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PubMed2004

Development of biodegradable poly(propylene fumarate)/poly(lactic-co-glycolic acid) blend microspheres. II. Controlled drug release and microsphere degradation.

This article describes the effects of six processing parameters on the release kinetics of a model drug Texas red dextran (TRD) from poly(propylene fumarate)/poly(lactic-co-glycolic acid) (PPF/PLGA) blend microspheres as well as the degradation of these microspheres. The microspheres were fabricated using a double emulsion-solvent extraction technique in which the following six parameters were varied: PPF/PLGA ratio, polymer viscosity, vortex speed during emulsification, amount of internal aqueous phase, use of poly(vinyl alcohol) in the internal aqueous phase, and poly(vinyl alcohol) concentration in the external aqueous phase. We have previously characterized these microspheres in terms of microsphere morphology, size distribution, and TRD entrapment efficiency. In this work, the TRD release profiles in phosphate-buffered saline were determined and all formulations showed an initial burst release in the first 2 days followed by a decreased sustained release over a 38-day period. The initial burst release varied from 5.1 (+/-1.1) to 67.7 (+/-3.4)% of the entrapped TRD, and was affected most by the viscosity of the polymer solution used for microsphere fabrication. The sustained release between day 2 and day 38 ranged from 7.9 (+/-0.8) to 27.2 (+/-3.1)% of the entrapped TRD. During 11 weeks of in vitro degradation, the mass of the microspheres remained relatively constant for the first 3 weeks after which it decreased dramatically, whereas the molecular weight of the polymers decreased immediately upon placement in phosphate-buffered saline. Increasing the PPF content in the PPF/PLGA blend resulted in slower microsphere degradation. Overall, this study provides further understanding of the effects of various processing parameters on the release kinetics from PPF/PLGA blend microspheres thus allowing modulation of drug release to achieve a wide spectrum of release profiles.

Biocompatible Materials↗
PubMed2007

Enhanced antigen-specific primary CD4+ and CD8+ responses by codelivery of ovalbumin and toll-like receptor ligand monophosphoryl lipid A in poly(D,L-lactic-co-glycolic acid) nanoparticles.

The purpose of this research was to investigate the use of biodegradable poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA-NP) as a vaccine delivery system to codeliver antigen, ovalbumin (OVA) along with monophosphoryl lipid A (MPLA) as adjuvant for induction of potent CD4(+) and CD8(+) T cell responses. The primary CD4(+) T responses to OVA/MPLA NP were investigated using OVA-specific T cells from DO11.10 transgenic mice. Following adoptive transfer of these cells, mice were immunized s.c. by NP formulations. For assessing the CD8(+) responses, bone marrow derived dendritic cells (DCs) were pulsed with different OVA formulations, then, cocultured with CD8(+) T cells from OT-1 mice. T cell proliferation/activation and IFN-gamma secretion profile have been examined. Particulate delivery of OVA and MPLA to the DCs lead to markedly increase in in vitro CD8(+) T cell T cell proliferative responses (stimulation index >3000) and >13-folds increase in in vivo clonal expanded CD4(+) T cells. The expanded T cells were capable of cytokine secretion and expressed an activation and memory surface phenotype (CD62L(lo), CD11a(hi), and CD44(hi)). Codelivery of antigen and MPLA in PLGA-NP offers an effective method for induction of potent antigen specific CD4(+) and CD8(+) T cell responses.

Animals↗
PubMed1995

In vivo and in vitro elimination of aliphatic polyanhydrides.

The hydrolysis and elimination processes of biopolyanhydrides has been studied using a polymer series of linear aliphatic diacids. This polymer series degrade into their monomer counterparts at about the same rate but differ in the water solubility of their degradation products. Polymers based on natural diacids of the general structure -[OOC-(CH2)x-CO]n- where x is between 4 and 12 were implanted subcutaneously in rats and the elimination of the polymers from the implantation site was observed. The in vitro hydrolysis of this polymer series was studied by monitoring the weight loss, release of monomer degradation products and the content of anhydride bonds in the polymer as a function of time. A dependence was found between the monomer solubility and the rate of polymer elimination in both in vivo and in vitro. The elimination time for polymers based on soluble monomers (x = 4-8) was 7-14 days, while the polymers based on low monomer solubility (x = 10-12) were eliminated only after 8 weeks. The in vitro degradation of polyanhydrides in the presence of several common hydrolytic enzymes found around implants did not affect polymer degradation. All polymers were biocompatible and found to be useful as carriers for drug delivery.

