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Non-invasive in vivo characterization of release processes in biodegradable polymers by low-frequency electron paramagnetic resonance spectroscopy.

Using stable free radicals (nitroxides) whose spectra reflect microviscosity and pH, low-frequency electron paramagnetic resonance (EPR) spectroscopy was used to characterize the release pattern of subcutaneous implants of poly(D,L-lactide-co-glycolide) (PLGA) continuously and non-invasively in living mice. No significant changes occurred during the first days after implantation. After about 1 week, the recorded EPR spectra gave direct evidence for the formation of compartments with high mobility and increasing acidity in the delivery system. The contribution of the mobile part of the spectrum increased with time, but no remarkable decay of the overall signal intensity was observed during the second week. The EPR signals decayed rapidly after 3 weeks. The experimental data are consistent with bulk hydrolysis as the dominating mechanism of release and are not consistent with a surface-controlled pattern of degradation. The formation of acidic compartments in the delivery system may have significant effects on drug stability, drug solubility, bioavailability, pharmacokinetics, and ultimately on therapeutic efficiency. In particular, the finding of areas of low pH within the polymer raise the possibility that hydrolysable drugs may undergo degradation in the implant prior to their release. Our results demonstrate that EPR is a valuable tool for characterizing such drug delivery systems in vivo.

Animals↗

Liposome technology for drug delivery against mycobacterial infections.

Mycobacteria are intracellular pathogens that invade and reside inside macrophages. There has been a rapid resurgence in infections caused by the genus mycobacteria. Chemotherapy of mycobacterial infections is prolonged, hepatotoxic and very often inadequate in achieving optimal drug concentrations inside the cells. Recent advances in controlled delivery systems for drugs such as liposomes have sparked a renewed interest in their potential application for the treatment of mycobacterial infections. The versatility of liposomes in incorporation of hydrophilic/hydrophobic components, non-toxic nature, biodegradability, biocompatibility and property of sustained release makes them attractive candidates for the delivery of antitubercular drugs. Liposome research in the area of mycobacterial diseases has evolved and matured through several phases; from the laboratory to the clinics. This review, thus focuses on the use of liposomes for the treatment of various types of mycobacterial diseases.

Animals↗

[Local liberation of IGF-I and TGF-beta 1 from a biodegradable poly(D,L-lactide) coating of implants accelerates fracture healing].

In vitro and in vivo studies have demonstrated an osteoinductive effect of growth factors like IGF-I and TGF-beta 1. However, for therapeutic use in fracture treatment, the local application of these bioactive molecules is still an unsolved problem. The controlled release of growth factors from a biodegradable coating of osteosynthetic implants could stimulate fracture healing locally. Coated implants could stabilise the fracture and work as a local drug delivery system. Previous studies demonstrated a high mechanical stability of a thin 10 microns poly(D,L-lactide) (PDLLA) coating on metallic implants that withstands even an intramedullary insertion process. After an initial peak, 80% of incorporated growth factors IGF-I and TGF-beta 1 were continuously released within 42 days. The effect of locally applied IGF-I and TGF-beta 1 from a biodegradable PDLLA coating of intramedullary implants on fracture healing were investigated in a rat model. A fracture of the right tibia of 5-month-old female Sprague-Dawley rats was stabilised with coated versus uncoated titanium K-wires. X-ray examinations and blood analysis were performed, body weight and body temperature monitored throughout the experimental period. After 42 days both tibiae were dissected for mechanical torsional testing and histomorphometric analyses. The results demonstrate a nearly completely consolidated fracture in the X-ray examinations, a significant higher maximum load and torsional stiffness in the biomechanical tests and a progressed remodeling in the histological and histomorphometric analyses after 42 days in the group treated with growth factors compared to the controls. Interestingly, the PDLLA coating itself had a positive effect on fracture healing even without incorporated growth factors. No systemic change of serum parameters including IGF-I and IGF binding proteins and no differences in body weight and body temperature were seen in any group. These findings suggest that the local application of growth factors from a biodegradable poly(D,L-lactide) coating of osteosynthetic implants accelerates fracture healing significantly without systemic side effects.

Animals↗

Particulate delivery systems for vaccines.

