Biomedical subjects

N A Peppas

Publications and source records attributed to N A Peppas.

At least 37 records · Page 2Linked to original sources

PubMed2000

Dynamic behavior of glucose oxidase-containing microparticles of poly(ethylene glycol)-grafted cationic hydrogels in an environment of changing pH.

Poly(diethylaminoethyl-g-ethylene glycol) microparticles were prepared by suspension polymerization of diethylaminoethyl methacrylate, poly(ethylene glycol) monomethacrylate and the crosslinking agent tetra(ethylene glycol) dimethacrylate in silicone oil using redox initiators. Particles of different sizes, crosslinking ratios and graft molecular weights were prepared. The changes in the swelling of the particles were studied as the pH was changed between 3.0 and 7.4. The particles showed rapid swelling/deswelling dynamics in response to changes in pH. It was evident that faster response could be obtained from smaller particles. Changing the crosslinking ratio resulted in changes in the extent of swelling, as well as the speed of response. It was also found that longer graft lengths were responsible for increasing the effect of relaxation of the swelling of the network.

Biocompatible Materials↗

PubMed2000

Hydrogels in pharmaceutical formulations.

The availability of large molecular weight protein- and peptide-based drugs due to the recent advances in the field of molecular biology has given us new ways to treat a number of diseases. Synthetic hydrogels offer a possibly effective and convenient way to administer these compounds. Hydrogels are hydrophilic, three-dimensional networks, which are able to imbibe large amounts of water or biological fluids, and thus resemble, to a large extent, a biological tissue. They are insoluble due to the presence of chemical (tie-points, junctions) and/or physical crosslinks such as entanglements and crystallites. These materials can be synthesized to respond to a number of physiological stimuli present in the body, such as pH, ionic strength and temperature. The aim of this article is to present a concise review on the applications of hydrogels in the pharmaceutical field, hydrogel characterization and analysis of drug release from such devices.

Animals↗

PubMed2000

Diffusional characteristics of freeze/thawed poly(vinyl alcohol) hydrogels: applications to protein controlled release from multilaminate devices.

The incorporation of a model protein, bovine serum albumin (BSA), into poly(vinyl alcohol) (PVA) hydrogel films during the freezing and thawing process and its subsequent release behavior were investigated. The effect of the number of freezing and thawing cycles as well as the stability of BSA were examined. BSA release profiles were not significantly different from gels prepared after 3 or 5 cycles. However, the rate and overall amount of PVA dissolution were considerably higher for gels prepared after 3 cycles. These observations were then applied to the development of novel, freeze/thawed PVA laminates. Laminates containing gel layers prepared after 3 or 5 cycles were successfully prepared with good stability over a 6 month swelling period. These structures, containing distinct layers of very specific properties, could be used to achieve zero-order release behavior.

Diffusion↗

PubMed2000

Modeling of drug release from swellable polymers.

The water Swelling and drug diffusion from initially hydrophilic, glassy polymer matrices were modeled using concentration-dependent diffusion equations for water and drug. The transport equation for water incorporated a relaxation-dependent mechanism. These equations were solved with an appropriate boundary condition incorporating a relaxation-dependent Deborah number. Experimental results from drug release from PVA and PHEMA samples were used to determine the validity of the model.

Diffusion↗

PubMed2000

Hydrophilic matrices for controlled drug delivery: an improved mathematical model to predict the resulting drug release kinetics (the "sequential layer" model).

PURPOSE: The aims of this study were (i) to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics. METHODS: Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively. RESULTS: By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs. CONCLUSIONS: The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.

Chemistry, Pharmaceutical↗

PubMed2000

Physicochemical foundations and structural design of hydrogels in medicine and biology.

