Release Of Macromolecular Drugs Research Articles

3D-printed construct from hybrid suspension as spatially and temporally controlled protein delivery system.

Protein delivery systems have been extensively applied in controlled releasing of protein or polypeptides for therapeutic treatment or tissue regeneration. While 3 D printing technology shows great promise in novel dosage form with tailoring dose size and drug release profile, 3 D printable protein delivery system has to face many difficult challenges. In this study, we developed a hybrid suspension combining Eudragit polyacrylate colloid as matrix material and Pluronic polyether hydrogel as diffusion channel for protein release. This hybrid suspension can be 3 D-printed into construct with complex shape and inner structures thanks to its pseudoplastic and thixotropic rheological properties. The protein can be incorporated in hybrid suspension either in its original or nanoparticle capsulated form. The experiment shows that the protein release from construct is a function of drying time, molecular weight (MW) of chitosan, as well as their own structural/diffusional properties. Also, the theoretical derivation suggests polyacrylate matrix tortuosity, chitosan erosion rate as well as hydrogel diffusion coefficient all contributed to the extended duration of release profile. In addition, cytotoxicity test through cell culture confirmed that the construct fabricated from hybrid suspension exhibit relative good bio-compatibility. Finally, heterogeneous constructs with zoned design were fabricated as protein delivery system, which demonstrated the capability of hybrid suspension technique for spatial and temporal release of macromolecular drugs to realize pharmaceutical effectiveness or guild cell organization.

Dual-Diffusivity Stochastic Model for Macromolecule Release from a Hydrogel.

A three-dimensional model has been developed to describe the multiphase release of macromolecular drugs encapsulated in a hydrogel. The heterogeneity of network mesh size was considered by assigning varying diffusion coefficients to the network lattices randomly. Using a stochastic approach, the random nature of diffusion of drug molecules was captured within the network. The simplest form of distribution containing two diffusion coefficients was tested. To generate the drug release profiles for experimental validation under the limitation of computational cost, a simple scaling relationship was employed. Unlike the single-diffusivity model, the dual-diffusivity model showed good agreement with the experimental data in describing the release profiles of macromolecular drugs of three different sizes from chemically cross-linked dextran hydrogels.

Silk fibroin degumming affects scaffold structure and release of macromolecular drugs

Silk fibroin (SF) is a natural polymer with tremendous potential as a matrix for drug delivery systems as well as for tissue engineering. Silk sericin (SS) removal (degumming) is a critical step during SF purification, potentially affecting SF integrity and resulting in structural changes such as partial hydrolysis and inhibition of micelle formation. In addition to SF composition itself, the molecular weight and charge of encapsulated drugs may significantly affect drug release from SF matrices. The effect of these parameters on drug release was investigated by varying SF degumming time and charge of the model compound encapsulated in SF films. With increasing degumming time, average SF molecular weight decreased, molecular weight distribution became broader and formation of SF micelles was impaired. However, β-sheet content was not affected by degumming time, suggesting that degradation occurred mainly in hydrophilic domains of SF. The release of differently charged dextran derivatives, used as macromolecular model drugs, was significantly affected by SF degumming. Release of neutral dextran increased with increasing degumming time. In contrast, negatively charged dextran showed an inverse effect potentially due to reduced SF charge density with increased degumming time. Interestingly, positively charged dextran were shown to partly form polyelectrolyte complexes with SF by isothermal titration calorimetry but also exhibited phase separation during film drying resulting in fast burst release. These results demonstrate that both, SF preparation as well as drug charge significantly affect drug release from SF matrices.

Multilayered mucoadhesive hydrogel films based on thiolated hyaluronic acid and polyvinylalcohol for insulin delivery

A multilayered hydrogel film system based on hyaluronic acid-cysteamine (HA-Cym) and polyvinylalcohol (PVA) was fabricated. It contained a drug-impermeable backing layer, a supporting layer preventing direct contact between the loaded drug and the backing layer, a drug-loading layer and a mucoadhesive layer. Scanning electron microscopy demonstrated the presence of the distinct layers. The composition and preparation procedure of the films influenced their mucoadhesion, swelling, in vitro release of insulin and loaded insulin stability. Vacuum drying and crosslinked PVA with glutaraldehyde might reduce mucoadhesion, and they partially decreased the bioactivity of loaded insulin. Lyophilized hydrogel film with uncrosslinked PVA as a mucoadhesive layer possessed high mucoadhesion and showed no influence on the bioactivity of loaded insulin. The application of vacuum-dried PVA-crosslinked HA-Cym/PVA hydrogel film as a drug-impermeable backing layer would provide a controllable unidirectional insulin release. Therefore, such a multilayered hydrogel film system could be a promising mucoadhesive delivery system for controlled macromolecular drug release.

