Glycolide Monomers Research Articles

Microfluidic Production of Polymeric Core-Shell Microspheres for the Delayed Pulsatile Release of Bovine Serum Albumin as a Model Antigen.

For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee’s compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(dl-lactide-co-glycolide) (PLGA) with various dl-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines.

In-vitro degradation behavior and biological properties of a novel maleated poly (D, L-lactide-co-glycolide) for biomedical applications

Synthesized biodegradable polymers with controlled degradability and good biological safety would be useful in biomedical applications. In this work a novel maleated poly(D,L-lactide-co-glycolide) (MPLGA) was melt copolymerized from maleic anhydride, D,L-lactide and glycolide monomers. The degradation behavior in phosphate-buffered solution (PBS) was investigated and the biological properties were studied by using fibroblastic cells cultured in an extract of MPLGA and by an in-vitro cell cytotoxicity test. The results indicated that the MPLGA was successfully obtained using the melt-copolymerization method. The maleic anhydride groups in the MPLGA led to a faster degradation in PBS than PLGA. Fibroblastic cells showed normal morphologies in MPLGA extracts, and the MPLGA materials showed no cell cytotoxicity. The in-vitro biological properties indicated that the obtained MPLGA had good biocompatibility and would be useful for medical applications.

Preparation and Properties of Novel Maleated Poly (D, L-lactide-co-glycolide) Porous Scaffolds for Tissue Engineering

ABSTRACTThree-dimensional biodegradable porous scaffolds play an important role in tissue engineering. A new polymer based on maleated poly(lactic-co-glycolic acid) (MPLGA) was synthesized using direct melt copolymerization from maleic anhydride (MAH), D, L-lactide, and glycolide monomers. MPLGA porous biodegradable scaffolds were prepared by a solution-casting/salt-leaching method. The effects of content and size of the NaHCO3 porogen on the compressive strength of the MPLGA scaffolds were investigated, and the effect of content of the porogen on the porosity of the MPLGA scaffolds was also studied. The results indicated that MAH was grafted onto PLGA successfully and MPLGA scaffolds with interconnective and open pore structure were obtained. Increasing content of NaHCO3 porogen resulted in an increase of porosity and decrease of the compressive strength of the MPLGA scaffolds with the compressive strength of the scaffolds also decreasing with increasing porogen size.

Improved route to PAHA polyesters

Poly(α-hydroxy acid) (PAHA) polyesters form products such as cell-penetrating nanoparticles for drug and gene delivery and biodegradable sutures and implants, but they’ve been hard to synthesize. Rong Tong and Quanyou Feng at Virginia Tech now report a polymerization that could make them more accessible (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b01462). PAHAs can be customized by varying the side chains of the lactide and glycolide monomers used to make them. But adding those monomer side chains is difficult, and synthesizing PAHAs from lactides and glycolides requires multistep, low-yield reactions. In 2006, Didier Bourissou of Paul Sabatier University and coworkers showed that PAHAs could also be made from O-carboxyanhydride (OCA) monomers, which are much easier to prepare and modify. But OCA polymerizations were slow and had undesired side reactions, uncontrolled stereochemistry, and broad and unpredictable molecular weight distributions. In Tong and Feng’s new approach to OCA polymerization, a photo...

Synthesis and characterization of novel maleated poly(d,l-lactide-co-glycolide) by direct melt copolymerization

Novel maleated poly(d,l-lactide-co-glycolide) (MPLGA) was melt copolymerized directly from maleic anhydride, d,l-lactide and glycolide monomers with stannous octoate as catalyst and benzoyl peroxide as initiator. FTIR, 1H NMR, GPC and maleation content were employed to qualitatively characterize the synthesized MPLGA. The effects of the catalyst dosage, reaction time and reaction temperature on weight average molecular mass, polydispersity index and maleation content of MPLGA were also investigated. The results indicated that the novel MPLGA was successfully obtained using melting-copolymerization method. MPLGA, with a weight average molecular mass of about 5.39 × 104 Da, a polydispersity index of 1.51 and a maleation content of 7.1 wt%, was obtained when polymerization was conducted with catalyst dosage of 0.03 wt% for 36 h at 140 °C. The results indicated that the introduction of maleic anhydride into PLGA may offer new and important options for biomaterial applications.

