Biomedical Applications of Lactoferrin on the Ocular Surface.

Lactoferrin (LF) is a first-line defense protein with a pleiotropic functional pattern that includes anti-inflammatory, immunomodulatory, antiviral, antibacterial, and antitumoral properties. Remarkably, this iron-binding glycoprotein promotes iron retention, restricting free radical production and avoiding oxidative damage and inflammation. On the ocular surface, LF is released from corneal epithelial cells and lacrimal glands, representing a significant percentage of the total tear fluid proteins. Due to its multifunctionality, the availability of LF may be limited in several ocular disorders. Consequently, to reinforce the action of this highly beneficial glycoprotein on the ocular surface, LF has been proposed for the treatment of different conditions such as dry eye, keratoconus, conjunctivitis, and viral or bacterial ocular infections, among others. In this review, we outline the structure and the biological functions of LF, its relevant role at the ocular surface, its implication in LF-related ocular surface disorders, and its potential for biomedical applications.

Efficacy and safety of a new medicated nail hydrolacquer in the treatment of adults with toenail onychomycosis: A randomised clinical trial.

BACKGROUND: A new water-soluble formulation with ciclopirox has shown a higher penetration than other ciclopirox nail lacquers currently marketed, thus providing a higher concentration of ciclopirox into the nail. OBJECTIVE: To evaluate the efficacy and safety of a new ciclopirox nail hydrolacquer compared with its vehicle and an active comparator (hydroxypropyl chitosan-based 80 mg/g ciclopirox nail lacquer) for the treatment of toenail fungal infection. METHODS: Phase III, multicenter, randomised, double-blind, clinical trial in patients with distal mild to moderate toenail onychomycosis due to dermatophyte fungi. Patients were randomised to apply topically a ciclopirox nail hydrolacquer, its vehicle or a reference product once daily for 48 weeks with a follow-up period of 4 weeks up to week 52. RESULTS: A total of 381 patients were included. No statistically significant differences were observed between patient groups in the proportion of subjects achieving a complete cure. At week 52, a higher percentage of patients in the ciclopirox nail hydrolacquer group achieved a mycological cure (negative for culture and DTS/KOH test, with results: 32.0% ciclopirox nail hydrolacquer, 23.2% vehicle and 27% reference product, respectively), and similar results were found for improvement (mycological cure and reduction of diseased nail ≥20%, with results: 27.2% ciclopirox nail hydrolacquer, 21.6% vehicle and 20.6% reference product, respectively). Regarding mycological results, only ciclopirox nail hydrolacquer demonstrated significant statistical superiority versus vehicle negativizing dermatophyte culture (p = .039) with no recurrences, relapses or re-infections in a four-week follow-up patients with complete cure. The safety profile was comparable to the vehicle and reference product and consistent with the previously reported. CONCLUSIONS: A new water-soluble formulation for a ciclopirox nail lacquer showed similar efficacy to the reference product to eradicate toenail onychomycosis and superiority in the mycological cure defined by negative culture, thus preventing reinfections and recurrences. Efficacy and safety data demonstrate the positive benefit-risk profile of this new topical antifungal preparation. [Correction added on 13 April 2023, after first online publication: The results and conclusions in the Abstract contained incorrect information and were revised in this version.].

Mucoadhesive PLGA Nanospheres and Nanocapsules for Lactoferrin Controlled Ocular Delivery.

BACKGROUND: the present work describes the preparation, characterization and optimization of eight types of PLGA-based nanosystems (nanospheres and nanocapsules) as innovative mucoadhesive drug delivery systems of lactoferrin, in order to achieve a preclinical consistent base as an alternative pharmacological treatment to different ocular syndromes and diseases. METHODS: All different nanoparticles were prepared via two modified nanoprecipitation techniques, using a three-component mixture of drug/polymer/surfactant (Lf/PLGA/Poloxamer), as a way to overcome the inherent limitations of conventional PLGA NPs. These modified polymeric nanocarriers, intended for topical ophthalmic administration, were subjected to in vitro characterization, surface modification and in vitro and in vivo assessments. RESULTS: An appropriate size range, uniform size distribution and negative ζ potential values were obtained for all types of formulations. Lactoferrin could be effectively included into all types of nanoparticles with appropriate encapsulation efficiency and loading capacity values. A greater, extended, and controlled delivery of Lf from the polymeric matrix was observed through the in vitro release studies. No instability or cytotoxicity was proved for all the formulations by means of organotypic models. Additionally, mucoadhesive in vitro and in vivo experiments show a significant increase in the residence time of the nanoparticles in the eye surface. CONCLUSIONS: all types of prepared PLGA nanoparticles might be a potential alternative for the topical ophthalmic administration of lactoferrin.