Comb-Shaped Conjugates Comprising Hydroxypropyl Cellulose Backbones and Low-Molecular-Weight Poly(N-isopropylacryamide) Side Chains for Smart Hydrogels: Synthesis, Characterization, and Biomedical Applications

Hydroxypropyl cellulose (HPC) possesses a lower critical solution temperature (LCST) above 40 °C, while the poly(N-isopropylacrylamide) (P(NIPAAm)) exhibits a LCST of about 32 °C. Herein, comb-shaped copolymer conjugates of HPC backbones and low-molecular-weight P(NIPAAm) side chains (HPC-g-P(NIPAAm) or HPN) were prepared via atom transfer radical polymerization (ATRP) from the bromoisobutyryl-functionalized HPC biopolymers. By changing the composition ratio of HPC and P(NIPAAm), the LCSTs of HPNs can be adjusted to be lower than the body temperature. The MTT assay from the HEK293 cell line indicated that HPNs possess reduced cytotoxicity. Some of the hydroxyl groups of HPNs were used as cross-linking sites for the preparation of stable HPN hydrogels. In comparison with the HPC hydrogels, the cross-linked HPN hydrogels possess interconnected pore structures and higher swelling ratios. The in vitro release kinetics of fluorescein isothiocyanate-labeled dextran and BSA (or dextran-FITC and BSA-FITC) as model drugs from the hydrogels showed that the HPN hydrogels are suitable for long-term sustained release of macromolecular drugs at body temperature.

Network structure and macromolecular drug release from poly(vinyl alcohol) hydrogels fabricated via two crosslinking strategies

Injectable hydrogels have potential biomedical applications ranging from tissue fillers to drug delivery vehicles. This study focussed on evaluating the structure of poly(vinyl alcohol) (PVA) hydrogels of variable solid content and high molecular weight model drug release from the networks formed via either conventional photo-polymerization compared with chemical initiation of polymerization using an oxidation-reduction (redox) reaction. Swelling behaviour was characterised in water to assess the structural properties. Model drugs, FITC-Dextran, 20 kDa (FD20) and 4 kDa (FD4) were loaded in the hydrogels prior to curing and drug release studies conducted. Redox-cured hydrogels were more swollen than UV-cured systems, lost approximately 20% of their polymer mass compared to only 5% from UV-cured hydrogels and subsequently exhibited networks of larger mesh sizes. Also, networks of variable solid contents showed different structural properties with systems of higher polymer concentration exhibiting a smaller mesh size. The difference in structural properties of the networks affected release of FD20, being faster in redox-cured than UV-cured hydrogels, and slower from systems of higher solid content. Release of FD4 was faster than FD20 from networks of same solid content. This study suggested that PVA hydrogels can be cured by redox-initiation to function as a controlled delivery system for macromolecular drugs.

Self-assembled supramolecular hydrogels formed by biodegradable PEO–PHB–PEO triblock copolymers and α-cyclodextrin for controlled drug delivery

A materials design of a new supramolecular hydrogel self-assembled between alpha-cyclodextrin and a biodegradable poly(ethylene oxide)-poly[(r)-3-hydroxybutyrate]-poly(ethylene oxide) (PEO-PHB-PEO) triblock copolymer was demonstrated. The cooperation effect of complexation of PEO segments with alpha-cyclodextrin and the hydrophobic interaction between PHB blocks resulted in the formation of the supramolecular hydrogel with a strong macromolecular network. The in vitro release kinetics studies of fluorescein isothiocyanate labeled dextran (dextran-FITC) model drug from the hydrogel showed that the hydrogel was suitable for relatively long-term sustained controlled release of macromolecular drugs, which many simple triblock copolymer hydrogel systems could not achieve. The hydrogel was found to be thixotropic and reversible, and can be applied as a promising injectable drug delivery system.

In vitro release dynamics of insulin from a loaded hydrophilic polymeric network.

