Precise control of synthetic hydrogel network structure via linear, independent synthesis-swelling relationships.

Hydrogel physical properties are tuned by altering synthesis conditions such as initial polymer concentration and polymer-cross-linker stoichiometric ratios. Traditionally, differences in hydrogel synthesis schemes, such as end-linked poly(ethylene glycol) diacrylate hydrogels and cross-linked poly(vinyl alcohol) hydrogels, limit structural comparison between hydrogels. In this study, we use generalized synthesis variables for hydrogels that emphasize how changes in formulation affect the resulting network structure. We identify two independent linear correlations between these synthesis variables and swelling behavior. Analysis through recently updated swollen polymer network models suggests that synthesis-swelling correlations can be used to make a priori predictions of the stiffness and solute diffusivity characteristics of synthetic hydrogels. The same experiments and analyses performed on methacrylamide-modified gelatin hydrogels demonstrate that complex biopolymer structures disrupt the linear synthesis-swelling correlations. These studies provide insight into the control of hydrogel physical properties through structural design and can be used to implement and optimize biomedically relevant hydrogels.

Biodegradable cationic nanogels with tunable size, swelling and pKa for drug delivery.

Cationic polymers have garnered significant interest for their utility in intracellular drug delivery and gene therapy. However, due to their associated toxicities, novel synthesis approaches must be explored to develop materials that are biocompatible. The novel library of nanoparticles synthesized in this study exhibit tunable hydrodynamic diameters, composition and pH-responsive properties as a function of synthesis parameters. In addition, differences in the responsiveness of these nanoparticles under different pH conditions affords greater control over intracellular drug release.

Hybrid responsive hydrogel carriers for oral delivery of low molecular weight therapeutic agents.

Hydrogels have been influential in the development of controlled release systems for a wide variety of therapeutic agents. These materials are attractive as carriers for transmucosal and intracellular drug delivery because of their inherent biocompatibility, tunable physicochemical properties, basic synthesis, and ability to be physiologically responsive. Due to their hydrophilic nature, hydrogel-based carrier systems are not always the best systems for delivery of small molecular weight, hydrophobic therapeutic agents. In this work, versatile hydrogel-based carriers composed of copolymers of methyl methacrylate (MMA) and acrylic acid (AA) were designed and synthesized to create formulations for oral delivery of small molecular weight therapeutic agents. Through practical material selection and careful design of copolymer composition and molecular architecture, we engineered systems capable of responding to physiological changes, with tunable physicochemical properties that are optimized to load, protect, and deliver their payloads to their intended site of action. The synthesized carriers' ability to respond to changes in pH, to load and release small molecular weight drugs, and biocompatibility were investigated. Our results suggest these hydrophilic networks have great potential for controlled delivery of small-molecular weight, hydrophobic and hydrophilic agents.

Polycationic nanoparticles synthesized using ARGET ATRP for drug delivery.

This work provides a systemic comparison for ARGET ATRP and UV-initiated polycationic nanoparticles for drug delivery and a guide to deciding which type of polycationic nanoparticles have the best properties for specific applications. Polycationic nanoparticles were synthesized using a previously developed UV-initiated photoemulsion polymerization or a newly developed ARGET ATRP synthesis technique. The effect of the ratio of hydrophobic monomer in the feed was evaluated. Increasing the feed ratio of hydrophobic monomer was necessary to maintain biocompatibility and pH-responsive membrane disruptive characteristics when switching from the UV-initiated polymerization to ARGET ATRP. The resulting polycationic nanoparticles have utility as drug delivery carriers for hydrophobic drugs and/or nucleic acids.

An inulin and doxorubicin conjugate for improving cancer therapy.

Chemotherapy is one of the primary treatment mechanisms for treating cancer. Current chemotherapy is systemically delivered and causes significant side effects; therefore the development of new chemotherapeutic agents or enhancing the effectiveness of current chemotherapeutic could prove vital to patients and cancer care. The purpose of this research was to develop a new conjugate composed of doxorubicin (chemotherapeutic) and inulin (polysaccharide chain) and evaluate its potential as a new therapeutic agent for cancer treatment. The synergistic effect of inulin conjugated to doxorubicin has allowed the same cytotoxic response to be maintained or improved at lower doses as compared to doxorubicin. Supporting results include cytotoxicity profiles, calf thymus DNA binding studies, confocal microscopy, and transport studies.