Design, optimization, and in vitro characterization of idebenone-loaded PLGA microspheres for LHON treatment.

Biodegradable poly(lactic-co-glycolic acid) microspheres (PLGA MSs) are attractive delivery systems for site-specific maintained release of therapeutic active substances into the intravitreal chamber. The design, development, and characterization of idebenone-loaded PLGA microspheres by means of an oil-in-water emulsion/solvent evaporation method enabled the obtention of appropriate production yield, encapsulation efficiency and loading values. MSs revealed spherical shape, with a size range of 10-25 µm and a smooth and non-porous surface. Fourier-transform infrared spectroscopy (FTIR) spectra demonstrated no chemical interactions between idebenone and polymers. Solid-state nuclear magnetic resonance (NMR), X-ray diffractometry, differential scanning calorimetry (DSC) and thermogravimetry (TGA) analyses indicated that microencapsulation led to drug amorphization. In vitro release profiles were fitted to a biexponential kinetic profile. Idebenone-loaded PLGA MSs showed no cytotoxic effects in an organotypic tissue model. Results suggest that PLGA MSs could be an alternative intraocular system for long-term idebenone administration, showing potential therapeutic advantages as a new therapeutic approach to the Leber's Hereditary Optic Neuropathy (LHON) treatment by intravitreal administration.

Design, development, and characterization of an idebenone-loaded poly-ε-caprolactone intravitreal implant as a new therapeutic approach for LHON treatment.

Leber's Hereditary Optic Neuropathy (LHON) is a hereditary mitochondrial neurodegenerative disease of unclear etiology and lack of available therapeutic alternatives. The main goal of the current pilot study was based on the evaluation of the feasibility and characteristics of prolonged and controlled idebenone release from a PCL intravitreal implant. The design, development, and characterization of idebenone-loaded PCL implants prepared by an homogenization/extrusion/solvent evaporation method allowed the obtention of high PY, EE and LC values. In vitro characterization was completed by the assessment of mechanical and instrumental properties. The in vitro release of idebenone from the PCL implants was assessed and the implant erosion was monitored by the mass loss and surface morphology changes. DSC was used to estimate stability and interaction among implant's components. The present work demonstrated the controlled and prolonged idebenone delivery from the PCL implants in an in vitro model. A consistent preclinical base was established, supporting the idea of idebenone-loaded PCL implants as a new strategy of long-term sustained intraocular delivery for the LHON treatment.

Budget impact analysis of two pharmaceutical management models in relation to the administration of intravenous anti-infective therapy in a Spanish nursing home.

OBJECTIVE: To perform a cost-effectiveness and budget impact analysis from the perspective of the Spanish public healthcare system (SHS) to compare the number of overnight hospital stays avoided under a community and a hospital pharmacy model due to the administration of intravenous anti-infective therapy (IVAT) at a nursing home with 145 beds. METHODS: Analytical, observational, retrospective cohort study of a nursing home in Galicia (north-west Spain) that switched from a community to a hospital pharmaceutical management model. We compared the number of IVAT administrations, the number of hospital transfers and stays avoided, and mean annual costs avoided by the SHS before and after the switch. Costs were calculated using official SHS rates. RESULTS: The switch from the community to the hospital pharmacy model resulted in 2.8 more IVAT administrations (95% CI, 2.71 to 2.88) and 20.79 fewer overnight hospital stays (95% CI, 20.07 to 21.51) per 100 nursing home beds a month (p<0.001). The net monthly avoided cost for the SHS was 9971.52 €2019. The budget impact analysis showed that implementation of this model throughout Galicia and Spain would respectively avoid costs of 13.78 and 221.21 million €2019 a year. CONCLUSIONS: Hospital pharmacy models can contribute to a better optimisation of public healthcare resources and help improve the sustainability of the SHS.

Design, Optimization, and Characterization of Lactoferrin-Loaded Chitosan/TPP and Chitosan/Sulfobutylether-ß-cyclodextrin Nanoparticles as a Pharmacological Alternative for Keratoconus Treatment.

