubility restricted its clinical application. The aim of this study was to improve the aqueous solubility of CUR and make more favorable changes to bioactivity by preparing curcumin-loaded phospholipid-sodium deoxycholate-mixed micelles (CUR-PC-SDC-MMs). CUR-PC-SDC-MMs were prepared by the thin-film dispersion method. Based on the results of single factor exploration, the preparation technology was optimized using the central composite design-response surface methodology with drug loading and entrapment efficiency (EE%) as indicators. The images of transmission electron microscopy showed that the optimized CUR-PC-SDC-MMs were spherical and well dispersed. The average size of the mixed micelles was 66.5?nm, the zeta potential was about ?26.96?mV and critical micelle concentration was 0.0087?g/l. CUR was encapsulated in PC-SDC-MMs with loading capacity of 13.12%, EE% of 87.58%, and the solubility of CUR in water was 3.14?mg/ml. The release results in vitro showed that the mixed micelles presented sustained release behavior compared to the propylene glycol solution of CUR. The IC₅₀ values of CUR-loaded micelles and free drug in human breast carcinoma cell lines were 4.10?μg/ml and 6.93?µg/ml, respectively. It could be concluded from the above results that the CUR-PC-SDC-MMs system might serve as a promising nanocarrier to improve the solubility and bioactivity of CUR.     

Eudragit-coated dextran microspheres of 5-fluorouracil for site-specific delivery to colon

Objective of the present investigation was to prepare and evaluate the potential of enteric coated dextran microspheres for colon targeting of 5-fluorouracil (5-FU). Dextran microspheres were prepared by emulsification-crosslinking method and the formulation variables studied included different molecular weights of dextran, drug:polymer ratio, volume of crosslinking agent, stirring speed and time. Enteric coating (Eudragit S-100) of dextran microspheres was performed by oil-in-oil solvent evaporation method using different coat:core ratios (4:1 or 8:1). Uncoated and coated dextran microspheres were characterized by particle size, surface morphology, entrapment efficiency, DSC, in vitro drug release in the presence of dextranase and 2% rat cecal contents. The release study of 5-FU from coated dextran microspheres was pH dependent. No release was observed at acidic pH; however, the drug was released quickly where Eudragit starts solublizing there was continuous release of drug from the microspheres. Organ distribution study was suggested that coated dextran microspheres retard the release of drug in gastric and intestinal pH environment and released of drug from microspheres in colon due to the degradation of dextran by colonic enzymes.     

Preparation oral levofloxacin colon-specific microspheres delivery: in vitro and in vivo studies

The aim of this study was to prepare levofloxacin-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde-crosslinked microspheres were prepared using a spray-drying method, and characterized in terms of the morphological examination, particle size distribution, entrapment efficiency, drug loading and in vitro release. Pharmacokinetics and colon biodistribution studies were used to evaluate that microspheres have more advantage than the conventional formulations. The surface morphology of the freeze-dried microspheres were smooth, discrete with a regular spherical to near-spherical shape. Size of the microspheres after freeze-drying was 4.96?±?0.76?μm and well-distributed. The zeta potential of microspheres was ?29.3?±?2.1?mV. An average drug loading of 9.3?±?0.4% and encapsulation efficiency of 81.1?±?4.7% of levofloxacin microspheres were obtained with the optimized preparation parameters. The cumulative release rate of levofloxacin microspheres was followed by a sustained release and fitted for classic Higuchi kinetic model. In vivo studies showed that chitosan microspheres are thought to have the potential to maintain levofloxacin concentration within target ranges for a long time, decreasing side effects caused by concentration fluctuation, ensuring the efficiency of treatment and improving patient compliance by reducing dosing frequency. It also does not cause any harmful or toxic effect in colon and rectum as evaluated by histopathologic studies.     

Effect of palmitic acid on the characteristics and release profiles of rotigotine-loaded microspheres

Background: The initial burst release is a major obstacle to the development of microsphere-formulated drug products.

Purpose: To investigate the influence of palmitic acid on the characteristics and release profiles of rotigotine-loaded poly(d,l-lactide-co-glycolide) microspheres.

Materials and methods: Rotigotine-loaded microspheres (RMS) were prepared using the oil-in-water emulsion solvent evaporation technique. The in vitro characteristics of the RMS were evaluated with scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and a particle size analyzer. The in vitro drug release and in vivo pharmacokinetics of the RMS were investigated.

Results and discussion: The SEM results showed that the addition of palmitic acid changed the surface morphology of the microspheres from smooth to dimpled and then to non-smooth as the palmitic acid content increased. DSC revealed the existence of molecularly dispersed forms of palmitic acid in the microspheres. The in vitro and in vivo release profiles indicated that the addition of 5% and 8% palmitic acid significantly decreased the burst release of rotigotine from the microspheres, and the late-stage release was delayed as the palmitic acid content increased across the investigated range (5–15%).

Conclusion: The addition of palmitic acid to the microspheres significantly affects the release profile of rotigotine from RMS.     

Recent advances in testing of microsphere drug delivery systems

ABSTRACT

Introduction: This review discusses advances in the field of microsphere testing.

Areas covered: In vitro release-testing methods such as sample and separate, dialysis membrane sacs and USP apparatus IV have been used for microspheres. Based on comparisons of these methods, USP apparatus IV is currently the method of choice. Accelerated in vitro release tests have been developed to shorten the testing time for quality control purposes. In vitro-in vivo correlations using real-time and accelerated release data have been developed, to minimize the need to conduct in vivo performance evaluation. Storage stability studies have been conducted to investigate the influence of various environmental factors on microsphere quality throughout the product shelf life. New tests such as the floating test and the in vitro wash-off test have been developed along with advancement in characterization techniques for other physico-chemical parameters such as particle size, drug content, and thermal properties.