Pharmacokinetic Modeling of the Glucoregulatory System.

A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurrs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartmental model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body.

[New intelligent and targetted drug delivery systems. Pharmaceutical and biomedical applications]. / Vecteurs de médicaments innovants et "intelligents": leurs applications pharmaceutiques.

Biomaterials are widely used in numerous medical applications. Chemical engineering has played a central role in this research and development. We review herein polymers as biomaterials, materials and approaches used in drug and protein delivery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials.

Devices based on intelligent biopolymers for oral protein delivery.

The primary goal of bioadhesive controlled drug delivery is to localize a delivery device within the body to enhance the drug absorption process in a site-specific manner. An important contributor to good adhesion is the presence of molecular adhesion promoters such as polymer-tethered structure (e.g., poly(ethylene glycol) chains grafted to crosslinked networks) or even linear chains which are free to diffuse across the gel/gel interface. Recently, we have developed a very promising class of carriers for drug and especially protein delivery. Copolymer networks of poly(methacrylic acid) grafted with poly(ethylene glycol) exhibit reversible, pH-dependent swelling behavior due to the formation of interpolymer complexes between protonated pendant acid groups and the etheric groups on the graft chains. Gels containing equimolar amounts of MAA/EG exhibited the lowest degree of swelling at low pH increased complexation. The average network mesh size or correlation length was dramatically affected by the pH of the swelling solution. The in vitro release of insulin from P(MAA-g-EG) gels containing PEG grafts of molecular weight 1000 indicates a significant release of insulin as the gel decomplexes and insulin is freed through the structure. The results of additional in vitro studies have shown that insulin release rates can be controlled by appropriate adjustment of the structure of the gels.

Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications.

This review presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical or pharmaceutical applications. The structural basis of these hydrogels is discussed with reference to the specific chemical interactions, which dictate gel formation. The synthesis and chemistry of these hydrogels is discussed using specific pharmaceutical examples. Covalent crosslinking leads to formation of hydrogels with a permanent network structure, since irreversible chemical links are formed. This type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. pH-controlled drug delivery is made possible by the addition of another polymer. Ionically crosslinked hydrogels are generally considered as biocompatible and well-tolerated. Their non-permanent network is formed by reversible links. Ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared to covalently crosslinked chitosan hydrogels. This extends their potential application, since dissolution can occur in extreme acidic or basic pH conditions.

Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system.

The objective of this study was to investigate the swelling characteristics of various swellable polymers in swelling layers that induce the rupturing of an outer polymer coating in pulsatile drug delivery systems (DDS). An apparatus was designed to measure simultaneously the swelling energy/force and water uptake of discs, made of polymers. The swelling energy of several excipients decreased in the following order: croscarmellose sodium (Ac-Di-Sol) > low-substituted hydroxypropyl cellulose (L-HPC) > sodium starch glycolate (Explotab) > crospovidone (Kollidon CL) > hydroxypropyl methylcellulose (Methocel K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling behavior of Ac-Di-Sol depended on the ionic strength and the pH of the medium due to a competition for free water and the acidic nature of this polymer. Analysis of the time-dependent swelling force data with a previously developed exponential equation confirmed a diffusion-controlled swelling force development, predominantly controlled by the penetration rate of the medium. The swelling behavior and the rupture of the outer polymeric coating of a pulsatile DDS were demonstrated in simulation tests.

Time-dependent mechanical properties of polymeric coatings used in rupturable pulsatile release dosage forms.

The mechanical properties of polymer films used in pharmaceutical coatings of pulsatile drug delivery systems were evaluated in the dry and the wet state by a newly developed puncture test, which allowed the time-dependent measurement of the mechanical properties on the same film specimen. Force, puncture strength, energy at break, modulus, and strain were investigated as a function of water exposure time with respect to the type of polymer and the type and concentration of plasticizer and pore former (hydroxypropyl methylcellulose, HPMC). Eudragit RS films were very flexible, had a high strain, and broke upon puncture with only small cracks. In contrast, ethylcellulose films were more brittle with a lower strain and showed complete film rupture. Increased amounts of the hydrophilic pore former, HPMC, resulted in a reduced puncture strength and in an increase in water uptake and weight loss of the films. The puncture strength decreased with increasing plasticizer concentration and was lower with the lipophilic dibutyl sebacate than with the hydrophilic triethyl citrate.

