Local drug delivery system for the treatment of osteomyelitis: In vitro evaluation

Local antimicrobial delivery is a potential area of research conceptualized to provide alternative and better methods of treatment for cases, as osteomyelitis where avascular zones prevent the delivery of drugs from conventional routes of administration. Drug-loaded polymers and calcium phosphates as hydroxyapatites have been tried earlier. Bioactive glasses are bone-filling materials used for space management in orthopedic and dental surgery. A new bioactive glass (SSS2) was synthesized and fabricated into porous scaffold with a view to provide prolonged local delivery of gatifloxacin and fluconazole as suitable for the treatment of osteomyelitis. The new SSS2 was characterized by Fourier transform infrared (FTIR) and X-ray diffraction (XRD) analyses. In addition, the bioactivity of the SSS2 glass and resulting scaffold was examined by in vitro acellular method and ascertained by FTIR and XRD. The pore size distribution was analysed by mercury intrusion porosimetry and the release of drugs from scaffolds were studied in vitro. The glass and the resulting scaffolds were bioactive indicating that they can bond with bone in vivo. The scaffolds were porous with pores predominantly in the range of 10–60 µm, released the drugs effectively for 6 weeks and deemed suitable for local delivery of drugs to treat osteomyelitis.     

In vitro evaluation of S-(+)-ibuprofen as drug candidate for intra-articular drug delivery system

Intra-articular drug delivery systems (DDSs) are envisaged as interesting alternative to locally release non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to reduce pain in patients with osteoarthritis. The present study examines the efficacy of S-(+)-ibuprofen on cartilage degradation as drug candidate for DDS loading. Humeral cartilage and joint capsule explants were collected from healthy sheep shoulder joints and they were cultured in mono- or in co-culture for 13?days with LPS in combination with S-(+)-ibuprofen at 50?µM and 1?mM. S-(+)-ibuprofen (50?µM) blocked prostaglandins production in LPS-activated explants but did not reduce cartilage degradation. By contrast, 1?mM S-(+)-ibuprofen treatment of cartilage explants reduced nitric oxide synthesis by 51% (p?=?0.0072), proteoglycans degradation by 35% (p?=?0.0114) and expression of serum amyloid protein – the main protein induced upon LPS challenge – by 44% (p?相似文献   

In vitro evaluation of idebenone-loaded solid lipid nanoparticles for drug delivery to the brain

Context: Solid lipid nanoparticles (SLN) are regarded as interesting drug delivery systems and their preparation techniques have gained a great deal of attention.

Objective: To evaluate the feasibility of preparing idebenone (IDE) loaded SLN from O/W microemulsions by the phase-inversion temperature (PIT) method. Since SLN have been proposed to improve drug delivery to the brain, IDE was chosen as model drug due to its activity in the treatment of neurodegenerative diseases.

Materials and Methods: Cetyl palmitate was used as solid lipid to prepare SLN containing two surfactant/cosurfactant mixtures, isoceteth-20/glyceryl oleate (SLN A) and ceteth-20/glyceryl oleate (SLN B) by the PIT method.

Results and discussion: All the formulations tested showed a mean particle diameter ranging from 30 to 95?nm and a single peak in size distribution. Stability tests showed that SLN B were more stable than SLN A. IDE release was dependent both on the type of primary surfactant used and the amount of loaded drug. IDE-loaded SLN were effective in inhibiting 2,2′-azobis-(2-amidinopropane)dihydrochloride (APPH)-induced lactic dehydrogenase (LDH) release and reactive oxygen species (ROS) production in primary cultures of astrocytes obtained from rat cerebral cortex. It is noteworthy that SLN B2 (containing ceteth-20 as primary surfactant and 0.7% w/w IDE) were able to prevent entirely both the LDH release and ROS production induced by APPH.

Conclusion: The PIT method provided SLN with good technological properties. The tested SLN could be regarded as interesting carriers to overcome the blood brain barrier and increase the efficacy of the loaded drug.     

