Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug

doi:10.1016/S0168-3659(97)00191-0

Journal of Controlled Release

Volume 52, Issues 1–2, 2 March 1998, Pages 41-51

https://doi.org/10.1016/S0168-3659(97)00191-0 Get rights and content

Abstract

Thermosensitive polymer networks were synthesized from poly(ethylene glycol), hexamethylene diisocyanate and 1,2,6-hexanetriol in stoichiometric proportions. By varying the amount of 1,2,6-hexanetriol and the molar mass of the poly(ethylene glycol), a wide range of networks with different crosslinking densities was prepared. The networks obtained were characterized by the temperature dependence of their degree of equilibrium swelling in water and by their Young's moduli. For each network, the molecular weight between crosslinks was estimated. The structure of the hydrogels was analysed with respect to scaling laws, and it was found that the results obtained with PEG 1500 and PEG 6000 hydrogels are in agreement with theoretical predictions, whereas those obtained with PEG 400 hydrogels are in disagreement. The release properties of PEG hydrogels were studied by the determination of the diffusion coefficient for acebutolol chlorhydrate and by an analysis of the effect of temperature on these coefficients. Finally, these release properties were correlated with the swelling and structural properties of the hydrogels.

Introduction

Thermosensitive hydrogels are a class of hydrogels of great interest in the pharmaceutical and biomedical fields, as evidenced by the large amount of published literature 1, 2, 3, 4, 5, 6. They include various polymers, such as N-substituted acrylamide, methylacrylamide, poly(ethylene oxide), etc.

In addition to their fundamental scientific interest, thermosensitive hydrogels have been used in a large number of applications such as sensors, switchs, separation membranes, adsorbents, mechano-transducers, dehydrants and materials for drug delivery system [7]. Several authors 8, 9have reported that the kinetics, duration, and rate of drug release from hydrogels are influenced by the structural properties of polymer and, more particularly, the degree of crystallinity, size of crystallites, degree of swelling and molecular weight between crosslinks.

Recently, hydrogels based on poly(ethylene glycol) (PEG) have attracted considerable attention in controlled release technology because of their good biocompatibility and excellent physicochemical properties. Graham and McNeill 10, 11reported the prolonged delivery of a variety of bioactive materials, such as prostaglandin E₂, caffeine and melatonin, from these hydrogels. Merril et al. [12]studied the diffusion of tricyclic antidepressants, cyanocobalamin and proteins through poly(ethylene oxide) hydrogels prepared by electron beam irradiation of aqueous solutions, and have related the diffusion coefficients to the molecular weight between crosslinks.

In this paper we describe the preparation of networks based on poly(ethylene glycol). A wide range of PEG networks of various crosslinking densities was obtained by varying the amount of crosslinking agent and the molar mass of the polymer (400≤ M ≤10 000).

These systems have been characterized by their degree of swelling as a function of temperature (T<LCST (lower critical solution temperature)), by their Young's modulus and by their molecular weight between crosslinks determined from the classical theory of gelation. The relationship between Young's modulus and polymer concentration was established, and compared with theoretical predictions proposed by de Gennes in order to discuss the structure of the networks.

The release properties of these hydrogels were studied by the determination of the diffusion coefficient for acebutolol and by correlation of these values with network characteristics. The effect of temperature on the release properties of hydrogels was also determined and analysed in terms of competition between swelling and diffusion processes.

Section snippets

Hydrogel synthesis

The hydrogels were obtained by chemical crosslinking of the poly(ethylene glycol) through urethane groups by incorporating diisocyanate and triol according to the procedure described by Graham et al. [13].

Hydrogel synthesis

The xerogels obtained were opaque and off-white, except for the xerogels based on PEG 400 and PEG 1500 (1/2) which were transparent. In the hydrated state, opaque hydrogels became transparent. To obtain reproducible hydrogels, special precautions were taken: changes in mixing efficiency, the mixing temperature and the drying conditions were the major sources of variability.

By using a polypropylene mould (Nalgène^®), or a glass mould lubricated with silicon wax (Rhodorsil^®), homogeneous networks

Conclusion

A thermosensitive series of hydrogels from poly(ethylene glycol) has been synthesized. A wide range of hydrogels was obtained by varying of PEG molar mass (from 400 to about 6000) and the amount of crosslinking agent.

