Structured drug-eluting bioresorbable films: microstructure and release profile

Bioresorbable drug-eluting films can be used in many biomedical applications. Examples for such applications include biodegradable medical support devices which combine mechanical support with drug release and antibiotic-eluting film coatings for prevention of bacterial infections associated with orthopedic implants or during gingival healing. In the current study, bioresorbable drug-loaded polymer films are prepared by solution processing. Two film structures are studied: A polymer film with large drug crystals located on its surface (A-type) and a polymer film with small drug particles and crystals distributed within the bulk (B-type). The basic mode of drug dispersion/location in the film (A or B-type) is found to be determined mainly by the process of film formation and depends mainly on the solvent evaporation rate, whereas the drug's hydrophilicity has a minor effect on this structuring process. Most release profiles from A-type films exhibit a burst effect of approximately 30% and a second release stage that occurs at an approximately constant rate and is determined mainly by the polymer weight loss rate. An extremely high burst release is exhibited only by a very hydrophilic drug. The matrix (monolithic) nature of the B-type film enables release profiles that are determined mainly by the host polymer's degradation profile, with a very low burst effect in most of the studied systems. In addition to the drug location/ dispersion in the film, the host polymer and drug type also strongly affect the drug's release profile from the film. It has been demonstrated that appropriate selection of the process parameters and film components (polymer and drug) can yield film structures with desirable drug release behaviors. This can lead to the engineering of new bioresorbable drug-eluting film-based implants for various applications.     

Drug controlled release from structured bioresorbable films used in medical devices--a mathematical model

A mathematical model for predicting drug release profiles from structured bioresorbable films was developed and studied. These films, which combine good mechanical properties with desired drug release profiles, are designed for use in various biomedical applications. Our structured polymer/drug films are prepared using a promising technique for controlling the drug location/dispersion in the film. The present model was used for predicting drug release profiles from two film types that is films in which the drug is located on the surface (A-type) and films in which the drug is located in the bulk (B-type). The model is based on Fick's 2nd law of diffusion and assumes that the drug release profile from the films is affected by the host polymer's characteristics, the drug location/dispersion in the film and the drug's characteristics. This semiempirical model uses the weight loss profile of the host polymers as well as the change in their degree of crystallinity with degradation. Our study indicates that the model correlates well with in vitro release results, exhibiting a mean error of less than 7% for most studied cases. It also shows that the host polymer's degradation has a greater effect on the drug release profile than the degree of crystallinity. This new model exhibits a potential for simulating the release profile of bioactive agents from structured films for a wide variety of biomedical applications.     

Porous silicon-poly(ε-caprolactone) film composites: evaluation of drug release and degradation behavior

This work focuses on an evaluation of novel composites of porous silicon (pSi) with the biocompatible polymer ε-polycaprolactone (PCL) for drug delivery and tissue engineering applications. The degradation behavior of the composites in terms of their morphology along with the effect of pSi on polymer degradation was monitored. PSi particles loaded with the drug camptothecin (CPT) were physically embedded into PCL films formed from electrospun PCL fiber sheets. PSi/PCL composites revealed a release profile of CPT (monitored via fluorescence spectroscopy) in accordance with the Higuchi release model, with significantly lower burst release percentage compared to pSi microparticles alone. Degradation studies of the composites, using gravimetric analysis, differential scanning calorimetry (DSC), and field emission scanning electron microscopy (FESEM), carried out in phosphate-buffered saline (PBS) under simulated physiological conditions, indicated a modest mass loss (15%) over 5 weeks due to pSi dissolution and minor polymer hydrolysis. DSC results showed that, relative to PCL-only controls, pSi suppressed crystallization of the polymer film during PBS exposure. This suppression affects the evolution of surface morphology during this exposure that, in turn, influences the degradation behavior of the polymer. The implications of the above properties of these composites as a possible therapeutic device are discussed.     