Novel synthesis and characterization of a collagen-based biopolymer initiated by hydroxyapatite nanoparticles

In this study, we developed a novel synthesis method to create a complex collagen-based biopolymer that promises to possess the necessary material properties for a bone graft substitute. The synthesis was carried out in several steps. In the first step, a ring-opening polymerization reaction initiated by hydroxyapatite nanoparticles was used to polymerize d,l-lactide and glycolide monomers to form poly(lactide-co-glycolide) co-polymer. In the second step, the polymerization product was coupled with succinic anhydride, and subsequently was reacted with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide as the cross-linking agent, in order to activate the co-polymer for collagen attachment. In the third and final step, the activated co-polymer was attached to calf skin collagen type I, in hydrochloric acid/phosphate buffer solution and the precipitated co-polymer with attached collagen was isolated. The synthesis was monitored by proton nuclear magnetic resonance, infrared and Raman spectroscopies, and the products after each step were characterized by thermal and mechanical analysis. Calculations of the relative amounts of the various components, coupled with initial dynamic mechanical analysis testing of the resulting biopolymer, afforded a preliminary assessment of the structure of the complex biomaterial formed by this novel polymerization process.

Thermal Properties and Degradation Behavior of Linear and Branched Poly(L‐lactide)s and Poly(L‐lactide‐co‐glycolide)s

AbstractPoly(lactide)s and poly(lactide‐co‐glycolide)s with different number of arms are synthesized from L‐lactide and glycolide monomers using stannous(II) 2‐ethylhexanoate and alcohols containing 1, 2, 25, and 51 hydroxyl groups. 1‐dodecanol is used to produce the 1‐arm polymer, poly(ethylene glycol) for the 2‐arm polymer, and polyglycidols of appropriate molecular weight are used to initiate the 25‐ and 51‐arm branched polyesters. The polymers are characterized by 1H NMR and GPC. The thermal properties of the polymers are studied using DSC. Their degradation behavior is indestigated using a combination of thermogravimetry, FTIR spectroscopy, and isoconversional kinetic analysis.

Synthesis and Characterization of Poly(D,L-Lactide-co-Glycolide) Copolymer

The copolymer poly(D,L-lactide-co-glycolide) is one of the most interesting polymers for medical applications. This interest is justified by the fact that it is bioreabsorbable, biocompatible and non-toxic, while its degradation kinetics can be modified by the copolymerization ratio of the monomers. In this study, copolymers were synthesised at 175?C by opening the rings of the cyclic dimers of the D,L-lactide and glycolide monomers in the presence of stannous octoate initiator and lauryl alcohol co-initiator. The application of vacuum to the reaction medium, coupled with adequate stirring, is essential for obtaining good results. The following analytical techniques were used to characterise the synthesised copolymers: Differential Scanning Calorimetry (DSC), Thermogravimetry (TG), Nuclear Magnetic Resonance Spectroscopy (NMR) and Fourier Transform Infrared Spectroscopy (FTIR). Both the input monomers and the reaction products were analysed. Important characteristics, such as melting temperature, glass transition temperature, thermal stability, chemical composition and the ratio of the monomers in the synthesised copolymer, were obtained from these analyses. These results helped to infer the absence of residual monomers in the synthesised copolymers.

A Strategy for Control of "Random" Copolymerization of Lactide and Glycolide: Application to Synthesis of PEG-b-PLGA Block Polymers Having Narrow Dispersity.

Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable copolymer that is also acceptable for use in a variety of biomedical applications. Typically, a random PLGA polymer is synthesized in a bulk batch polymerization using a tin-based catalyst at high temperatures. This methodology results in relatively broad polydispersity indexes (PDIs) due to transesterification, and the polymer product is often discolored. We report here the use of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), a known, effective, and convenient organocatalyst for the ring-opening polymerization of cyclic esters, to synthesize random copolymers of lactide and glycolide. The polymerization kinetics of the homo- and copolymerizations of lactide and glycolide were explored via NMR spectroscopy. A novel strategy that employs a controlled addition of the more reactive glycolide monomer to a solution containing the lactide monomer, the poly(ethylene glycol) (PEG) macroinitiator, and DBU catalyst was developed. Using this tactic (semi-batch polymerization), we synthesized a series of block copolymers that exhibited excellent correlation of the expected and observed molecular weights and possessed narrow PDIs. We also measured the thermal properties of these block copolymers and observed trends based on the composition of the block copolymer. We also explored the need for experimental rigor in several aspects of the preparations and have identified a set of convenient reaction conditions that provide polymer products that retain the aforementioned desirable characteristics. These polymerizations proceed rapidly at room temperature and without the need for tin-based catalysts to provide PEG-b-PLGAs suitable for use in biomedical investigations.