Hydrogels are cross-linked hydrophilic polymers that can imbibe water or biological fluids. Their biomedical and pharmaceutical applications include a very wide range of systems and processes that utilize several molecular design characteristics. This review discusses the molecular structure, dynamic behavior, and structural modifications of hydrogels as well as the various applications of these biohydrogels. Recent advances in the preparation of three-dimensional structures with exact chain conformations, as well as tethering of functional groups, allow for the preparation of promising new hydrogels. Meanwhile, intelligent biohydrogels with pH- or temperature-sensitivity continue to be important materials in medical applications.

Biomedical Engineering↗

PubMed1999

Poly(ethylene glycol)-containing hydrogels in drug delivery.

The use of hydrogels as carriers for protein delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion controlled delivery of proteins from hydrogels containing poly(ethylene glycol) (PEG) can be possible and controlled by the three-dimensional structure. In addition, a number of these hydrogel carriers are mucoadhesive and can be used for protein delivery. PEG star polymer gels have also been prepared by gamma-irradiation and have been used for protein delivery with and without molecular imprinting. The presence of a large number of functional groups in a small volume makes these polymers important for use in biological and pharmaceutical applications. PEG star polymer hydrogels were synthesized using gamma-irradiation and were characterized using swelling techniques. Equilibrium swelling studies were conducted to investigate the effects of molecular weight, number of star arms, concentration, and radiation dose.

Animals↗

PubMed1999

Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery.

Microparticles of novel, bioadhesive graft copolymers of polymethacrylic acid and polyethylene glycol (P(MAA-g-EG)) were prepared. The aims of this study were to investigate the uptake and release kinetics of budesonide from P(MAA-g-EG) in vitro as well as the pharmacokinetics following nasal administration of the polymer contained budesonide. The loading of budesonide into the pH-sensitive polymers was examined using various ethanol solutions. Ethanol was required for drug solubilization but hindered hydrogel swelling at pH 7.2. Maximum loading of the drug in the polymer was obtained using 25% ethanol solutions. The release of budesonide from the polymer swollen in 25% ethanol solutions obeyed classical Fickian release behavior after an initial rapid drug burst. For nasal administration of budesonide-containing P(MAA-g-EG) the plasma concentration of budesonide was kept constant following a peak concentration of the drug approximately 45 min after administration.

Adhesiveness↗

PubMed1999

Observation of swelling process and diffusion front position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices containing a soluble drug.

The behavior of gel layer thickness in swellable hydroxypropyl methyl cellulose matrices loaded with increasing amounts of soluble and colored drug and exhibiting swelling, diffusion and erosion fronts, was studied using a colorimetric technique. The effect of the drug loading on the front position in the gel layer, in particular, on the presence of a diffusion front and its movement, was investigated. In addition, the swelling, diffusion and erosion front positions at different releasing times were measured and a theoretical analysis of the overall process was provided. It was found that the diffusion front was visible in systems with more than 30% drug, due to the presence of an undissolved drug layer. The physical analysis of such systems clearly showed the importance of drug solubility and loading in the observation of the diffusion front.

Diffusion↗

PubMed1999

Dimensionless analysis of swelling of hydrophilic glassy polymers with subsequent drug release from relaxing structures.

Two dimensionless parameters, the diffusional Deborah number, De, and the swelling interface number, Sw, were used as indicators of solvent and solute transport behavior in swellable hydrogel systems. Polymer relaxation and concentration-dependent diffusion led to dynamically swelling polymers which displayed Fickian, Case II, or anomalous transport behavior. Experimental systems studied included crosslinked samples of poly(vinyl alcohol), designated PVA, and poly(2-hydroxyethyl methacrylate-co-methyl methacrylate), designated P(HEMA-co-MMA). Model solutes with molecular weights ranging from 200 to 17,000 were used to investigate release properties from these networks. Characteristic polymer relaxation times and swelling front velocities were determined experimentally. To gain an understanding of how polymer morphology and solute properties affected transport behavior, the calculated values of De and Sw were correlated to the diffusional exponent, n, used commonly to indicate the time dependence of sorption and release. The swelling interface number was found to correlate particularly with the transport kinetics, indicating anomalous and Case II solute transport when the Sw values were near 1.0.

