Control of protein delivery from amphiphilic poly(ether ester) multiblock copolymers by varying their water content using emulsification techniques.

Protein-containing films and microspheres, based on poly(ethylene glycol)-poly(butylene terephthalate) (PEG-PBT) multiblock copolymers, were prepared from water-in-oil (w/o) emulsions. The properties of the matrices could be controlled by the water-to-polymer ratio (w/p) in the w/o emulsion. A linear increase in water uptake of the matrices was observed with increasing emulsion w/p. This could be explained by an increase in the number of dispersed water-rich domains in the polymer matrix. At low volume fraction of the dispersed phase (epsilon), lysozyme release was mainly dependent on the permeability of the swollen polymer bulk. Above a critical volume fraction (the percolation threshold epsilon(c)), the dispersed water-rich phase formed an interconnected network, which largely enhanced the permeability of the matrix. Determination of the permeability of PEG-PBT matrices for vitamin B(12) as a function of epsilon confirmed the formation of such an interconnected network. This interconnected network could be used to achieve controlled release of a large protein (bovine serum albumin, BSA) from PEG-PBT films and microspheres. Due to its hydrodynamic diameter, BSA was screened by the polymer network when epsilon was low. However above epsilon(c), the fraction released BSA increased with increasing volume fraction of the dispersed phase. A very rapid BSA release could be obtained, with the majority of the incorporated BSA released within 1 day, as well as a slow and continuous release, lasting for over 150 days. When BSA-containing microspheres were prepared with a volume fraction just below the percolation threshold, a delayed release was observed. This was attributed to the effect of polymer degradation on matrix permeability.     

Delivering DNA from photocrosslinked, surface eroding polyanhydrides.

Sustained delivery of DNA has the potential to enhance long-term gene therapy; however, precise control of a wide range of DNA release profiles may be needed. In this work, multifunctional anhydride monomers were photocrosslinked to produce hydrophobic, highly crosslinked polymer networks that degrade by surface erosion. Surface-eroding polymers can deliver molecules of a wide range of sizes at sustained, steady rates, which is advantageous for DNA delivery, where the high molecular weight may complicate control of the release profiles. When plasmid DNA was released from photocrosslinked polyanhydride matrices, DNA recovery was low (approximately 25%). Electrophoresis indicated that the plasmid DNA was released primarily in the relaxed and supercoiled forms, yet the relative fraction of released DNA in the supercoiled form decreased over time. To improve DNA recovery and reduce the damaging effects of polymer degradation, DNA was pre-encapsulated in alginate microparticles, which served as a temporary coating that quickly dissolved upon microparticle release from the polyanhydride matrix. As photocrosslinked polyanhydrides have highly predictable drug release profiles that depend on the polymer erosion rate and implant geometry and not on the entrapped molecule size, they can serve dual purposes in many biomaterial applications where structural support and drug release would be beneficial.     

Influence of micro-environmental pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices.

The purpose of this investigation is to understand the influence of gastrointestinal (GI) pH on the gel layer formation and its dynamics for various hydrophilic/swellable matrices, in the process of developing a pH-independent controlled release system for a basic drug, oxybutynin hydrochloride (OXB). Cylindrical matrices (8-mm diameter) without and with fumaric acid, were readily prepared by direct compression. Formulations were evaluated for in vitro drug release, and gel layer dynamics was studied by viscosity measurements and texture profiling analysis. In the in vitro drug release study, OXB, which shows pH-dependent solubility, showed faster release from all the matrices in pH 1.2 medium. Release rates enhanced to a lesser extent with change of medium from pH 6.8 to pH 1.2, for HPMC polymer matrices. Anionic polymer matrices showed drastic differences in the release rates when medium was changed from pH 6.8 to pH 1.2. Addition of fumaric acid to matrices demonstrated pH-independent drug release, which was attributed to the micro-environmental pH manipulation within the hydrated gel layer. Viscosity and texture profiling studies revealed that saturation solubility of drug at swelling front play a major role in the pH-dependent drug release from HPMC matrices, while both saturation solubility and the altered gel consistency as a function of pH are involved with anionic polymer matrices. Presence of fumaric acid in HPMC matrices showed efficient retardation and pH-independent drug release. In conclusion, understanding the influence of GI physiological pH on the gel layer dynamics and manipulating the micro-environmental pH provides efficient and predictable in vivo performance from these swellable cylindrical matrices.     

Controlled release of biomolecules from temperature-sensitive hydrogels prepared by radiation polymerization.