Local antibiotic delivery systems for the treatment of osteomyelitis – A review

Osteomyelitis, an inflammatory process accompanied by bone destruction, is caused by infective microorganisms. The high success rates of antimicrobial therapy by conventional routes of administration in controlling most infectious diseases have not yet been achieved with osteomyelitis for several reasons. Local and sustained availability of drugs have proven to be more effective in achieving prophylactic and therapeutic outcomes. This review introduces osteomyelitis – its present options for drug delivery and their limitations, and the wide range of carrier materials and effective drug choices. Local drug delivery for osteomyelitis is a topic of importance for more than 20 years. Carrier materials used for local delivery of antibiotics may be classified as nonbiodegradable and biodegradable. Commonly used non biodegradable carrier materials are polymethyl methacrylate (PMMA), Acrylic beads, PMMA bone cement etc. and biodegradable materials are hydroxyapatite block, bioactive glass ceramics, collagen sponge, polylactide/ployglycolide implants. Both the systems release antibiotic at concentrations exceeding the minimum inhibitory concentrations (MICs) for the most common pathogens involved in osteomyelitis without causing any adverse systemic effects although non biodegradable beads are to be removed from the surgical site after completion of antibiotic release.     

In vitro evaluation of a novel pH sensitive drug delivery system based cockle shell-derived aragonite nanoparticles against osteosarcoma

ABSTRACT

Background: Osteosarcoma (OS) is a highly malignant primary bone cancer. Severe side effects and multidrug resistance are obstacles faced with chemotherapy against OS. With the hope to overcome the obstacles of the conventional chemotherapy, various targeted drug delivery systems using nanotechnology have been explored in the past few decades. Biogenic calcium carbonate (CaCO₃) has great potential to be a smart drug delivery system.

Results: In this study, cockle shells-derived aragonite nanoparticles (ANPs) were developed and loaded with doxorubicin (DOX). The physicochemical properties of the DOX-loaded ANPs (DOX-ANPs) were characterised by various techniques. The results of drug-loading study demonstrated that DOX was loaded onto ANPs at high loading and encapsulation efficiency (11.09% and 99.58%, respectively). The pH-sensitive release of DOX from DOX-ANPs was successful. At lower pH values (4.8), the release of DOX was much quicker than that at pH 7.4. Additionally, cellular uptake study using fluorescence microscopy showed obviously cellular uptake of DOX-ANPs through endocytosis. Moreover, the flow cytometric analysis revealed DOX-ANPs-induced cell cycle arrest, which was consistent with the mechanism of DOX. DOX-ANPs also showed an efficient cytotoxicity against OS cancer cells, close to the toxicity effect of free DOX at the same concentration. Morphological observations showed microvilli disappearance, chromatin condensation, cell shrinkage, membrane blebbing, and formation of apoptotic bodies, which confirmed both DOX-ANPs- and DOX-induced apoptosis of OS cancer cells in vitro.

Conclusion: Our findings indicated that ANPs could act as a pH-sensitive drug delivery against OS.     

In vitro and in vivo performance of a multiparticulate pulsatile drug delivery system

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

Bioactive borate glass scaffolds: in vitro and in vivo evaluation for use as a drug delivery system in the treatment of bone infection