Anhydrides↗
PubMed2004

Characterization of perivascular poly(lactic-co-glycolic acid) films containing paclitaxel.

The objectives of this study were to investigate the use of poly(lactic-co-glycolic acid) (PLGA) for the formulation of paclitaxel loaded films and to characterize these films for potential application as perivascular "wraps" to prevent restenosis. Films were manufactured from PLGA blended with either methoxypolyethylene glycol (MePEG) or a diblock copolymer composed of poly(D,L-lactic acid)-block-methoxypolyethylene glycol, PDLLA-MePEG (diblock) by solvent evaporation on teflon discs. Elasticity was determined by gravimetric stress/strain analysis. Thermal analysis was determined using differential scanning calorimetry (DSC). Changes in film composition and degradation in aqueous media were determined using gel permeation chromatography (GPC). Paclitaxel release from films was measured by incubation of the films in phosphate buffered saline (PBS) with drug analysis by HPLC methods. The addition of MePEG or diblock to PLGA caused a concentration dependent increase in the elasticity of films, due to plasticizing effects. DSC analysis showed that MePEG and diblock caused a concentration dependent decrease in the glass transition temperature (Tg) of PLGA indicating miscibility of the polymers. When placed in aqueous media, more than 75% of MePEG dissolved out of the PLGA films within 2 days, whereas diblock partitioned slowly and in a controlled manner out of the films. Paclitaxel release from PLGA/MePEG films was very slow with less than 5% of the encapsulated drug being released over 2 weeks. The addition of 30% diblock to paclitaxel loaded PLGA films caused a substantial increase (five- to eight-fold) in the release rate of paclitaxel. PLGA films containing 30% diblock and either 1% or 5% paclitaxel were partially or completely degraded following perivascular implantation in rats.

Animals↗
PubMed2006

A novel chitosan oligosaccharide-stearic acid micelles for gene delivery: properties and in vitro transfection studies.

Stearic acid (SA) grafted chitosan oligosaccharide (CSO) (CSO-SA), which was synthesized by an 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-mediated coupling reaction, was demonstrated to form micelle like structure by self-aggregation in aqueous solution. The critical micelle concentration (CMC) of CSO-SA with 15.4% amino substituted degree of CSO was about 0.035 mg/ml. The micelles with 1mg/ml CSO-SA concentration had 70.6 nm volume average hydrodynamic diameter with a narrow size distribution and 46.4+/-0.1 mV surface potential. Due to the cationic property, the micelles could compact the plasmid DNA to form micelle/DNA complexes nanoparticles, which can efficiently protect the condensed DNA from enzymatic degradation by DNase I. The volume average hydrodynamic diameter of CSO-SA micelle/DNA complex increased from 203 nm to 318 nm and decreased to 102 nm due to the variation of zeta potential when the N/P ratio increased from 0.25 to 3.6 and from 3.6 to 58. The IC(50) value of the CSO-SA micelle against A549 cells was 543.16 microg/ml, while the IC(50) of Lipofectamine 2000 was about 6 microg/ml. The in vitro transfection efficiency of CSO-SA micelles was investigated by using plasmid DNA (pEGFP-C1). The transfection efficiency with CSO-SA/DNA (N/P ratio is 29) was increased with the post-transfection time (in 76h), while the optimal transfection of Lipofectamine 2000/DNA was obtained at 24h. The transfection of CSO-SA was not interfered in the presence of 10% fetal bovine serum, which showed remarkable enhancement effect. The optimal transfection efficiency of CSO-SA micelles in A549 cells was about 15%, which was higher than that of CSO (about 2%) and approach to that of Lipofectamine 2000 (about 20%). The low cytotoxic biodegradable CSO-SA micelles could be used as an effective DNA condensation carrier for gene delivery system.

Cations↗
PubMed1999

Modulated release of IdUrd from poly (D,L-lactide-co-glycolide) microspheres by addition of poly (D,L-lactide) oligomers.