Preparation of poly(methacrylic acid-g-poly(ethylene glycol)) nanospheres from methacrylic monomers for pharmaceutical applications.

Nanospheres of poly(methacrylic acid-grafted-poly(ethylene glycol)) were prepared by solution/precipitation polymerization. As colloidal drug delivery carriers, they present unique properties that render them promising candidates for oral protein delivery. The polymerization was carried out in water and the resulting suspension was freeze-dried. As with many colloidal systems, the freeze-dried suspension showed strong agglomeration after drying. The effects of preparation conditions on the particle size and redispersion were investigated using photon correlation spectroscopy. Furthermore, the ability of different types and concentrations of stabilizers (cryoprotectants and steric stabilizers) in preventing this phenomenon was addressed. Pluronics, block copolymers widely used as nonionic surfactants, were the most effective in stabilizing the particles during the freeze-drying process. Pluronic P123, however, increased significantly the particle size of the nanospheres. On the other hand, lyophilizates obtained in the presence of Pluronic F68 had good redispersion properties and no change in particle size was observed.

Morphology of poly(methacrylic acid)/poly(N-isopropyl acrylamide) interpenetrating polymeric networks.

The morphology of interpenetrating polymeric networks (IPNs) composed of the temperature-sensitive poly(N-isopropyl acrylamide) (PNIPAAm) and the pH-sensitive poly(methacrylic acid) (PMAA) were investigated by scanning electron microscopy (SEM). The IPN hydrogels were prepared by a sequential UV polymerization method. SEM studies were conducted on IPN hydrogel samples dried by different methods, and the influence on the IPN structure was discussed. The environmental conditions induced morphological changes for these dual sensitive IPN hydrogels which were studied by cryogenic SEM, when the gels were analyzed in their wet state. The results showed that the porous size in the IPN was strongly influenced by the environmental pH and temperature. Decrease in pH and increase in temperature resulted in significant pore size decrease for the swollen IPNs hydrogels.

Understanding and predicting drug delivery from hydrophilic matrix tablets using the "sequential layer" model.

PURPOSE: The objectives of this work were (i) to study and understand the physicochemical phenomena which are involved in the swelling and drug release from hydrophilic matrix tablets using the "sequential layer" model, and (ii) to predict the effect of the initial radius height and size of the tablets on the resulting drug release profiles. METHODS: Tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC) grades with different average molecular weights as matrix-forming polymers. The in vitro release of chlorpheniramine maleate, propranolol HCl, acetaminophen, theophylline and diclofenac sodium was studied in phosphate buffer (pH 7.4) and 0.1 M HCl, respectively. The initial drug loading varied from 1 to 70%, while the radius and height of the tablets varied from 1 to 8 mm. RESULTS: The "sequential layer" model considers water and drug diffusion with non-constant diffusivities and moving boundary conditions, non-homogeneous polymer swelling, drug dissolution, and polymer dissolution. We showed that this model was able to predict the resulting drug release kinetics accurately in all cases. CONCLUSIONS: The "sequential layer" model can be used to elucidate the swelling and drug release behavior from hydrophilic matrix tablets and to simulate the effect of the device geometry on the drug release patterns. Hence, it can facilitate the development of new pharmaceutical products.

Marrow-derived cells populate scaffolds composed of xenogeneic extracellular matrix.

