Solvent-Free Processing of Drug-Loaded Poly(ε-Caprolactone) Scaffolds with Tunable Macroporosity by Combination of Supercritical Foaming and Thermal Porogen Leaching.

Demand of scaffolds for hard tissue repair increases due to a higher incidence of fractures related to accidents and bone-diseases that are linked to the ageing of the population. Namely, scaffolds loaded with bioactive agents can facilitate the bone repair by favoring the bone integration and avoiding post-grafting complications. Supercritical (sc-)foaming technology emerges as a unique solvent-free approach for the processing of drug-loadenu7d scaffolds at high incorporation yields. In this work, medicated poly(ε-caprolactone) (PCL) scaffolds were prepared by sc-foaming coupled with a leaching process to overcome problems of pore size tuning of the sc-foaming technique. The removal of the solid porogen (BA, ammonium bicarbonate) was carried out by a thermal leaching taking place at 37 °C and in the absence of solvents for the first time. Macroporous scaffolds with dual porosity (50-100 µm and 200-400 µm ranges) were obtained and with a porous structure directly dependent on the porogen content used. The processing of ketoprofen-loaded scaffolds using BA porogen resulted in drug loading yields close to 100% and influenced its release profile from the PCL matrix to a relevant clinical scenario. A novel solvent-free strategy has been set to integrate the incorporation of solid porogens in the sc-foaming of medicated scaffolds.

Imprinted Contact Lenses for Ocular Administration of Antiviral Drugs.

A variety of ocular diseases are caused by viruses, and most treatments rely on the use of systemic formulations and eye drops. The efficient ocular barriers that oppose antiviral drug penetration have prompted the development of improved topical delivery platforms. The aim was to design hydrogel contact lenses endowed with an affinity for acyclovir (ACV) and its prodrug valacyclovir (VACV), first-choice drugs against herpes simplex virus (HSV) ocular keratitis, and that can sustain the release of therapeutic doses during daily wearing. Functional monomers suitable for interaction with these drugs were screened using computational modeling. Imprinted and non-imprinted hydrogels were prepared with various contents in the functional monomer methacrylic acid (MAA) and characterized in terms of swelling, transmittance, mechanical properties, and ocular compatibility (hen's egg test on chorioallantoic membrane (HET-CAM) assay). The values were in the range typical of soft contact lenses. Compared to ACV, the capability to load VACV was remarkably higher due to stronger electrostatic interactions with MAA. The advantages of the imprinting technology were evidenced for VACV. Stability of VACV loading solution/hydrogels under steam heat sterilization and subsequent drug release was investigated. Permeability studies through bovine and porcine cornea and sclera of the drug released from the hydrogels revealed that VACV accumulates in the cornea and can easily cross the sclera, which may facilitate the treatment of both anterior and posterior eye segments diseases.

Optimization of Drug Permeation from 8% Ciclopirox Cyclodextrin/Poloxamer-Soluble Polypseudorotaxane-Based Nail Lacquers.

Cyclodextrin/poloxamer-soluble polypseudorotaxane-based nail lacquers have demonstrated significant capacity for promoting the permeation of drugs into the nail plate. Furthermore, previous studies have shown that the use of hydroalcoholic blends as vehicles promotes drug permeation. The work described herein studies the effect of the type of alcohol used in the lacquer preparation, and the composition of the vehicle is optimized to obtain soluble doses of 8% and to promote the diffusion of ciclopirox base and olamine across the nail. Permeation studies on different types of alcohols show that optimum results are achieved with short-chain alcohols, and that results become less satisfactory the higher the number of alcohol carbons. In addition, solubility and penetration studies on the bovine hoof have enabled the composition of the lacquer to be optimized for both forms of ciclopirox. The results suggest that optimized lacquers have better ciclopirox diffusion and penetration properties than the commercial reference lacquer. Lastly, in vivo studies in which optimized ciclopirox olamine lacquer was applied for 45 days to the nails of healthy volunteers showed that it caused no negative effects or changes to the nail surface. These results demonstrate the significant potential of cyclodextrin/poloxamer-soluble polypseudorotaxane-based nail lacquers for the ungual administration of drugs.

Effect of Penetration Enhancers on Drug Nail Permeability from Cyclodextrin/Poloxamer-Soluble Polypseudorotaxane-Based Nail Lacquers.

