Microparticle-embedded fibroin/alginate beads for prolonged local release of simvastatin hydroxyacid to mesenchymal stem cells.

In the present work, we propose silk fibroin/alginate (SF/Alg) beads embedding simvastatin-loaded biodegradable microparticles as a versatile platform capable of tuning SVA release and in so doing osteogenic effects. In a first part of the study, microparticles of poly(lactic-co-glycolic) acid incorporating simvastatin either as lactone (SVL) or as hydroxyacid form (SVA) were prepared by spray-drying. While SVA-loaded microparticles released the drug in three days, long-term release of SVA could be obtained from SVL-loaded microparticles. In this latter case, SVL was promptly transformed to the osteogenic active SVA during release. When tested on mesenchymal stem cells, a time- and dose-dependent effect of SVL-loaded microparticles on cell proliferation and alkaline phosphatase (ALP) activity was found. Thereafter, SVL-loaded microparticles were embedded in SF/Alg beads to limit the initial simvastatin burst and to achieve easier implantation as well. Microparticle-embedded beads showed no cytotoxicity while ALP activity increased. If correctly exploited, the developed system may be suitable as osteogenic polymer scaffolds releasing correct amount of the drug locally for long time-frames.

Preparation of antioxidant active films based on chitosan: diffusivity study of α-tocopherol into food simulants.

New active films based on chitosan and polycaprolactone blends and containing α-tocopherol were designed for food packaging applications. Mechanical properties, stability against temperature and swelling degree in 50 % ethanol (v/v) were evaluated. Migration kinetics of α-tocopherol from the developed films into butter and food simulants [50 % ethanol (v/v), 95 % ethanol (v/v), and isooctane] at different temperatures were studied. α-Tocopherol was quantified in the food simulants by means of high performance liquid chromatography with diode-array detection at 292 nm. The proposed method exhibited a good sensitivity with a limit of detection of 0.1 mg/L. The kinetics release of α-tocopherol was characterized by determining the partition and the diffusion coefficients by using a mathematical modeling based on Fick's Second Law. The diffusion coefficients obtained ranged between 1.03 × 10(-13) and 2.24 × 10(-12) cm(2)/s for 95 % ethanol (v/v) at 4 and 20 °C, respectively. Developed films maintained the antioxidant activity for more than 20 days.

Bone critical defect repair with poloxamine-cyclodextrin supramolecular gels.

The aim of this study was to evaluate the osteoinductive capacity of a poloxamine (Tetronic(®) 908, T) and α-cyclodextrin (αCD) supramolecular gel (T-CD) as scaffold in a critical size defect in rat calvaria. The T-CD gel was evaluated solely and after being loaded with simvastatin (SV) and bone morphogenetic protein (BMP-2) separately and in combinations in order to reduce the doses of the active substances. Three doses of SV (7.5, 75, 750 µg) and two doses of BMP-2 (3 and 6 µg) were tested. The histology and histomorphometrical analysis showed improved bone repair with T-CD compared to T, probably due to better release control of both SV and BMP-2. In addition, as T-CD eroded more slowly than poloxamine alone, it remained longer in the defect site. Although synergism was not obtained with BMP-2 and SV, according to the observed regeneration of the defect, the dose of BMP-2 and SV can be reduced to 3 µg and 7.5 µg, respectively.

Bioinspired superamphiphobic surfaces as a tool for polymer- and solvent-independent preparation of drug-loaded spherical particles.

Superamphiphobic surfaces were evaluated as a tool to prepare spherical particles from polymers and solvents of very diverse nature, under mild conditions and with 100% drug encapsulation yield. Different from bioinspired superhydrophobic surfaces suitable only for aqueous dispersions, the superamphiphobic platforms allowed the formation of spherical droplets when solvents of any polarity were deposited onto them. Spherical poly(d,l-lactide-co-glycolide) (PLGA) particles were synthesized by placing drops of PLGA/ciprofloxacin suspensions in dioxane on a superamphiphobic surface followed by solvent evaporation. The particles prepared covering a wide range of PLGA/ciprofloxacin weight ratios delivered a 20% dose in the first 24h and then sustained the release of the remaining drug for more than 1month. The particles, both freshly prepared and after being 26days in the release medium, showed efficiency against different types of microorganisms. The developed polymer- and solvent-independent approach could be useful for microencapsulation with very high efficiency of active substances of varied nature into size-tunable particles for a wide range of applications in an affordable and cost-effective manner.

