Ocular inserts for controlled release of antibiotics

Ocular inserts impregnated with antibiotics (erythromycin and erythromycin estolate) which have sustained release characteristics were prepared, mainly for the purpose of trachoma therapy. In vitro experiments showed that the elution rate of a drug with low solubility in water (erythromycin estolate) is constant when the water content of the hydrogel insert is more than 30%. In the case of a drug with higher solubility (erythromycin), the elution rate depends on the water content. Some in vivo experiments using rabbit eyes were also reported.     

Polyanhydrides for controlled release of bioactive agents

This report is a review of the development of a drug delivery system based on biorodible polyanhydrides. With the water labile anhydride linkage, a wide range of matrix degradation and drug release rates can be obtained from these drug-carriers. In addition to monolithic formulations, the feasibility of an injectable system by microencapsulation is demonstrated. The possibility of enhancing the release externally by an ultrasonic source has also been explored. The polymers tested showed good tissue biocompatibility and their breakdown products showed no adverse toxicological effects. Preliminary in vivo results confirmed the efficacy of these devices.     

Aliphatic polyesters and cellulose-based polymers for controlled release applications

The general technologies for fabricating drug delivery systems are briefly discussed in the present review. Furthermore, two types of commonly used polymers, biodegradable aliphatic polyesters for parenteral administration and cellulose-based polymers for oral uses, are presented by means of selected examples of their properties and applications to control drug release.     

New hydrophilic polyesters and related polymers as bioerodible polymeric matrices

A survey is reported on our activity performed in the last few years on the preparation of new synthetic and semisynthetic polymeric materials endowed with bioerodible-biodegradable characteristics and designed for applications in the practice of controlled release of active principles of pharmaceutical and agrochemical significance. The presentation of the results will be arranged into the following sections: (1) hydroxyl containing polyesters, that comprise polymerization products based on racemic and optically active glyceric acid, or attained by polyaddition reactions among cyclic anhydrides, including also carbon dioxide, with monoglycidyl ethers of reversibly protected polyols. In this class are also presented the related polyhydroxylated systems obtained by selective grafting functional epoxides on cyclodextrins. (2) Bioerodible carboxyl containing plolymeric systems as derived from the alternating copolymerization of maleic anhydride with alkyl vinyl ethers followed by partial esterification of maleic anhydride groups. (3) Linear and cross-linked functional polymers of synthetic and semisynthetic origin with hydrogel forming capability. Typical examples of their applications in the release of drugs and phytodrugs are also presented.     

Co-extrusion of biocompatible polymers for scaffolds with co-continuous morphology

A methodology for the preparation of porous scaffolds for tissue engineering using co-extrusion is presented. Poly(epsilon-caprolactone) is blended with poly(ethylene oxide) in a twinscrew extruder to form a two-phase material with micron-sized domains. Selective dissolution of the poly(ethylene oxide) with water results in a porous material. A range of blend volume fractions results in co-continuous networks of polymer and void spaces. Annealing studies demonstrate that the characteristic pore size may be increased to larger than 100 microm. The mechanical properties of the scaffolds are characterized by a compressive modulus on the order of 1 MPa at low strains but displaying a marked strain-dependence. The results of osteoblast seeding suggest it is possible to use co-extrusion to prepare polymer scaffolds without the introduction of toxic contaminants. Polymer co-extrusion is amenable to both laboratory- and industrial-scale production of scaffolds for tissue engineering and only requires rheological characterization of the blend components. This method leads to scaffolds that have continuous void space and controlled characteristic length scales without the use of potentially toxic organic solvents.     

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.     

In vitro release characteristics of hard shell capsule products coated with aqueous- and organic-based enteric polymers

In this article, an overview of the rationale for the use of enteric coated (EC) dosage forms is presented. The benefits and disadvantages inherent in the use of aqueous dispersions and organic solutions of the various polymers to generate these products are discussed. The comparative dissolution stability of a hard shell capsule product coated with enteric polymers applied as either aqueous dispersions, or as organic solutions, were assessed under accelerated conditions of storage. Polymethacrylic acid methacrylate copolymer, cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP), along with the corresponding commercially available aqueous dispersions, Eudragit L30D, Aquateric, and Coateric, were employed in these studies as enteric polymers. Diethyl phthalate (DEP) was used as the plasticizer and procainamide HCl 250 mg capsules served as the substrate. Storage of the coated capsules at 37 degrees C/80% RH and at 45 degrees C for 2 months revealed that, while the stability of Eudragit L30D coatings are comparable or superior to the corresponding organic-based coatings, Coateric films are markedly unstable when compared with PVAP coatings applied through the use of organic vehicles. After storage at 37 degrees C/80% RH, Aquateric-based capsules demonstrated stability comparable to CAP organic-based coatings only when a protective seal coat was present. The performance failures of the capsules that occur upon storage primarily result in a loss of gastric resistance. Scanning Electron Microscopy (SEM) and thermomechanical analysis (TMA) of the different coatings revealed differences in the film-forming properties of the polymer films and provide an explanation for the changes that occur during storage of the coated capsules.     