Highly porous bioresorbable scaffolds with controlled release of bioactive agents for tissue-regeneration applications

Highly porous poly(dl-lactic-co-glycolic acid) films with controlled release of horseradish peroxidase (HRP) as a model protein have been successfully developed and studied. These films, which are prepared by freeze-drying inverted emulsions, are designed for use in tissue-regeneration applications. The effects of the emulsion’s formulation and host polymer’s characteristics on the film’s microstructure and HRP release profile over 4 weeks were investigated. A dual pore size population is characteristic for most films, with large 12–18 μm pores and small 1.5–7 μm pores, and porosity in the range of 76–92%. An increase in the polymer content and its initial molecular weight, organic/aqueous (O:A) phase ratio and lactic acid content, or a decrease in the HRP content, all resulted in a decreased burst effect and a more moderate release profile. A simultaneous change in two or three of these formulation parameters (compared to a reference formulation) resulted in a synergistic effect on the HRP release profile. A constant HRP release rate was achieved when a composite film was used. Human gingival fibroblast adhesion to the films indicated good biocompatibility. Appropriate selection of the emulsion’s parameters can therefore yield highly porous films with the desired protein-release behavior which can serve as scaffolds for bioactive agents in tissue-regeneration applications.     

The effect of initial polymer morphology on the degradation and drug release from polyglycolide

Polyglycolide is a degradable polyester which has been proposed for use as a matrix for controlled drug release. This paper assesses the effects of the initial morphology of the polymer on its behaviour during hydrolytic degradation. The initial morphology does not have a dramatic effect on the progress of degradation, the levels of crystallinity attained during the early stages of degradation being independent of the initial morphology. A sudden increase in both the mass loss and water uptake of the samples occurs after 10 days regardless of the initial morphology, and this is attributed to the formation of a porous surface layer, which occurs when the polymer matrix reaches a critical molecular weight. However, the initial morphology does affect the release profiles of a model drug, theophylline, from the matrices. Samples with a higher initial crystallinity release more drug at earlier stages of the degradation. This is probably due to a partitioning of drug molecules to the surfaces and an increase in the concentration of drug in the amorphous phase.     

Sustained release system for highly water-soluble radiosensitizer drug etanidazole: irradiation and degradation studies

Etanidazole (one nitro-imidazole hypoxic radiosensitizer) is formulated as polymer matrix type controlled release devices in this study. A novel double polymer drug carrier, unlike the double wall microparticles, is fabricated for the purpose of drug delivery, with the following objectives in mind: (1) to have a high encapsulation efficiency, (2) to achieve a pusatile release profile suitable for the radiation schedule of radiotherapy, (3) to elucidate the degradation profile of these microparticles. Irradiation of the microparticles were also studied to investigate effects on release and degradation. At a dosage of 50 Gy (total dosage during a radiotherapy treatment period) showed no apparent effects on the tri-phase release profile. It consists of an initial burst in the first 72 h, followed by a slow and steady drug release phase, and finally a faster degradation controlled phase corresponding to the degradation state of the different microparticles. At 25 kGy (sterilization dosage), the release profiles of the drug carrier were drastically modified. The faster erosion of the polymer with high dosage irradiation hastened the drug release and shortened the release time span, accompanied by decreases in the polymer molecular weight and glass transition temperatures, which was not apparent from SEM imaging. Degradation studies suggested a heterogeneous degradation process, with the outer layer and inner matrix degrading at different rates. The modifiable tri-phase release profile using microparticles of different polymer blends implies that the release properties of the drug carriers can be modified for different treatment regimes.     

Microstructure and drug-release studies of sirolimus-containing poly(lactide-co-glycolide) films

Sirolimus-containing poly(lactide-co-glycolide) (PLGA) films were prepared by solution casting and removing the residual solvent, 1,4-dioxane, by liquid and supercritical carbon dioxide (CO(2) ) extraction. The effect of lactide:glycolide ratio, stereochemistry of PLGA, and extraction condition (i.e., temperature and pressure) on the polymer and drug morphologies was studied using wide-angle X-ray scattering and differential scanning calorimetry. The polymer and drug crystallinity increased after liquid and supercritical CO(2) extraction, and the level of drug crystallinity within the film depended on the extraction conditions. Generally, higher levels of drug crystallinity were observed in the films with amorphous polymer matrices, and the drug crystallinity increased with temperature and pressure of the extraction conditions. In vitro drug elution from these films was studied using a USP 4 apparatus. Polymer crystallinity was found to be the determining factor for drug release, whereby films with higher polymer crystallinity eluted less drug compared to films with amorphous polymer matrices.     