Poly(acryloyl-L-proline methyl ester)-based hydrogels containing 1 and 5% of a crosslinking agent were studied as drug delivery systems. The drug loading properties were investigated by matrix incubation into solutions containing biomolecules with molecular weight ranging between 300 and 65,000 Da. The loading yield was found to depend on both the crosslinking degree and the molecular weight of the drug. In vitro release studies were carried out with both swollen and dry matrices loaded with gentamicin, isoniazid and insulin. Gentamicin and isoniazid were released by a bimodal Fickian diffusion with a remarkable burst that was found to depend on both matrix crosslinking degree and physical state. In vivo, the subcutaneous implantation into mice of the isoniazid loaded matrices allowed for an efficient drug release for 800 h. In vitro insulin was released from the swollen matrices for 1500 h by diffusional Fickian mechanism while the dry ones displayed a lag time followed by Fickian diffusion release. The subcutaneous implantation of the insulin-loaded matrices into diabetic mice induced a remarkable decrease in the glucose concentrations in blood. In particular, the dry 1% matrices were found to maintain a low glucose level for 700 h.     

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.     

Control of drug release from polymer matrices impregnated with magnetic beads —a proposed mechanism and model for enhanced release

The need to regulate drug release rates in applications such as suppression of diabetic symptoms and birth control has previously led to the development of delivery systems containing small magnetic beads uniformly imbedded within drug-laden polymer matrices. An oscillating magnetic field imposed on such systems triggers a significant increase in release rate. A mechanism for enhanced release is proposed here, which draws upon the similarity between the observed increase in mass transfer by pulsation, e.g., promotion of axial diffusion in a cylinder with pulsed (but zero net) flow and enhanced drug release by the oscillating field. A mathematical model is derived based on this analogy. Its predictions are consistent with general observations and provide correlations of release rates with the frequency and amplitude of the oscillating magnetic field and the intrinsic drug diffusivity.     

Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization.

The objective of the present study was to synthesize novel pH-sensitive block copolymers forming supramolecular assemblies and to explore their potential as poorly water-soluble drug carriers for oral delivery. Diblock copolymers of polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n-butyl acrylate (nBA) were synthesized by atom transfer radical polymerization (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e., indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods. Process parameters for emulsion method were studied to maximize drug loading. Progesterone release was evaluated in vitro as a function of pH. Polymers with controlled molecular weights and low polydispersities were obtained by ATRP. All polymers exhibited pH-dependent aggregation behaviour and their critical aggregation concentration (CAC) decreased with increase in the hydrophobic block length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and emulsion methods, respectively. Polymer composition, drug concentration and solubilization of polymer in water or dichloromethane (DCM) affected the loading. Progesterone release from supramolecular assemblies increased when the pH of the release medium was raised from 1.2 to 7.2. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of poorly water-soluble drugs.     

Modifying the release of leuprolide from spray dried OED microparticles.

A range of oligosaccharide ester derivatives (OEDs) have been designed as drug delivery matrices for controlled release. The synthetic hormone analogue, leuprolide, was encapsulated within these matrices using hydrophobic ion pairing and solvent spray drying. The particles produced modified the release of leuprolide in vitro (dissolution in phosphate buffered saline) and in vivo (subcutaneous and pulmonary delivery in the rat). Release rate was dependent on drug loading and could be manipulated by choice of OED and by combining different OEDs in different ratios. Leuprolide encapsulated in the OEDs retained biological activity as evidenced by elevation in plasma luteinising hormone levels following subcutaneous injection of leuprolide recovered from OED particles in vitro prior to in vivo administration.     

Biodegradable cisplatiim microspheres prepared by the solvent evaporation method: Morphology and release characteristics

Various cisplatin-loaded microsphere systems have been prepared from d,l-lactic acid stereocopolymers and d,l-lactic acid/glycolic acid copolymers using a solvent evaporation process. The morphology of these systems depends very much on different factors: addition of extra cisplatin in the dispersing phase, drug loading, polymer molecular weights and polymer concentration in the organic phase. In vitro release profiles have been determined for the various systems. It has been found that drug release depends on the amount of entrapped drug, on the presence of extra cisplatin in the dispersing phase, and on polymer molecular weights. In contrast, the release of cisplatin seems to be independent of the presence ofglycolic units within polylactic chains, and of radiosterilisation, although irradiation dramatically affected polymer molecular weights of completed microspheres. Results are discussed with respect to microsphere processing and morphology, especially cisplatin crystal distributions within the microspheres. It is concluded that the viscosity of the organic phase, in which the polymer is dissolved at the processing stage, is a critical factor. Data collected are discussed in terms of a predominantly diffusional release mechanism by either polymer matrices or dissolution in channels depending upon cisplatin crystal distribution in microspheres and, to some extent, upon polymer degradation.     

