Análisis por FTIR y DSC de complejos polielectrolito entre Eudragit® E100 y ácido benzoico como evidencia de hidrólisis de los grupos éster del polímero / FTIR and DSC analysis of polyelectrolyte complexes between Eudragit® E100 and benzoic acid as evidence of hydrolysis of the polymer ester groups

RESUMEN La obtención de complejos polielectrolito entre el polímero catiónico Eudragit® E100 y moléculas aniónicas, con neutralización adicional de un ácido inorgánico, ha sido una práctica recurrente en el área de investigación de estos sistemas de liberación controlada. En el presente trabajo se buscó estudiar el efecto de la adición del ácido fuerte en el polímero, para ello se llevó a cabo la obtención por evaporación de solvente de diez complejos (de diferente composición entre Eudragit® E100 y ácido benzoico o ácido clorhídrico) y de cuatro ionómeros (sin el activo), a los cuales se les realizó análisis por FTIR y DSC. Los resultados demostraron la obtención de los respectivos complejos polielectro-lito y de los ionómeros; además los espectros de FTIR revelaron la relación directa entre la reacción de hidrólisis de los grupos ésteres del polímero y la proporción de HCl adicionada. Los termogramas, por su parte, evidenciaron la existencia de una reacción en el polielectrolito (PE), la cual se favoreció en aquellas composiciones en las que el proceso de hidrólisis ocurrió en mayor magnitud. El proceso de hidrólisis que se describe en el presente estudio debe tenerse en consideración en las futuras investigaciones en el campo, ya que su ocurrencia podría tener implicaciones en las diversas variables que se evalúan en este tipo de sistemas.

SUMMARY Polyelectrolyte complexes obtention between Eudragit® E100 (cationic polymer) and anionic molecules with additional neutralization of inorganic acids is a common practice in the development of these systems. In the present work the addition of strong acid effect on polymer structure was evaluated through FTIR and DSC analysis of a set of ten complexes with different composition (between Eudragit® E100 and benzoic acid) and four ionomers (without the preservative) obtained by solvent evaporation technique. Results demonstrated the complexes and ionomers formation. FTIR spectra revealed direct relationship between polymer ester groups hydrolysis reaction and the amount of HCl added. The thermograms, on the other hand, evidenced the existence of a reaction in the polyelectrolyte, which was favored in those compositions with more hydrolysis process. The degradation reaction described in this study should be taken into consideration in future research, since its occurrence could have implications in variables evaluated in this type of systems.

Polysaccharides-based multiparticulated interpolyelectrolyte complexes for controlled benznidazole release.

Polysaccharides-based delivery systems and interpolyelectrolyte complexes (IPECs) are interesting alternatives to control the release of drugs, thereby improving therapies. Benznidazole (BZ) is the selected drug for Chagas disease pharmacotherapy. However, its side effects limit its efficacy and safety. We developed novel multiparticulated BZ-loaded IPECs based on chitosan and alginic acid, and investigated their physicochemical and pharmacotechnical properties. IPECs were obtained using the casting solvent method, followed by wet granulation. They presented ionic interaction between the biopolymers, revealed that free BZ was uniformly distributed and showed adequate flow properties for hard gelatin-capsule formulation. The multiparticles exhibited mucoadhesion properties and revealed modulation of BZ release, depending on the release media, in accordance with the fluid uptake. The IPECs developed possess interesting properties that are promising for the design of novel alternatives to improve Chagas disease pharmacotherapy, which would diminish BZ's adverse effects and/or allow a reduction in the frequency of BZ administration.

Multi-kinetic release of benznidazole-loaded multiparticulate drug delivery systems based on polymethacrylate interpolyelectrolyte complexes.