Nail delivery has interest for local treatment of nail diseases. Nevertheless, the low permeability of drugs in the nail plaque precludes the efficacy of local treatments. The use of penetration enhancers can increase drug permeability and improve the efficacy of the treatment of nail pathologies. In this work, different chemical substances have been evaluated as potential penetration enhancers. With this aim, the effect of different substances such as sodium lauryl sulfate (SLS), polyethylene glycol 300 (PEG 300), carbocysteine, N-acetylcysteine, lactic acid, potassium phosphate, Labrasol® and Labrafil® in the microstructure, nail surface and drug permeability has been evaluated. The models obtained by mercury intrusion porosimetry and PoreXpert™ software show a more porous structure in nails treated with different enhancers. Permeation studies with bovine hooves and nails revealed that all the hydroalcoholic lacquers developed, and particularly those prepared with SLS, provide better nail penetration of the drugs ciclopirox olamine and clobetasol propionate. Results have shown that the increase of the drug penetration in the nail is caused by the formation of a porous random microstructure and by the decrease of the contact angle between lacquers and the surface or the nail plaque. The presence of SLS produces an improvement in the spreading of the solution on the nail surface and promotes the penetration of the solution into the nail pores. The hydroalcoholic lacquer, elaborated with cyclodextrin/poloxamer soluble polypseudorotaxane and sodium lauryl sulfate as an enhancer, allowed the rate of diffusion and penetration of the active ingredient within the nail to be significantly higher than obtained with the reference lacquers when using either ciclopirox olamine or clobetasol propionate as the active ingredient.

Effect on Nail Structure and Transungual Permeability of the Ethanol and Poloxamer Ratio from Cyclodextrin-Soluble Polypseudorotaxanes Based Nail Lacquer.

Aqueous-based nail lacquers have shown potential in promoting the diffusion of drugs into the nail. In our laboratory, we have recently developed a transungual delivery system based on an aqueous dispersion of cyclodextrin-poloxamer soluble polypseudorotaxanes, supramolecular host-guest assemblies that improves the drug permeation into the nail. However, the high-water content and the rheological and adhesive properties of this lacquer negatively affect properties that play a fundamental role in the patients' acceptance such as stickiness, nail film formation or drying rate, properties. In this work, we have optimized the composition of these lacquers to improve these properties whilst maintaining good drug permeation profiles. Incorporating ethanol into the vehicle and reducing the proportion of Poloxamer 407 (PL), provided a good strategy. The use of hydro-ethanolic mixtures (>50% ethanol) and the reduction of the poloxamer concentration significantly improved the lacquer drying speed by reducing the stickiness and promoting film formation on the nail surface. Additionally, in a surprising way, the use of hydro-ethanolic vehicles further enhanced the permeation of ciclopirox olamine and clobetasol propionate, used for the treatment of onychomycosis and nail psoriasis respectively, into the nail and hooves.

Microstructural alterations in the onychomycotic and psoriatic nail: Relevance in drug delivery.

Despite the important nail alterations caused by onychomycosis and psoriasis few studies have characterized the microstructure of the diseased nail plate and the diffusion and penetration of drugs through this altered structure. This work aimed to characterize the microstructure of the healthy, onychomycotic and psoriatic human nail using Raman spectroscopy, scanning electron microscopy, optical microscope profilometry and mercury intrusion porosimetry followed by analysis of the structure with PoreCor® software. The results showed that onychomycotic nails have higher porosity and lower amounts of disulphide bonds compared to healthy nails. This suggests that the presence and action of fungi on the nail plate makes this structure more permeable to water and drugs. Psoriatic nails had increased porosity compared to healthy nails but lower than fungal infected specimens. In vitro permeation studies showed that diseased nails were more permeable to ciclopirox (onychomycosis) and clobetasol (psoriasis) although drug permeation was highly variable and likely to be influenced by the degree of alteration of the nail structure. On the whole, this work provides new and valuable information about the microstructure and porosity of diseased nails and a plausible explanation of the increased drug permeability observed in this work and elsewhere.

Evaluation of the promoting effect of soluble cyclodextrins in drug nail penetration.