Material properties and bone marrow stromal cells response to In situ crosslinkable RGD‐functionlized lactide‐co‐glycolide scaffolds

In situ crosslinkable biomaterials with degradation profiles that can be tailored to a particular application are indispensable for treating irregularly shaped defects and for fabrication of shape-selective scaffolds. The objective of this work was to synthesize ultra low molecular weight functionalized PLA and PLGA macromers that can be grafted with bioactive peptides and crosslinked in situ to fabricate biodegradable functional scaffolds. In situ crosslinkable lactide-co-glycolide macromer (cMLGA; "c" for crosslinkable, "M" for macromer, and "LGA" for lactide-co-glycolide) was synthesized by anionic polymerization of lactide and glycolide monomers followed by condensation polymerization with fumaryl chloride. The cMLA (100% L-lactide) and cMLGA macromers formed porous crosslinked scaffolds with NVP as the crosslinker. The mass loss of the crosslinked cMLA and cMLGA was linear with incubation time in vitro (zero-order degradation) and the degradation rate depended on the ratio of lactide to glycolide. cMLGA scaffold with 1:1 lactide to glycolide ratio completely degraded after 4 weeks while the cMLA lost less than 40% of its initial mass after 35 weeks. When cMLA scaffold was functionalized with acrylated integrin-binding Ac-GRGD amino acid sequence, bone marrow stromal (BMS) cells attached and spread on the cMLA scaffold and exhibited focal-point cell adhesion. The mRNA expression levels of collagen-1alpha, osteonectin, and osteopontin for BMS cells seeded in the scaffolds with 1 and 5% Ac-GRGD were upregulated compared with those without Ac-GRGD. cMLGA is attractive as in situ crosslinkable macromer for fabrication of functional scaffolds with degradation characteristics that can be tailored to a particular application.

“Clickable” Polyglycolides: Tunable Synthons for Thermoresponsive, Degradable Polymers

“Click” chemistry is a powerful method for post-polymerization modification of polymers and other materials. Because of the importance of lactide-based functional polymers in materials and medical applications, we synthesized 3,6-dipropargyl-1,4-dioxane-2,5-dione, an acetylene-functionalized glycolide monomer. Its subsequent polymerization and copolymerization with lactide provided a new polyglycolide homopolymer as well as random and block copolymers that have pendant acetylene groups available for the attachment of chemical functionality using “click” chemistry. A protocol was devised to permit “click” functionalization of polyglycolides with no degradation in molecular weight. As one demonstration of the power of this approach to substituted polyglycolides, we have prepared a family of degradable, thermoresponsive materials that exhibit lower critical solution temperatures (LCST) from room temperature to >60 °C.

Effect of glycolide monomer on release behavior of gentamicin sulfate‐loaded PLGA microparticles

AbstractFor the treatment of osteomyelitis and the prevention of infections after orthopedic surgery, topically implantable gentamicin sulfate (GS)‐loaded poly(D,L‐lactide‐co‐glycolide) microparticles (GSMP) containing glycolide monomer (GM), as a biodegradable and nontoxic material, were prepared by melt‐extrusion method without organic solvent for controlled release. After preparation of polymer blend, the powders of different size (90–1200 μm) were obtained by means of freezer‐mill. The influences of GM and particle size were investigated on the GS release patterns. GSMP containing GM (in case of 10% loaded) showed a near‐zero order release from 2 to 7 days with the initial burst. GM affected to increase of GS release rate during the in vitro release test. The pH variations of the media were investigated to determine effect of GM on pH drop of media. The morphological evaluations, change of molecular weight, and thermal property of microparticles were characterized by scanning electron microscope, gel permeation chromatography, and differential scanning calorimeter, respectively. Bacterial inhibition zone test was established to identify antibiosis of GS. It showed antibiotic areas except control sample. From these results, the authors expected that GSMP containing GM would be a good dosage form as a topically implantable device that can get rid of lag period of GSMP. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 1019–1025, 2007

Co-effect of aqueous solubility of drugs and glycolide monomer on in vitro release rates from poly(D,L-lactide- co-glycolide) discs and polymer degradation