Biocompatible Materials↗

PubMed1999

Highly crosslinked, PEG-containing copolymers for sustained solute delivery.

Novel ionizable polymer networks were prepared from oligo(ethylene glycol) (OEG) multiacrylates and acrylic acid (AA) employing bulk radical photopolymerization techniques. The properties of these materials exhibited a complex dependence on the network structure and composition, and the materials were therefore used in the design of controlled release devices with precisely controlled properties. The release kinetics of model solute proxyphylline exhibited a strong compositional dependence, with measured diffusion coefficients varying over several orders of magnitude, depending on the polymer network structure and the pH of the release medium. Varying the OEG chain length provided a means of coarsely adjusting the proxyphylline release rate, while varying the AA content and the pH offered a more precise measure of control.

Acrylates↗

PubMed1999

Complexation graft copolymer networks: swelling properties, calcium binding and proteolytic enzyme inhibition.

Graft copolymer networks of poly(methacrylic acid-g-ethylene glycol) were prepared by free radical solution UV-polymerization of methacrylic acid (MAA) and poly(ethylene glycol) monomethacrylate. Dynamic swelling studies indicated that complexation/decomplexation processes occurred due to hydrogen bonding between the carboxylic groups of the poly(methacrylic acid) (PMAA) and the ether groups of poly(ethylene glycol) (PEG). The effects of copolymer composition, graft chain molecular weight, environmental pH and ion content on network structure and gel behavior were studied. The largest change in swelling ratio and mesh size of the gel structure was observed in gels containing the highest content of PEG and the longest molecular weight PEG grafts. Complexation was greatest in hydrogels containing the longest PEG grafts and equimolar amounts of MAA and PEG. The swelling was much less pronounced in the presence of calcium chloride compared to sodium chloride which could be attributed to the complexation of calcium of the carboxylic groups in the polymer. The copolymers showed significant but less binding of calcium compared to poly(acrylates) like Carbopol 934P and polycarbophil. The P(MAA-g-EG) copolymers inhibited trypsin but to a lesser extent than the known protease inhibitors Carbopol 934P and polycarbophil. Results suggest that P(MAA-g-EG) copolymers are good drug delivery carrier candidates due to their pH-sensitive and controllable swelling behavior. Additionally, they possess some protease inhibition effect along with their bioadhesive properties which make them promising carriers for peptides or proteins.

Biocompatible Materials↗

PubMed1999

Drug volume fraction profile in the gel phase and drug release kinetics in hydroxypropylmethyl cellulose matrices containing a soluble drug.

In the present work, the drug volume fraction profiles of a colored and very soluble drug, buflomedil pyridoxal phosphate, in the gel layer of initially glassy hydroxypropylmethyl cellulose matrices were studied, using image analysis of pictures of the matrices during swelling and release. The goal was to correlate the drug release kinetics with the dynamic behavior of the drug gradient in the gel layer. An inert (nonswellable) matrix, manufactured by substituting hydroxypropylmethyl cellulose with an inert polymer and containing the same amount of buflomedil pyridoxal phosphate, was prepared as well. The drug color gradient in the partially extracted region and the flux of this matrix were compared to the swellable matrix. The drug gradient in the dissolved drug gel layer of swellable matrices was observed. It was demonstrated that drug release kinetics does not only depend on drug diffusion and matrix erosion, but also on drug dissolution in the gel and on polymer relaxation.

Diffusion↗

PubMed1999

A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets.

A novel mathematical model for the water transport into and drug release from hydroxypropyl methylcellulose (HPMC) tablets is presented. Fick's second law of diffusion is used to describe the mass transfer processes in the three-component system drug/polymer/water. Numerical solutions of the respective set of partial differential equations are provided, considering axial and radial diffusion within cylindrical tablets. It is shown that the diffusion coefficients strongly depend on the water concentration (parameters quantifying this dependence have been determined). Swelling of the device is considered using moving boundary conditions, whereas dissolution processes are neglected. Experiments proved the applicability of the theory. The practical benefit of the new model is to calculate the required shape and dimensions of HPMC tablets to achieve a desired release profile.