This review focuses on the use of particulate delivery systems for the purposes of immunization. This includes poly(lactide-co-glycolide) (PLGA), ISCOMs, liposomes, niosomes, virosomes, chitosan, and other biodegradable polymers. These systems are evaluated in terms of their use as carriers for protein subunit and DNA vaccines. There is an extensive focus on recent literature, the understanding of biological interactions, and relation of this to our present understanding of immunological mechanisms of action. In addition, there is consideration of formulation techniques including emulsification, solvent diffusion, DNA complexation, and entrapment. The diversity of formulation strategies presented is a testament to the exponential growth and interest in the area of vaccine delivery systems. A case study for the application of particulate vaccine carriers is assessed in terms of vaccine development and recent insights into the possible design and application of vaccines against two of the most important pathogens that threaten mankind and for which there is a significant need: Mycobacterium tuberculosis and human immunodeficiency virus. This review addresses the rationale for the use of particulate delivery systems in vaccine design in the context of the diversity of carriers for DNA- and protein-based vaccines and their potential for application in terms of the critical need for effective vaccines.

Drug Delivery Systems↗

Bone morphogenetic protein-2 application by a poly(D,L-lactide)-coated interbody cage: in vivo results of a new carrier for growth factors.

OBJECT: Growth factors such as bone morphogenetic protein-2 (BMP-2) have been proven to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum method to deliver such growth factors remains a matter of discussion. The purpose of this study was to determine the safety and efficacy of a new poly(D,L-lactide) (PDLLA) carrier system for BMP-2 and to compare this carrier system with a collagen sponge carrier in a sheep cervical spine interbody fusion model. METHODS: Thirty-two sheep underwent C3-4 discectomy and fusion: Group 1, titanium cage (eight animals); Group 2, titanium cage coated with a PDLLA carrier (eight animals); Group 3, titanium cage coated with a PDLLA carrier including BMP-2 (150 microg) (eight animals); and Group 4, titanium cage combined with a collagen sponge carrier including BMP-2 (150 microg) (eight animals). Blood samples, body weight, and temperature were assessed. Radiographs were obtained pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After the sheep were killed 12 weeks postoperatively, flexion-extension radiography was performed to evaluate fusion sites. Quantitative computerized tomography scans were obtained to assess bone mineral density (BMD), bone mineral content (BMC), and bone callus volume (BCV). Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral, and elastic zone were determined. Histomorphological and -morphometrical analyses were performed, and polychrome sequential labeling was used to determine the timeframe of new bone formation. There were no differences among the groups concerning blood counts, body weight, and temperature. Compared with the noncoated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus, as well as slightly higher values for BMC, BCV, and the bone volume/total volume ratio. In comparison with the cage-alone group, the BMP-2 groups showed significantly higher values for BMD and biomechanical stiffness. Histomorphological, -morphometrical, and polychrome sequential labeling analyses demonstrated greater progression of callus formation in the BMP-2 groups than in any other group. Compared with BMP-2 delivered using a collagen sponge carrier, BMP-2 application with a PDLLA carrier resulted in a higher BCV and a greater progression of interbody callus formation in the histomorphometrical analysis. CONCLUSIONS: The use of cervical spine interbody fusion cages coated with PDLLA as a delivery system for growth factors was effective. In this 12-week follow-up study, the PDLLA coating showed no adverse effects. The slight but not significant positive effect of the PDLLA carrier on interbody fusion might be a result of the degradation process of the biodegradable carrier. Compared with collagen sponge delivery of BMP-2, the PDLLA-coated interbody cages significantly increased the results of interbody bone matrix formation. In this new combination (implant + PDLLA + growth factor) the cage represents a "real fusion" cage, because it not only serves as a mechanical device for spinal fixation but also as a local drug delivery system.

Animals↗

Inactive Vibrio cholerae whole-cell vaccine-loaded biodegradable microparticles: in vitro release and oral vaccination.

