Santiago D. Palma

An efficient ternary complex of acetazolamide with HP-ß-CD and TEA for topical ocular administration

In order to enhance the ocular bioavailability of acetazolamide (ACZ), a multicomponent complex with hydroxypropyl-ss-cyclodextrin (HP-ss-CD) and triethanolamine (TEA) was prepared to be applied topically. In vitro corneal permeation across isolated rabbit cornea of proposed ACZ formulations and the marketed AZOPT(R) formulation (1% w/v brinzolamide) was studied. Formulations were also tested for their effect on the intraocular pressure (IOP) in rabbits. (1)H- and (13)C-NMR experiments were undertaken to verify the real inclusion of ACZ in the ACZ-HP-ss-CD-TEA multicomponent complex. The binding of ACZ to HP-ss-CD in the presence of TEA is described. The increase of TEA concentration decreases the apparent equilibrium constant for the ACZ-HP-ss-CD complex. The ternary system ACZ-HP-ss-CD-TEA seemed to be able to reduce IOP in about 30%. This effect was sustained for 4 h after instillation. In vitro corneal permeation studies demonstrated that the ACZ permeation was increased. RMN experiments indicated that TEA can weaken the association between ACZ and HP-ss-CD increasing the drug ocular hypotensive effect by increasing the free drug available for absorption. Our formulations were considered practically non-irritant. These results indicate that the ternary system ACZ-HP-ss-CD-TEA might be a useful tool for formulating aqueous ACZ eye drop solutions.

Drugs solubilization in ascorbyl–decanoate micellar solutions

Abstract Alkanoyl-6- O -ascorbic acid esters are obtained upon esterification of ascorbic acids primary hydroxyl groups with fatty acids. Being more hydrophobic than vitamin C, they dissolve in lipophilic media, and behave as surfactants in water, where they produce micellar aggregates or spreading monolayers, depending on the side chain length. These amphiphiles keep the same antioxidant activity of vitamin C, and can be used for solubilization and protection of hydrophobic species from oxidative degradation. In this paper we report a study on the micellar aggregates formed by decanoyl-6- O -ascorbic acid in water, through surface tension, conductivity, and solubility experiments, and on its coagels produced at low temperatures, by means of differential scanning calorimetry and scanning electron microscopy. Solubilization of some hydrophobic molecules (phenacetin, danthron, and griseofulvin) in ascorbyl–decanoate (ASC10) micelles confirms that the supramolecular assemblies significantly enhance the solubility of these drugs in the liquid phase.

Novel bioadhesive hyaluronan-itaconic acid crosslinked films for ocular therapy.

New hyaluronic acid (HA)-itaconic acid (IT) films have been previously synthesized and used as potential topical drug delivery systems (DDS) for ocular administration. In this study we explored homogeneous and heterogeneous crosslinking reactions of HA using glutaraldehyde (GTA) and polyethylene glycol diglycidyl ether (PEGDE) in the presence of IT, a naturally occurring compound that is non-toxic and readily biodegradable. We have studied the morphology, mechanical properties and in vitro biocompatibility between these new materials and ocular surface cells (human corneal epithelial cell line) and evaluated the biopharmaceutical performance of the designed formulations. Although all the synthesized materials exhibited good mechanical properties, the PEGDE modified films exhibited the best biocompatibility, with in vivo assays showing good adhesive performance and minimal irritation. PEGDE films were also tested for their effects in the treatment of intraocular pressure (IOP) in rabbits using timolol maleate (TM) as the model drug. These results may be useful for further design of novel bioadhesive matrix containing drugs by topical application in ophthalmology.

Evaluation of the surfactant properties of ascorbyl palmitate sodium salt

In this paper we report on the physicochemical surface properties of ascorbyl palmitate (Asc16) and of its sodium salt (Asc16Na) with a view to their use as surfactants. Asc16Na was synthesized from ascorbyl palmitate by neutralizing the -OH groups in position 3 of the ascorbyl ring. The acid-base properties, thermal analysis and stability of Asc16Na monomers were determined. Self-assembling parameters of micellar aggregates in aqueous dispersions through critical micellar concentration (CMC) and critical micellar temperature (CMT) were measured. Asc16Na micellar dispersions efficiently solubilize poorly soluble drugs such as phenacetin and griseofulvin, and enhance their apparent solubility in aqueous environments. Stability tests showed that Asc16Na is more unstable than ascorbyl palmitate. Ascorbyl palmitate and its sodium salt are insoluble at room temperature in water, but their solubilities strongly depend on temperature, and largely increase above the CMT. Although Asc16Na is insoluble at room temperature, it is more soluble than Asc16, and its CMT significantly lowers in the undissociated acidic form. The apparent solubilities of phenacetin and griseofulvin are increased in Asc16Na aqueous solutions. The Asc16Na potential use as surfactant is restricted by its low stability in water, therefore the addition of some antioxidant species is necessary.

