Linear poly(ethylene oxide)-based polyurethane hydrogels: polyurethane-ureas and polyurethane-amides.

Over the last 30 years, water-swellable and water-insoluble hydrogels have been extensively investigated and developed, leading to a large family of materials which have found uses in a wide range of biomedical applications. While hydrogels usually present a crosslinked structure, linear polyurethane-ureas (PUUs) based on poly(ethylene oxide) have been shown to be able to absorb and swell with aqueous media without dissolving. This behavior is due to the phase separated domain morphology, where hydrogen bonded urethane/urea hard segment domains are dispersed in a PEO soft segment domain. This work investigates the possibility of obtaining linear poly(ethylene oxide)-based polyurethane-amide (PUA) hydrogels using two amide diols as chain extenders, a mono amide diol (AD) and a diamide diol (DD), and a dicarboxylic acid (maleic acid, MA). Poly(ethylene oxide) based PUAs were obtained using a "one-shot" bulk polymerization technique. The chemicophysical characterization and water-solubility tests showed that these materials, while having molecular weights similar to the PUUs, do not possess sufficient phase separation, hydrogen bonding and hydrophobicity of the hard segment domains to exhibit hydrogel behavior. Crosslinked PUAs using maleic acid as chain extender show interesting hydrogel properties.

Hydrogels: their future, Part II.

A multitude of new materials with diverse properties can be made from poly(ethylene oxide). Part I of this two-part article described the range of biomaterial syntheses, properties and applications that can be obtained. The production of a novel class of responsive hydrogels for transducing and sensing applications is reviewed in Part II.

Hydrogels: their future, Part I.

Hydrogels can be made from a wide variety of water-interactive or water-soluble polymers. They comprise a large family of materials with diverse properties, including some with "smart" responses to their environment. Part I of this two-part article will address the range of biomaterial syntheses, properties and applications that can be obtained from one ubiquitous and biocompatible structure: poly(ethylene oxide). Part II will discuss the applications of a novel class of intelligent materials.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels: 3. Device geometry.

The diffusive release from hydrogels can be determined by both composition and geometry. This paper presents a theoretical and experimental comparison of the release characteristics of proxyphylline in water-swollen slabs, spheres, and cylinders of a urethane cross-linked poly(ethylene oxide). Contrary to general conventional wisdom it was found that practically cylinders and spheres, which have considerable potential advantages for oral delivery, can provide good 'anomalous' rates for which the 'exponent of release' into water from the dry xerogels is c. 0.8 compared with 1.0 for zero order. An exponent of 0.94 was found for release into water from 'larger' xerogel flat slabs thus confirming that these configurations can provide essentially constant delivery formulations from which the active agent cannot be 'dumped'. For up to 40% total drug release, the theoretical release profiles were essentially of identical form for all three geometries in the swollen state and, as expected in theory and practice, showed an exponent for release of close to 0.5. However, the experimental release of proxyphylline was found to be more sustained from swollen spheres of these polymers than theory would predict. The half life times for release were further extended by approximately two and a half times for the initially dry devices compared with the initially swollen ones.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 4. Extended constant rate release from partly-coated spheres.

Spheres of poly(ethylene oxide) xerogel from 4-17 mm diameter were impregnated with the drug, proxyphylline, or the herbicide, 2,4-DNa and then partly coated with a water-impermeable elastomer. When placed in water the active additive was released over periods ranging from hours to weeks at a nearly constant rate. The effect of the hydrogel sphere dimensions and the window size through the elastomer, on water uptake and consequent release of the active agent were examined. These devices superficially possess a configuration similar to some commercial osmotic devices though the active-agent release from the devices of this paper is, in fact, diffusive and not osmotically driven. They appear to provide a very versatile and simple design allowing relatively constant release of the active agent over periods of hours to months merely by changing the device geometry.

Distributed sensor for water and pH measurements using fiber optics and swellable polymeric systems.

We report on the design, construction and test of a generic form of sensor for making distributed measurements of a range of chemical parameters. The technique combines optical time-domain reflectometry with chemically sensitive water-swellable polymers (hydrogels). Initial experiments have concentrated on demonstrating a distributed water detector; however, gels have been developed that enable this sensor to be readily adapted to distributed pH measurements.

Porogens in the preparation of microporous hydrogels based on poly(ethylene oxides).

To enable the synthesis of hydrogels containing microporosity, a family of pore generating additives (porogens) were synthesized from poly(ethylene glycols) (PEGs) with different molecular weights using naphthyl acetic acid. The products formed were characterized by UV-vis, differential scanning calorimetry and solution nuclear magnetic resonance techniques. Subsequently, poly(ethylene oxide)-urethane hydrogels were synthesized incorporating the above mentioned PEG porogens to modify the structure of the hydrogel. These highly water soluble PEG porogens were inert and extracted out in water. The hydrogels obtained exhibited significant increase in the equilibrium water uptake. This was attributed to the formation of a microporous structure in the hydrogel. It was also evidenced by the observed increase in the diffusion coefficients of the drugs proxyphylline and vitamin B12 through this hydrogel. The proportional increase was greater for the higher molecular weight vitamin B12 than for the proxyphylline. These results may be useful in developing porous hydrogels for controlled release technology.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 2. Dispersion in an initially dry slab.