The results of swelling characterization have shown that:

The process of crosslinking was dependent on polymer-precursor and preparation conditions.

The swelling ability was very temperature dependent and varied considerably (up to approximately 5 times their dry weight).

Analysis of

References (23)

N.B Graham et al.
Hydrogels for controlled drug delivery
Biomaterials
(1984)
E.W Merrill et al.
Partitioning and diffusion of solutes in hydrogels of poly(ethylene oxide)
Biomaterials
(1993)
N.B Graham et al.
Interaction of poly(ethylene oxide) with solvents: 3. Synthesis and swelling in water of crosslinked poly(ethylene glycol) urethane networks
Polymer
(1989)
N.B Graham et al.
Interaction of poly(ethylene oxide) with solvent: 5. The densities of water/Poly(ethylene glycol) mixtures
Eur. Polym. J.
(1993)
A Gutowska et al.
Thermosensitive interpenetrating polymer networks: synthesis, characterization, and macromolecular release
Macromolecules
(1994)
Y.H Bae et al.
`On-off' thermocontrol of solute transport. I. temperature dependence of swelling of N-isopropylacrylamide networks modified with hydrophobic components in water
Pharm. Res.
(1991)
L.C. Dong, A.S. Hoffman, Thermally reversible hydrogels, in: R.M. Ottenbrite, S.J. Huang, K. Park, (Eds.), Hydrogels...
Y Gnanou et al.
Hydrophilic polyurethane networks based on poly(ethylene oxide): synthesis, characterization and properties. Potential applications as biomaterials
Macromolecules
(1984)
N.B. Graham, Poly(ethylene oxide) and related hydrogels, in: N.A. Peppas (Ed.), Hydrogels in Medicine and Pharmacy,...
S.W Kim et al.
Hydrogels: swelling, drug loading, and release
Pharm. Res.
(1992)

O. Hirasa, S. Ito, A. Yamauchi, Thermoresponsive polymer hydrogel, in: D. De Rossi, K. Kajiwara, Y. Osada, A.Yamauchi...

Cited by (81)