Soluble derivatives of ß-cyclodextrin (CD) have a high capacity to solubilise hydrophobic molecules and to interact with proteins and membrane component. As consequence CD derivatives shows a significant activity as drug absorption enhancers through different delivery routes, such as the oral, nasal, ocular or topical route. In this paper, the effect of two CD derivatives -methyl-ß-cyclodextrin (MBCD) and hydroxypropyl-ß-cyclodextrin (HPB)- on the structure and permeability of the nail plate has been studied using the drug model ciclopirox olamine. Results shows that MBCD and HPB interacting with the nail plate components, modifying their microporous structure and swelling characteristics. The ability of the cyclodextrins to interact with aromatic amino acids and to stabilise and unfold protein structures could be the most likely mechanisms responsible of the nail microstructure modifications. Aditionally CD allows to increase the soluble dose of ciclopirox olamine in aqueous lacquers made with poloxamer and N-acetylcysteine via the formation of high solubility complexes with the drug. Finally the studies of diffusion and penetration obtained using bovine hoof model confirm the enhancing effect of the cyclodextrins on the penetration and accumulation of the drug in the nail structure. Results shows the great potential of the CD for the elaboration of aqueous based nail lacquers containing hidrofobic drugs.

Drug structural features affect drug delivery from hyperbranched polyesteramide hot melt extrudates.

The aim of this study was firstly to evaluate the utility of Hybrane S1200 as a hot melt extrusion (HME) carrier to prepare instant-release multiparticulate systems for very poorly-soluble drugs such as ketoconazole or nifedipine. Hybrane S1200 allows an easy extrusion of its drug mixtures at a relatively low temperature, not higher than 90°C, and with no need of any additional aid. Extrudates containing 10% of nifedipine or ketoconazole form monophasic systems. Nifedipine extrudate shows no drug release in drug dissolution rate tests while ketoconazole extrudate release reaches only 60% of drug content. Additionally, a turbidity in the dissolution medium due to the formation of a kind of polymer vesicles (ranging 3-0.2µm in size) is observed. These facts could suggest a chemical interaction between the polymer and both drugs, triggered by the HME process. Both nifedipine and ketoconazole share characteristic acid-base profiles that could facilitate a degradation processes within the polymer, thus modifying Hybrane's water-solubility and polar nature. Such modified polymer structure, when in aqueous medium, forms the aforementioned stable vesicles that may encapsulate the drugs, thus making its delivery difficult or even preventing it.

Evaluation of the hyperbranched polymer Hybrane H1500 for production of matricial controlled-release particles by hot-melt extrusion.

Extrudates of the hyperbranched polymer Hybrane H1500 prepared by hot melt extrusion, with five particle sizes (from <250 µm to 1.5-2.0 mm) and three drug content (10, 20 and 30%) of acetaminophen or caffeine, were evaluated in this study as potential multiparticulate controlled release systems. Hybrane H1500 extrudates (of very low porosity), experienced a very slow hydration, with a limited swelling capacity, and they do not behave as true gels when fully hydrated. Hot melt extrusion provokes the conversion of the acetaminophen into an amorphous state inside the extrudates, whereas for those containing caffeine, some crystals remain for the highest drug proportions (20 and 30%). From both drug extrudates a wide range of dissolution profiles are obtained. Drug release rate depends mostly on extrudate particle size, and in those extrudates containing caffeine, a slight effect of the drug proportion is observed. Dissolution profiles' kinetic analysis suggests that drug release is controlled by the diffusion of the drug through the polymeric hydrated structure, although this mechanism is only clearly and efficiently displayed for the greatest extrudate particles (1.5-2.0 mm).

Utility of the hyperbranched polymer Hybrane S1200 for production of instant-release particles by hot melt extrusion.

Particles composed of 90:10 or 80:20 mixtures of the hyperbranched poly(esteramide) Hybrane S1200 and the poorly water-soluble drug hydrochlorothiazide were produced by hot melt extrusion at maximum temperatures of 90°C without any need for addition of a plasticizer. In dissolution rate assays in USP 29 apparatus II, particles of the smallest size category (<250 µm) containing 10% of hydrochlorothiazide released 95% of their load within 5 min. This fast release is attributed to the combination of the high solubility of Hybrane S1200, the dispersion of the drug in non-crystalline form in the polymer matrix (attested to by the results of powder X-ray diffractometry, and scanning electron microscopy), and to the fact that the main interaction between drug and polymer is through hydrogen bonds (attested to by ATR-IR difference spectra).

