High throughput research and evaporation rate modeling for solvent screening for ethylcellulose barrier membranes in pharmaceutical applications.

CONTEXT: Ethylcellulose is commonly dissolved in a solvent or formed into an aqueous dispersion and sprayed onto various dosage forms to form a barrier membrane to provide controlled release in pharmaceutical formulations. Due to the variety of solvents utilized in the pharmaceutical industry and the importance solvent can play on film formation and film strength it is critical to understand how solvent can influence these parameters. OBJECTIVE: To systematically study a variety of solvent blends and how these solvent blends influence ethylcellulose film formation, physical and mechanical film properties and solution properties such as clarity and viscosity. MATERIALS AND METHODS: Using high throughput capabilities and evaporation rate modeling, thirty-one different solvent blends composed of ethanol, isopropanol, acetone, methanol, and/or water were formulated, analyzed for viscosity and clarity, and narrowed down to four solvent blends. Brookfield viscosity, film casting, mechanical film testing and water permeation were also completed. RESULTS AND DISCUSSION: High throughput analysis identified isopropanol/water, ethanol, ethanol/water and methanol/acetone/water as solvent blends with unique clarity and viscosity values. Evaporation rate modeling further rank ordered these candidates from excellent to poor interaction with ethylcellulose. Isopropanol/water was identified as the most suitable solvent blend for ethylcellulose due to azeotrope formation during evaporation, which resulted in a solvent-rich phase allowing the ethylcellulose polymer chains to remain maximally extended during film formation. Consequently, the highest clarity and most ductile films were formed. CONCLUSION: Employing high throughput capabilities paired with evaporation rate modeling allowed strong predictions between solvent interaction with ethylcellulose and mechanical film properties.

Exploring the drug migration process through ethyl cellulose-based films from infrared-spectral insights.

Using novel time-dependent ATR-FTIR technique and two-dimensional correlation analysis (2 Dcos), the migration behavior of drugs with varying water solubilities was investigated with ethyl cellulose (EC) films prepared with different kinds of pore formers and/or plasticizers. Three major stages were determined for drug migration: (1) water migrated from the drug-saturated solution to the other side of the EC film, (2) upon saturation of the film, water migration ceased and enough pore former was dissolved, and (3) upon dissolution of enough pore former, channels were formed between both sides of the EC film causing drug migration to begin and water migration to return. Further investigations demonstrated a reduction or elimination in second stage with increasing water solubility of the pore former and/or decreasing water solubility of the drug. These results offer a mechanistic understanding of water and drug migration across EC films not previously studied and might provide an effective guide for the preparation of EC pharmaceutical coating with desired drug release behavior.

pH-responsive hydrogels containing PMMA nanoparticles: an analysis of controlled release of a chemotherapeutic conjugate and transport properties.

Biopolymers composed of a pH-responsive, hydrophilic poly(methacrylic acid-grafted-ethylene glycol) network polymerized in the presence of poly(methyl methacrylate) nanoparticles were designed for the oral delivery of chemotherapeutics for the treatment of colon cancer. An inulin-doxorubicin conjugate, designed to target the colon and improve doxorubicin efficacy, was loaded into these polymer carriers at an efficiency of 54%. Release studies indicated these polymer carriers minimized conjugate release in low pH conditions and released the conjugate at neutral pH conditions using a two-step pH experiment modeling the stomach and the small intestine. At lower concentration levels, the presence of the polymer carriers did not disrupt tight junctions as determined by transepithelial electrical resistance studies using Caco-2 and HT29-MTX cell lines which are an accurate model of the GI tract epithelia. Permeability values of unmodified doxorubicin and the inulin-doxorubicin conjugate in the presence of the polymer carriers were also determined using the same cell models and ranged from 1.87 to 3.80 × 10 (-6) cm/s.

pH-responsive hydrogels with dispersed hydrophobic nanoparticles for the oral delivery of chemotherapeutics.