Improved Albendazole Dissolution Rate in Pluronic 188 Solid Dispersions

Solids dispersions (SDs) have been proposed as an alternative to improve the dissolution rate of low solubility drugs. SDs containing albendazole (ABZ; 5, 10, 25, and 50% w/w) and Pluronic 188 (P 188) as hydrophilic carrier were formulated. The obtained SDs were assessed in comparison to physical mixtures (PMs). Drug–polymer interactions in solid state were investigated using Fourier-transform infrared spectroscopy, scanning electron microscopy, and X-ray diffraction analysis. No chemical interaction was found between ABZ and poloxamer. The dissolution profiles indicated that ABZ incorporated in SDs and PMs was rapidly released, reaching rapidly the steady state. Increased dissolution rates are usually observed at the highest polymer proportions. However, an opposite effect for SDs as well as for PMs was observed in the assays described here. The systems with the lowest P 188 percentages (SD4, SD3; PM4, PM3) tended to be more effective in increasing the ABZ dissolution rate. Such a result can be attributed to the fact that concentrated aqueous solutions of Poloxamer may form thermo-reversible gels. The physical–mechanical properties indicated that SDs possess improved flow and compacting properties compared to PMs. Thus, ABZ SDs would be more convenient for solid dosage form design and manufacture.

Design of Peumus boldus tablets by direct compression using a novel dry plant extract.

A solid pharmaceutical dosage formulation using a novel dry plant extract of Peumus boldus MOL. (Monimiaceae) (Pb) is proposed. The botanical evaluation of plant material, through morphological and anatomical diagnosis, is presented. This evaluation permits to identify the herb to be used correctly. The analysis of the most extractive solvent mixture and the attainment of plant extract (fluid and dry) are reported. Several formulations (tablets) containing a novel dry plant extract of Pb and common excipients for direct compression are evaluated. The following formulation: dry plant extract of Pb (170 mg), Avicel PH101 (112 mg), Lactose CD (112) and magnesium stearate (6 mg), compressed at 1000 mPa, showed the best pharmaceutical performance.

Cystic echinococcosis therapy: Albendazole-loaded lipid nanocapsules enhance the oral bioavailability and efficacy in experimentally infected mice

Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE.

Surface phase behavior and domain topography of ascorbyl palmitate monolayers.

Ascorbyl palmitate (ASC(16)) is a molecule of potential pharmacological interest due to its antioxidant properties and amphiphilic nature. The surface behavior of ASC(16) was studied using Langmuir monolayers and Brewster angle microscopy. This molecule formed stable monolayers at room temperature that showed phase transition from a liquid-expanded to liquid-condensed or crystalline phase, depending on the subphase conditions. Using a theoretical approach, we were able to explain the behavior of the ASC(16) film at different bulk pH values and salt conditions based on the surface pH and the dissociation fraction of the film. Both condensed phases corresponded to highly packed conditions with the crystalline phase occurring at a low charge density, showing molecular tilting and preferential growth at characteristic angles, while the liquid-condensed phase formed in highly charged surfaces revealed small flowerlike domains probably as a consequence of internal dipole repulsion. A smaller perpendicular dipole moment was observed for the crystalline than the liquid-condensed phase which may explain the domain features. In conclusion, ASC(16) showed a complex surface behavior that was highly sensitive to subphase conditions.

Crosslinked soy protein films and their application as ophthalmic drug delivery system.

In this research, the potential of soy protein (SPI) based-films as drug delivery devices for ocular therapy was developed. Hence, crosslinked films with a natural and non-cytotoxic crosslinking agent, genipin (Gen), coated with poly(lactic acid) (PLA), were prepared. Filmogenic solutions were loaded with timolol maleate (TM) as a model drug, to be used as drug delivery devices, a novel application for this material. The mechanical properties of the films were studied, observing that with the presence of PLA coating, more rigid materials with improved properties were obtained. Furthermore, the release behavior of TM was evaluated in aqueous medium, it being influenced by the degree of film crosslinking. Furthermore, it was determined that PLA coating decreased TM release rate compared to that of uncoated films. Similarly, this behavior was observed via indirect estimation of the release by assessing the hypotensive effectiveness of the films by in-vivo assays. Through intraocular pressure (IOP) determination tests in rabbits, it was demonstrated that, through the use of high crosslinked and coated films, a significant decrease in IOP could be achieved for prolonged time periods. These results suggest that the use of soy protein-based films as drug delivery systems is highly suitable.

Enhanced chemoprophylactic and clinical efficacy of albendazole formulated as solid dispersions in experimental cystic echinococcosis.

Cystic echinococcosis is a chronic, complex, and still neglected disease. Although albendazole has demonstrated efficacy, only about one-third of patients experience complete remission or cure and 30-50% of treated patients develop some evidence of a therapeutic response. Different strategies have been developed in order to improve the albendazole water solubility and dissolution rate. The aim of the current work was to investigate the chemoprophylactic and clinical efficacy of an albendazole:poloxamer 188 solid dispersion formulation on mice infected with Echinococcus granulosus metacestodes. Albendazole formulated as solid dispersion had greater chemoprophylactic and clinical efficacy than albendazole alone. The improved in therapeutic efficacy could be a consequence of the increase in the systemic availability of albendazole sulfoxide. The work reported here demonstrates that in vivo treatment with albendazole:poloxamer 188 impairs the development of the hydatid cysts. This new pharmacotechnically based strategy could be a suitable alternative for treating cystic echinococcosis in humans.