Controlled release of complexed DNA from polycaprolactone film: comparison of lipoplex and polyplex release

This report investigates the comparative in vitro controlled release and transfection efficiencies of pDNA-lipofectamine complex (lipoplex) and pDNA-poly(ethylene imine) complex (polyplex), from a biodegradable polycaprolactone (PCL) film. The effect of molecular weight of gelatin used as a porogen on in vitro release and transfection efficiency was also studied. A sustained release profile was obtained for naked pDNA and lipoplex from polymeric films for a month, while the release of polyplexes (PEI/DNA) is simply a burst at day 5, with little or no release thereafter. The release of polyplexes from PCL films is retarded due to interaction between the polyplexes and the polymer. A high burst release was seen for naked pDNA which was suppressed in the presence of gelatin. The extent of suppression of the burst effect by gelatin increased with its molecular weight. For complexed pDNA (lipoplex), the release was slow, but could be accelerated using gelatin; again the acceleration in release is dependant on the molecular weight of the gelatin used. The addition of gelatin as a porogen has no effect on the release of polyplexes from PCL films. The bioactivity of released plasmid DNA and complexes was studied by in vitro transfection using COS-7 cells. Transfection was observed from released lipoplexes samples till day 9 from PCL film with lower MW gelatin and till day 18 in the case of PCL films with higher MW gelatin. The results also showed that the bioactivity of released lipoplexes was superior to that of the naked pDNA.     

In vitro study of drug-loaded bioresorbable films and support structures

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable poly(L-lactic acid) (PLLA) films containing dexamethasone were prepared by solution processing methods. Their in vitro studies focused on the mechanical properties with respect to morphology and degradation and erosion processes. Novel expandable support devices (stents) developed from these films were studied. Such a stent would support conduits, such as the neonatal trachea to treat tracheal malacia, until the airway matures, and would then be totally resorbed, obviating the need for a removal operation. The PLLA films showed good initial mechanical properties. They can accommodate drug incorporation on the film surface and also in the bulk. Water incubation of the films results in a decrease in their tensile mechanical properties, due to chain scission and morphological changes. These changes can vary from degradation and small changes in morphological features to erosion, leading to a microporous structure, depending on the polymer. The cumulative release of dexamethasone from the films is linear. The rate of release is determined by the film's structure (drug location/dispersion). The stents demonstrated good mechanical properties. The initial radial compression strength of the stent is determined mainly by the polymer structure. Drug incorporation has a minor effect on the initial stent strength. Exposure to radial compression stress results in elastic reversible deformation or a sudden brittle fracture, depending on the polymer. A 20-week in vitro study of the stents showed that they are applicable for supporting body conduits, such as the trachea.     

In vitro study of drug-loaded bioresorbable films and support structures

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable poly(L-lactic acid) (PLLA) films containing dexamethasone were prepared by solution processing methods. Their in vitro studies focused on the mechanical properties with respect to morphology and degradation and erosion processes. Novel expandable support devices (stents) developed from these films were studied. Such a stent would support conduits, such as the neonatal trachea to treat tracheal malacia, until the airway matures, and would then be totally resorbed, obviating the need for a removal operation. The PLLA films showed good initial mechanical properties. They can accommodate drug incorporation on the film surface and also in the bulk. Water incubation of the films results in a decrease in their tensile mechanical properties, due to chain scission and morphological changes. These changes can vary from degradation and small changes in morphological features to erosion, leading to a microporous structure, depending on the polymer. The cumulative release of dexamethasone from the films is linear. The rate of release is determined by the film's structure (drug location/dispersion). The stents demonstrated good mechanical properties. The initial radial compression strength of the stent is determined mainly by the polymer structure. Drug incorporation has a minor effect on the initial stent strength. Exposure to radial compression stress results in elastic reversible deformation or a sudden brittle fracture, depending on the polymer. A 20-week in vitro study of the stents showed that they are applicable for supporting body conduits, such as the trachea.     