Bone regeneration induced by an in situ gel-forming poloxamine, bone morphogenetic protein-2 system.

The aim of this study was to confirm previously shown, in vitro osteogenic induction by the Tetronics T908 and T1307 in a critical-size, rat calvaria defect. In vivo, the osteogenic activity of the hydrogels was comparable to in vitro, but less pronounced. However, similar to in vitro, the system was strongly potentiated by incorporating 6.5 microg of bone morphogenetic protein-2 in solution or pre-encapsulated in poly(lactic-co-glycolic) acid microspheres. These two systems extended the in vivo release of bone morphogenetic protein-2, determined with 125I- bone morphogenetic protein-2, for one and two additional weeks, respectively, time enough to fill approximately 40% and 90% of the defect with well-organized bone. Furthermore, the structural characteristics of Tetronic hydrogels together with their biocompatibility, injectability, and adaptability to multiple defect sizes and shapes suggest their role as new, potential bone morphogenetic protein-2 delivery, low-cost scaffolds for minor as well as critical bone defects.

Acrylic polymer-grafted polypropylene sutures for covalent immobilization or reversible adsorption of vancomycin.

Glycidyl methacrylate (GMA) and acrylic acid (AAc) were separately grafted onto polypropylene (PP) monofilament sutures by means of pre-irradiation using a (60)Co γ-source, with the purpose of loading vancomycin via (i) covalent immobilization through the glycidyl groups of GMA and (ii) ionic interaction with AAc moieties. The effect of absorbed radiation dose, monomer concentration, temperature and reaction time on the grafting degree was evaluated in detail. GMA grafting ranged from 25% to 800% while the grafting yield of AAc onto PP could be tuned between 9% and 454%, at doses from 5 to 50 kGy and a dose rate 13.7 kGy/h. Grafting of GMA or AAc decreased the decomposition temperature and made the sutures swellable to a certain extent. GMA grafting led to a continuous, smooth and thick coating, which was suitable for immobilization of up to 1.9 µg vancomycin per gram. The immobilized vancomycin enabled a reduction in the Staphylococcus aureus CFU adhered to the suture surface. On the other hand, dried AAc-functionalized sutures exhibited a rough and cracked surface which was responsible for a minor increase in the coefficient of friction. PP-g-AAc sutures exhibited pH-dependent swelling and remarkably high capability to host vancomycin (up to 109.9 mg/g), particularly those with an intermediate degree of grafting. Some AAc-functionalized sutures were shown able to inhibit bacterial growth after successive challenges with fresh lawns. Therefore, tuning the yield of grafting of GMA or AAc may enable the preparation of drug-suture combination products that retain or release, respectively, antimicrobial agents.

Free and copolymerized γ-cyclodextrins regulate the performance of dexamethasone-loaded dextran microspheres for bone regeneration.

Polymeric particles acting as sources of biological cues to promote tissue regeneration are currently an interesting topic in bone tissue engineering research. In this study, microspheres of dextran-methacrylate (dextran-MA) and γ-cyclodextrins (γ-CD) for the delivery of osteogenic agents were prepared by means of photopolymerization on biomimetic superhydrophobic surfaces. The effects of the incorporation of the γ-CD units as free entities or as structural monomers (acrylamidomethyl-γ-cyclodextrin, γ-CD-NMA) on dexamethasone loading and release performance were evaluated in detail in order to achieve osteogenic differentiation of human stem cells. The copolymerization of dextran-MA with γ-CD-NMA improved the loading capacity of the particles and also provided a sustained release of dexamethasone for several days. The biological studies revealed that such microspheres were cytocompatible and capable of inducing the differentiation of human adipose-derived stem cells (hASCs) to osteoblasts, as determined from an increase of alkaline phosphatase (ALP) activity between days 3 and 7. Such results were also confirmed using ALP staining. Therefore, immobilization of γ-CDs onto the dextran-MA network may be particularly useful for the development of cytocompatible implantable spherical biomaterials for bone tissue engineering purposes.

Poly-(cyclo)dextrins as ethoxzolamide carriers in ophthalmic solutions and in contact lenses.

