In vivo evaluation of biodegradable progesterone microspheres in mares.
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Animals↗
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Results for “Biodegradable Delivery Systems”
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Antibacterial poly(D,L-lactic acid) coating of medical implants using a biodegradable drug delivery technology.
OBJECTIVES: Biomaterial-associated bacterial infections present common and challenging complications with medical implants. The purpose of this study was to determine the antibacterial properties of a low molecular weight biodegradable poly(D,L-lactic acid) coating with integrated antibiotics gentamicin and teicoplanin. METHODS: Coating of Kirschner-wires was carried out by a solvent casting technique under aseptic conditions with and without incorporated antibiotics. Release kinetics of gentamicin and teicoplanin were studied in phosphate-buffered saline. Initial bacterial adhesion of Staphylococcus epidermidis on coated and bare implants was determined by radiolabelling and counts of detached viable organisms. RESULTS: The incorporated antibiotics showed a continuous release over a period of at least 96 h with an initial peak of release in the first 6 h. Attachment of non-viable microorganisms, detected by radiolabelled bacteria, was increased significantly by the polymer coatings (P < 0.05). In contrast, the number of viable bacteria was reduced by the pure polymer (P < 0.01) and further by the polymer-antibiotic combinations (P < 0.05). CONCLUSIONS: Poly(D,L-lactic acid) coating of implants could offer new perspectives in preventing biomaterial-associated infections. Combinations with other drugs to formulate custom-tailored implant surfaces are feasible.
Absorbable Implants↗
Microencapsulated dopamine (DA)-induced restitution of function in 6-OHDA-denervated rat striatum in vivo: comparison between two microsphere excipients.
Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated-striatal tissue assures a prolonged release of the transmitter in vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.
Animals↗
Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers. Part II: biodegradation.
A series of previously-synthesized lactic/glycolic acid polymers (PLGA) with various molar ratios of lactic to glycolic acid and various molecular weights were further studied with regard to their biodegradation behavior, and in particular, the factors affecting the biodegradation rate. The biodegradation of PLGA is affected by many factors including polymer composition, molecular weight, and nature of the incubating media. The biodegradation rate of PLGA containing higher content of lactic acid moiety is lower than those containing a lower content of lactic acid moiety. PLGAs with a higher molecular weight, degrade faster than those with a lower molecular weight, i.e. the molecular weight decreases more rapidly for higher molecular weight PLGAs than their lower molecular weight counterparts. Nature or properties of the hydrolysis/incubating media may have an effect on the biodegradation of PLGAs. A basic medium may slow down the biodegradation of PLGA in comparison with samples in an acidic medium. The rate of pH reduction for the incubating medium can be divided into three deferent phases, giving an inverted S-type pH profile for the non-buffered incubating media.
Biocompatible Materials↗
Solid tumor chemotherapy and in vivo distribution of fluorouracil following administration in poly(L-lactic acid) microspheres.
The physicochemical properties and in vivo distribution of poly(L-lactide) (L-PLA) microspheres containing 5-fluorouracil (5-FU) prepared by a solvent evaporation method were evaluated for potential use in the treatment of liver cancers. Two different molecular weight polymers of L-PLA [L-PLA1 (152,500 Da) and L-PLA2 (52,000 Da)] were used to prepare 5-FU-loaded microspheres. The mean particle size of the microspheres was 3-6 microns, and there was a direct relationship between the mean particle size and the molecular weight of the polymers. The drug release behavior from microspheres exhibited a diffusion mechanism in different dissolution media, with the molecular weight of the polymer being a major factor in controlling the drug release and degradation rates. Following intravenous injection of 99mTc-labeled L-PLA microspheres, with or without 5-FU, or free 5-FU into mice, L-PLA2 microspheres localized mainly in the liver. The disappearance rate of radioactivity from the tissue was very slow in comparison to that of free 5-FU. The results were confirmed by histological examination of liver tissue following administration of fluorescein particles. In addition, growth of a human liver tumor as first transplant generation under the renal capsule of immunocompetent rats and antitumor activity of L-PLA2 microspheres were investigated. Histological examination by optical microscopy showed that there was no neoplastic tissue of the kidney or in other tissues examined after treatment.