Structured drug-loaded bioresorbable films for support structures

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable PLLA films containing dexamethasone were developed through solution processing. The effect of processing parameters on the film morphology and the resulting mechanical properties was studied. A model describing the structuring of these films is suggested. Generally, the solvent evaporation rate determines the kinetics of drug and polymer crystallization and thus, both the mode of drug dispersion in the polymer and the resulting mechanical properties. Two types of structured films were studied: (1) a polymer film with drug located on its surface, obtained due to drug skin formation accompanied by a later polymer core formation; and (2) a polymer film with small drug particles and crystals distributed within the bulk, obtained by parallel solidification of the two components. A prototypical application of these films is an expandable biodegradable support structure (stent), which we have developed. This stent demonstrated good initial mechanical properties. The film structure has only a minor effect on the stent radial compression strength, but more significantly affects the tensile mechanical properties.     

Structured drug-loaded bioresorbable films for support structures.

Bioresorbable films can serve simultaneously as anatomic support structures and as drug delivery platforms. In the present study, bioresorbable PLLA films containing dexamethasone were developed through solution processing. The effect of processing parameters on the film morphology and the resulting mechanical properties was studied. A model describing the structuring of these films is suggested. Generally, the solvent evaporation rate determines the kinetics of drug and polymer crystallization and thus, both the mode of drug dispersion in the polymer and the resulting mechanical properties. Two types of structured films were studied: (1) a polymer film with drug located on its surface, obtained due to drug skin formation accompanied by a later polymer core formation; and (2) a polymer film with small drug particles and crystals distributed within the bulk, obtained by parallel solidification of the two components. A prototypical application of these films is an expandable biodegradable support structure (stent). which we have developed. This stent demonstrated good initial mechanical properties. The film structure has only a minor effect on the stent radial compression strength, but more significantly affects the tensile mechanical properties.     

Degradation of porous poly(D,L-lactic-co-glycolic acid) films based on water diffusion

Poly(D,L-lactic-co-glycolic acid) has been extensively used as a controlled release carrier for drug delivery due to its good biocompatibility, biodegradability, and mechanical strength. Effects of dense and porous film's degradation behavior have been systematically investigated up to 17 weeks in Hank's Simulated Body Fluid at 37 degrees C. The degradation of the films was studied by measuring changes in weight, molecular weight and its distribution, morphology, composition etc.. A special thing was that the differences in water diffusion in dense and porous structure films caused the different degradation behavior. According to the characteristic changes of various properties of films, the degradation process is suggested to be roughly divided into four stages, tentatively named as water absorption stage, dramatic loss of molecular weight or micro-pores formed stage, loss of weight or enlarged-pores formed stage, pores diminished or pores collapse stage.     

Antibiotic-eluting bioresorbable composite fibers for wound healing applications: Microstructure,drug delivery and mechanical properties

Novel antibiotic-eluting composite fibers designed for use as basic wound dressing elements were developed and studied. These structures were composed of a polyglyconate core and a porous poly(dl-lactic-co-glycolic acid) shell loaded with one of three antibiotic drugs: mafenide acetate, gentamicin sulphate and ceftazidime pentahydrate. The shell was prepared by the freeze-drying of inverted emulsions. The fiber investigation focused on the effects of the emulsion’s formulation on the shell microstructure and on the resulting profile of drug release from the fibers. Albumin was found to be the most effective surfactant for stabilizing the inverted emulsions and also to have a beneficial holdup effect on the release kinetics of the hydrophilic antibiotic drugs, especially mafenide acetate, probably through a specific interaction. An increase in the organic:aqueous phase ratio, polymer content or molecular weight of the host polymer resulted in a decrease in the burst release and a more moderate release profile due to changes in shell microstructure. The first two parameters were found to be more effective than the third. The diverse release profiles obtained in the current study and the good mechanical properties indicate that our new composite fibers have good potential for use in wound healing applications.     