INTRODUCTION: The source of cells that participate in wound repair directly affects outcome. The extracellular matrix (ECM) and other acellular biomaterials have been used as therapeutic scaffolds for cell attachment and proliferation and as templates for tissue repair. The ECM consists of structural and functional proteins that influence cell attachment, gene expression patterns, and the differentiation of cells. OBJECTIVE: The objective of this study was to determine if the composition of acellular matrix scaffolds affects the recruitment of bone marrow-derived cellular elements that populate the scaffolds in vivo. METHODS: Scaffolds composed of porcine tissue ECM, purified Type I collagen, poly(L)lactic coglycolic acid (PLGA), or a mixture of porcine ECM and PLGA were implanted into subcutaneous pouches on the dorsum of mice. The origin of cells that populated the matrices was determined by first performing bone marrow transplantation to convert the marrow of glucose phosphate isomerase 1b (Gpi-1(b)) mice to cells expressing glucose phosphate isomerase 1a (Gpi-1(a)). RESULTS: A significant increase in Gpi-1(a) expressing cells was present in sites implanted with the porcine ECM compared to sites implanted with either Type I collagen or PLGA. Use of recipient mice transplanted with marrow cells that expressed beta-galactosidase confirmed that the majority of cells that populated and remodeled the naturally occurring porcine ECM were marrow derived. Addition of porcine ECM to the PLGA scaffold caused a significant increase in the number of marrow-derived cells that became part of the remodeled implant site. CONCLUSION: The composition of bioscaffolds affects the cellular recruitment pattern during tissue repair. ECM scaffolds facilitate the recruitment of marrow-derived cells into sites of remodeling.

Surface modifications and molecular imprinting of polymers in medical and pharmaceutical applications.

Recent developments in the field of biomaterials are based on molecular design of polymers with improved surface and bulk properties. Novel techniques of surface modification by addition of tethered chains can lead to materials with the ability to recognize biological and pharmaceutical compounds. Methods based on molecular imprinting can increase the recognition capabilities of such systems. Chain tethering can also can improve the mucoadhesive behavior of a delivery device and the effectiveness of a drug by allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels are well-suited for mucoadhesion due to their flexibility and nonabrasive characteristics which reduce damage-causing attrition to the tissues in contact. However, the adhesive and drug delivery capabilities of these devices can continue to be improved as presently known bioadhesive materials are modified and more bioadhesive materials are discovered. Tethering of long PEG chains on PAA hydrogels and their copolymers can be achieved by grafting reactions involving thionyl chloride, followed by PEG grafting. The ensuing materials exhibit mucoadhesive properties due to enhanced anchoring of the chains with the mucosa. Theoretical calculations can lead to optimization of the tethered structure.

Micropatterning of biomedical polymer surfaces by novel UV polymerization techniques.

The "living" radical polymerization with an iniferter was used to create micropatterned biomedical surfaces. Novel, photosensitive biomedical polymers were created by the incorporation of dithiocarbamate groups from iniferters. A second monomer layer was then irradiated onto the photosensitive polymer substrate created with the iniferter to form a copolymer. Patterns were created on the films by application of modified microfabrication-based photolithographic techniques. The technique was used to create patterns with depths from 5 to 80 microm. In addition, various polymers were incorporated, including polyethylene glycol methacrylates, styrene, and methacrylic acid, to synthesize regions with different physico-chemical properties. Applications include novel surfaces for biosensors and biomaterials for the selective adhesion of cells and proteins.

Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC).

The objective of this article is to review the spectrum of mathematical models that have been developed to describe drug release from hydroxypropyl methylcellulose (HPMC)-based pharmaceutical devices. The major advantages of these models are: (i) the elucidation of the underlying mass transport mechanisms; and (ii) the possibility to predict the effect of the device design parameters (e.g., shape, size and composition of HPMC-based matrix tablets) on the resulting drug release rate, thus facilitating the development of new pharmaceutical products. Simple empirical or semi-empirical models such as the classical Higuchi equation and the so-called power law, as well as more complex mechanistic theories that consider diffusion, swelling and dissolution processes simultaneously are presented, and their advantages and limitations are discussed. Various examples of practical applications to experimental drug release data are given. The choice of the appropriate mathematical model when developing new pharmaceutical products or elucidating drug release mechanisms strongly depends on the desired or required predictive ability and accuracy of the model. In many cases, the use of a simple empirical or semi-empirical model is fully sufficient. However, when reliable, detailed information are required, more complex, mechanistic theories must be applied. The present article is a comprehensive review of the current state of the art of mathematical modeling drug release from HPMC-based delivery systems and discusses the crucial points of the most important theories.