Animals↗
[Preparation and degradation behavior of PELGE nanoparticles].
A series of poly (lacticacid-co-glycolicacid)-poly(ethylene glycol) (PLGA-PEG, PELGA) block copolymers and poly (ethylene glycol)-poly (lacticacid-co-glycolicacid)-poly (ethylene-glycol) (PELGE) was synthesized by ring-opening polymerization. PELGA nanoparticles and PELGE nanoparticles were prepared using the emulsion-solvent evaporation technique (O/W). To study the behavior and mechanism of the degradation of PELGA-NP and PELGA-NP, we determined the lactic acids by UV spectrophotometry. The method confirmed that degradation was much faster for polymers with a decrease in the LA content of the polymers or an increase in the PEG content of the polymers.
Biocompatible Materials↗
Current status of biodegradable stents.
Coronary angioplasty remains limited by abrupt closure and restenosis. Metallic stents are useful for suboptimal PTCA results or threatened closure and can reduce restenosis in de novo lesions. However, they are permanent devices that are used to treat a short-term problem and have only limited potential for local drug delivery. Several catheters have been designed for specific delivery of drugs or gene products. Unfortunately drug delivery efficiency and long-term retention remain problematic. To overcome these limitations and provide a scaffold for the remodeling vessel as well as a vehicle for sustained local drug delivery, bioabsorbed stents have been proposed as an alternative. This article describes the limitations of the current metallic stents, reviews the initial animal studies of polymeric stents, and proposes the biodegradable stent as a local drug delivery device to prevent restenosis and acute closure post-PTCA.
Angioplasty, Balloon, Coronary↗
A biodegradable injectable thermoplastic for localized camptothecin delivery.
Camptothecin is an example of a potent drug with a short half-life that would benefit from a localized drug depot system that maintains its stability prior to being released. For this reason, a thermoplastic, biodegradable polymer drug depot was prepared and characterized, and the in vitro release of camptothecin examined. epsilon-Caprolactone oligomers were prepared by ring-opening polymerization initiated by various alcohols. The polymers were characterized via differential scanning calorimeter (DSC) for thermal transitions, and via a parallel plate rheometer for melt viscosity. Camptothecin was loaded into the oligomers and released into PBS buffer. The viscosity of the oligomers was alterable by the initiator used. The oligomers were semi-crystalline with melting points between 37 and 45 degrees C. Camptothecin was released from the oligomers in a diffusion-controlled manner, with the release rate increasing as the melt viscosity of the oligomer decreased. The unreleased camptothecin remained in its active lactone form for a period of up to 16 weeks.
Biocompatible Materials↗
Implantable, polymeric systems for modulated drug delivery.
The ability to deliver therapeutic agents to a patient in a pulsatile or staggered release profile has been a major goal in drug delivery research over the last two decades. This review will cover methods that have been developed to control drug delivery profiles with implantable polymeric systems. Externally and internally controlled systems will be discussed, spanning a range of technologies that include pre-programmed systems, as well as systems that are sensitive to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation. Implantable systems have the potential to improve the quality of life for patients undergoing therapy with a variable dosing regime by eliminating the need for multiple intravenous injections. Ideally, these systems would also result in increased patient compliance with a given therapy due to the relative ease of self-dosing.
Biodegradation, Environmental↗
Formation of and coalescence from the inclusion complex of a biodegradable block copolymer and alpha-cyclodextrin. 2: A novel way to regulate the biodegradation behavior of biodegradable block copolymers.