This paper reports the release characteristics of a radiosensitizer, 5-iodo-2'-deoxyuridine (IdUrd), from poly (D,L-lactide-co-glycolide) 50: 50 (PLGA) microparticles obtained by a phase separation technique. Poly (D,L-lactide) oligomers (D,L-PLA) were incorporated into the PLGA matrix in order to accelerate the overall drug release rate and regulate the triphasic release profile exhibited by the standard PLGA microparticles. For D,L-PLA (800), the burst effect was large and the IdUrd release was complete between 28 and 35 days. These results were attributed to rapid pore formation on the periphery of the microsphere in the early stages of incubation, due to hydrosolubility of the smallest oligomers (D,L-PLA (800)). In the case of D,L-PLA (1,100), drug release occurred over a six week period, the standard time course of conventional radiation therapy. The period during which the radiosensitizer was incorporated in human brain tumor cell nuclei after its entrapment in biodegradable microspheres was determined by using an organotypical tissue culture. The presence of radiosensitizer in the DNA of tumor cell nuclei was detected by immunohistochemical labelling of tumor fragments. IdUrd release from standard microspheres (7+/-0.5 weeks) was longer than from oligomer-containing batches. For D,L-PLA (800)-containing microspheres, the radiosensitizer was entirely released within 4. 5+/-0.5 weeks. The microspheres containing D,L-PLA (1,100) allowed an IdUrd release over a 5 to 6 week period. The ex vivo data were consistent with the in vitro findings in terms of release duration.

Biodegradation, Environmental↗
PubMed1999

Adsorption of serum albumin to thin films of poly(lactide-co-glycolide).

Protein adsorption has been implicated in the variability of drug release from biodegradable microspheres. We used optical reflectometry to measure the extent and kinetics of bovine serum albumin (BSA) adsorption to smooth spin-cast films prepared from two poly(lactide-co-glycolide) (PLG) samples that have different end-groups, one being a hydrophilic carboxylic end group and the other a hydrophobic ester end group. One of us has previously shown that these end-groups influence microsphere degradation (Tracy et al. , 1998, Factors affecting the degradation rate of poly(lactide-co-glycolide) microspheres in vivo and in vitro. Biomaterials: submitted for publication.). Both films were moderately hydrophobic, and their wettability was independent of the type of end-group. BSA adsorbed readily to both native PLG films, attaining as much as 50% surface coverage by area and was insensitive to the type of end-group. Aging the films in water for 24 h prior to BSA exposure decreased the hydrophobicity of the films and this in turn correlated with a significant decrease in the initial BSA adsorption rate. This was consistent with the often-observed trend that surface hydrophobicity favors protein adsorption. In spite of the lower adsorption affinity revealed by this decreased initial adsorption rate, the final adsorbed amounts on the aged films exceeded those attained on native films, presumably due to the increase in total surface area produced by partial PLG erosion.

Adsorption↗
PubMed2006

Cochlear protection by local insulin-like growth factor-1 application using biodegradable hydrogel.

OBJECTIVE: The aim of this experimental study was to examine the potential of local recombinant human insulin-like growth factor-1 (rhIGF-1) application through a biodegradable hydrogel for the treatment of cochleae. METHODS: A hydrogel immersed with rhIGF-1 was placed on the round window membrane of Sprague-Dawley rats while a hydrogel immersed with physiological saline was applied to control animals. On day 3 after drug application, the animals were exposed to white noise at 120 dB sound pressure level (SPL) for 2 hours. Cochlear function was monitored using measurements of auditory brain stem responses (ABRs) at frequencies of 8, 16, and 32 kHz. The temporal bones were collected 7 or 30 days after noise exposure and the loss of hair cells was quantitatively analyzed. RESULTS: Local rhIGF-1 treatment significantly reduced the elevation of ABR thresholds on days 7 and 30 after noise exposure. Histologic analysis revealed that local rhIGF-1 treatment significantly prohibited the loss of outer hair cells. CONCLUSIONS: These findings demonstrate that local IGF-1 application through the biodegradable hydrogel has the potential for protection of cochleae from noise trauma.

Administration, Topical↗
PubMed2000

Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers: I. Synthesis and characterization.