Algorithms↗

PubMed1999

Oral delivery of insulin using pH-responsive complexation gels.

The goal of oral insulin delivery devices is to protect the sensitive drug from proteolytic degradation in the stomach and upper portion of the small intestine. In this work, we investigate the use of pH-responsive, poly(methacrylic-g-ethylene glycol) hydrogels as oral delivery vehicles for insulin. Insulin was loaded into polymeric microspheres and administered orally to healthy and diabetic Wistar rats. In the acidic environment of the stomach, the gels were unswollen due to the formation of intermolecular polymer complexes. The insulin remained in the gel and was protected from proteolytic degradation. In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid gel swelling and insulin release. Within 2 h of administration of the insulin-containing polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. These effects lasted for up to 8 h following administration.

Administration, Oral↗

PubMed1999

HPMC-matrices for controlled drug delivery: a new model combining diffusion, swelling, and dissolution mechanisms and predicting the release kinetics.

PURPOSE: The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery. METHODS: The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Fick's second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution. RESULTS: Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process. CONCLUSIONS: The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.

Delayed-Action Preparations↗

PubMed1999

A model-based algorithm for blood glucose control in type I diabetic patients.

A model-based predictive control algorithm is developed to maintain normoglycemia in the Type I diabetic patient using a closed-loop insulin infusion pump. Utilizing compartmental modeling techniques, a fundamental model of the diabetic patient is constructed. The resulting nineteenth-order nonlinear pharmacokinetic-pharmacodynamic representation is used in controller synthesis. Linear identification of an input-output model from noisy patient data is performed by filtering the impulse-response coefficients via projection onto the Laguerre basis. A linear model predictive controller is developed using the identified step response model. Controller performance for unmeasured disturbance rejection (50 g oral glucose tolerance test) is examined. Glucose setpoint tracking performance is improved by designing a second controller which substitutes a more detailed internal model including state-estimation and a Kalman filter for the input-output representation. The state-estimating controller maintains glucose within 15 mg/dl of the setpoint in the presence of measurement noise. Under noise-free conditions, the model-based predictive controller using state estimation outperforms an internal model controller from literature (49.4% reduction in undershoot and 45.7% reduction in settling time). These results demonstrate the potential use of predictive algorithms for blood glucose control in an insulin infusion pump.

Algorithms↗

PubMed1999

Solute transport analysis in pH-responsive, complexing hydrogels of poly(methacrylic acid-g-ethylene glycol).

We report on the preparation and properties of hydrogels of poly(methacrylic acid-g-ethylene glycol) that exhibit pH-responsive swelling behavior due to the reversible formation/dissociation of interpolymer complexes. Because of their nature, these materials may be useful in drug delivery applications. In this work, we studied the diffusional behavior of three solutes of varying molecular size in the complexing hydrogels as a function of solution pH. The ability of these gels to control the solute diffusion rates was strongly dependent on the molecular size of the solute and the environmental pH. The diffusion coefficients for solutes were calculated as a function of pH and were lower in acidic than neutral or basic media due to the formation of interpolymer complexes in the gels. However, the ratio of the solute radius to the network mesh size also was a significant factor in the overall behavior of these gels. The diffusion coefficient of the smallest solute, proxyphylline, studied only changed by a factor of five between the complexed and uncomplexed state. However, for the largest solute, FITC-dextran, which has a molecular radius ten times greater than proxyphylline, the diffusion coefficients of the drugs in complexed and uncomplexed gels varied by almost two orders of magnitude. These results are explained in terms of mesh size characteristics of the gels.

Aminophylline↗