A biodegradable block copolymer (PCL-b-PLLA, M(n) = 1.72 x 10(4), M(w)/M(n) = 1.37) of poly(epsilon-caprolactone) (PCL) and poly(L-lactide) (PLLA) with very low crystallinity was obtained by forming the inclusion complex between alpha-cyclodextrin molecules and PCL-b-PLLA followed by coalescence of the guest polymer chains. Films of the as-synthesized and coalesced copolymer samples, PCL and PLLA homopolymers of approximately the same chain lengths as the corresponding blocks of PCL-b-PLLA, and a physical blend of PCL/PLLA homopolymers with the same molar composition as PCL-b-PLLA were prepared by melt-compression molding between Teflon plates. Subsequently, the in vitro biodegradation behavior of these films was studied in phosphate buffer solution containing lipase from Rhizopus arrhizus, by means of ultraviolet spectra, attenuated total reflectance FTIR spectra, differential scanning calorimetry, wide-angle X-ray diffraction measurements, and weight loss analysis. PCL segments were found to degrade much faster than PLLA segments, both in the pure state and in copolymer or blend samples. Consistent with our expectation, suppression of the phase separation, as well as a decrease of crystallinity, in the coalesced copolymer sample led to a much faster enzymatic degradation than that of either as-synthesized copolymer or the PCL/PLLA physical blend sample, especially during the early stages of biodegradation. Thus the biodegradation behavior of biodegradable block copolymers, which is of decisive importance in drug delivery and controlled release systems, may be regulated by the novel and convenient means recently reported by us.(1)
Biocompatible Materials↗
Stent development and local drug delivery.
Stent implantation has become the new standard angioplasty procedure. In-stent re-stenosis remains the major limitation of coronary stenting. Re-stenosis is related to patient-, lesion- and procedure-specific factors. Patient-specific factors can not be influenced to any extent. Procedure-specific factors are affected by implantation technique and stent characteristics. Design and material influence vascular injury and humoral and cellular response. Radiation has been shown to have inhibitory effects on smooth muscle cell growth and neo-intima formation, but in clinical trials the outcome has been hampered by re-stenosis at the edges of the radioactive stent ('candy wrapper'). New approaches target pharmacological modulation of local vascular biology by local administration of drugs. This allows for drug application at the precise site and time of vessel injury. Systemic release is minimal and this may reduce the risk of toxicity. The drug and the delivery vehicle must fulfil pharmacological, pharmacokinetic and mechanical requirements and the application of eluting degradable matrices seems to be a possible solution. Numerous pharmacological agents with antiproliferative properties are currently under clinical investigation, e.g. actinomycin D, rapamycin or paclitaxel. Another approach is for stents to be made of biodegradable materials as an alternative to metallic stents. Their potential long-term complications, such as in-stent re-stenosis and the inaccessibility of the lesion site for surgical revascularization, needs to be assessed. Current investigational devices and the line of (pre)clinical investigation are discussed in detail. Currently, there is little experimental, and only preliminary clinical, understanding of the acute and long-term effects of drug-eluting or biodegradable stents in coronary arteries. The clinical benefit of these approaches still has to be proven.
Angioplasty, Balloon, Coronary↗
An in vitro evaluation of PCL-TCP composites as delivery systems for platelet-rich plasma.
In this study, we first investigated the in vitro degradation properties of biodegradable, bioresorbable polycaprolactone-20% tricalcium phosphate (PCL-TCP) composites immersed in simulated body fluid (SBF) and phosphate buffered saline (PBS). Then, the release profiles of the growth factors present in platelet-rich plasma (PRP) loaded onto the composites incubated in SBF and PBS were compared. Composites immersed in both buffers showed water uptake of 13.7%+/-0.75 at day 1, followed by a constant uptake of 12.1%+/-0.3 until day 12. Henceforth the water uptake declined for SBF- and increased for PBS-soaked composites. The weight loss data did not reveal any trend. SBF- and PBS-soaked samples displayed 1-2% weight loss for 2 and 5 of the ten time points measured respectively. The original protein retention (PR) of the composites was 49.1%+/-1.50. After immersion in SBF and PBS for 4 weeks, the PR was augmented to 88.5%+/-1.40 and 69.1%+/-1.40 correspondingly. PRP after activation contained 164.7+/-24.8, 194+/-43 and 18.3+/-4.75 ng/ml of TGF-beta1, PDGF-BB and IGF-1. Microscopic analysis verified the attachment of PRP to the rods and pores of the composites. Interestingly, the buffers played an important role in determining the release profiles of TGF and PDGF. Firstly, PBS-soaked composites manifested a tri-phasic burst-like profile that was absent in SBF. Secondly, SBF-soaked composites experienced delayed release of the growth factors and total release was not achieved (64.4% for TGF and 60.5% for PDGF), whereas total release was realized for PBS-soaked composites. Lastly, release profiles from SBF-soaked composites were growth factor mediated in terms of their amounts and sizes. This was not observed for PBS-soaked composites. IGF-1, on the other hand, exhibited a progressive reduction in levels over the entire experimental period for both buffers. The mechanisms of release were theorized to be a combination of diffusion, degradation and bioactivity. Since SBF is analogous to our body fluids in terms of its ionic constituents, we expect the elution profiles derived from SBF-soaked samples to more accurately emulate the in vivo situation. In conclusion, this study has deemed PCL-TCP composites as suitable delivery systems for platelet-rich plasma.