The objective of this work was to evaluate borate bioactive glass scaffolds (with a composition in the system Na₂O–K₂O–MgO–CaO–B₂O₃–P₂O₅) as devices for the release of the drug Vancomycin in the treatment of bone infection. A solution of ammonium phosphate, with or without dissolved Vancomycin, was used to bond borate glass particles into the shape of pellets. The in vitro degradation of the pellets and their conversion to a hydroxyapatite-type material in a simulated body fluid (SBF) were investigated using weight loss measurements, chemical analysis, X-ray diffraction, and scanning electron microscopy. The results showed that greater than 90% of the glass in the scaffolds degraded within 1 week, to form poorly crystallized hydroxyapatite (HA). Pellets loaded with Vancomycin provided controlled release of the drug over 4 days. Vancomycin-loaded scaffolds were implanted into the right tibiae of rabbits infected with osteomyelitis. The efficacy of the treatment was assessed using microbiological examination and histology. The HA formed in the scaffolds in vivo, resulting from the conversion of the glass, served as structure to support the growth of new bone and blood vessels. The results in this work indicate that bioactive borate glass could provide a promising biodegradable and bioactive material for use as both a drug delivery system and a scaffold for bone repair.     

In vitro comparative evaluation of monolayered multipolymeric films embedded with didanosine-loaded solid lipid nanoparticles: a potential buccal drug delivery system for ARV therapy

Drug delivery via the buccal route has emerged as a promising alternative to oral drug delivery. Didanosine (DDI) undergoes rapid degradation in the gastrointestinal tract, has a short half-life and low oral bioavailability, making DDI a suitable candidate for buccal delivery. Recent developments in buccal drug delivery show an increased interest toward nano-enabled delivery systems. The advantages of buccal drug delivery can be combined with that of nanoparticulate delivery systems to provide a superior delivery system. The aim of this study was to design and evaluate the preparation of novel nano-enabled films for buccal delivery of DDI. Solid lipid nanoparticles (SLNs) were prepared via hot homogenization followed by ultrasonication and were characterized before being incorporated into nano-enabled monolayered multipolymeric films (MMFs). Glyceryl tripalmitate with Poloxamer 188 was identified as most suitable for the preparation of DDI-loaded SLNs. SLNs with desired particle size (PS) (201?nm), polydispersity index (PDI) (0.168) and zeta potential (?18.8?mV) were incorporated into MMFs and characterized. Conventional and nano-enabled MMFs were prepared via solvent casting/evaporation using Eudragit RS100 and hydroxypropyl methylcellulose. Drug release from the nano-enabled films was found to be faster (56% versus 20% in first hour). Conventional MMFs exhibited higher mucoadhesion and mechanical strength than nano-enabled MMFs. SLNs did not adversely affect the steady state flux (71.63?±?13.54?µg/cm²?h versus 74.39?±?15.95?µg/cm²?h) thereby confirming the potential transbuccal delivery of DDI using nano-enabled MMFs. Nano-enabled buccal films for delivery of DDI can be successfully prepared, and these physico-mechanical studies serve as a platform for future formulation optimization work in this emerging field.     

Macro-to-micro porous special bioactive glass and ceftriaxone-sulbactam composite drug delivery system for treatment of chronic osteomyelitis: an investigation through in vitro and in vivo animal trial

A systematic and extensive approach incorporating in vitro and in vivo experimentation to treat chronic osteomyelitis in animal model were made using antibiotic loaded special bioactive glass porous scaffolds. After thorough characterization for porosity, distribution, surface charge, a novel drug composite were infiltrated by using vacuum infiltration and freeze-drying method which was subsequently analyzed by SEM-EDAX and studied for in vitro drug elution in PBS and SBF. Osteomyelitis in rabbit was induced by inoculation of Staphylococcus aureus and optimum drug-scaffold were checked for its efficacy over control and parenteral treated animals in terms of histopathology, radiology, in vivo drug concentration in bone and serum and implant-bone interface by SEM. It was optimized that 60P samples with 60-65% porosity (bimodal distribution of macro- to micropore) with average pore size ~60 μm and higher interconnectivity, moderately high antibiotic adsorption efficiency (~49%) was ideal. Results after 42 days showed antibiotic released higher than MIC against S. aureus compared to parenteral treatment (2 injections a day for 6 weeks). In vivo drug pharmacokinetics and SEM on bone-defect interface proved superiority of CFS loaded porous bioactive glass implants over parenteral group based on infection eradication and new bone formation.     