An approach is proposed using Vibrio cholerae (VC)-loaded microparticles as oral vaccine delivery systems for improved vaccine bioavailability and increased therapeutic efficacy. The VC-loaded microparticles were prepared with 50:50 poly(DL-lactide-co-glycolide) (PLG), 75:25 poly(DL-lactide-co-glycolide) and poly(lactide acid) (PLA)/PEG blend copolymers by the solvent evaporation method. VC was successfully entrapped in three types of microparticles with loading efficiencies and loading levels as follows: 50:50 PLG systems: 97.8% and 55.4 +/- 6.9 micro g/mg; 75:25 PLG systems: 89.2% and 46.5 +/- 4.4 micro g/mg; PLA/PEG-blended systems: 82.6% and 53.7 +/- 5.8 micro g/mg. The different distributions of VC in the core region and on the surface were as follows: 50:50 PLG systems 25.7 +/- 1.9 and 6.2 +/- 0.9 micro g/mg; 75:25 PLG systems: 25.8 +/- 2.2 and 3.6 +/- 0.4 micro g/mg; PLA/PEG-blended systems: 32.4 +/- 2.1 and 5.2 +/- 1.0 micro g/mg, respectively. In vitro active release of VC was affected mainly by matrix type and VC-loaded location in microparticles. The therapeutic immunogenic potential of VC loaded with 50:50 PLG, 75:25 PLG and PLA/PEG-blended microparticles was evaluated in adult mice by oral immunization. Significantly higher antibody responses and serum immunoglobin Ig G, IgA and IgM responses were obtained when sera from both VC-loaded 75:25 PLG and PLA/PEG-blended microparticles immunized mice were titrated against VC. The most immunogenicity in evoking serum IgG, IgA and IgM responses was immunized by VC-loaded PLA/PEG-blended microparticles, and with VC challenge in mice, the survival rate (91.7%).

Administration, Oral↗

Biodegradable PLGA microspheres as a sustained release system for a new luteinizing hormone-releasing hormone (LHRH) antagonist.

A sustained release poly(DL-lactide-co-glycolide) (PLGA) microsphere delivery system to treat prostate cancer for a luteinizing hormone-releasing hormone (LHRH) antagonists, LXT-101 was prepared and evaluated in the paper. LXT-101 microspheres were prepared from PLGA by three methods: (1) double-emulsion solvent extraction/evaporation technique, (2) single-emulsion solvent extraction/evaporation technique, and (3) S/O/O (solid-in-oil-in-oil) method. The microspheres were investigated on drug loading, particle size, surface morphology and in vitro release profiles. An accelerated release approach was also established in order to expedite the evaluation periods. The in vivo evaluation of the microspheres was made by monitoring testosterone levels after subcutaneous administration to rats. The LXT-101 PLGA microspheres showed smooth and round surfaces according to a scanning electron microscopic investigation, and average particle size of ca. 30 mum according to laser diffractometry. The drug encapsulation efficiency of microspheres was influenced by LA/GA ratio of PLGA, salt concentrations, solvent mixture and preparation methods. Moreover, LA/GA ratio of PLGA, different preparation methods and different peptide stabilizers affected in vitro release of drugs. In vivo study, the testosterone levels were suppressed to castration up to 42 d as for the 7.5 mg/kg dose. And in vivo performance of LXT-101 microspheres was dose-dependent. The weights of rat sexual organs decreased and histopathological appearance of testes had little changes after 4-month microspheres therapy. This also testified that LXT-101 sustained release microspheres could exert the efficacy to suppress the testosterone level to castration with little toxicity. In conclusion, the PLGA microspheres could be a well sustained release system for LXT-101.

Animals↗

Local, non-viral IL-12 gene therapy using a water soluble lipopolymer as carrier system combined with systemic paclitaxel for cancer treatment.

Development of improved gene transfer methods is needed for gene therapy to achieve its clinical potential. The use of biocompatible polymeric gene carriers has shown effectiveness in overcoming the current problems associated with viral vectors in safety, immunogenicity and mutagenesis. Previous work has demonstrated that repeated, local, non-viral interleukin-12 (IL-12) gene delivery successfully slows down tumor progression, while improving immunogenicity. Combining IL-12 gene delivery with systemic paclitaxel (PCT) chemotherapy as a treatment for various subcutaneous mouse mammary carcinomas, we used PCT with either a biodegradable polymeric solubilizer, HySolv or Cremophor EL for systemic treatment and injected water soluble lipopolymer (WSLP)/plasmid-encoding IL-12 gene (p2CMVmIL-12) complexes local once every week. The amount of lung metastases being essential for survival as well as subcutaneous tumor volume were compared against untreated controls. We showed inhibition of tumor growth and decreased lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the PCT only treated groups. Compared to Cremophor, HySolv performed better alone or in combination with IL-12. Using polymeric vectors as gene carrier systems in combination with improved systemic therapies provide evidence for the efficacy and feasibility of polymer-based drug delivery systems. Especially local cytokine gene delivery showed augmentation of systemic chemotherapy while reducing the hosts risk for further systemic toxicity.

Animals↗

Enhancement of protective immune responses to Venezuelan equine encephalitis (VEE) virus with microencapsulated vaccine.