Absorption↗
Preparation of gelatin microparticles by co-lyophilization with poly(ethylene glycol): characterization and application to entrapment into biodegradable microspheres.
Gelatin microparticles were prepared by co-lyophilization with poly(ethylene glycol) (PEG) as a protein micronization adjuvant. Aqueous solutions containing gelatin and PEG at various mixing ratios were freeze-dried. The lyophilizates were dispersed in methylene chloride and subjected to particle size analysis. The particle size decreased as the PEG/gelatin ratio increased. The microparticles isolated from the suspension had spherical microdomains with sizes ranging from 1 to 10 microm, which indicated that phase separation between PEG and gelatin during freezing was involved in the formation mechanism of gelatin microparticles. By using this technology, gelatin microparticles with an average size of less than 10 microm, with high purity of more than 90% and with good dispersibility could be obtained with high yield. The gelatin microparticles with average sizes from 5 to 20 microm were applied to encapsulation into biodegradable PLGA/PLA microspheres via a solid-in-oil-in-water emulsion process. The entrapment efficiency was highly dependent on the particle size and the size distribution, signifying that solid microparticles with an average diameter of less than 5 m and an maximal diameter of less than 10 microm would be required for effective encapsulation. These gelatin microparticles would be useful for studying and developing various drug delivery systems.
Biodegradation, Environmental↗
Design and characterisation of poly(lactide-co-glycolide) small particulate systems for the delivery of immunostimulant CpG oligonucleotide.
The aim of this study was to develop and characterize biodegradable small particles of poly(lactide-co-glycolide) (PLGA) as oral vehicle for immunostimulatory oligonucleotide (ODN-CpG). Three different polymers were used as surface stabilizing agents (SSA): polyvinyl alcohol (PVA), hydrophobically modified hydroxyethylcellulose (HMHEC), or polyethylenimine (PEI). Particle surface was characterized as well as ODN-CpG release kinetics. All particles were found to be around 1 microm. Particles of PLGA-PVA and PLGA-HMHEC were spherical in shape with a smooth surface whereas PLGA-PEI particles were porous. The presence of ODN-CpG within the particle matrix was confirmed in all particle type using scanning laser confocal microscopy. Particle surface assayed by XPS, zeta potential analysis, and evaluation of particle surface hydrophobicity suggested that a significant amount of SSA remains associated onto particle surface. Release profiles evidenced that ODN-CpG release was strongly dependent on particle surface properties. 100% of encapsulated ODN-CpG was released from PLGA-PVA and PLGA-HMHEC particles 37 days after incubation in a buffer solution, whereas only 25% were released from PLGA-PEI particles. ODN-CpG can therefore be nicely entrapped in several types of small particles displaying a prolonged and controlled release upon time. In addition, particle surface is not modified by the presence of ODN-CpG.
Adjuvants, Immunologic↗
Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints.
The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. In this study, we aimed to prepare celecoxib-loaded chitosan microspheres for intra-articular administration and to compare the retention of the celecoxib solution and chitosan microspheres in the joint cavity. The microspheres were characterized for entrapment efficiency, particle size and surface morphology by scanning electron microscopy. In-vitro drug release studies of microspheres revealed that the microspheres are able to control the release of celecoxib over a period of 96 h. Biodistribution studies of celecoxib and chitosan microspheres were performed by radiolabelling with( 99m)Tc and injecting intraarticularly in rats. The study indicated that following intra-articular administration the distribution of the drug to the organs, like liver and spleen, is very rapid compared with that of the microspheres. Compared with the drug solution, a 10-fold increase in the concentration of the drug in the joint was observed 24 h post intra-articular injection (P < 0.005) when drug was encapsulated in microspheres.
Animals↗
Local delivery of growth factors from coated titanium plates increases osteotomy healing in rats.