Efficient ophthalmic therapy requires the development of strategies that can provide sufficiently high drug levels in the ocular structures for a prolonged time. This work focuses on the suitability of poly-(cyclo)dextrins as carriers able to solubilize the carbonic anhydrase inhibitor (CAI) ethoxzolamide (ETOX), which is so far used for oral treatment of glaucoma. Topical ocular treatment should notably enhance the efficiency/safety profile of the drug. Natural α-, ß- and γ-cyclodextrins and a maltodextrin were separately polymerized using citric acid as cross-linker agent under mild conditions. The resultant hydrophilic polymers exhibited larger capability to solubilize ETOX than the pristine (cyclo)dextrins. Moreover, they provided sustained drug diffusion in artificial lachrymal fluid. Interestingly the poly-(cyclo)dextrins solutions facilitate the loading of remarkably high doses of ETOX in poly(2-hydroxyethyl methacrylate)-based contact lenses. Exploiting ionic interactions between functional groups in the contact lenses and remnant free carboxylic acids in the citric acid linkers of poly-(cyclo)dextrins led to the retention of the drug-loaded poly-(cyclo)dextrins and, in turn, to sustained release for several weeks.

Dexamethasone-loaded poly(ε-caprolactone)/silica nanoparticles composites prepared by supercritical CO2 foaming/mixing and deposition.

A supercritical carbon dioxide (scCO2)-assisted foaming/mixing method (SFM) was implemented for preparing dexamethasone (DXMT)-loaded poly(ε-caprolactone)/silica nanoparticles (PCL/SNPs) composite materials suitable for bone regeneration. The composites were prepared from PCL and mesoporous SNPs (MCM-41/SBA-15) by means of scCO2-assisted SFM at several operational pressures, processing times and depressurization conditions. DXMT was loaded into SNPs (applying a scCO2 solvent impregnation/deposition method - SSID) and into PCL/SNPs composites (using the SFM method). The effects of the employed operational and compositional variables on the physicochemical and morphological features as well as in the in vitro release profiles of DXMT were analyzed in detail. This work demonstrates that the above-referred scCO2-based methods can be very useful for the preparation of DXMT-loaded PCL/SNPs composites with tunable physicochemical, thermomechanical, morphological and drug release properties and suitable for hard-tissue regeneration applications.

Cytocompatibility and P-glycoprotein inhibition of block copolymers: structure-activity relationship.

Amphiphilic polymeric micelles greatly improve the solubilization and sustained release of hydrophobic drugs and provide a protective environment for the cargo molecules in aqueous media, which favors lower drug administration doses, reduces adverse side effects, and increases blood circulation times and passive targeting to specific cells. These capabilities depend, among other variables, on the structure and composition of the polymer chains. Composition and, in particular, block length have been shown to play an important role in the modification of cellular responses such as drug internalization processes or transduction pathways when polymeric unimer/micelles are in close contact with cells. Here we present a detailed study about the role copolymer structure and composition play on cell viability and cellular response of several cell lines. To do that, more than 30 structurally related copolymers with diblock and triblock architectures containing different hydrophobic blocks and poly(ethylene oxide) as the common hydrophilic unit have been analyzed regarding cytocompatibility and potential as "active" cell response modifiers by testing their influence on the P-gp pump efflux mechanism responsible of multidrug resistance in cancerous cells. An empirical threshold for cell viability could be established at a copolymer EO/POeffective value above ca. 1.5 for copolymers with triblock structure, whereas no empirical rule could be observed for diblocks. Moreover, some of the tested copolymers (e.g., BO12EO227BO12 and EO57PO46EO57 that notably increased and C16EO455C16 that decreased the P-gp ATPase activity) were observed to act as efficient inhibitors of the P-gp efflux pump promoting an enhanced doxorubicin (DOXO) accumulation inside multidrug resistant (MDR) NCI-ADR-RES cells.

Doxorubicin-loaded micelles of reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers as efficient "active" chemotherapeutic agents.