Venezuelan equine encephalomyelitis (VEE) virus is a mosquito-borne arbovirus of major human health significance in the New World. Currently two forms of VEE virus are used for immunization of humans and horses, i.e. a live attenuated and a formalin-inactivated vaccine. Clinical evidence suggests that these vaccines are not fully efficacious and may produce certain undesirable side-effects. In the present study, microspheres composed of biocompatible and biodegradable poly (DL-lactide-co-glycolide) (DL-PLG) were evaluated for their effectiveness as a delivery system of whole, inactivated VEE virus vaccine for the induction of protective immune responses. Mice receiving 50 micrograms VEE virus in microspheres composed of an equimolar ratio of DL-lactide and glycolide (50:50 DL-PLG) exhibited a primary circulating IgG antibody response which was approximately 32-times higher than the response induced with the same dose of unencapsulated (free) virus. A similar difference in responses was seen with antigen doses ranging from 3.1 to 50 micrograms. A rapid increase in antibody activity was seen after the secondary immunization (day 50). Formalin fixation of inactivated VEE virus was important for immunogenicity since the circulating anti-VEE virus antibody response induced with microencapsulated nonformalin-fixed virus vaccine was lower than that induced with microencapsulated formalin-fixed virus vaccine. Furthermore, at low antigen concentrations, DL-PLG microsphere vaccines prepared with the solvent methylene chloride induced higher antibody responses than those prepared using ethyl acetate as the solvent. Microencapsulated vaccine also induced higher VEE virus neutralization titers than did free virus vaccine. Finally, the microencapsulated virus was more effective than the free virus in inducing immune responses protective against systemic challenge with virulent VEE virus. These results demonstrate that DL-PLG microspheres containing formalin-fixed, inactivated VEE virus were effective in augmenting circulating IgG antibody levels and neutralization titers to the VEE virus following systemic immunization and in affording enhanced protection against systemic challenge with virulent VEE virus. The effects of antigen form and the microsphere processing solvent on the immunogenicity of the vaccine are discussed.

Adjuvants, Immunologic↗

Macroporous biodegradable natural/synthetic hybrid scaffolds as small intestine submucosa impregnated poly(D,L-lactide-co-glycolide) for tissue-engineered bone.

Poly(D,L-lactide-co-glycolide) (PLGA), a biodegradable synthetic polymer, is widely used in a variety of tissue-engineered applications, including drug-delivery systems. However, the PLGA scaffolds, macroporous and three-dimensional structure, are difficult to cell attachment and in-growth due to surface hydrophobicity. In order to introduce in new bioactive functionality from porcine small intestine submucosa (SIS) as natural source for PLGA, we fabricated SIS-powder-impregnated PLGA (SIS/PLGA) hybrid scaffolds. Fabrication parameters, including ratios of SIS, PLGA and salt, were optimized to produce the desired macroporous foam. The scaffolds had a relatively homogeneous pore structure, good interconnected pores from the surface to core region and showed an average pore size in the range 69.23-105.82 microm and over 90% porosity. The SIS/PLGA scaffolds degraded with a rate depending on the contents of the SIS. After the fabrication of the SIS/PLGA hybrid scaffolds the wettability of the scaffold was greatly enhanced, resulting in uniform cell seeding and distribution. So, it was observed that BMSC attachment to the SIS/PLGA scaffolds increased gradually with increasing SIS contents. Scaffolds of PLGA alone and SIS/PLGA were implanted subcutaneously under dorsal skin of athymic nude mouse to observe the osteoconductivity. It was found from the result that the effects of the SIS/PLGA scaffolds on bone formation are stronger than control PLGA scaffolds. In summary, the SIS/PLGA scaffolds have osteoconductive effects to allow remodeling and replacement by osseous tissue.

Absorbable Implants↗

Biodegradable, endosome disruptive, and cationic network-type polymer as a highly efficient and nontoxic gene delivery carrier.