Development of multiple-unit colon-targeted drug delivery system by using alginate: in vitro and in vivo evaluation

Drug delivery systems to the colon are being actively investigated. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. In this study, a pH- and enzyme-controlled, colon-targeted tablets (PECCTT) was established by using outer pH-coated layer and inner alginate-coated compression layer. The influence of the amount of alginate and enteric coat thickness on drug release had been investigated and the formulation that contained 30% alginate in compression layer and 13% weight gain in pH-coated layer was proved to protect the drug release from stomach and small intestine, the lag time was 7.04 ± 0.17 h, and 84.45 ± 1.3% of prednisone was released at 12 h. The results of drug release behaviors and SEM study indicated that drug release mechanism of PECCTT was corrosion. Hybrid scanner combining SPECT and CT was employed to monitor (99m)Tc-contained tablets in the human gastrointestinal tract (GIT) and to obtain the images of the disintegration process. The results showed that the tablet remained intact during its transit through the upper GIT, the anatomical site of disintegration was found to be the sigmoidal colon, and the disintegration of the tablet started at 8 h post-dose in the volunteer.     

Development of multiple-unit colon-targeted drug delivery system by using alginate: in vitro and in vivo evaluation

Drug delivery systems to the colon are being actively investigated. However, it is difficult to ensure that an oral preparation disintegrates specifically in the human colon. In this study, a pH- and enzyme-controlled, colon-targeted tablets (PECCTT) was established by using outer pH-coated layer and inner alginate-coated compression layer. The influence of the amount of alginate and enteric coat thickness on drug release had been investigated and the formulation that contained 30% alginate in compression layer and 13% weight gain in pH-coated layer was proved to protect the drug release from stomach and small intestine, the lag time was 7.04?±?0.17?h, and 84.45?±?1.3% of prednisone was released at 12?h. The results of drug release behaviors and SEM study indicated that drug release mechanism of PECCTT was corrosion. Hybrid scanner combining SPECT and CT was employed to monitor ^99mTc-contained tablets in the human gastrointestinal tract (GIT) and to obtain the images of the disintegration process. The results showed that the tablet remained intact during its transit through the upper GIT, the anatomical site of disintegration was found to be the sigmoidal colon, and the disintegration of the tablet started at 8?h post-dose in the volunteer.     

Design and evaluation of a self-microemulsifying drug delivery system for apigenin

Objective of this study was to prepare, characterize and evaluate a self-microemulsifying drug delivery system (SMEDDS) with the aim to improve the solubility and dissolution of apigenin. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of apigenin loaded SMEDDS was optimized by a simplex lattice experiment design. The optimal formulation of SMEDDS obtained was comprised of 60% Cremophor^®EL, 30% Transcutol^®HP and 10% Capryol? 90. The equilibrium solubility of apigenin in SMEDDS was about 15 mg/g, and it could increase the solubility of apigenin in water for about 7500 folds. Apigenin loaded SMEDDS could turn into microemulsion when diluted with distilled water and the droplets were spherical under transmission electron microscope (TEM), the average particle size was 17.1 nm and zeta potential ?5.18 mV. In vitro dissolution studies showed about 95% of apigenin was released within 10 min. All of the results showed that SMEDDS could enhance the solubility and dissolution of apigenin, and would be a potential carrier to improve the oral absorption of apigenin, a poorly water soluble drug.     