A series of lactic/glycolic acid polymers with various molar ratios of lactic to glycolic acid and various molecular weights were synthesized using the ring-opening polymerization method. The polymerization conditions for the lactic/glycolic acid polymer synthesis were as follows: 150 degrees C, 700 microm Hg, 3 h, 0.03 wt% of catalyst (stannous 2-ethyl-hexanoate) concentration. The molecular weight of these polymers was controlled by using a molecular weight controller, lauryl alcohol. The synthesized polymers have been characterized with respect to polymer composition, molecular weight, inherent viscosity, and glass transition temperature. The characterization experiments show a good correlation between the polymer compositions and the feed ratios of lactic to glycolic acid. The molecular weight of the lactic/glycolic polymers, ranging from 10,876 to 166,630 D and the intrinsic viscosity of the polymers, ranging from 0.16 to 0.86 dl g(-1), are controlled by the amount of molecular weight controller used. The effect of the amount of the molecular weight controller on the polymer molecular weight and the polymer inherent viscosity was studied. Results indicate that the molecular weight and inherent viscosity of the polymers have a log-log linear relationship with the amount of molecular weight controller used. The lactic/glycolic acid polymers are amorphous, glassy, and transparent. The glass transition temperature of the polymers range from 21.95 to 51.29 degrees C, depending on the polymer molecular weight and the composition.

Biocompatible Materials↗
PubMed1994

Sustained release of antimicrobials in the middle ear using a biodegradable support.

The ototoxicity of a poly-L-lactic acid biodegradable support incorporating a therapeutically releasable amount of ampicillin was studied. This device has a shape that allows placement in the middle ear via a myringotomy incision. Once in the middle ear, it expands without mechanical interference and provides extended release of ampicillin. In vitro studies documented sustained release of ampicillin, and in vivo efficacy was demonstrated in otitis media induced in chinchillas and cats. Previous histopathologic studies showed a lack of inflammatory reaction from the device itself and documented its biodegradable characteristics. There was no evidence of ototoxicity on morphometry of the organ of Corti (hair cell counts) in chinchillas exposed to these devices for 3 weeks with and without ampicillin.

Ampicillin↗
PubMed2000

Poly (DL-lactide-co-glycolide) based delivery systems for vaccines and drugs.

Current vaccination and drug delivery strategies emphasize on the development of controlled release techniques for persistent and sustained effects. In the recent years, polymer based systems for the delivery of bioactive agents have gained considerable attention due to their marked adjuvanticity, established biodegradability and biocompatibility, excellent mechanical strength and controlled release profiles. This review deals with the potential applications of synthetic polymers mainly PLG polymers in delivery of vaccines and drugs.

Drug Carriers↗
PubMed2000

Controlled release of liposomes from biodegradable dextran microspheres: a novel delivery concept.

PURPOSE: To design liposome-loaded microspheres, which release the liposomes in a time-controlled manner and in intact form. METHODS: Liposomes were encapsulated in biodegradable dextran-based microspheres, which were prepared using an aqueous two phase system consisting of poly(ethylene glycol) and methacrylated dextran. The effects of liposome size and membrane fluidity, microsphere water content, degree of methacrylate substitution, and type of dextran derivative used, on encapsulation efficiency, release, and integrity of the liposomes were investigated. RESULTS: Liposomes were entrapped in dextran-based microspheres quantitatively and with full preservation of their integrity. Liposomes with a low, as well as with a high membrane fluidity, were released from the microspheres in their intact form and with preservation of their size. Release kinetics depended only on the degradation rate of the microspheres. For rapidly degrading systems, pulsed release was observed and the time after which the pulse occurred (from 5 until 25 days) could be tailored by the gel characteristics such as initial water content, degree of methacrylate substitution, and type of hydrolytically sensitive spacer present in the cross-links. This delay time was not dependent on the size of the liposomes in the range studied (0.1-0.2 microm). Microspheres which degraded more slowly showed, after a certain delay time, sustained release of the liposomes extended up to 100 days. CONCLUSIONS: A novel drug delivery concept based on the encapsulation of liposomes in biodegradable dextran-based microspheres was designed. The system released the liposomes in intact form in a controlled way after a prolonged period of time.

Calorimetry, Differential Scanning↗
PubMedDate not supplied

Chitosan surface-modified hydroxycamptothecin loaded nanoparticles with enhanced transport across Caco-2 cell monolayer.

This study explored the feasibility of using surface-modified nanoparticulate drug delivery system to enhance the transepithelial transport of antitumor drugs. An antitumor drug, 10-hydroxycamptothecin, was encapsulated into nanoparticles made of biodegradable poly(caprolactone-co-lactide)-PEG-poly(caprolactone-co-lactide) by a novel two-step nano-precipitation method. The obtained nanoparticles had a drug loading content of 10.4% and a size of 256.3 nm, exhibiting a steady and sustained in vitro release profile. By incubation in chitosan containing medium, the drug-loaded nanoparticles could be subsequently surface-modified with chitosan. The surface modification was monitored by dynamic light scattering method, zeta potential observation, and transmission electron microscopy, and its degree could be easily adjusted by varying the concentration of chitosan in the incubation medium. Caco-2 cell monolayer was used as an in vitro model to evaluate the intestinal 10-hydroxycamptothecin absorption. The absorptive transport of 10-hydroxycamptothecin could be improved to some extent by drug loaded nanoparticles and could be further enhanced in the case of surface-modified nanoparticles, suggesting that chitosan surface-modified nanoparticles may be a promising oral delivery system for antitumor drugs.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Biodegradable microspheres containing influenza A vaccine: immune response in mice.