Morphology, drug distribution, and in vitro release profiles of biodegradable polymeric microspheres containing protein fabricated by double-emulsion solvent extraction/evaporation method

The surface and internal morphology, drug distribution and release kinetics at 22 degrees C of polyesters such as PCL (polycaprolactone) and PLGA (poly(DL-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM (confocal laser scanning microscope) micrographs reveal that the polyvinylalcohol (PVA as an emulsifier) concentration in the external water phase strongly influences drug distribution within microspheres and release profiles. The presence of PVA in the internal water phase enhances the stabilization of inner water droplets against coalescence. This results in a more uniform drug distribution and a slower BSA release. Different oil-phase volumes and polymer concentrations yield different solvent exchange and precipitation mechanisms, which lead to different morphologies. A low oil-phase volume yields microspheres with a porous matrix and defective skin surface, which gives a high initial BSA burst as well as a fast release profile. Microspheres fabricated from a low polymer concentration have less defective skin surface, but with a less tortuous inner matrix which results in a more rapid BSA release. A higher BSA loading yields a larger concentration gradient between the emulsion droplet and the continuous water phase as well as between the microspheres and the in vitro medium. The former results in a lower encapsulation efficiency, whereas the latter yields a faster initial burst and a more rapid release profile. High stirring speed can reduce microsphere size, but decreases the yield of microspheres.     

Rheological properties of PLGA film-based implants: correlation with polymer degradation and SPf66 antimalaric synthetic peptide release

This paper reports on the rheological properties of poly(D,L-lactic-co-glycolic acid) polymers (PLGA) dispersions used to form films and of the implants prepared by compression of SPf66 antimalaric peptide between several films, before application and during drug release. 25% PLGA (M(w)=48,000Da) dispersions in dichloromethane showed viscous Newtonian behaviour, being easy flowing and adaptable to the moulds. Evolution of viscoelastic properties, polymer molecular weight, and SPf66 release pattern from the implants immersed in various media was evaluated. Oscillatory shear test showed that freshly prepared implants have an elastic modulus, G', greater than the viscous modulus, G", being both practically independent of angular frequency. After 6 weeks immersion in a pH 7.4 phosphate buffer, G' and G" increased in almost one order of magnitude, despite of a significant polymer degradation. Polymer molecular weight decreased slowly during the first 10 days of immersion (a similar pattern was obtained at pHs 2 and 7.4) and then the degradation process accelerated (degradation index on day 7 equals to 0.89, and on day 14 equals to 16.5). SPf66 release profile followed a pattern similar to that of the polymer degradation index. These observations are explained in terms of changes in polymer structure and conformation that happen in the implant.     

In vitro degradation of insulin-loaded poly (n-butylcyanoacrylate) nanoparticles

Poly (n-butyl cyanoacrylate) (PBCA) nanoparticles were prepared by a dispersion polymerisation process in water at pH 3 and using dextran as a stabilising agent. The drug insulin was introduced during the latter stages of particle synthesis and was found not to interfere with the polymer structure, molecular weight, and the particle size. Nanoparticles were exposed to the enzyme esterase in phosphate buffered saline solution at 37 degrees C for time periods up to 4h. Esterase catalyses the degradation of the PBCA through hydrolysis of the side chain on the repeat unit with the release of butanol, and this was monitored as an indicator of degradation. The release of both butanol and insulin occurred via similar biphasic processes, with an initial burst release from the surface, followed by a slower diffusionally hindered release associated with particle erosion. Hydrolysis of the nanoparticle polymer was confirmed by infrared spectroscopy. Particle size reduces with time of exposure to esterase, but is greatest in the first 30 min of exposure. Despite the hydrolysis reaction, and reduction in particle size, there was no reduction in residual polymer molecular weight suggesting a progressive loss of entire chains from the active surface. Polymer loss is thought to occur through either solvation of degradation residue or through complete depolymerisation of hydrolysed chains.     