In vitro evaluation of compression-coated glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu2+)-loaded microparticles for colonic drug delivery

Glycyl-L-histidyl-L-lysine-Cu(II) (GHK-Cu(2+))-loaded Zn-pectinate microparticles in the form of hydroxypropyl cellulose (HPC) compression-coated tablets were prepared and their in vitro behavior tested. GHK-Cu(2+) delivery to colon can be useful for the inhibition of matrix metalloproteinase, with the increasing secretion of tissue inhibitors of metalloproteinases (TIMPS),which are the major factors contributing in mucosal ulceration and inflammation in inflammatory bowel disease. The concentration of peptide was determined spectrophotometrically. The results obtained implied that surfactant ratio had a significant effect on percent production yield (1.25 to 1.75 w/w; 72.22% to 80.84%), but cross-linking agent concentration had not. The entrapment efficiency (EE) was found to be in the range of 58.25-78.37%. The drug-loading factor significantly increased the EE; however, enhancement of cross-linking agent concentration decreased it. The release of GHK-Cu(2+) from Zn-pectinate microparticles (F1-F8) in simulated intestinal fluid was strongly affected by cross-linking agent concentration and drug amount (50 mg for F1-F6; 250 mg for F7-F8), but not particularly affected by surfactant amount. Release profiles represented that the microparticles released 50-80% their drug load within 4 h. Therefore, the optimum microparticle formulation (F8) coated with a relatively hydrophobic polymer HPC to get a suitable colonic delivery system. The optimum colonic delivery tablets prepared with 700 mg HPC-SL provided the expected delayed release with a lag time of 6 h. The effects of polymer viscosity and coat weight on GHK-Cu(2+) release were found to be crucial for the optimum delay of lag time. The invention was found to be promising for colonic delivery.     

Damar Batu as a novel matrix former for the transdermal drug delivery: in vitro evaluation

Purpose: Damar Batu (DB) is a novel film-forming biomaterial obtained from Shorea species, evaluated in this study for its potential application in transdermal drug delivery system. Methods: DB was characterized initially in terms of acid value, softening point, molecular weight (M_w), polydispersity index (M_w/M_n), and glass transition temperature (T_g). Neat, plasticized films of DB were investigated for mechanical properties. The biomaterial was further investigated as a matrix-forming agent for transdermal drug delivery system. Developed matrix-type transdermal patches were evaluated for thickness and weight uniformity, folding endurance, drug content, in vitro drug release study, and skin permeation study. Results: On the basis of in vitro drug release and in vitro skin permeation performance, formulation containing DB/Eudragit RL100 (60 : 40) was found to be better than other formulations and was selected as the optimized formulation. IR analysis of physical mixture of drug and polymer and thin layer chromatography study exhibited compatibility between drug and polymer. Conclusion: From the outcome of this study, it can be concluded that applying suitable adhesive layer and backing membrane-developed DB/ERL100, transdermal patches can be of potential therapeutic use.     

Design and evaluation of transdermal drug delivery system for curcumin as an anti-inflammatory drug

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing herbal drug, curcumin (CUR), with different ratios of hydrophilic (hydroxyl propyl methyl cellulose K4M [HPMC K4M]) and hydrophobic (ethyl cellulose [EC]) polymeric systems by the solvent evaporation technique. Different concentrations of oleic acid (OA) were used to enhance the transdermal permeation of CUR. The physicochemical compatibility of the drug and the polymers was also studied by differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results suggested no physicochemical incompatibility between the drug and the polymers. Formulated transdermal films were physically evaluated with regard to drug content, tensile strength, folding endurance, thickness, and weight variation. All prepared formulations indicated good physical stability. In vitro permeation studies of formulations were performed by using Franz diffusion cells. The results followed Higuchi kinetics, and the mechanism of release was diffusion-mediated. Formulation prepared with hydrophilic polymer containing permeation enhancer showed best in vitro skin permeation through rat skin as compared with all other formulations. This formulation demonstrated good anti-inflammatory activity against carrageenan-induced oedema in Wistar albino rats similar to standard formulation.     