Amphiphilic polymer carriers were formed by polymerizing a hydrophilic, pH-responsive hydrogel composed of poly(methacrylic-grafted-ethylene glycol) (P(MAA-g-EG)) in the presence of hydrophobic PMMA nanoparticles. These polymer carriers were varied in PMMA nanoparticle content to elicit a variety of physiochemical properties which would preferentially load doxorubicin, a hydrophobic chemotherapeutic, and release doxorubicin locally in the colon for the treatment of colon cancers. Loading levels ranged from 49% to 64% and increased with increasing nanoparticle content. Doxorubicin loaded polymers were released in a physiological model where low pH was used to simulate the stomach and then stepped to more neutral conditions to simulate the upper small intestine. P(MAA-g-EG) containing nanoparticles were less mucoadhesive as determined using a tensile tester, polymer samples, and fresh porcine small intestine. The cytocompatibility of the polymer materials were assessed using cell lines representing the GI tract and colon cancer and were noncytotoxic at varying concentrations and exposure times.

pH-Responsive Hydrogels with Dispersed Hydrophobic Nanoparticles for the Delivery of Hydrophobic Therapeutic Agents.

To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH-responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA-g-EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA-g-EG) hydrogel structure. The pH-responsive behavior of P(MAA-g-EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle-containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38 - 51 % and increased with increasing hydrophobic content. Release studies from neat P(MAA-g-EG) and the ensuing P(MAA-g-EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies.

Porous inorganic-organic shape memory polymers.

Thermoresponsive shape memory polymers (SMPs) are a type of stimuli-sensitive materials that switch from a temporary shape back to their permanent shape upon exposure to heat. While the majority of SMPs have been fabricated in the solid form, porous SMP foams exhibit distinct properties and are better suited for certain applications, including some in the biomedical field. Like solid SMPs, SMP foams have been restricted to a limited group of organic polymer systems. In this study, we prepared inorganic-organic SMP foams based on the photochemical cure of a macromer comprised of inorganic polydimethylsiloxane (PDMS) segments and organic poly(ε-caprolactone) (PCL) segments, diacrylated PCL(40)-block-PDMS(37)-block-PCL(40). To achieve tunable pore size with high interconnectivity, the SMP foams were prepared via a refined solvent-casting/particulate-leaching (SCPL) method. By varying design parameters such as degree of salt fusion, macromer concentration in the solvent and salt particle size, the SMP foams with excellent shape memory behavior and tunable pore size, pore morphology, and modulus were obtained.

Amphiphilic Interpenetrating Networks for the Delivery of Hydrophobic, Low Molecular Weight Therapeutic Agents.

To investigate the delivery of hydrophobic therapeutic agents, a novel class of interpenetrating networks (IPNs) were synthesized and composed of two networks: methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and poly(n-butyl acrylate) (PBA). The hydrophilic P(MAA-g-EG) networks are pH-responsive hydrogels capable of triggered release of an encapsulated therapeutic agent, such as a low molecular weight drug or a protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). PBA is a hydrophobic homopolymer that can affect the IPN swelling behavior, the therapeutic agent loading efficiencies in IPNs, and solute release profiles from IPNs. In dynamic swelling conditions, IPNs had greater swelling ratios than P(MAA-g-EG), but in equilibrium swelling conditions the IPN swelling ratio decreased with increasing PBA content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 21 - 44%. Release studies from neat P(MAA-g-EG) and the ensuing IPNs indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophilicity of the carriers used in these studies.

Photo-cross-linked PDMSstar-PEG hydrogels: synthesis, characterization, and potential application for tissue engineering scaffolds.

Inorganic-organic hydrogels with tunable chemical and physical properties were prepared from methacrylated star polydimethylsiloxane (PDMS(star)-MA) and diacrylated poly(ethylene glycol) (PEG-DA) for use as tissue engineering scaffolds. A total of 18 compositionally unique hydrogels were prepared by photo-cross-linking, varying weight ratios of PEG-DA and PDMS(star)-MA of different molecular weights (M(n)): PEG-DA (M(n) = 3.4k and 6k g/mol) and PDMS(star)-MA (M(n) = 1.8k, 5k, and 7k g/mol). Introduction of PDMS(star)-MA caused formation of discrete PDMS-enriched microparticles dispersed within the PEG matrix. The swelling ratio, mechanical properties in tension and compression, nonspecific protein adhesion, controlled introduction of bioactivity, and cytotoxicity of hydrogels were studied. This library of inorganic-organic hydrogels with tunable properties provides a useful platform to study the effect of scaffold properties on cell behavior.