Competitive displacement of drugs from cyclodextrin inclusion complex by polypseudorotaxane formation with poloxamer: implications in drug solubilization and delivery.

The competitive interactions between the poly-[propylene oxide] (POO)-poly-[ethylene oxide] (PEO) block copolymer poloxamer 407 (Pluronic F127) and two drugs, triamcinolone acetonide and ciclopirox olamine, by the formation of inclusion complexes with two cyclodextrin hydrophilic derivatives, hydroxypropyl-ß-cyclodextrin (HPßCD; molar substitution (MS) 0.65) and partially methylated-ß-cyclodextrin (MßCD; MS 0.57), were studied by means of one-dimensional (1)H NMR, 2D ROESY experiments, solubility studies and drug release studies. 1D and 2D NMR and solubility studies indicate that both triamcinolone acetonide and ciclopirox olamine form stable inclusion complexes with the cyclodextrin derivatives. In the case of ciclopirox olamine the complex was more stable at pH 1. Effective complexation of poloxamer with the two cyclodextrins (CDs) was also evidenced by NMR analysis, and competitive displacement of the drugs from the CD cavity by the polymer was observed. Drug solubility in CD solutions was not modified by the addition of polymers, indicating that a decrease in solubility due to the competitive displacement is probably compensated by the solubilizing effect of polymer micellization. Finally, polypseudorotaxanes formation has a significant influence on the release of the drugs studied. Changes in the release rate depend on the stability of drug-CD inclusion complex and on cyclodextrin concentration in the bulk solution; so polypseudorotaxane formation can be employed to modulate drug controlled release from thermosensitive hydrogels.

Modelling of porosity and waterfronts in cellulosic pellets for understanding drug release behavior.

The microstructure of cellulose microcrystalline-Carbopol pellets, prepared under different drying conditions (oven-dried or freeze-dried), was experimentally characterized using mercury intrusion porosimetry and then computationally modelled using Pore-Cor software. Connectivity (mean number of throats per pore), pore skew (sigma), throat skew (q) and correlation level were estimated and simultaneously optimized from the mercury intrusion porosimetry cumulative curves using the Boltzmann-annealed simplex algorithm. Unit cells with percolation properties close to the real ones were generated. Water penetration rate in the simulated structures was also modelled using Pore-Cor and the waterfront position was calculated using the Bosanquet equation. A close correlation was found between the simulated water flow rate in the unit cell and the experimental theophylline first-order release rate constant. Thus, modelling of network microstructure and waterfronts appears as an useful tool for predicting drug release rate from matrix pellets.

Incidence of drying on microstructure and drug release profiles from tablets of MCC-lactose-Carbopol and MCC-dicalcium phosphate-Carbopol pellets.

The influence of intragranular excipients (lactose or dicalcium phosphate) and the drying procedure and conditions (oven-drying and freeze-drying after freezing at -30 or -196 degrees C) on the properties of tablets of MCC-Carbopol pellets was evaluated. The drying procedure caused remarkable differences in pellet size and porosity (freeze-dried pellets were 3-fold more porous than those oven dried). Theophylline release from pellets was completed in less than 30 min and followed first-order kinetics, with a rate closely related to the intragranular porosity. The total porosity of the tablets (5-10%) was conditioned by the compression force (10-20 N), the drying procedure applied to the pellets and the coexcipient nature. Their intergranular porosity ranged inversely to the initial porosity of pellets due to the greater deformability of the most porous ones. A wide range of theophylline release rates were achieved depending on the drying procedure; tablets prepared from freeze-dried pellets sustained the release for 3h. Most profiles showed a bimodal kinetics with an initial zero-order release (while the tablets did not completely disintegrate) that changed, after a certain time, to a first-order kinetics. The intergranular porosity determined drug release rate up to disintegration. Then, the release kinetics became first-order and the rate constant, which was conditioned by the intragranular porosity, showed a complex dependence on the drying procedure, the compression force, and the nature of coexcipient. In sum, the modulation of drug release profiles from tablets of MCC-Carbopol pellets through an adequate control of the effects of the coexcipient nature, the drying procedure of pellets, and the compression force on the inter- and intragranular porosity opens interesting possibilities to control the release of hydrosoluble drugs.

Microstructural and drug release properties of oven-dried and of slowly or fast frozen freeze-dried MCC-Carbopol pellets.