Five reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers, BOnEOmBOn, with BO ranging from 8 to 21 units and EO from 90 to 411 were synthesized and evaluated as efficient chemotherapeutic drug delivery nanocarriers and inhibitors of the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line. The copolymers were obtained by reverse polymerization of poly(butylene oxide), which avoids transfer reaction and widening of the EO block distribution, commonly found in commercial poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamers). BOnEOmBOn copolymers formed spherical micelles of 10-40 nm diameter at lower concentrations (one order of magnitude) than those of equivalent poloxamers. The influence of copolymer block lengths and BO/EO ratios on the solubilization capacity and protective environment for doxorubicin (DOXO) was investigated. Micelles showed drug loading capacity ranging from ca. 0.04% to 1.5%, more than 150 times the aqueous solubility of DOXO, and protected the cargo from hydrolysis for more than a month due to their greater colloidal stability in solution. Drug release profiles at various pHs, and the cytocompatibility and cytotoxicity of the DOXO-loaded micelles were assessed in vitro. DOXO loaded in the polymeric micelles accumulated more slowly inside the cells than free DOXO due to its sustained release. All copolymers were found to be cytocompatible, with viability extents larger than 95%. In addition, the cytotoxicity of DOXO-loaded micelles was higher than that observed for free drug solutions in a MDR ovarian NCI-ADR-RES cell line which overexpressed P-gp. The inhibition of the P-gp efflux pump by some BOnEOmBOn copolymers, similar to that measured for the common P-gp inhibitor verapamil, favored the retention of DOXO inside the cell increasing its cytotoxic activity. Therefore, poly(butylene oxide)-poly(ethylene oxide) block copolymers offer interesting features as cell response modifiers to complement their role as efficient nanocarriers for cancer chemotherapy.

Poly(styrene oxide)-poly(ethylene oxide) block copolymers: From "classical" chemotherapeutic nanocarriers to active cell-response inducers.

Two poly(styrene oxide)-poly(ethylene oxide) (PSO-PEO) triblock copolymers with different chain lengths were analyzed as potential chemotherapeutic nanocarriers, and their ability to inhibit the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line were measured in order to establish possible cell-responses induced by the presence of the copolymer molecules. Thus, EO33SO14EO33 and EO38SO10EO38 polymeric micelles were tested regarding doxorubicin (DOXO) entrapment efficiency (solubilization test), physical stability (DLS), cytocompatibility (fibroblasts), release profiles at various pHs (in vitro tests), as well as P-gp inhibition and evasion and cytotoxicity of the DOXO-loaded micelles in an ovarian MDR NCI-ADR/RES cell line and in DOXO-sensitive MCF-7 cells. EO33SO14EO33 and EO38SO10EO38 formed spherical micelles (~13nm) at lower concentration than other copolymers under clinical evaluation (e.g. Pluronic®), exhibited 0.2% to 1.8% loading capacity, enhancing more than 60 times drug apparent solubility, and retained the cargo for long time. The copolymer unimers inhibited P-gp ATPase activity in a similar way as Pluronic P85, favoring DOXO accumulation in the resistant cell line, but not in the sensitive cell line. DOXO loaded in the micelles accumulated more slowly inside the cells, but caused greater cytotoxicity than free drug solutions in the NCI-ADR-RES cell line, which overexpressed P-gp. Hence, PSO-PEO block copolymers offer interesting features as new biological response modifiers to be used in the design of efficient nanocarriers for cancer chemotherapy.

Syringeable Pluronic-α-cyclodextrin supramolecular gels for sustained delivery of vancomycin.

The ability of Pluronic® F127 to form supramolecular gels in the presence of αCD has been explored as a way to design syringeable gel formulations able to sustain drug release while using the lowest proportion of both components. The effects of αCD concentration range (0-9.7% w/v) in copolymer (6.5%, 13% and 20%) gel features were evaluated at 4, 20 and 37°C. An effective complexation of Pluronic and αCD was evidenced as a change in the surface pressure of the π-A isotherm of Pluronic on a subphase of CD solution and the apparition of new peaks in the X-ray spectra. Once the Pluronic and αCD solutions were mixed, the systems became progressively turbid solutions or white gels. The greater the αCD concentration was, the faster the gel formation. The supramolecular hydrogels were thixotropic and those containing 5% or more αCD had G' values above G″ at room temperature, but they were still easily syringeable. The values of both moduli increased as temperature raised; the effect being more evident for 13% and 20% w/v copolymer. The gels prepared with low proportions of αCD exhibited phase separation in few days, particularly when stored at 4 or 37 °C. By contrast, those prepared with 6.5% copolymer were stable for at least two months when stored at 20 °C. The gels were able to sustain vancomycin release for several days; the higher the αCD proportion, the slower the release was. Furthermore, the drug-loaded gels showed activity against Staphylococcus aureus. The results obtained highlight the role of the αCD concentration on the tuning of the rheological features and drug release profiles from Pluronic gels.