Expert opinion: Although significant developments have been made in microsphere release testing, there is still a lack of guidance in this area. Microsphere storage stability studies should be extended to include microspheres containing large molecules. An agreement needs to be reached on the use of particle sizing techniques to avoid inconsistent data. An approach needs to be developed to determine total moisture content of microspheres.     

Development and evaluation of chitosan microspheres for tetanus,diphtheria and divalent vaccines: a comparative study of subcutaneous and intranasal administration in mice

Context: There is a need to use the new technologies to induce immunity with minimum number of vaccination sessions to ensure compliance with reducing cost. Objectives: To develop single shot vaccines of tetanus, diphtheria and divalent toxoids microsphere’s formulations and to induce their immune response after intranasal and subcutaneous administration in mice. Materials and methods: The microspheres were prepared using different concentrations of chitosan. Microsphere’s morphology, particle size analysis, encapsulation efficiency and antigen integrity were performed and the best formulations were selected for in vitro and in vivo testing in mice. Results: The developed microspheres have a yield percent of 70.3–91.5%. In vitro release of antigens indicated that tetanus release was increased up to 75 and 81% post T5 and TD5 formulations respectively, whereas diphtheria cumulative release increased up to 74 and 69% post D3 and TD5, respectively. Discussion: Antibody levels produced were lower than that obtained from alum adsorbed vaccine but higher than the minimum level required to induce immunogenicity (>0.01 IU/mL). The subcutaneous route of administration was superior over the intranasal route in producing higher antibody levels. Conclusion: Chitosan microspheres were developed successfully and prove that chitosan represents a good candidate for vaccines delivery.     

Floating-bioadhesive gastroretentive Caesalpinia pulcherrima-based beads of amoxicillin trihydrate for Helicobacter pylori eradication

Abstract

Context: An oral dosage form containing floating bioadhesive gastroretentive microspheres forms a stomach-specific drug delivery system for the treatment of Helicobacter pylori.

Objectives: To prepare and evaluate controlled release floating bioadhesive gastroretentive chitosan-coated amoxicillin trihydrate-loaded Caesalpinia pulcherrima galactomannan (CPG)-alginate beads (CCA-CPG-A), for H. pylori eradication.

Materials and methods: CCA-CPG-A beads were prepared by ionotropic gelation, using 2³ factorial design with quantity of drug, combination of CPG with sodium alginate and concentration of calcium chloride as variables. Beads facilitated mucoadhesion to gastric mucosa with floating nature caused by chitosan coating for wide distribution throughout GIT. Developed beads were evaluated for characteristics like beads size-morphology, entrapment efficiency, DSC, XRD, FTIR, swelling ratio, in vitro mucoadhesion, in vitro drug release, in vitro floating and in vitro H. pylori growth inhibition studies. CCA-CPG-A beads were studied in Wistar rats for in vivo gastric mucoadhesion, in vivo H. pylori growth inhibition studies using PCR amplification of isolated DNA, rapid urease test.

Result: Developed beads possess drug release of 79–92%, entrapment efficiency of 65–89%, mucoadhesion of 61–89%. In vivo mucoadhesion study showed more than 85% mucoadhesion of beads even after 7th hour. In vitro–in vivo growth inhibition study showed complete eradication of H. pylori.

Discussion: CPG-alginate and chitosan in beads interacts with gastric mucosubstrate surface for prolonged gastric residence with floating bioadhesion mechanism for H. pylori eradication in rats.

Conclusion: Floating bioadhesive CCA-CPG-A beads offer a promising drug delivery system for H. pylori eradication at lower dose, reduced adverse effect and enhance bioavailability.     

VEGF-controlled release within a bone defect from alginate/chitosan/PLA-H scaffolds

VEGF and its receptors constitute the key signaling system for angiogenic activity in tissue formation, but a direct implication of the growth factor in the recruitment, survival and activity of bone forming cells has also emerged. For this reason, we developed a composite (alginate/chitosan/PLA-H) system that controls the release kinetics of incorporated VEGF to enhance neovascularization in bone healing. VEGF release kinetics and tissue distribution were determined using iodinated (¹²⁵I) growth factor. VEGF was firstly encapsulated in alginate microspheres. To reduce the high in vitro burst release, the microspheres were included in scaffolds. Matrices were prepared with alginate (A-1, A-2), chitosan (CH-1, CH-2) or by coating the CH-1 matrix with a PLA-H (30 kDa) film (CH-1-PLA), the latter one optimally reducing the in vitro and in vivo burst effect. The VEGF in vitro release profile from CH-1-PLA was characterized by a 13% release within the first 24 h followed by a constant release rate throughout 5 weeks. For VEGF released from composite scaffolds in vitro, bioactivity was maintained above 90% of the expected value. Despite the fact that the in vivo release rate was slightly faster, a good in vitro–in vivo correlation was found. The VEGF released from CH-1 and CH-1-PLA matrices implanted into the femurs of rats remained located around the implantation site with a negligible systemic exposure. These scaffolds provided a bone local GF concentration above 10 ng/g during 2 and 5 weeks, respectively, in accordance to the in vivo release kinetics. Our data show that the incorporation of VEGF into the present scaffolds allows for a controlled release rate and localization of the GF within the bone defect.     

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?µm 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.