Mathematical modeling and in vitro study of controlled drug release via a highly swellable and dissoluble polymer matrix: polyethylene oxide with high molecular weights.

A mathematical model is developed to describe the transport phenomena of a water-soluble small molecular drug (caffeine) from highly swellable and dissoluble polyethylene oxide (PEO) cylindrical tablets. Several important aspects in drug release kinetics were taken into account simultaneously in this theoretical model: swelling of the hydrophilic matrix and water penetration, three-dimensional and concentration-dependent diffusion of drug and water, and polymer dissolution. The moving boundary conditions are explicitly derived, and the resulting coupled partial differential equations are solved numerically. In vitro study of swelling, dissolution behavior of PEOs with different molecular weights and drug release are also carried out. When compared with experimental results, this theoretical model agrees with the water uptake, dimensional change and polymer dissolution profiles very well for pure PEO tablets with two different molecular weights. Drug release profiles using this model are predicted with a very good agreement with experimental data at different initial loadings. The overall drug release process is found to be highly dependent on the matrix swelling, drug and water diffusion, polymer dissolution and initial dimensions of the tablets. Their influences on drug release kinetics from PEO with two different molecular weights are also investigated.     

Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease.

This study describes the formulation, characterisation and preliminary clinical evaluation of mucoadhesive, semi-solid formulations containing hydroxyethylcellulose (HEC, 1-5%, w/w), polyvinylpyrrolidine (PVP, 2 or 3%, w/w), polycarbophil (PC, 1 or 3%, w/w) and tetracycline (5%, w/w, as the hydrochloride). Each formulation was characterised in terms of drug release, hardness, compressibility, adhesiveness (using a texture analyser in texture profile analysis mode), syringeability (using a texture analyser in compression mode) and adhesion to a mucin disc (measured as a detachment force using the texture analyser in tensile mode). The release exponent for the formulations ranged from 0.78+/-0.02 to 1. 27+/-0.07, indicating that drug release was non-diffusion controlled. Increasing the concentrations of each polymeric component significantly increased the time required for 10 and 30% release of the original mass of tetracycline, due to both increased viscosity and, additionally, the unique swelling properties of the formulations. Increasing concentrations of each polymeric component also increased the hardness, compressibility, adhesiveness, syringeability and mucoadhesion of the formulations. The effects on product hardness, compressibility and syringeability may be due to increased product viscosity and, hence, increased resistance to compression. Similarly, the effects of these polymers on adhesiveness/mucoadhesion highlight their mucoadhesive nature and, importantly, the effects of polymer state (particularly PC) on these properties. Thus, in formulations where the neutralisation of PC was maximally suppressed, adhesiveness and mucoadhesion were also maximal. Interestingly, statistical interactions were primarily observed between the effects of HEC and PC on drug release, mechanical and mucoadhesive properties. These were explained by the effects of HEC on the physical state of PC, namely swollen or unswollen. In the preliminary clinical evaluation, a formulation was selected that offered an appropriate balance of the above physical properties and contained 3% HEC, 3% PVP and 1% PC, in addition to tetracycline 5% (as the hydrochloride). The clinical efficacy of this (test) formulation was compared to an identical tetracycline-devoid (control) formulation in nine periodontal pockets (>/=5 mm depth). One week following administration of the test formulation, there was a significant improvement in periodontal health as identified by reduced numbers of sub-gingival microbial pathogens. Therefore, it can be concluded that, when used in combination with mechanical plaque removal, the tetracycline-containing semi-solid systems described in this study would augment such therapy by enhancing the removal of pathogens, thus improving periodontal health.     

Mechanism of drug release from poly( -lactic acid) matrix containing acidic or neutral drugs

The release profiles of acidic and neutral drugs from poly( -lactic acid) [P(L)LA] matrices were investigated to reveal their release mechanism. Cylindrical matrices (rods; 10 mm×1 mm diameter) were prepared by the heat compression method. The acidic and neutral drugs investigated were dissolved in the P(L)LA rods. It was found that the release profiles consisted of two sequential stages. At the first release stage, P(L)LA remained in an amorphous state and the drugs diffused through the hydrated matrices. At the second release stage, P(L)LA transformed to a semicrystalline state and the drugs diffused through water-filled micropores developed by polymer crystallization. In addition, the drugs were also found to precipitate out as crystals in the rods, resulting in a transformation of the rods into drug-dispersed matrices. On the basis of these findings, we derived a modified diffusion equation for the drug release at the second stage. This equation showed good fits to the release profiles of these drugs. Furthermore, the availability of the derived equation was supported by the acceleration in the fractional drug release rate noted both with decreases in the drug content in the rod and increases in the pH of the medium.     