Ascorbic acid specifically reduces the misclassification of nonirritating reactive chemicals in the OptiSafe™ macromolecular eye irritation test
2022, Toxicology in Vitro
Recently, we showed that the addition of physiological concentrations of ascorbic acid, a tear antioxidant, to the OptiSafe™ macromolecular eye irritation test reduced the false-positive (FP) rate for chemicals that had reactive chemistries, leading to the formation of reactive oxygen species (ROS) and molecular crosslinking. The purpose of the current study was to 1) increase the number of chemicals tested to comprehensibly determine whether the antioxidant-associated reduction in OD is specific to FP chemicals associated with ROS chemistries and 2) determine whether the addition of antioxidants interferes with the detection of true positive (TP) and true negative (TN) ocular irritants. We report that when ascorbic acid is added to the test reagents, retesting of FP chemicals with reactive chemistries show significantly reduced OD values (P < 0.05). Importantly, ascorbic acid had no significant effect on the OD values of TP or TN chemicals regardless of chemical reactivity. These findings suggest that supplementation of ascorbic acid in alternative ocular irritation tests may help improve the detection of TN for those commonly misclassified reactive chemicals.
Primary and secondary aqueous two-phase systems composed of thermo switchable polymers and bio-derived ionic liquids
2017, Journal of Chemical Thermodynamics
The liquid-liquid equilibrium (LLE) data for aqueous two-phase systems (ATPSs) comprising poly(propylene glycol) 400 (PPG 400) and cholinium-aminoate-based ([Ch][AA]) ionic liquid were determined experimentally at T = (288.15 and 308.15) K, while the LLE data at T = 298.15 K was adopted from our previous work for comparison. The experimental binodal data were satisfactorily fitted to a temperature-dependent nonlinear empirical expression. The reliability of tie-line data was confirmed by fitting the experimental data with the Othmer-Tobias and Bancroft equations. Furthermore, for the first time, the electrolyte nonrandom two-liquid model (e-NRTL) was used to correlate the tie-line data of PPG 400 + [Ch][AA] + water systems. The correlations of LLE data using these models provide a good description of the experimental values. The effect of temperature on the phase-forming capabilities of the corresponding [Ch][AA] was assessed using the experimental binodal data and the salting-out coefficient ( $k_{2}$ ) derived from the Setschenow-type equation. The values of $k_{2}$ were well correlated to the phase-forming abilities of [Ch][AA], and were found to increase at higher temperature. Upon heating to 308.15 K, the solution of (PPG 400)-rich top phase from the primary PPG 400 + [Ch][AA] + water systems formed the secondary ATPSs. The LLE data of the secondary PPG 400 + [Ch][AA] + water systems was also determined. The PPG 400 was concentrated in the top phase of the secondary ATPS; this could serve as a means to recover PPG 400 from the primary ATPS via the formation of secondary ATPS.
Mechanical characterization of oligo(ethylene glycol)-based hydrogels by dynamic nanoindentation experiments
2015, Journal of the Mechanical Behavior of Biomedical Materials
Citation Excerpt :
Dynamic Mechanical Analysis (DMA) was used by Cauich-Rodriguez et al. (1996) to characterize the viscoelastic properties of hydrogel blends over the frequency range of 0.1 to 50 Hz. Additionally, uniaxial confined or unconfined compression has been extensively used due to the ease of sample preparation and simple test methodology (Iza et al., 1998; Thomas et al., 2004; Roberts et al., 2011). While these test methods are among the types needed to investigate the hydrogels constitutive behavior in the time and frequency domains, the wide variety also reflects the fact that each technique has limitations.
Oligo(ethylene glycol)-based (OEG) hydrogel samples of varying cross-link densities and degrees of swelling were characterized through dynamic nanoindentation testing. Experiments were performed using a non-standard nanoindentation method, which was validated on a standard polystyrene sample. This method maximizes the capability of the instrument to measure the stiffness and damping of highly compliant, viscoelastic materials. Experiments were performed over the frequency range of 1 to 50 Hz, using a 1 mm diameter flat punch indenter. A hydration method was adopted to avoid sample dehydration during testing. Values of storage modulus $(E')$ ranged from 3.5 to 8.9 MPa for the different OEG-hydrogel samples investigated. Samples with higher OEG concentrations showed greater scatter in the modulus measurements and it is attributed to inhomogeneities in these materials. The $(E')$ values did not show a strong variation over frequency for any of the samples. Values of loss modulus $(E ″)$ were two orders of magnitude lower than the storage modulus, resulting in very low values of loss factor ( $E ″ / E'$ <0.1). These are characteristics of strong gels, which present negligible viscous properties.
Bone Tissue Engineering Around Dental Implants
2015, Stem Cell Biology and Tissue Engineering in Dental Sciences
Adequate alveolar ridge bone height is necessary for patients to receive and benefit from dental implant placement. Regeneration of the alveolar ridge remains a clinical challenge. Bone tissue engineering shows promise to provide a means to regain bone volume, including gains of vertical bone height, and enhance the successful outcomes of dental implants. The unique requirements of the mandibular ridge geometry and the intraoral environment are that traditional bone tissue engineering technologies, created primarily to fill bone defects, be modified and optimized for maximal effect in the protruding alveolar ridge site. This chapter reviews the osteogenic molecules, biomaterial scaffolds, and cells that have been evaluated in this challenging tissue site. A rigid scaffold retaining device that creates a protected environment for regeneration plays a key role in achieving successful bone growth around dental implants. Implant-guided bone tissue engineering shows great promise for effectively accomplishing vertical alveolar ridge bone augmentation while minimizing complications.