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.     

Gallic acid loaded disulfide cross-linked biocompatible polymeric nanogels as controlled release system: synthesis,characterization, and antioxidant activity

In this article, a sustained release formulation of the antioxidant gallic acid (GA) is presented in the form of glutathione responsive disulfide cross-linked poly(ethylene glycol)-based nanogels synthesized via aqueous inverse miniemulsion using atom transfer radical polymerization. The particle size was found to be in the range from 227?±?51.78 to 573.3?±?207.2?nm at three drug loading levels achieved i.e. 6.6, 14.26, and 18.29 wt.% of the nanogels with loading efficiency in the range of 60–70%. The release profile of the GA studied at three drug loading levels suggested a controlled release and the nanogels were capable of scavenging radicals and retained the antioxidant activity. The GA-loaded nanogels were found to be biocompatible on human cervical cancer cell lines (HeLa). DCFH-DA (2,7-dichlorofluorescin diacetate) assay evidenced that the nanogels were capable of scavenging the reactive oxygen species in cellular environment.     

Swelling properties of various polymers used in controlled release systems

The effect of powder packing and porosity of specimens on the swelling properties of polymeric materials was studied, in various swelling liquids, such as distilled water and 0.1 N hydrochloric acid solution. Capsules, tablets and films of hydroxypropyl methylcellulose, poly(ethylene oxide) and sodium alginate were prepared, and their weight uptake after immersion into the above solutions was recorded as a function of time, in order to assess the swelling process. Measurements of some characteristics of the as-received powders were also performed in an attempt to classify the specimens prepared according to their porosity. Within the experimental conditions of this work, it was shown that the porosity of polymeric specimens is a dominant factor that controls their swelling behaviour. Increased porosity leads to fast initial rates of weight uptake and high extent of equilibrium swelling. On the other hand, dissolution and possible degradation of polymers susceptible to acid hydrolysis results in some variations from the above mentioned behaviour. With respect to the application in controlled release systems, the overall delivery rate from a polymeric specimen is expected to be a function of both swelling and disintegration characteristics of a specimen, and therefore, the weight uptake can be considered a measure of the release only in the case of polymers with low water solubility and increased stability to hydrolysis.     

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.     

Antimicrobial activity of polymers coated with iodine-complexed polyvinylpyrrolidone

Polymer-associated infection is a problem of increasing importance in modern medicine. In a new approach to prevent such infections we have modified polyvinylfluoride (TEDLAR) films by graft copolymerization with N-vinylpyrrolidone to which iodine can be complexed. Grafting reaction was performed by the preirradiation technique using an electron accelerator. Grafted films were then treated in Lugol's solution for at least 24 h. Release of free iodine from the films was determined either by titration or using the agar disc diffusion test, showing an iodine release for up to 4-5 days. The antimicrobial activity of the films was tested in bacterial adhesion measurements. Bacterial and fungal cells in the range of 10(3) to 10(6) cfu/cm2 polymer were found on control samples without iodine, whereas on iodine-complexed films no viable cells could be detected at least for 5 days or even longer. Thus, microbial adhesion and growth can be inhibited by iodine-containing polymers.     

Poly(lactic-co-glycolic acid) electrospun fibrous meshes for the controlled release of retinoic acid

Poly(lactic-co-glycolic acid) (PLGA) meshes loaded with retinoic acid (RA) were prepared by applying the electrospinning technique. The purpose of the present work was to combine the biological effects of RA and the advantages of electrospun meshes to enhancing the mass transfer features of controlled release systems and cell interaction with polymeric scaffolds. The processing conditions for the fabrication of three-dimensional meshes were optimized by studying their influence on mesh morphology. Tensile testing showed that RA loading influenced the meshes’ mechanical properties by increasing their strength and rigidity. Moreover, the drug release and degradation profiles of the electrospun systems were compared to analogous RA-loaded PLGA films prepared by solvent casting. The results of this study highlight that the electrospun meshes preserved their fibrous structure after 4 months under in vitro physiological conditions and showed a sustained controlled release of the loaded agent in comparison to that observed for cast films. The bioactivity of the loaded RA was investigated on murine preosteoblasts cells by evaluating its influence on cell proliferation and morphology.     

Swelling properties of various polymers used in controlled release systems.