Hydrolytic degradation and drug release properties of ganciclovir-loaded biodegradable microspheres

The in vitro hydrolytic degradation of ganciclovir (GCV)-loaded biodegradable microspheres of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers were studied. Microspheres of size 120+/-40 microm were prepared using an oil-in-water emulsification/solvent evaporation technique. The effects of polymer molecular weight, lactide (LA) to glycolide (GA) ratio and GCV payload on the degradation and drug release profiles were investigated in vitro in phosphate-buffered solution (pH 7.0) at 37 degrees C. GCV accelerated the hydrolysis process of the low (5-7 wt.%) GCV-loaded microspheres due to a basic catalytic effect, giving a larger degradation rate, k', compared with blank and high (18-20 wt.%) GCV-loaded microspheres. In the high GCV-loaded microspheres, hydrolysis of the polymer backbone occurred with little and/or no autocatalytic effect, resulting in a smaller k' compared with low GCV-loaded microspheres. This was due to pores and microchannels created at the surface following the initial burst release, which increased water uptake and the dissolution and diffusion of GCV and degradation products from the matrix. The rate of hydrolytic degradation was also affected by the LA to GA ratio. For polymers of similar LA to GA ratio, those with a higher degree of blockiness had faster hydrolytic degradation rates irrespective of the initial molecular weight. The release profile had a biphasic pattern, which closely followed the degradation profile of the polymer. The time taken for the complete release of GCV was controlled by the diffusion phase and was dependent on the hydrolytic degradation rate of the polymers.     

Gentamicin-loaded bioresorbable films for prevention of bacterial infections associated with orthopedic implants

Adhesion of bacteria to biomaterials and the ability of many microorganisms to form biofilms on foreign bodies are well-established as major contributors to the pathogenesis of implant-associated infections. Treatment of bone infection remains problematic, due to the difficulty of systemically administered antibiotics to locally penetrate bone. The current research addresses this issue by focusing on the development and study of novel gentamicin-loaded bioresorbable films designed to serve as "coatings" for fracture fixation devices and prevent implant-associated infections. Poly(L-lactic acid) and poly (D,L-lactic-co-glycolic acid) films containing gentamicin were developed through solution processing. The effects of polymer type, drug content, and processing conditions on the drug release profile were studied with respect to film morphology. The examined films generally exhibited a burst effect followed by a moderate approximately constant rate of release. The drug contents in the surrounding medium exceeded the required minimal effective concentration. Various gentamicin concentrations that were released from the films with time exhibited efficacy against bacterial species known to be involved in orthopedic infections. The developed systems can be applied on the surface of any metallic or polymeric fracture fixation device, and may therefore comprise a significant contribution to the field of orthopedic implants.     

A novel model and experimental analysis of hydrophilic and hydrophobic agent release from biodegradable polymers

Many factors affect the rate of drug release from biodegradable polymers. Here, we focus on investigating the effect of drug type on the degradation of P(DL)LGA 53/47 films and their ultimate release profiles. A freely water-soluble drug (metoclopramide monohydrochloride) exhibited an initial burst, whereas a water-insoluble drug (paclitaxel) exhibited an initial latent period with very little drug release. The onset of the second-stage release of the hydrophobic drug was delayed as compared with the hydrophilic drug. Overall, complete release of metoclopramide monohydrochloride was achieved much earlier than paclitaxel. In addition, the hydrophobic drug exhibited an extra stage of release when compared with the two-stage release for the hydrophilic drug. A novel model was developed to describe the underlying drug release mechanisms and kinetics. The model postulated that the total fraction of drug release from bulk-degrading polymer is a summation of three mechanisms: burst release, relaxation induced/drug-dissolution controlled release, and diffusional release. All the three steps are important for hydrophobic drugs. However, for hydrophilic drugs, burst and diffusional release steps are sufficient to account for the whole release process. The proposed model showed very good match with the experimental data.