The success of gene therapy is largely dependent on the delivery vector system. Efficient transfection and nontoxicity are two of the most important requirements of an ideal gene delivery vector. To generate both an efficient and nontoxic vector, we rationally constructed polymeric vectors to have simultaneous multiple functions, i.e., controlled degradation, an endosome disruptive function, and positive charges. Remarkably, the transfection efficiency of network poly(amino ester) (n-PAE) synthesized in this manner was comparable to that of polyethylenimine (PEI), one of the most efficient polymeric gene delivery vectors reported to date. However, there was a marked difference in cytotoxicity between the polymers. The majority of PEI-transfected cells were granulated and dead, whereas most of the cells transfected with n-PAE were viable and healthy. Successive events of efficient endosome escape of n-PAE/DNA polyplex and n-PAE biodegradation should result in high transfection efficiency and favorable cell viability response. The n-PAE-mediated transfection was also very efficient in the presence of serum. These data show that the approach we applied is a very appropriate way of making an ideal gene delivery carrier.

Biodegradation, Environmental↗

Polymer delivery of chemotherapy for squamous cell carcinoma of the head and neck.

BACKGROUND: The role of chemotherapy for the treatment of squamous cell carcinoma of the head and neck is limited by the systemic toxicity of chemotherapeutic agents. An attractive alternative is the controlled and sustained release of anticancer agents from a resorbable polymer delivery system that is implanted next to the tumor. The advantages are a high locoregional drug concentration with low systemic levels and a delivery system that is not limited by poor blood supply caused by previous radiation therapy or surgery. METHODS/SUBJECTS: The polymer used in this study was a biodegradable polyanhydride made up of fatty acid dimer and sebacic acid, Poly (FAD-SA), loaded with cisplatin. The tumor animal model was the nude mouse carrying human floor of mouth squamous cell carcinoma xenografts. Polymer-cisplatin pharmacokinetics and the effect of polymer delivery of cisplatin (5% and 7% drug/polymer at a weight/weight load) on tumor growth rates were evaluated. MAIN RESULT: Thirty-five days after implantation of the polymer, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation, the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. CONCLUSION: This study demonstrates that continuous release of cisplatin directly at the tumor site, using an implantable polymer, is effective against human head and neck squamous cell carcinoma xenografts in nude mice.

Animals↗

Biodegradable poly(epsilon -caprolactone) nanoparticles for tumor-targeted delivery of tamoxifen.

To increase the local concentration of tamoxifen in estrogen receptor (ER) positive breast cancer, we have developed and characterized nanoparticle formulation using poly(epsilon -caprolactone) (PCL). The nanoparticles were prepared by solvent displacement method using acetone-water system. Particle size analysis, scanning electron microscopy, zeta potential measurements, and differential scanning calorimetry (DSC) were used for nanoparticle characterization. Biodegradation studies were performed in the presence and absence of Pseudomonas lipase in phosphate-buffered saline (PBS, pH 7.4) at 37 degrees C. Tamoxifen loading over different concentrations was analyzed by high-performance liquid chromatography (HPLC) and the optimum loading concentration was determined. In vitro release studies were performed in 0.5% (w/v) sodium lauryl sulfate (SLS) containing PBS at 37 degrees C. Cellular uptake and distribution of fluorescent-labeled nanoparticles was examined in MCF-7 breast cancer cells. SEM micrographs and Coulter analysis showed nanoparticles with spherical shape and uniform size distribution (250-300 nm), respectively. Zeta potential analysis revealed a positive surface charge of +25 mV on the tamoxifen-loaded formulation. Being hydrophobic crystalline polyester, PCL did not degrade in PBS alone, but the degradation was enhanced by the presence of lipase. The maximum tamoxifen loading efficiency was 64%. Initial burst release of tamoxifen was observed, probably due to significant surface presence of the drug on the nanoparticles. A large fraction of the administered nanoparticle dose was taken up by MCF-7 cells through non-specific endocytosis. The nanoparticles were found in the perinuclear region after 1 h. Results of the study suggest that nanoparticle formulations of selective ER modulators, like tamoxifen, would provide increased therapeutic benefit by delivering the drug in the vicinity of the ER.

Absorbable Implants↗

Advances and potential applications of chitosan derivatives as mucoadhesive biomaterials in modern drug delivery.

Pharmaceutical technologists have been working extensively on various mucoadhesive polymeric systems to create an intimate and prolonged contact at the site of administration. Chitosan is one of the most promising polymers because of its non-toxic, polycationic biocompatible, biodegradable nature, and particularly due to its mucoadhesive and permeation enhancing properties. Due to its potential importance in controlled drug delivery applications, pharmaceutical scientists have exploited this mucoadhesive polymer. However, chitosan suffers from limited solubility at physiological pH and causes presystemic metabolism of drugs in intestinal and gastric fluids in the presence of proteolytic enzymes. These inherent drawbacks of chitosan have been overcome by forming derivatives such as carboxylated, various conjugates, thiolated, and acylated chitosan, thus providing a platform for sustained release formulations at a controlled rate, prolonged residence time, improved patient compliance by reducing dosing frequency, enhanced bioavailability and a significant improvement in therapeutic efficacy. We have explored the potential benefits of these improved chitosan derivatives in modern drug delivery.