PEO-PPO block copolymers for passive micellar targeting and overcoming multidrug resistance in cancer therapy.

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic® or Lutrol®) and the X-shaped poloxamines (Tetronic®), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.

Estradiol sustained release from high affinity cyclodextrin hydrogels.

Hydrogels for loading estradiol and controlling its release were prepared cross-linking various cyclodextrins with ethyleneglycol diglycidylether. To select the more adequate cyclodextrins, estradiol solubility diagrams in water with beta-cyclodextrin (betaCD), methyl-beta-cyclodextrin (MbetaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD), and sulfobutyl-beta-cyclodextrin (SBbetaCD) were made in absence and presence of hydroxypropyl methylcellulose (HPMC) applying or not autoclaving. Although all cyclodextrins showed enough complexation capability, the low solubility of betaCD and the high anionic character of SBbetaCD hindered the cross-linking process, and these cyclodextrins were discarded for preparing hydrogels. Hydrogels prepared with MbetaCD (20%, 25%) or HPbetaCD (20%, 25%, and 30%), with or without HPMC 0.25%, absorbed 4-10 times their weight in water and loaded up to 24 mg estradiol per gram, which is 500 times greater than the amount of drug that can be dissolved in their aqueous phase. Positive linear correlation was found between the stability constant and the network/water partition coefficients of drug. The hydrogels sustained the release up to one week; the affinity of estradiol for the cyclodextrin units controlling the process, as shown by the negative correlation with the release rate constants. These results highlight the potential of cyclodextrin complexation for the development of hydrogels useful in loading hydrophobic drugs and controlling their release.

Drug solubilization and delivery from cyclodextrin-Pluronic aggregates.

Colloidal systems based on Pluronic F127 (PF127) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) have been characterized with a view to their potential use as delivery systems of hydrophobic drugs. Complexation of PF127 and HPbetaCD was evaluated by surface tension measurements, 1H-NMR spectroscopy and transmission electron microscopy. The critical micellar concentration, CMC, at 25 degrees C of PF127 (0.39 mM in pH 5.8 and 7.4 phosphate buffers, and 0.59 mM in pH 4.5 acetic/acetate and lactic/lactate buffers) was shifted to higher values by the addition of 38.17 mM HPbetaCD (CMC(app) = 1.18 mM). This is related to the threading of HPbetaCD onto the PF127 chains, as confirmed by 1H NMR experiments. HPbetaCD at this concentration notably raised the sol-gel transition temperature; the minimum PF127 concentration required for providing gelling systems in physiological environments being 13.4 mM. Both HPbetaCD and PF127 by themselves are able to notably increase the solubility of sertaconazole (SN). At HPbetaCD concentrations below 80 mM, an additive effect of both components on SN solubility was observed. At greater HPbetaCD concentrations, a non-additive increase occurred, which is related to the complexation of some PF127 unimers with HPbetaCD molecules, decreasing the total number of micelles and HPbetaCD cavities available for interacting with SN. The 13.4 mM PF127/38.17 mM HPbetaCD system, able to increase up to 100 times the SN solubility in pH5.8 phosphate buffer, showed temperature-dependent drug diffusion coefficients, able to control the release for one week at 37 degrees C.

Structural properties of biodegradable polyesters and rheological behaviour of their dispersions and films.

This paper focuses on the dependence of the rheological properties of PLA-PEG and PLGA dispersions and films on the polymer structural properties, in order to obtain useful information to predict and explain the performance of polyester films as drug-delivery systems. In this study, one PLA-PEG and three PLGA polymers of different molecular mass were synthesized and characterized by NMR, GPC, DSC and TGA-FT-IR. To characterize the viscoelastic behaviour of concentrated solutions in dichloromethane and of the films obtained by a solvent-casting technique, oscillatory shear rheometry was used. The polymer dispersions showed a characteristic Newtonian viscous behaviour, but with different consistency index depending on the nature of the polymer. Freshly prepared, PLGA and PLA-PEG films had elastic modulus (G') greater than viscous modulus (G"). The decrease in both moduli caused by an increase in temperature from 25 to 37 degrees C was especially marked for the polymers with T(g) below or around 25 degrees C (PLGA 27 kDa and PLA-PEG 27 kDa). After being immersed in pH 7.4 aqueous solution for one week, PLGA films showed a significant increase in both G' and G", due to the promotion of polymer-polymer interactions in a non-solvent medium. In contrast, the PLA-PEG film became softer and more hydrated, due to the amphiphilic character of the polymer. The water taken up by the film acted as a plasticizer and induced the softening of the system. These results suggest that the presence of PEG chains exerts a strong influence on the mechanical properties of polyesters films and, possibly, the performance as coating or matrices of drug-delivery systems.