Different methods for the stabilization of long bone fractures are used in clinic. Besides the development of further stabilization devices, the use of new materials, the modification of the surfaces, and the local application of stimulating factors for enhancement of healing are from great interest. Previous studies successfully used a biodegradable poly(d,l-lactide) coating as a local drug delivery system of growth factors from intramedullary (IM) implants to enhance fracture healing. In this study, we developed a new rat model (n = 60) for plate osteosynthesis and used a plate for stabilization and as a local drug delivery system for the growth factors IGF-I and TGF-beta1. A four-hole titanium plate was used for stabilization of a 0.6-mm osteotomy gap of the femur. The space between the inner holes was coated with 50 microg IGF-I and 10 microg TGF-beta1 incorporated in the poly(d,l-lactide) coating or with the coating alone. After 42 days, biomechanical tests and histomorphological analyses were performed to investigate osteotomy healing. Radiologically small differences were detectable between the groups. The biomechanical torsional testing revealed a significantly higher maximum load of the osteotomized femura after treatment with growth factors compared to the uncoated group. In the histomorphometric analyses measuring the callus composition, a significantly higher percentage of mineralized tissue in the osteotomy callus was assessed in the growth factor treated group compared to the uncoated. In conclusion, the local application of IGF-I and TGF-beta1 from a biodegradable coating enhances the osteotomy healing as shown in the biomechanical testing and the histomorphometry. Bioactive plates could be used in clinic for fracture stabilization and for local and controlled application of growth factors to stimulate bone healing.
Animals↗
A biodegradable fibrin scaffold for mesenchymal stem cell transplantation.
A potential therapy to enhance healing of bone tissue is to deliver isolated mesenchymal stem cells (MSCs) to the site of a lesion to promote bone formation. A key issue within this technology is the development of an injectable system for the delivery of MSCs. Fibrin gel exploits the final stage of the coagulation cascade in which fibrinogen molecules are cleaved by thrombin, convert into fibrin monomers and assembled into fibrils, eventually forming fibers in a three-dimensional network. This gel could have many advantages as a cell delivery vehicle in terms of biocompatibility, biodegradation and hemostasis. The objective of this study was to explore the possibility of using fibrin gel as a delivery system for human MSCs (HMSCs). To this end we have determined the optimal fibrinogen concentrations and thrombin activity for loading HMSCs in vitro into the resultant fibrin gels to obtain cell proliferation. We found that a concentration of 18 mg/ml of fibrinogen and a thrombin activity of 100 IU/ml was optimal for producing fibrin scaffolds that would allow good HMSCs spreading and proliferation. In these conditions, cells were able to proliferate and expressed alkaline phosphatase, a bone marker, in vitro. When implanted in vivo, HMSCs were able to migrate out of the fibrin gel and invade a calcium carbonate based ceramic scaffold suggesting that fibrin gel could serve as a delivery system for HMSCs.
Aged↗
Antinociceptive effects of hydromorphone, bupivacaine and biphalin released from PLGA polymer after intrathecal implantation in rats.
Intraspinal drug delivery, based on the concept of controlling pain by delivering drug to a nociceptive target rich in opioid and other relevant receptors is increasingly used clinically. The therapeutic ratio for opioids or other centrally acting agents is potentially greater if they are administered intrathecally (i.t.) than outside the central nervous system (CNS). The present study was designed with the ultimate goal of formulating a controlled release system for intrathecal analgesia characterized by effectiveness, rapid onset and few side effects for chronic pain control. A biodegradable copolymer poly(L-lactide-co-glycolide) (PLGA) was used to prepare a rod-shaped drug delivery system containing hydromorphone (HM), bupivacaine (BP), both HM and BP, or biphalin (BI). In vitro drug release kinetics of these systems showed a zero-order release rate for HM and BP from PLGA (85:15) rods. Drug-loaded rods were implanted i.t. Control groups received only placebo implants. Measurement of analgesic efficacy was carried out with tail flick and paw-withdrawal tests. In vivo studies showed potent, prolonged analgesia in comparison to controls for all active treatments. Analgesic synergy was observed with HM and BP. With further refinements of drug release rate, these rods may offer a clinically relevant alternative for intrathecal analgesia.
Analgesics↗