Adhesives↗

The potential of antisense as a CNS therapeutic.

Antisense offers a precise and specific means of knocking down expression of a target gene, and is a major focus of research in neuroscience and other areas. It has application as a tool in gene function and target validation studies and is emerging as a therapeutic technology in its own right. It has become increasingly obvious, however, that there are a number of hurdles to overcome before antisense can be used effectively in the CNS, most notably finding suitable nucleic acid chemistries and an effective delivery vehicle to transport antisense oligonucleotides (AS-ODNs) across the blood-brain barrier (BBB) to their site of action. Despite these problems, a number of potential applications of AS-ODNs in CNS therapeutics have been validated in vitro and, in some cases, in vivo. Here the authors outline available nucleic acid chemistries and review progress in the development of non-invasive delivery vehicles that may be applicable to CNS therapeutics. Further to this, they discuss a number of experimental applications of AS-ODNs to CNS research and speculate on the development of antisense techniques to treat CNS disease.

Alzheimer Disease↗

Feasibility study of a passive aeration reactor equipped with vertical pipes for compost stabilization of cow manure.

Pilot-scale composting was carried out with cow manure to evaluate the performances of two passive aeration systems: a conventional passive aeration system equipped with horizontal pipes and an unusual passive aeration method based on air delivery by means of vertical pipes. The effects of both types of passive aeration apparatus were investigated in order to determine the degree of composting rate by continuously monitoring temperature, moisture content, organic matter, electrical conductivity, pH and C/N ratio in the piles. Temperatures in the range of thermophily (55-65 degrees C) were reached in all runs within 1-2 days then lasting for about 1 week, a span long enough for pathogen abatement. Results suggest that passive aeration carried out by vertical pipes is more effective for air delivery into compost piles than conventional passive aeration of air adduction with horizontal pipes. The variation in the number of vertical pipes was revealed to be an important parameter for the control of composting rate and temperature. Composting rates estimated from the heat balance equation were substantially in agreement with those computed through the conversion ratio of total organic matter decrement. The conversion ratios and composting rates obtained in this study using passive aeration with vertical pipes were well aligned with those found using forced air delivery systems.

Animals↗

[Study on targeting drug delivery system--the animal behavior in vivo after hepatic arterial embolization of methotrexate microsphere].

The cross-linked MTX-gelatin microsphere was chosen as an experimental model. Pharmacokinetics and biodegradable period of the microsphere were studied after hepatic arterial embolization in vivo in dogs. After hepatic arterial infusion, the concentration of MTX-ms in peripheral vein blood increased rapidly and declined slowly. In contrast, the peak time of the drug concentration of infused MTX solution appeared at once and decreased rapidly. The half-life of MTX-ms in vivo was 2.14 times as much as that of MTX solution. During the assay period of sixteen hours the drug concentration of MTX-ms in hepatic vein blood was constantly higher than that of MTX solution. The follow-up angiography revealed that microsphere is a kind of peripheral embolic agent and its degradable time in vivo is about one month. Both sustained release and embolization effectiveness of microsphere will be significant in treatment of hepatic cancer.

Animals↗

The potential of chitosan in ocular drug delivery.

This paper presents an overview of the potential of chitosan-based systems for improving the retention and biodistribution of drugs applied topically onto the eye. Besides its low toxicity and good ocular tolerance, chitosan exhibits favourable biological behaviour, such as bioadhesion- and permeability-enhancing properties, and also interesting physico-chemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles. The review summarizes the techniques for the production of chitosan gels, chitosan-coated colloidal systems and chitosan nanoparticles, and describes their mechanism of action upon contact with the ocular mucosa. The results reported until now have provided evidence of the potential of chitosan gels for enhancing and prolonging the retention of drugs on the eye surface. On the other hand, chitosan-based colloidal systems were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye (chitosan-coated colloidal systems containing indometacin) or their accumulation into the corneal/conjunctival epithelia (chitosan nanoparticles containing ciclosporin). Finally, the tolerance, toxicity and biodegradation of the carriers under evaluation were reviewed.

Administration, Topical↗