The objective of this study was to investigate the effect of aqueous solubility of model drugs and glycolide monomer (GM) from poly(D,L -lactide-co-glycolide) (PLGA) discs on in vitro release rates and polymer degradation. 5-Fluorouracil (5-FU), a water-soluble compound, and dexamethasone in a water-insoluble base form were selected as model drugs. Glycolide monomer, that has moderate solubility in water, was a non-toxic and biodegradable additive as a derivative material of hydrolysis of PLGA in order to obtain desirable drugs release rates. PLGA discs with or without GM were formulated by means of compression molding method. The prepared polymeric discs were incubated at 37°C in phosphate-buffered saline (PBS, pH 7.4) and characterized at scheduled time points for water uptake, mass loss, diameter and morphology change, molecular weight and composition change using scanning electron microscopy (SEM), gel-permeation chromatography (GPC), and 1H-NMR, respectively. The supernatants were taken out of the sample vials and were analyzed for drug release. The 5-FU release was found to be increasing in proportion to the drug loading amount with an initial burst for 5 days, while dexamethasone release showed inverse relationship with the increasing drug loading amount. However, the release behaviors of 5-FU and dexamethasone polymeric discs containing GM showed faster release rates than control discs (without GM) and did not show lag periods during the in vitro release test due to adding GM, which acted as a channeling agent that has moderate solubility in water. Polymer degradation was found to be affected by aqueous solubility of drugs and GM. In conclusion, we observed that drugs release rates were influenced by their aqueous solubility and loading amount and also GM plays a major role in controlling drug release rates regardless of solubility of drugs. This system appears to be promising for controlled drug delivery aimed at local therapy.

Effect of lactide/glycolide monomers on release behaviors of gentamicin sulfate-loaded PLGA discs

In order to develop the desirable drug release patterns such as no lag time and exact zero-order release rate, gentamicin sulfate (GS)-loaded poly( d, l-lactide-co-glycolide) (PLGA) discs containing lactide monomer (LM) or glycolide monomer (GM) were prepared. LM or GM was applied for the controlling drug release pattern due to its non-toxic and biodegradable nature. Water absorption, mass loss, pH change, and morphology of discs were examined to study the effect of LM or GM addition. GS release showed near zero-order profile in the GS-loaded polymeric discs prepared in the presence of LM or GM (10%). The channel of GS-loaded PLGA containing LM or GM was formed by the dissolution of LM or GM. Water uptake of disc increased till 21 days from the beginning of the test. The pH variations of media declined in the same manner with the result of mass loss. The antibiosis of GS was also confirmed by bacterial inhibition zone test using the prepared polymeric discs. From these results, we expected that the polymeric discs containing LM or GM would be a good dosage form as a topically implantable device which can get rid of lag period from PLGA matrix.

Tetracycline-HCl-loaded poly( dl-lactide-co-glycolide) microspheres prepared by a spray drying technique: influence of γ-irradiation on radical formation and polymer degradation

Tetracycline-HCl (TCH)-loaded microspheres were prepared from poly(lactide-co-glycolide) (PLGA) by spray drying. The drug was incorporated in the polymer matrix either in solid state or as w/o emulsion. The spin probe 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPOL) and the spin trap tert-butyl-phenyl-nitrone (PBN) were co-encapsulated into the TCH-loaded and placebo particles. We investigated the effects of γ-irradiation on the formation of free radicals in polymer and drug and the mechanism of chain scission after sterilization. γ-Irradiation was performed at 26.9 and 54.9 kGy using a 60Co source. The microspheres were characterized especially with respect to the formation of radicals and in vitro polymer degradation. Electron paramagnetic resonance (EPR) spectroscopy, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), high-performance liquid chromatography (HPLC), gas chromatography–mass spectroscopy (GC–MS), and scanning electron microscopy (SEM) were used for characterization of the microspheres. Using EPR spectroscopy, we successfully detected γ-irradiation induced free radicals within the TCH-loaded microspheres, while unloaded PLGA did not contain radicals under the same conditions. The relatively low glass transition temperature of the poly( dl-lactide-co-glycolide) (37–39°C) seems to favor subsequent reactions of free radicals due to the high mobility of the polymeric chains. Because of the high melting point of TCH (214°C), the radicals can only be stabilized in drug loaded microspheres. In order to determine the mechanism of polymer degradation after exposure to γ-rays, the spin trap PBN and the spin probe TEMPOL were encapsulated in the microspheres. γ-Irradiation of microspheres containing PBN resulted in the formation of a lipophilic spin adduct, indicating that a polymeric radical was generated by random chain scission. Polymer degradation by an unzipping mechanism would have produced hydrophilic spin adducts of PBN and monomeric radicals of lactic or glycolic acid. These degradation products were not detected by EPR. This result is confirmed by the observation that possible diamagnetic reaction products of low molecular weight, consisting of TEMPOL and lactide or glycolide monomers, could not be detected by GC–MS. While an irradiation dose-dependent decrease in molecular weight of PLGA could be verified in agreement with the literature, TCH content of the microspheres was not affected by the exposure to γ-rays. It can be concluded that EPR spectroscopy in combination with GPC, DSC, and HPLC allows a detailed characterization of the impact of γ-sterilization on biodegradable parenteral drug delivery systems.