This research study describes the design, optimization, and characterization of two different types of chitosan-based nanoparticles as novel drug delivery systems of a protein drug, lactoferrin. A preclinical consistent base was obtained for both nanosystems, being considered as the first pharmacological treatment for keratoconus as an alternative to current invasive clinical methods. Both types of nanoparticles were obtained via the ionotropic gelation technique. The size and morphology of the nanoparticles were studied as a function of the preparation conditions. A mean size of 180.73 ± 40.67 nm, a size distribution [polydispersity index (PDI)] of 0.170 ± 0.067, and positive ζ-potential values, ranging from 17.13 to 19.89 mV, were achieved. Lactoferrin was successfully incorporated into both types of nanocarriers. In vitro release profiles showed a lactoferrin enhanced, prolonged, and controlled delivery from the polymeric matrix. These formulations also demonstrated no stability or cytotoxicity problems, as well as appropriate mucoadhesive properties, with a high permanence time in the ocular surface. Thus, both types of nanoparticles may be considered as nanocarriers for the controlled release of lactoferrin as novel topical ophthalmic drug delivery systems.

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery.

We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-ß-CD (HPßCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa's ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.

Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis.

Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs.

[Cysteamine ophthalmic hydrogel for the treatment of ocular cystinosis]. / Hidrogel oftálmico de cisteamina para el tratamiento de la cistinosis ocular.

Ocular cystinosis is a rare disease characterised by the deposit of cystine crystals on the corneal surface, which hinder patients' eyesight. Oral cysteamine is given as cysteamine; however, it does not reach the cornea due to the lack of corneal vascularization making necessary its  administration by the topical ocular route. The aim of the present study is to  determine the stability of an ophthalmic hydrogel of cysteamine, which can be  potentially prepared at hospital pharmacy departments, under different preservation conditions during a follow-up of 30 days. Different physical  and chemical parameters were evaluated: osmolality, pH and  cysteamine concentration, which has been measured by a method of ultra  performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS).  Descriptive assays were also performed, such as transparency measurement and  microbiological assays in order to verify its sterility. The obtained results  allow us to conclude that the cysteamine hydrogel is stable during 30 days,  being recommendable its preservation in refrigerated conditions.

La cistinosis ocular es una enfermedad rara que se caracteriza por el depósito de  cristales de cistina a nivel corneal, los cuales dificultan la visión de  los pacientes. La cisteamina oral se administra en forma de cisteamina, pero  esta no alcanza la córnea debido a la falta de vascularización corneal, por lo que  es necesaria la aplicación tópica ocular. El objetivo del presente trabajo es  determinar la estabilidad de un hidrogel oftálmico de cisteamina, potencialmente  formulable en servicios de farmacia hospitalaria, conservado  este bajo diferentes condiciones de almacenamiento durante un periodo de 30  días. Los parámetros físicos y químicos evaluados han sido la osmolalidad, el pH  y la concentración de cisteamina, siendo esta última valorada mediante un  método de cromatografía líquida de ultra alta presión, empleando un detector de  masas en tándem (UPLC-MS/MS). Los ensayos descriptivos se han basado  en la medición de la transparencia y los ensayos microbiológicos en la realización  de pruebas de esterilidad. Los resultados obtenidos permiten  concluir que el hidrogel de cisteamina es estable durante un periodo de 30 días,  recomendándose que su conservación sea en nevera.

Preclinical PET Study of Intravitreal Injections.

Purpose: This work aimed at describing the time course of vitreous clearance through the use of positron emission tomography (PET) as a noninvasive tool for pharmacokinetic studies of intravitreal injection. Methods: The pharmacokinetic profile of intravitreal injections of molecules labeled with 18Fluorine (18F) was evaluated in adult Sprague Dawley rats by using a dedicated small-animal PET/computed tomography scanner. Different conditions were studied: three molecules radiolabeled with 18F (18F-FDG, 18F-NaF, and 18F-Choline), three volumes of intravitreal injections (7, 4, and 2 µL), and absence or presence of eye inflammation (uveitis). Results: Our results showed that there are significant pharmacokinetic differences among the radiolabeled molecules studied but not among the injected volumes. The presence or absence of uveitis was an important factor in vitreous clearance, since the elimination of the drug was clearly increased when this condition is present. Conclusions: Intravitreal pharmacokinetic studies based on the use of dedicated PET imaging can be of potential interest as noninvasive tools in ophthalmic drug development in small animals.

Cysteamine polysaccharide hydrogels: Study of extended ocular delivery and biopermanence time by PET imaging.

Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine.

Improved release of triamcinolone acetonide from medicated soft contact lenses loaded with drug nanosuspensions.

Drug nanosuspensions (NSs) show a significant potential to improve loading and release properties of the poorly water soluble drug triamcinolone acetonide (TA) from poly(hydroxyethyl methacrylate) (pHEMA) soft contact lenses. In this work, TA NSs were developed by a controlled precipitation method using a fractional factorial Plackett-Burmann design. Poloxamer 407 (PL) and polyvinyl alcohol (PVA) as stabilizing agents were selected. NSs were characterized in terms of their drug content, particle size and morphology. Results indicate that all studied factors, except homogenization speed and sonication, have significant influence on the drug incorporation yield into NSs. Drug nanoparticles showed an interesting size that may be suitable for their incorporation into topical ocular drug delivery systems, as hydrogels. pHEMA hydrogels and daily-wear Hilafilcon B commercial contact lenses (SCLs) were employed to study TA loading capacity and drug release properties using NSs as loading system. Hydrogels have been synthesised by copolymerization of 2-hydroxyethyl methacrylate (HEMA) with methacrylic acid (MA) in accordance with a previous work (García-Millán et al., 2015). Both synthesised hydrogels and SCLs were characterized in terms of their mechanical and physical properties and TA loading and release properties. Selected TA NS was further characterized by studying its physical-chemical stability during the loading process. Results show that the use of TA NSs as loading medium significantly increases drug loading capacity and release of soft contact lenses in comparison with drug saturated solution. Synthesised pHEMA hydrogels and SCLs lenses have good properties as ophthalmic drug delivery systems, but SCLs load higher quantities of drug and release TA in shorter time periods than synthesised pHEMA hydrogel.

In vivo eye surface residence determination by high-resolution scintigraphy of a novel ion-sensitive hydrogel based on gellan gum and kappa-carrageenan.

In last years, sensitive hydrogels have become a breakthrough in ophthalmic pharmaceutical technology aimed at developing new strategies to increase the residence time of active substances. In a previous paper, we qualitatively demonstrated the capacity of a new ion sensitive hydrogel to increase the residence time. Nevertheless, the clearance of the gel from the ocular surface was not quantifiable with the used methodology. The aim of the present work was to use a well-established approach based on scintigraphy to quantitatively estimate the residence time of the previously proposed hydrogel. The rat corneal residence time of a topic ophthalmic formulation containing gellan gum and kappa carragenan (0.82% w/v) labeled with 99mTc-DTPA radiotracer was evaluated and compared with the residence of an aqueous solution. Ophthalmic safety studies such as eye irritation or passage through the cornea were also carried out. After 1.5h of contact, 77% of the hydrogel remained in the ocular surface, presenting kinetics of disappearance one-phase decay and a half time of 262min. We conclude that the novel ophthalmic hydrogel developed with kappa carrageenan and gellan gum remains for long periods of time on the corneal surface, presenting a drop that fits an exponential decay.

Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations.

Purpose: This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations. Methods: The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures. Results: Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells. Conclusions: The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

Solid-state characterization of triamcinolone acetonide nanosuspensiones by X-ray spectroscopy, ATR Fourier transforms infrared spectroscopy and differential scanning calorimetry analysis.

The data presented in this article describe the physical state of the triamcinolone acetonide (TA) in nanosuspension stabilized with polyvinyl alcohol (PVA) and poloxamer 407 (PL). The data were assessed by X-ray spectroscopy, ATR Fourier transforms infrared spectroscopy measurements (FTIR), and Differential scanning calorimetry (DSC) analysis. PVA, PL and polymeric mixture (PVA and PL) were compared with nanosuspension and the interactions between drug triamcinolone acetonide and polymers were studied. The data are related and are complementary to the research article entitle "Improved release of triamcinolone acetonide from medicated soft contact lenses loaded with drug nanosuspensions" (García-Millán et al., 2017) [1].

In vitro and in vivo ocular safety and eye surface permanence determination by direct and Magnetic Resonance Imaging of ion-sensitive hydrogels based on gellan gum and kappa-carrageenan.