A monovalent influenza split vaccine was microencapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) and ABA triblock copolymers using a W/O/W double emulsion technique. To stabilize the antigen, influenza vaccine was also coencapsulated with liposomes. Antigen release from microspheres was determined in vitro using a hemagglutinin-specific ELISA. PLGA-microspheres with liposomes released immunoreactive hemagglutinin in a pulsatile manner, a preferred feature for the development of a single dose vaccine delivery system. Influenza hemagglutinin specific IgG and neutralizing antibody responses were studied in BALB/c mice following subcutaneous injection of different microsphere preparations. PLGA-microspheres elicited a significantly higher primary IgG response compared to nonencapsulated antigen. ABA-microspheres seemed to be less immunogenic than PLGA-microspheres based on the IgG antibody response, however, similar levels of neutralizing antibodies were observed after eight weeks with both polymers. Entrapment of the antigen in liposomes prior to microencapsulation did not further enhance the immune response. The immunopotentating effect of the antigen-loaded microspheres was prominently enhanced when they were given as suspension in fluid antigen, suggesting that free antigen may serve as priming and microencapsulated antigen as booster dose. Eight weeks after a single subcutaneous immunization with PLGA or ABA-microspheres neutralizing antibodies were as high as those obtained after two subcutaneous administrations of fluid vaccine four weeks apart. Microencapsulated influenza antigen may have potential for a single dose vaccine delivery system with adjuvant properties.

Animals↗
PubMed1998

Preparation and in vitro characterization of gentamycin-impregnated biodegradable beads suitable for treatment of osteomyelitis.

A new method for preparing poly(L-lactide) (PLA) biodegradable beads impregnated with an ionic aminoglycoside, gentamycin, is described. The process employs hydrophobic ion pairing to solubilize gentamycin in a solvent compatible with PLA, followed by precipitation with a compressed antisolvent (supercritical carbon dioxide). The resulting precipitate is a homogeneous dispersion of the ion-paired drug in PLA microspheres. The microspheres are approximately 1 microm in diameter and can be compressed into beads (3-6 mm in diameter) strung on surgical sutures for implantation. The bead strings exhibit no significant change in release kinetics upon sterilization with a hydrogen peroxide plasma (Ster-Rad). The kinetics of gentamycin release from the PLA beads are consistent with a matrix-controlled diffusion mechanism. While nonbiodegradable poly(methyl methacrylate) (PMMA) beads initially release gentamycin in a similar manner, the drug release from PMMA ceases after 8 or 9 weeks, while the PLA beads continue to release drug for over 4 months. Moreover, only 10% of the gentamycin is released from the PMMA beads, while PLA beads release more than 60% of their load, if serum is present in the release medium. The PLA system displays improved release kinetics relative to PMMA, is biodegradable, is unaltered by gas sterilization, can be used for a range of antibiotics, and can be manipulated without disintegration. These are all desirable properties for an implantable drug delivery system for the prevention or treatment of osteomyelitis.

Absorption↗
PubMed1997

Subgingival delivery of therapeutic agents in the treatment of periodontal diseases.

This article reviews the current status of controlled local delivery of antibacterial agents in the treatment of periodontitis. The principle of local intrapocket delivery of antibacterial agents and their delivery are discussed. The dosage forms include fibers, film/slabs, and injectable systems, some of which are degradable, while others are not and need to be removed at the termination of the treatment. The antibacterial agents used cover a range of antibiotics as well as antiseptics, and the composition of the delivery systems, their reported use, and the clinical results are summarized. The use of these systems in clinical practice is relatively recent, and therefore their application and integration into the dental office are not yet clearly defined. Clinical applications that have been tested are critically reviewed, and clinical situations in which controlled delivery of antibacterial agents may prove to be clinically useful are suggested for scientific evaluation.

Administration, Topical↗
PubMed1996

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↗