The mechanisms which control the release of dispersed water-soluble drugs from an initially dry hydrogel are complex. The release profile derives from a combination of several contributing factors which may change with time at different rates. It has been possible to isolate controlling factors and investigate their individual contributions to the release kinetics. The hydrogels presented in this paper owe their hydrophilicity to their poly(ethylene oxide) content. They swell and can absorb up to three times their dry weight in water. Having a glass transition temperature (Tg) below body temperature they are essentially different to those studied theoretically or experimentally, by other groups, which have Tg values above body temperature and are initially glassy. A range of diffusates was studied ranging from low water-soluble prostaglandin E2 to highly water-soluble lithium chloride. Device geometry was restricted to approximations to infinite slabs with more than 85% total surface area over the top and bottom surfaces so that release was predominantly one-dimensional and the controlling variable was thickness. The increase in surface area with time, drug-solubility in the water-swelling matrix and the presence of crystallinity were shown to be important factors governing the profile and level of release rate with time. It was observed that the release profile could be separated into three parts, the most important being the middle section from early in the release until at least the half-life time. This period could be characterized by the exponential time function, tn. The diffusional exponent, n, is an important indicator of the release mechanism and ranged from 0.79 to 1, i.e. good anomalous to zero order. This is a highly desirable range of values for controlled release devices. The value of n decreases at late-time. The very early-time release can also show a burst or lag effect depending on the diffusate solubility and its loading in the xerogel.

Properties controlling the diffusion and release of water-soluble solutes from poly(ethylene oxide) hydrogels. 1. Polymer composition.

This study examines the state of water-association with poly(ethylene oxide), as evidenced by diffusivity, in a series of crosslinked polyurethanes made from poly(ethylene glycols) of a range of molecular weights. As a subsidiary underpinning exercise the correlation of diffusivity with water content at relatively high levels of swelling (> 45%) using a variety of semi-empirical equations was analyzed. Three water-soluble compounds with similar molecular weights and which exhibit minimal interaction with the polymer, as shown by their partition coefficients, were chosen for this part of the research programme. These were proxyphylline, morphine hydrochloride and caffeine. The best statistical correlations of the data were obtained for plots of: (a) diffusivity against weight percent water; and (b) log diffusivity against the reciprocal of the weight percent of water in the hydrogels. Proxyphylline results for the high levels of swelling compositions were augmented with data from lower swelling compositions and a clear break in the slope of diffusivity against percentage of water in the swollen hydrogel was obtained. This indicated a change in the nature of the diffusion at this point. The probability of this transition point corresponding to a change for diffusion through water bound as trihydrate to diffusion in free water is discussed.

Blood interactions with novel polyurethaneurea hydrogels.

The influence on blood of polyurethaneurea hydrogels in vitro was investigated based on poly(ethylene oxide). A hydrogel was compared with the regenerated cellulose membrane Cuprophan in terms of complement activation, as determined by measurement of C3a concentration. The hydrogel induced less complement activation and the presence of poly(ethylene oxide) is likely to be beneficial to platelet reactivity. The ability to vary the polymer composition and the solubility of the polymers in organic solvents makes the polyurethaneurea hydrogels strong candidates for composite biomaterials.

The morphine hydrogel suppository. A new sustained release rectal preparation.

The morphine hydrogel suppository (MHS), a monolithic sustained release rectal preparation, has been developed and evaluated in three pilot studies. Two release profiles have been prepared. The first, MHS(B), has a high initial release rate followed by a constant release for the remainder of a 12-h period. The second, MHS(S), has the same constant release rate for 12 h. MHS(B) is intended to attain and maintain analgesic or near analgesic plasma concentrations of morphine, and MHS(S) to maintain that concentration for successive 12-h periods. The pilot studies suggest that MHS may be of value in the management of postoperative pain.

Hydrogels for controlled drug delivery.

Physical properties such as number average molecular weight Mn, specific hydrates and changing diffusion coefficient of crystalline/rubbery hydrogels based on poly(ethylene glycol) Mn 3 000-8 000 which affect the diffusion of drugs through the water swollen matrix and across the polymer boundary are discussed. The advantage of starting with a dry, drug-impregnated polymer to obtain the desirable zero order release rate while the hydrogel absorbs water is illustrated. Drugs have been classified into five groups showing different release profiles. The effects of design and loading on the release profile, are described including the first clinical results of morphine loaded hydrogel suppositories.

Induction of labour with a sustained-release prostaglandin E2 vaginal pessary.

A new polymer vaginal pessary providing sustained constant release of prostaglandin E2 was administered to 66 patients before planned induction of labour. Effective ripening of the unfavourable cervix was achieved in each of 18 primigravidas, in eight of whom labour was initiated without further treatment. When the cervix was moderately favourable the need for orthodox induction of labour was obviated in 16 out of 23 primigravidas and 21 out of 23 multigravidas. This method of sustained release of prostaglandin E2 is simple and convenient and readily acceptable to the patient; it is an important step in the development of non-invasive methods of inducing labour.