Preparation of chitosan beads by simultaneous cross-linking/insolubilisation in basic pH. Rheological optimisation and drug loading/release behaviour.

A one-step procedure to prepare chitosan beads by simultaneous cross-linking with glutaraldehyde and insolubilisation in 1.5 M NaOH solution has been developed. The optimisation of the procedure was carried out by monitoring the evolution of the loss and storage moduli of chitosan solutions (1.5% (w/v), in acetic acid 0.2 M) in the presence of different proportions of glutaraldehyde. Increasing the chitosan molecular weight, glutaraldehyde concentration and/or process temperature from 20 to 37 degrees C, a reduction of time to reach the gel point was observed. The diameter of freshly prepared swollen beads was 3.2+/-0.4 mm and, after drying 0.48+/-0.18 mm. Swollen or previously dried beads were loaded with metronidazole by immersion in 0.1% (w/v), drug solution in a phosphate buffer pH 7.5, purified water, 0.2 M acetic acid or 0.1 M HCl. Beads synthesised at 37 degrees C experimented faster swelling than the ones prepared at 20 degrees C and even disintegrated in acetic acid. The amounts of metronidazole loaded (ranging from 1 to 286 mg/g dried beads) increased with swelling capacity of beads. The release studies carried out in 0.1 M HCl indicated that, regardless of the medium used to load the beads, all of them released the dose in less than 30 min. In summary, applying this one-step procedure and choosing the adequate glutaraldehyde proportion, it is possible to obtain particles of chitosan cross-linked with itself, which exhibit pH-sensitive swelling and which are able to release all the drug quickly into an acidic environment such as the stomach. The results obtained also highlight the importance of the pH of the medium for modulating the amount of drug loaded (it is remarkably greater at lower pHs) and the influence of temperature at which the beads are prepared on their tendency to disintegrate.

Glass transitions and viscoelastic properties of carbopol and noveon compacts.

Glass transitions of five varieties of Carbopol (acrylic acid polymers cross-linked with allyl sucrose or allyl pentaerythritol) and two varieties of Noveon (calcium salts of acrylic acid polymer cross-linked with divinylglycol) differing in cross-linking density and nature and content in residual solvents, were analysed (as compressed probes) by differential scanning calorimetry (DSC), modulated temperature differential scanning calorimetry (MTDSC), and oscillatory rheometry. All carbopol compacts showed a main glass transition, at a temperature between 130 and 140 degrees C, Tg, independently of their cross-linking degree and molecular weight. Additionally two batches of Carbopol 971P, which had greater contents in residual solvents, also presented a secondary transition at 65-70 degrees C. Sorption of water during storage of carbopol compacts at different relative humidity environments caused the Tg to strongly decrease. Compacts stored at 97.5% relative humidity have Tg below 0 degrees C and behave, at room temperature, as flexible hydrogels. The Gordon-Taylor/Kelley-Bueche equation only fit the dependence of Tg on water content well for carbopol compacts containing less than 15% water. The plasticizing effect of water was clearly evidenced in the considerable decrease in the storage and loss moduli of the compacts. Although the energy associated to the glass transitions of carbopol polymers, 0.40-0.50 Jg(-1) degrees C(-1), is high enough to be clearly detected by DSC, in some cases the evaporation of residual solvents may make it difficult to observe the Tg. This inconvenience is overcome using MTDSC or oscillatory rheometry. The decrease in Tg of carbopol caused by water sorption when compacts were stored at 97.5% R.H. explains why their loss (G") and storage (G') moduli at room temperature decreased four orders of magnitude. In contrast, in noveon varieties, calcium ions act as ionic cross-linkers of the carboxylic groups, providing rigid networks with much higher Tg, and storage and loss moduli. This explains that despite sorbing similar amounts of water to carbopol, the changes on the mechanical properties of noveon compacts were much less important (i.e., G' and G" decreased up to one order of magnitude).

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.