Mechanism of drug release from poly(L-lactic acid) matrix containing acidic or neutral drugs.

The release profiles of acidic and neutral drugs from poly(L-lactic acid) [P(L)LA] matrices were investigated to reveal their release mechanism. Cylindrical matrices (rods; 10 mmx1 mm diameter) were prepared by the heat compression method. The acidic and neutral drugs investigated were dissolved in the P(L)LA rods. It was found that the release profiles consisted of two sequential stages. At the first release stage, P(L)LA remained in an amorphous state and the drugs diffused through the hydrated matrices. At the second release stage, P(L)LA transformed to a semicrystalline state and the drugs diffused through water-filled micropores developed by polymer crystallization. In addition, the drugs were also found to precipitate out as crystals in the rods, resulting in a transformation of the rods into drug-dispersed matrices. On the basis of these findings, we derived a modified diffusion equation for the drug release at the second stage. This equation showed good fits to the release profiles of these drugs. Furthermore, the availability of the derived equation was supported by the acceleration in the fractional drug release rate noted both with decreases in the drug content in the rod and increases in the pH of the medium.     

Investigation of the factors influencing the release rates of cyclosporin A-loaded micro- and nanoparticles prepared by high-pressure homogenizer.

An oil-in-water solvent evaporation method was used to prepare cyclosporin A (CyA)-loaded particles varying in size (nanoparticles, 'small-sized' microparticles, 'large-sized' microparticles), polymer compositions [poly(D,L-lactide-co-glycolic acid) (PLGA) 50/50, PLGA 85/15, poly(D,L-lactic acid) (PLA)] and additive fatty acid ester (ethyl myristate; EM). The particles were characterized for drug loading and entrapment efficiency by high-performance liquid chromatography, particle size by dynamic light scattering and surface morphology by scanning electron microscopy (SEM). In vitro release kinetics were studied using a modified dialysis method. The results showed drug loadings ranging from 6.48 to 9.01% with high encapsulation efficiency (71.2-98.9%). SEM studies showed discrete and spherical particles with smooth surfaces, whereas rather gross surface defects resulted from the incorporation of EM as an additive. The release profiles of various formulations approximated zero-order release kinetics in the first 3 weeks with a negligible initial burst. In general, the smaller the particle size and the higher the glycolic acid content in the copolymer, the faster the release of CyA. The effect of EM on the release profile appeared to be rather complex since an increased release rate was observed from EM containing PLGA 50/50 particles, whereas the incorporation of EM into the PLGA 85/15 and PLA particles led to a decreased release rate. Further investigation needs to be performed to elucidate the reason why EM influences the CyA release differently depending on the particle size and polymer type.     

Precise control of PLG microsphere size provides enhanced control of drug release rate.

An important limitation in the development of biodegradable polymer microspheres for controlled-release drug delivery applications has been the difficulty of specifically designing systems exhibiting precisely controlled release rates. Because microparticle size is a primary determinant of drug release, we developed a methodology for controlling release kinetics employing monodisperse poly(D,L-lactide-co-glycolide) (PLG) microspheres. We fabricated 20-, 40- and 65-microm diameter rhodamine-containing microspheres and 10-, 50- and 100-microm diameter piroxicam-containing microspheres at various loadings from 1 to 20%. In vitro release kinetics were determined for each preparation. Drug release depended strongly on microsphere diameter with 10- and 20-microm particles exhibiting concave-downward release profiles while larger particles resulted in sigmoidal release profiles. Overall, the rate of release decreased and the duration increased with increasing microsphere size. Release kinetics from mixtures of uniform microspheres corresponded to mass-weighted averages of the individual microsphere release kinetics. Appropriate mixtures of uniform microspheres were identified that provided constant (zero-order) release of rhodamine and piroxicam for 8 and 14 days, respectively. Mixing of uniform microspheres, as well as control of microsphere size distribution, may provide an improved methodology to tailor small-molecule drug-release kinetics from simple, biodegradable-polymer microparticles.     

Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate

The aim of this work was to study the release mechanisms of drugs having different solubility (buflomedil pyridoxalphosphate 65%, sodium diclofenac 3.1%, nitrofutantoin 0.02% w/v,) from hydroxypropyl methylcellulose (HPMC) matrices by concomitantly studying swelling, diffusion and erosion fronts movement and drug delivery. The main goal was to clarify the role played by polymer swelling in drug transport. The results showed that the rate and amount of drug released from swellable matrices was dependent not only from drug dissolution and diffusion but also from solid drug translocation in the gel due to polymer swelling. In fact, as drug solubility decreased, the slower drug dissolution rate in the gel layer allowed drug particles to be transported close to the matrix erosion front. The presence of solid particles in the gel reduced the swelling and the entanglement of polymer chains and affected the resistance of gel towards erosion. As a consequence, the matrix became more erodible. The erosive delivery accelerated after the matrix had been completely transformed into the rubbery state, particularly when a considerable amount of solid drug particles remained in the gel phase.     

Critical factors in the release of drugs from sustained release hydrophilic matrices

Hydrophilic matrix systems are one of the most interesting drug delivery systems, and they are currently some of the most widely used to control the release rate of drugs. There are too much factors involved in drug release from hydrophilic matrix systems. The most important factors to be taken into account when developing a formulation based on hydrophilic matrices are the percentage, solubility and drug particle size; the type of polymer, the percentage incorporated, its degree of viscosity and the polymer particle size. Also important are the drug/polymer ratio and the amount of water entering the matrix. Other factors have been shown to be involved in the release of drugs, such as the percentage and mixtures of polymers and the dimensions of the matrix. The compression force is important among the formulation factors to the extent that it determines the amount of air trapped in the matrix. Knowledge of these factors involved in the release of the drugs is crucial for the optimal development of formulations based on hydrophilic systems.     

Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: influence of encapsulation technique and polymer composition on particle characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W double-emulsion technique. Biodegradable linear ABA block copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide) (PEO) B blocks and star-branched AB block copolymers containing A blocks of poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched poly(ethyleneoxide) B blocks were investigated for their potential as sustained release drug delivery systems. Microsphere characteristics were strongly influenced by the polymer composition. In the case of the linear block copolymers, a reduced lactic acid content in a linear block copolymer yielded smaller particles, a lower encapsulation efficiency, and a higher initial drug release both in the case of EPO and FITC-dextran. The investigation of the effects of several manufacturing parameters on microsphere formation showed that the process temperature plays an important role. Microsphere formation in a +1 degrees C environment resulted in higher drug loadings without increasing the amount of residual dichloromethane inside the particles. Other parameters such as the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion have less impact on microsphere characteristics. Branched block copolymers containing star-shaped PEO also showed potential for the preparation of drug loaded microspheres. A certain amount of glycolic acid in the copolymer was necessary for the successful preparation of non-aggregating microspheres at room temperature. Again, the processing temperature strongly affected particle characteristics. Microsphere preparation at +1 degrees C allows the formation of microspheres from a polymer not containing glycolic acid, a result which could not be achieved at room temperature. Moreover, compared to microsphere formation at room temperature, the effective FITC-dextran loading was increased. Concerning the EPO loaded microspheres, the amount of EPO aggregated was comparable to that using the linear ABA polymers. A continuous release of the protein from these star-shaped polymers could not be achieved. In conclusion, apart from microsphere preparation in a +1 degrees C environment the choice of the polymer represents the main factor for a successful entrapment of proteins into biodegradable microspheres.     

Controlled release of proteins from degradable poly(ether-ester) multiblock copolymers

A new series of multiblock poly(ether-ester)s based on poly(ethylene glycol) (PEG), butylene terephthalate (BT) and butylene succinate (BS) segments were introduced as matrices for controlled release applications. The release of two model proteins, lysozyme and bovine serum albumin (BSA), from poly(ether-ester) films were evaluated and correlated to the swelling and degradation characteristics of the polymer matrices. First- and zero-order profiles were found for the release of lysozyme, depending on the composition of the polymer matrix. The initial diffusion coefficient was correlated to the swelling of the matrix, which increased with longer PEG segments and lower BT/BS ratios of the polymer. High swelling matrices released the lysozyme according to diffusion-controlled first-order release profiles. Zero-order release profiles were obtained from less swollen matrices due to a combination of diffusion and degradation of the matrix. In contrast to the release of lysozyme, BSA was released from the poly(ether-ester) matrices via delayed release profiles. Both the delay time and the release rate could be tailored by varying the matrix composition. The BSA release rate was mainly determined by the degradation, whereas the delay time was determined by a combination of the swelling and the degradation rate of the polymer matrix.