Gellan gum, kappa-carrageenan and alginates are natural polysaccharides able to interact with different cations that can be used to elaborate ion-activated in situ gelling systems for different uses. The interaction between fluid solutions of these polysaccharides and cations presents into the tear made these biopolymers very interesting to elaborate ophthalmic drug delivery systems. The main purpose of this study is to evaluate the ability of mixtures of these polymers to obtain ion-activated ophthalmic in situ gelling systems with optimal properties for ocular use. To achieve this purpose different proportion of the biopolymers were analyzed using a mixture experimental design evaluating their transparency, mechanical properties and bioadhesion in the absence and presence of simulated tear fluid. Tear induces a rapid sol-to-gel phase transition in the mixtures forming a consistent hydrogel. The solution composed by 80% of gellan gum and 20% kappa-carrageenan showed the best mechanical and mucoadhesive properties. This mixture was evaluated for rheological behavior, microstructure, cytotoxicity, acute corneal irritancy, ex-vivo and in vivo ocular toxicity and in vivo corneal contact time using Magnetic Resonance Images (MRI) techniques. Result indicates that the system is safe at ophthalmic level and produces an extensive ocular permanence higher than 6h.

Drug loading optimization and extended drug delivery of corticoids from pHEMA based soft contact lenses hydrogels via chemical and microstructural modifications.

This paper proposes an approach to improve drug loading capacity and release properties of poly(2-hydroxyethyl methacrylate) (p(HEMA)) soft contact lenses based on the optimization of the hydrogel composition and microstructural modifications using water during the polymerization process. P(HEMA) based soft contact lenses were prepared by thermal or photopolymerization of 2-hydroxyethyl methacrylate (HEMA) solutions containing ethylene glycol di-methacrylate as crosslinker and different proportions of N-vinyl-2-pyrrolidone (NVP) or methacrylic acid (MA) as co-monomers. Transmittance, water uptake, swelling, microstructure, drug absorption isotherms and in vitro release were characterized using triamcinolone acetonide (TA) as model drug. Best drug loading ratios were obtained with lenses containing the highest amount (200 mM) of MA. Incorporation of 40% V/V of water during the polymerization increases the hydrogel porosity giving a better drug loading capacity. In vitro TA release kinetics shows that MA hydrogels released the drug significantly faster than NVP-hydrogels. Drug release was found to be diffusion controlled and kinetics was shown to be reproducible after consecutive drug loading/release processes. Results of p(HEMA) based soft contact lenses copolymerized with ethylene glycol dimethacrylate (EGDMA) and different co-monomers could be a good alternative to optimize the loading and ocular drug delivery of this corticosteroid drug.

Mucoadhesive tablets for controlled release of acyclovir.

Mucoadhesive chitosan (CS) and/or hydroxypropyl-methylcellulose (HPMC) tablets for gastric drug delivery of acyclovir (ACV) have been developed in order to improve the ACV oral bioavailability. Swelling, bioadhesive and dissolution studies were carried out in two acidic media (pH 1.5 and 4) in order to determine the tablets behaviour in both fed and fasted states. All the designed tablets showed good mucoadhesive properties on gastric mucosa due to the presence of CS and/or HPMC. In vitro dissolution of ACV from tablets was influenced by the swelling behaviour of each polymer. All data release of the studied tablets fitted to Hopfenberg model, which describes drug release from tablets displaying heterogeneous erosion. HPMC and CS/HPMC tablets revealed a sustained release for 24 h, but a complete dissolution of the tablets was not produced at this time. On the contrary, tablets which contained only CS as polymer were able to release the total amount of ACV for 4 h, due to the CS imbibition and erosion processes in pH 1.5 medium. These results allowed us to conclude that CS is the excipient to be chosen to obtain gastroretentive formulations, due to its demonstrated gastric compatibility.

Use of beta-cyclodextrins to prevent modifications of the properties of carbopol hydrogels due to carbopol-drug interactions.

Carbomers are carboxyvinylic derivatives that are widely used in the manufacture of hydrogel dosage forms. Because of their anionic nature and large number of acid groups, they tend to interact with cationic substances, and with other hydrophilic polymers containing alcohol groups. Here, we report a study of interactions between the carbomer Carbopol and the cationic drug propranolol hydrochloride in the solid state and in solution, and of the effects of such interactions on the properties of the hydrogel. We found that the drug forms an insoluble ionic complex with the polymer, modifying all of the hydrogel properties studied (swelling, release, bioadhesion). The inclusion of beta-cyclodextrin in the formulation reduces polymer/drug interactions, so that hydrogel properties remain unchanged. This is probably attributable to formation of inclusion complexes of beta-cyclodextrin and the drug, so that the drug is prevented from interacting with the polymer.