A hydrophilic semi-interpenetrating polymer network of polyvinyl alcohol (PVA), poly(ethylene glycol) (PEG) and crosslinked polyacrylamide (PAM) chains has been synthesized and its potential for controlled release of macromolecular drugs has been assessed by taking insulin as a representative drug. The semi-IPN was characterized by IR studies and network parameters such as the average molecular weight between crosslinks (Mc), crosslink density (q), and number of elastically effective chains (Ve) were evaluated. The effect of chemical architecture of the IPN was investigated on the percent loading of insulin and its subsequent release from the loaded device. Other parameters such as the thickness of the gel, molecular weight of PEG and pH and temperature of the release medium were also studied for their possible impact on the release of insulin. The whole release data was analyzed by Ficks power law and the influence of various factors on the plausible mechanism of insulin release was investigated.

Precipitation casting of polycaprolactone for applications in tissue engineering and drug delivery

Microporous materials have been produced by gradual precipitation from solutions of poly(epsilon-caprolactone) (PCL) in acetone induced by solvent extraction across a semi-permeable PCL membrane which is formed in situ at the polymer solution/non-solvent interface. Microparticulates of hydroxyapatite and inulin polysaccharide, respectively, were incorporated in precipitation cast PCL matrices to illustrate potential applications in hard tissue repair and macromolecular drug release. Microporous PCL and HA filled PCL materials were found to provide a favourable surface for attachment and growth of primary human osteoblasts in cell culture. The in vitro degradation characteristics of microporous PCL and inulin/PCL materials in PBS at 37 degrees C were monitored over 45 months. Microporous PCL demonstrated zero weight loss, minor changes in molecular weight characteristics and a fairly constant indentation resistance of around 1 MN/m2. Inulin-loaded PCL materials exhibited a total weight loss of approximately 17% after 12 months in PBS. The indentation resistance decreased by 50% from an initial value of 28 MN/m2 in the first 2 months and then remained stable. Precipitation cast materials based on PCL are expected to be useful for formulating long-term, controlled release devices for bioactive molecules such as growth factors and hormones and extended-residence supports for cell growth and tissue development.

Injectable drug-delivery systems based on supramolecular hydrogels formed by poly(ethylene oxide)s and alpha-cyclodextrin.

Polymeric hydrogels long have attracted interest for biomaterials applications because of their generally favorable biocompatibility. High in water content, they are particularly attractive for delivery of delicate bioactive agents, such as proteins. However, because they require covalent crosslinking for gelation, many hydrogels can be applied only as implantables, and incorporation of drugs by sorption may be time-consuming and limiting with regard to the loading level. Therefore a delivery formulation where gelation and drug loading can be achieved simultaneously, taking place in an aqueous environment and without covalent crosslinking, would be attractive. Herein is described a new class of injectable and bioabsorbable supramolecular hydrogels formed from poly(ethylene oxide)s (PEOs) and alpha-cyclodextrin (alpha-CD) for controlled drug delivery. The hydrogel formation is based on physical crosslinking induced by supramolecular self-assembling with no chemical crosslinking reagent involved. The supramolecular structure of the hydrogels was confirmed with wide-angle X-ray diffraction studies. The gelation kinetics was found to be dependent on the concentrations of the polymer and alpha-CD as well as on the molecular weight of the PEO used. The rheologic studies of the hydrogels showed that the hydrogels were thixotropic and reversible and that they could be injected through fine needles. The components of the supramolecular hydrogels potentially are biocompatible and nontoxic. Drugs can be encapsulated directly into the hydrogels in situ at room temperature without any contact with organic solvents. The supramolecular hydrogels were evaluated in terms of their in vitro release kinetics. The rate-controlling mechanism of macromolecular drug release might be the erosion of the hydrogels.

Time-programmed pulsatile release of dextran from calcium-alginate gel beads coated with carboxy-n-propylacrylamide copolymers

Time-programmed release of macromolecular drugs was achieved by utilization of calcium-alginate gel beads modified with coated copolymer layers. Modified calcium-alginate gel beads coated with poly(carboxy-n-propylacrylamide-co-dimethylacrylamide) [poly(CNPAAm-co-DMAAm)] (22.7 mol% of CNPAAm) of varying coating thickness from 25 to 125 microm were developed as drug carriers. Model macromolecular drugs used were fluorescein isothiocyanate (FITC)-labeled dextrans with different molecular weights ranging from 9400 to 145000. FITC-dextran release was strongly dependent on both copolymer coating thicknesses and the dextran molecular weights. Release of FITC-dextran (MW 9400) followed Fickian diffusion according to t(1/2) dependence, indicating that the drug diffusion is the main driving force for release of dextran MW 9400. Release of higher molecular weight FITC-dextrans (71,00 and 145,00) exhibited a burst-effect preceded by a preset lag time. These release profiles were governed by the dissociation of calcium ions from polyguluronate sequences in alginate molecules along with the diffusion of sodium ions into the gel bead core. This created osmotic pressure inside the gel, inducing breakage of the coated copolymer layer and accelerated drug release. Burst release of macromolecular drugs thus occurred after a certain lag period. The lag time was regulated by the copolymer coat thickness. A pulsatile release of FITC-dextran was demonstrated by combining a series of modified alginate gel beads in a single batch.

Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: is the erosion controlled by degradation, swelling or diffusion?

Erosion of biodegradable parenteral delivery systems (PDS) based on ABA copolymers consisting of poly(L-lactide-co-glycolide) (PLGA) A-blocks attached to polyethylene oxide (PEO) B-blocks, or PLGA is important for the release of macromolecular drugs. The degradation behavior of four types of PDS, namely extruded rods, tablets, films and microspheres, was studied with respect to molecular weight, mass, polymer composition and shape and microstructure of the PDS. For each device the onset time of bulk erosion (t(on)) and the apparent rate of mass loss (k(app)) were calculated. In the case of PLGA, the t(on) was 16.2 days for microspheres, 19.2 days for films and 30.1 days for cylindrical implants and tablets. The k(app) was 0.04 days(-1) for microspheres, 0.09 days(-1) for films, 0.11 days(-1) for implants and 0.10 days(-1) for tablets. The degradation rates were in the same range irrespective of the geometry and the micrographs of eroding PDS demonstrated pore formation; therefore, a complex pore diffusion mechanism seems to control the erosion of PLGA devices. In contrast, PDS based on ABA copolymers showed swelling, followed by a parallel process of molecular weight degradation and polymer erosion, independent of the geometry. The contact angles of ABA films increased either with decreasing PEO content or with increasing chain length of the PEO B-blocks. In summary, the insertion of a hydrophilic B-block leads to an erosion controlled by degradation of ABA copolymers, whereas for PLGA a complex pore diffusion of degradation products controls the rate of bulk erosion.

Effect of Ca 2+-alginate gel dissolution on release of dextran with different molecular weights

Release of macromolecular drug from calcium-alginate gel beads was investigated. Fluorescein isothiocyanate-labeled dextrans with molecular weight ranging from 9400 to 145000 were used as a model macromolecular drug. Dextran release was observed to be molecular weight-dependent, with the release pattern changing from pseudo first-order for dextran with 9400 molecular weight to sigmoidal for dextran with molecular weight of 145000. Release of a lower molecular weight dextran is mainly governed by the drug diffusion through the calcium-alginate gel matrix. With increasing dextran molecular weights, dextran release was strongly influenced by the dissolution of alginate matrix through the exchange of Ca2+ ions which act as a cross-linker. Rapid and complete release was achieved for dextran with 145000 molecular weight in a "burst" fashion showing a initial lag time. Minimal dextran release was observed in pseudo-gastric fluid at pH 1.2, while rapid dextran release within a narrow time range was achieved in simulated intestinal fluid at pH 6. 8. These results strongly suggest that calcium-alginate gel is a useful vehicle for pulsatile release of macromolecular drugs in oral drug delivery.

In Vitro Properties of an In Situ Forming Gel for the Parenteral Delivery of Macromolecular Drugs*

The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)–insulin and FITC–albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, α-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations >30% w/v IPC were required to form the gel, however, those mixtures containing >60% w/v IPC could not be easily injected via 18–22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, α-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.

In vivo properties of an in situ forming gel for parenteral delivery of macromolecular drugs.

This study characterizes the in vivo properties of an in situ forming gel, comprising of IPC of water-soluble polymers, PMA and PEG, for sustained release of macromolecular drugs. 40, 50, or 60% w/v formulations were injected subcutaneously in a rat model either alone, or containing model macromolecules, 3A2-ATG-psODN or REV-psODN, to (i) determine the approximate gelling and residence time of the gel at the site of injection (ii) assess the biological efficacy of the formulation using a MZ sleep time model and (iii) demonstrate specificity of the sequence and selectivity of the psODNs by measuring changes in microsomal enzyme levels and urine volumes. A sol to gel transition requires 15 min in vivo, and the 60% w/v IPC gel remains at the site of injection for up to 72 hr. The MZ sleep times and CYP3A2 expression due to 3A2-ATG-psODNs released from the gel are significantly different compared to that of REV-psODNs. The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .

A Theoretical Model of Erosion and Macromolecular Drug Release from Biodegrading Microspheres

A theoretical model is outlined for predicting the time evolution of total mass, mean molecular weight, and drug release for the case of a spherical bulk-eroding microsphere, prepared by a double emulsification procedure and containing a hydrophilic drug, such as a protein or peptide. Explicit analytical formulae are derived for calculating the time evolution of measurable macroscopic characteristics, such as drug release or mean molecular weight. Microsphere hydration, polymer erosion, and drug release phases are each described. Results indicate that polymer degradation by only random-chain scission or only end scission (or unzipping) cannot explain experimentally observed kinetics of particle mass loss and molecular weight change; thus, a combined model (incorporating both random and end scission) is proposed. A general methodology for determining the microscopic transport coefficients (such as polymer degradation rate constant or drug diffusion coefficient) from erosion and release data is outlined. This paradigm is applied to the specific case of 50:50 poly(D,L-lactic-co-glycolic acid (PLGA) microspheres encapsulating glycoprotein 120 (gp 120), a candidate AIDS vaccine. Predictions permit comparisons with experimental data for mean weight- and number-averaged molecular weights, as well as for mass loss and protein release. Other comparisons are made with data appearing in the literature for release of tetanus toxoid from PLA and PLGA microspheres of variable molecular weight. Agreement between theory and experiment is observed.

Polyanhydride blend microspheres: novel carriers for the controlled release of macromolecular drugs

Rigid injectable microspheres were prepared from polyanhydride blends comprising a soft, rapidly-degrading polymer, viz. poly(carboxyphenoxyvaleric acid) (PCPV) and a rigid, slow-degrading polymer, viz. poly(carboxyphenoxyhexane) (PCPH). The incorporation of the soft polymer led to the formation of more dense microspheres. In the release environment, the soft polymer in the blend microspheres degraded more rapidly leaving behind a microporous structure consisting mostly of the slow-degrading polymer. PNP was released very quickly through these pores, and the rate was independent of blend composition. On the other hand release of lysozyme, a macromolecular solute, could be controlled by varying the blend composition. The influence of blending and technique of microsphere preparation on the morphology and release profile was also investigated.

Mechanistic studies of macromolecular drug release from macroporous polymers. II. Models for the slow kinetics of drug release

Abstract The release of protein drugs such as bovine serum albumin (BSA) from poly mers such as macroporous poly(ethylene-co-vinyl acetate) (EVAc) matrices has been shown previously to be much slower than would be predicted from simple considerations of aqueous diffusion. Since drug is released through waterfilled pores, it is necessary to determine the mechanism underlying release retardation. Three mechanisms are considered: (1) concentration-dependent diffusion, (2) random pore topology, and (3) constricted pore geometry. The first two mechanisms are shown to be insufficient, in themselves or together, to account for the order of magnitude of retardation that is observed. The third mechanism, pore constrictions, can account for arbitrarily high retardations. Since the three mechanisms are essentially independent, their contributions to retardation can be considered to be multiplicative.

Mechanistic studies of macromolecular drug release from macroporous polymers. I. Experiments and preliminary theory concerning completeness of drug release

The release of the model polypeptide drug bovine serum albumin (BSA) from macroporous ethylene-vinyl acetate copolymer matrices has been investigated over a wide range of drug loadings and particle sizes. At low drug loadings a fraction of the drug is released relatively quickly from the matrix surface, but the remainder of the drug is virtually trapped within the matrix and is released at an extremely slaw rate. At high drug loadings all drug is released. A simple model of drug trapping, based on a modification to percolation theory, is proposed. The model predictions are qualitatively in agreement with the data, but are unable to predict certain quantitative features. It is suggested that the discrepancies are due to a nonuniform distribution of drug in the matrices, which is shown to exist by scanning electron microscopy.

Sintering Technique for the Preparation of Polymer Matrices for the Controlled Release of Macromolecules

A new method for making polymeric systems for the controlled release of macromolecular drugs is described. The method consists of mixing drug and polymer (ethylene-vinyl acetate copolymer) powders below the glass transition temperature of the polymer and compressing the mixture at a temperature above the glass transition point. The macromolecule is not exposed to organic solvent during the fabrication process. Kinetic studies indicate that there is sustained release, and the bioactivity of macromolecules tested is unchanged throughout the sintering and release processes.