The effect of powder packing and porosity of specimens on the swelling properties of polymeric materials was studied, in various swelling liquids, such as distilled water and 0.1 N hydrochloric acid solution. Capsules, tablets and films of hydroxypropyl methylcellulose, poly(ethylene oxide) and sodium alginate were prepared and their weight uptake after immersion into the above solutions was recorded as a function of time, in order to assess the swelling process. Measurements of some characteristics of the as received powders were also performed as an attempt to classify the specimens prepared according to their porosity. Within the experimental conditions of this work, it was shown that the porosity of polymeric specimens is a dominant factor that controls their swelling behaviour. Increased porosity leads to fast initial rates of weight uptake and high extent of equilibrium swelling. On the other hand, dissolution and possible degradation of polymers susceptible to acid hydrolysis, results in some variations from the above-mentioned behaviour. With respect to the application in controlled release systems, the overall delivery rate from a polymeric specimen is expected to be a function of both swelling and disintegration characteristics of a specimen and, therefore, the weight uptake can be considered a measure of the release only in the case of polymers with low water solubility and increased stability to hydrolysis.     

Bioactive polymers: in vitro and in vivo study of controlled release neomycin.

Neomycin is coupled on xanthan-a polysaccharide of microbial biosynthesis produced by Xanthomonas campestris-through ionic complexation. The kinetics of neomycin release, in vitro, at pH = 8.2 is studied. A controlled release of neomycin, following a zero order kinetics is observed, regardless of the eluent flow. Neomycin complexed on xanthan, administered in a unique daily dose to patients suffering from dysentery in the 100 cases taken in study, has shown a high clinical efficiency as compared with the treatments with ampicillin or furazolidone, administered for 5-10 days or longer.     

Fabrication of magnetic nanoparticles armed with quaternarized N-halamine polymers as recyclable antibacterial agents

Magnetic recyclable bactericidal nanocomposites (Fe₃O₄@PDMC) were well-designed and prepared by coating of Fe₃O₄ nanoparticles with quaternarized N-halamine polymers via the free radical polymerization process. In which, 5,5-dimethylhydantoinyl-(3-ethyl-methacrylamine)propyl dimethylammonium bromide (DEMPA), a new monomeric N-halamine precursor, was used as a coating material as well as the dual-functional bactericidal agent. The developed Fe₃O₄@PDMC nanocomposites exhibited suitable size and super-paramagnetic responsibility. The antibacterial results showed that the Fe₃O₄@PDMC nanocomposites had excellent biocidal abilities against Staphylococcus aureus (gram-positive) and Escherichia coli (gram-negative). Furthermore, the TTC (Triphenyl Tetrazolium Chloride)–dehydrogenase activity assay confirmed that the reductions of the bacteria were mainly attributed to powerful biocidal effects of the coating polymer instead of bacteria capture by the cationic surface. Interestingly, due to the magnetic responsive performance of Fe₃O₄, the as-prepared Fe₃O₄@PDMC nanocomposites can be recycled by a magnet and reused for antibacterium through the quenching/rechlorination procedure. All the results presented in this study show that the proposed Fe₃O₄@PDMC nanocomposites could be a competitive candidate for water purification systems and household sanitation.     

Gel casting of resorbable polymers. 1. Processing and applications.

A gel casting technique based on resorbable, synthetic, alpha-polyesters (or lactide-glycolide polymers) is described for producing medical implants such as bone graft substitutes and timed-release carriers for medication. This solution-based method enables production of thick-section solid and microporous materials, and blending of polymers and particulate fillers. Implant degradation rate, for example, may be adjusted by variation of polymer type, molecular weight range, crystallinity and morphology. Gel casting conditions are reported for solid and microporous materials and processing characteristics are interpreted in terms of established crystallization and dissolution behaviour of polymers.     

Silica sol-gel for the controlled release of antibiotics. I. Synthesis, characterization, and in vitro release

Room temperature processed silica sol-gel (xerogel) was investigated as a novel controlled release carrier of antibiotics (vancomycin). Xerogel characteristics, in vitro release properties, and bactericidal efficacy of the released antibiotic were determined. The xerogel/vancomycin composite showed a long-term sustained release (up to 6 weeks). In addition, bactericidal efficacy of released vancomycin was retained. The kinetics of release and the amount released were dose dependent. The initial, first-order release was followed by a near-zero-order release. The time to transition from the first- to zero-order release increased with vancomycin load (from 2 to 3 weeks with load increase from 2.2 to 11.1 mg/g). Regardless of the load, about 70% of the original vancomycin content was released by the transitional point, and the cumulative release after 6 weeks of immersion was about 90%. This study, combined with other reports documenting biocompatibility and controlled resorbability of the xerogel/drug composite in vivo, suggests that silica xerogel is a promising controlled release material for the treatment of bone infections.     

Sustained and controlled release of neuroactive substances in the CNS by encapsulation into implantable polymers

Implantable drug-polymer matrices have great potential as sources for drug administration into the CNS. Their size and release characteristics can be adjusted by design, they provide protection of the encapsulated drug from premature metabolism or inactivation, and they can provide long-term constant or modulated drug release into discrete regions of the brain. However, they may not prove useful for the administration of neuroactive substances which require adjustment or discontinuation of dosage.