Biodegradable drug delivery system for the treatment of bone infection and repair

A drug delivery system (DDS) which provides a sustained release of antibiotics at the focal site either singly, or in combination with a bone stimulating factor could both eliminate infection and increase the number of potentially healthy osteogenic cells. In this study, we address the use of a degradable gelatin DDS, for the combined release of therapeutic levels of both gentamicin and growth hormone (GH). An initial bolus release was observed during the first 24 h followed by a reduced, but sustained, release for both drugs up to 14 days. Bioactivity of gentamicin was demonstrated by growth inhibition of Staphylococcus aureus for over 96 h with a mean zone of inhibition of 29.4 mm (±0.19) for the time period studied. Furthermore, GH was shown to have a direct effect on primary human osteoblast-like (HOB) cells, stimulating proliferation and enhancing their differentiation. Site-specific drug delivery offers the advantage of localizing a drug directly at the target site, thus minimizing systemic effects. The results of this study suggest that gelatin is a good DDS for the combined release of drugs. In addition, gelatin is both biocompatible and biodegradable, thus making it a promising DDS for the management of acute and chronic bone and tissue infection such as osteomyelitis. © 1999 Kluwer Academic Publishers     

壳聚糖/羟基磷灰石-庆大霉素缓释材料的抗菌性能研究及AFM观察

制备壳聚糖/羟基磷灰石-庆大霉素(CS/HA-G)缓释材料,评价其抗茵性能在骨髓炎的治疗中的应用前景;并从微观角度初步探讨药物对大肠杆菌的作用机制.对CS/HA-G缓释材料进行体外缓释行为研究及抗茵实验;并以原子力显微镜(AFM)观察大肠杆茵在药物作用前后表面形态结构的变化.CS/HA-G对大肠杆茵的抑茵效果显著,维持有效释药时间长达30d以上.AFM观察显示药物作用于大肠杆菌后菌体高度和表面平均粗糙度(Ra)均下降,有内容物渗漏.CS/HA是一种理想的庆大霉素载体材料.CS/HA-G的缓释作用和缓释规律显示出该材料在大肠杆菌引发的骨髓炎的防治中具有极大的临床应用潜能.     

Multiparticulate drug delivery system of aceclofenac: development and in vitro studies

The aim of this study was to develop an enteric-coated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly(meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. The formulated pellets were characterized for percentage yield, size distribution, surface morphology studies, drug content, and flow properties. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. The practical yield was found to be 90-95%. The particle size of enteric-coated pellets was found to be in the range of 0.59-0.71 mm. The pellets were spherical in shape and surfaces of pellets were found to be rough and showing micropores. Enteric-coated pellets showed good flow properties and in vitro dissolution profile. Dissolution tests were carried out in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 (<5%) for a period of 2 h, and at pH 6.8, it shows the maximum release (85 +/- 5% release within 1 h) which indicates gastric resistance of the formulated pellets. The 20% wt/wt enteric-coated pellets were compared to that of marketed product (tablets), it was observed that pellets showed better release profile. The study concluded that the formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the aceclofenac.     

In vitro and in vivo anti-tumor effects of gemcitabine loaded with a new drug delivery system

In recent years, much attention has been given to liposomal formulation as an efficient drug loading system (DDS) in chemotherapy of cancer. In this study, the advantages of magnetic nanoparticles and Polyethylene Glyco (PEG) materials were considered to synthesize magnetic gemcitabine long-circulating liposomes (MGLL) and the potential of MGLL as a brand new delivery system was evaluated. MGLL was prepared using the reverse-phase evaporation method. In the optimized preparation, MGLL had an average diameter of 201 nm with a narrow size distribution measured by dynamic light scattering (DLS), which could be easily dispersed in ultrapure water under a stable state for 90 days. The encapsulation efficiency of gemcitabine in MGLL reached 87.2% as determined by HPLC. In vitro MTT assay showed that MGLL had significant cytotoxicity to MCF-7 cells compared with the conventional modalities. In vivo, the inhibition of tumor growth in MGLL group was more remarkable than that of other groups (P < 0.05). In conclusion, MGLL under optimized condition could be used as an effective carrier for tumor-targeted therapy.