Assessment of the safety, targeting, and distribution characteristics of a novel pH-sensitive hydrogel
2014, Colloids and Surfaces B: Biointerfaces
Citation Excerpt :
Hydrogels are three-dimensional polymeric networks which swell rapidly in water and de-swell in response to changes in the external environment [1–5]. These materials have been used widely in the field of biomedicine due to their properties of biocompatibility and biodegradability [6–11]. For example, they have great potential in applications such as targeted drug delivery system, enzyme immobilization, protein–ligand recognition, and as on–off switches for modulated drug delivery to artificial organs [12–15].
In our previous study, we synthesized a pH-sensitive hydrogel based on poly (ɛ-caprolactone) (PCL), Pluronic (Poloxamer) and methacrylic acid (MAA) using UV-initiated free-radical polymerization. In the present study, we evaluated the safety of the obtained GMA–PCFC–GMA copolymer and a P(CFC–MAA–MEG) hydrogel both in vitro and in vivo. The pharmacokinetics study and distribution characteristics of dexamethasone in rat blood and mouse colon were investigated in detail. The in vitro toxicity of the GMA–PCFC–GMA copolymer was evaluated using a cell viability assay with HEK293 cells. An acute oral toxicity test was conducted by orally administering mice with a total of 10,000 mg/kg body weight of the P(CFC–MAA–MEG) hydrogel. The mice were then observed continuously for 14 days. After which, they were sacrificed and their blood collected for routine blood and serum chemistry tests. Pharmacokinetic and colonic tissue distribution studies were conducted using high-performance liquid chromatography to detect the concentration of dexamethasone in rat blood and mouse colon tissue. All of the results indicated that both the GMA–PCFC–GMA copolymer and P(CFC–MAA–MEG) hydrogel were nontoxic. Moreover, the hydrogel significantly enhanced the colon-targeting behavior of dexamethasone. These results suggested that the novel hydrogel has great potential in colon-targeted drug delivery.
Drug absorption and release properties of crosslinked hydrogels based on diepoxy-terminated poly(ethylene glycol)s and aliphatic polyamines - A study on the effect of the gel molecular structure
2013, Materials Science and Engineering C
Citation Excerpt :
There are many reports in literature connecting the duration and release rate of a drug from a hydrogel with some of the structural properties of the hydrogel network, like crystallinity, swelling degree, molecular weight (MW) between the crosslinking points, and chemical structure of polymer chains. Most of these reports investigate the influence of one or two of the network parameters upon the release of no more than one drug [8–14], while only some of them take into account more parameters [15–17], and even fewer additionally discuss comparatively the influence of the drug structure [18]. Also, in most cases the analyzed hydrogels have ill-defined network structure, made up of meshes of different sizes, as resulted from a statistical crosslinking process (for example crosslinking copolymerization or irradiation), and chains with functional groups randomly distributed, and therefore, conclusions based on average properties can only be drawn.
Crosslinked hydrogels with well-defined chemical structures and characteristics were prepared through the reaction between diepoxy-terminated poly(ethylene glycol)s of various molecular weights and aliphatic polyamines of different hydrocarbon chain length and functionalities, and the influence of some network parameters (molecular weight between crosslinking points, crosslinking degree, hydrophobic character) upon the absorption and release of drugs of different capacity to interact with the polymer chains was comparatively investigated. Diclofenac sodium (DCFNa) and 5-fluorouracil (5FU) were used as model drugs, based on their dissimilar hydrophobic character and ability of DCFNa to form crown ether-like complexes with PEG chains through the sodium cation. The experiments showed that the most important interactions occurring in these systems were mainly the hydrophobic ones and to a lesser extent the complexation of the Na⁺ ion by the PEG chains. Both of them were in favor of DCFNa, resulting in a larger incorporation and a slower release of this one in comparison with 5FU. For both drugs, loading was larger for hydrogels with shorter PEG chains and/or crosslinked with amines with longer hydrocarbon chain or higher functionality. Drug release tests showed a lower rate for stronger drug–network interactions in agreement with the absorption experiments.

View all citing articles on Scopus

View full text

Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug

Abstract

Introduction

Section snippets

Hydrogel synthesis

Hydrogel synthesis

Conclusion

Biomaterials

Biomaterials

Polymer

Eur. Polym. J.

Thermosensitive interpenetrating polymer networks: synthesis, characterization, and macromolecular release

Macromolecules

`On-off' thermocontrol of solute transport. I. temperature dependence of swelling of N-isopropylacrylamide networks modified with hydrophobic components in water

Pharm. Res.

Hydrophilic polyurethane networks based on poly(ethylene oxide): synthesis, characterization and properties. Potential applications as biomaterials

Macromolecules

Hydrogels: swelling, drug loading, and release

Pharm. Res.