The influence of the procedure and conditions of drying (oven-drying and freeze-drying after slow or fast freezing) and of the CaCl(2) concentration in the wetting liquid on the physical characteristics and drug release behaviour of microcrystalline cellulose (MCC)-carbopol 40:60 pellets containing theophylline or ketoprofen has been evaluated. The microstructural, morphological and mechanical properties can be modulated, to a large extent, through the control of the drying step and the CaCl(2) proportion. The drying step determines the volumetric contraction of the pellets and, consequently, the porosity parameters. When freeze-drying is applied, the freezing conditions have a marked influence on total porosity and mean pore size of the pellets. Slowly frozen pellets present the lowest porosity but the pores are the greatest. Pore size appears as a critical factor for achieving controlled release; the greater the pores, the faster the entrance of water and, consequently, the drug release. Therefore, if freeze-drying is used to remove water from wet pellets, the control of the ice formation is essential to modulate the release profiles. The practical possibilities of such modulation are especially clear for a slightly-water soluble drug, such as ketoprofen.

A comparison of drug loading capacity of cellactose with two ad hoc processed lactose-cellulose direct compression excipients.

This study compares the drug loading capacity of Cellactose and two excipients of similar composition and similar particle size, prepared by dry granulation and extrusion-spheronization respectively. The drugs evaluated were acetaminophen and furosemide. Acetaminophen did not significantly affect the flow properties of any of the excipients, whereas furosemide markedly worsened flow properties, eliminating the differences initially existing among the three excipients. For both drugs, tablet mechanical properties were clearly better with Cellactose than with the other excipients. Acetaminophen dissolution rate was very similar regardless of the excipient used, but furosemide dissolution rate was lower from Cellactose tablets than from tablets prepared with the other excipients. This important difference is discussed in terms of micropore structure, specific surface area, and wettability of tablets, and is attributable to the special structure of Cellactose particles.

Powdered cellulose as excipient for extrusion-spheronization pellets of a cohesive hydrophobic drug.

This study compared a powdered cellulose (PC) and a microcrystalline cellulose (MCC) as sole excipients in the preparation of furosemide pellets by extrusion-spheronization. Pellets prepared with PC and 25 or 50% furosemide showed smaller mean size, a broader particle size distribution, similar sphericity, greater surface roughness and higher friability than equivalent pellets prepared with MCC. Furosemide release rate was markedly higher from PC pellets, which may be attributable to their higher micropore volume.

Soft contact lenses capable of sustained delivery of timolol.

The aim of this work was to evaluate the influence of the composition and the application of an imprinting technique on the loading capability of weakly crosslinked hydroxyethyl methacrylate (HEMA) hydrogels, with a view to their use as reloadable soft contact lenses for administration of timolol. Hydrogels were prepared by dissolution of ethylene glycol dimethacrylate (EGDMA, 10 mM) in HEMA with or without methacrylic acid (MAA) or methyl methacrylate (MMA; 100-400 mM) and with or without timolol maleate (10 mg/mL), initiation of polymerization by addition of 2,2'-azo-bis(isobutyronitrile) (AIBN, 10 mM), injection in molds, and curing in an oven at 50-70 degrees C. Unreacted reagents were removed by boiling. The dry hydrogels were clear and fully polymerized with smooth, poreless surfaces and presented optimal mechanical properties. The hydrogels were then characterized by determination of their swelling and timolol release kinetics in 0.9% NaCl, phosphate buffer (pH 7.4) and artificial lacrimal fluid, and of the timolol loading capacity of both nonimprinted hydrogels and de-timololized imprinted hydrogels at various pHs. Both water uptake and timolol release exhibited Fickian kinetics, except in the case of hydrogels made with 400 mM MAA. Timolol diffusion into 0.9% NaCl from HEMA or HEMA/MMA was slow; release from HEMA/MAA into phosphate buffer or lacrimal fluid was faster and increased with the MAA content of the polymer. Timolol loading was significant for HEMA/MAA hydrogels (imprinted or not) at pH 5.5-7.5, and specially for imprinted hydrogels containing 100 mM MAA, which absorb 12 mg timolol/g dry hydrogel. The results indicate that the incorporation of MAA as comonomer increases the timolol loading capacity to therapeutically useful levels while retaining appropriate release characteristics.