Interpolyelectrolyte complexes (IPEC) formulated as multiparticulate drug delivery systems (MDDS) are interesting carriers to improve drug' performance. Benznidazole (BZ) is the first-line drug for Chagas treatment; however, it presents side effects and toxicity, conditioning its efficacy and safety. The goal of this work was to obtain novel MDDS composed by IPEC based on different polymethacrylate carriers loaded with BZ and to investigate in vitro drug delivery performance for oral administration. Physicochemical characterizations were studied and preclinical studies in a murine model of acute Chagas disease were also performed. The MDDS composed by BZ-loaded IPEC based on polymethacrylates were obtained by casting solvent followed by wet granulation methods with yields >83%. FT-IR demonstrated ionic interaction between the polyelectrolytes. Confocal microscopy, DSC and PXRD revealed a fraction uniformly distributed of free BZ on the multiparticles. The rheological evaluation of the MDDS showed adequate flow features for their formulation in hard gelatin-capsules. The type and composition of IPEC conditioned the modulation of BZ release and fluid uptake results. MDDS based on more hydrophylic Eudragit® showed very fast dissolution (Q15min > 85%), while an extended release (Q120min ≤ 40%) for the hydrophobic ones was observed. Capsules containing a combination of two MDDS with different release profile of BZ showed promising properties to improve Chagas disease pharmacotherapy in the preliminary in vivo assay performed, in which the BZ-loaded MDDS exhibited efficacy to reduce parasitemia, while decreasing the levels of liver injury markers in comparison to BZ conventional treatment. Multi-kinetic BZ delivery systems developed are interesting pharmaceutical alternatives to improve the treatment of Chagas disease.

Ciprofloxacin-lidocaine-based hydrogel: development, characterization, and in vivo evaluation in a second-degree burn model.

The purpose of this work was to develop an effective carbomer hydrogel to be used to treat second-degree burns that combined ciprofloxacin and lidocaine (CbCipLid hydrogel). Its antibiotic and anesthetic efficacy and the physical and chemical properties of the CbCipLid hydrogel (release rate and kinetics, rheology, appearance, and drug content) were evaluated both before and after a sterilization cycle and also after 6 months of storage. For the in vivo studies, second-degree burns were developed in a rat model. Animals were divided into three groups: CbCipLid hydrogel, silver sulfadiazine cream (reference), and carbomer hydrogel (as control). The treatments were applied daily for 21 days, and the healing was monitored by macroscopic observation and histologic evaluation. The anesthetic effect was evaluated through the corneal touch threshold in a rabbit eye model. The CbCipLid hydrogel obtained is transparent and allows the loading of ciprofloxacin above its solubility at a neutral pH, with a rheology which is convenient for topical administration. Its physical and chemical properties remained unchanged after sterilization and for at least six additional months. Both ciprofloxacin and lidocaine are reversibly released from the CbCipLid hydrogel with a kinetics fitting the Higuchi model. The presence of a biologic-like fluid increased the rate of drug delivery through an ionic exchange mechanism. Treatment with the CbCipLid hydrogel decreased the wound-healing period, compared with the reference, and was associated with a greater number of fibroblasts and a faster rate of epithelialization and dermis reconstruction. These differences were assigned to the moist environment provided by the hydrogel and also to the presence of a therapeutic concentration of ciprofloxacin. Moreover, CbCipLid hydrogel provides an immediate anesthetic effect, which is significantly more intense than that of the reference. Based on these results, it is believed that the CbCipLid hydrogel could be a potential candidate in the prophylaxis/treatment of second-degree burns.

El adelantamiento del vasto medial ofrece buenos resultados clínicos y funcionales para la inestabilidad lateral femororrotuliana / Vastus medialis advancement provides good clinical and functional outcomes for lateral patellofemoral instability

Introducción La inestabilidad lateral femororrotuliana es una patología de etiología multifactorial aunque existen múltiples opciones para su tratamiento. El adelantamiento del vasto medial con liberación retinacular lateral asistida por artroscopia (AVMLRAA) se realiza cuando no hay alteraciones de alineación ni de la estructura ósea. El objetivo del estudio es evaluar los resultados clínicos y funcionales de pacientes con inestabilidad lateral femororrotuliana (ILFR) tratados con AVMLRAA. Material y métodos Estudio descriptivo y transversal realizado entre septiembre de 2014 y enero de 2016. Se incluyó a pacientes con ILFR tratados con AVMLRAA. Se presentan los resultados evaluados por las escalas de Tegner-Lysholm y Kujala antes de la cirugía y 12meses después de operados. Resultados Seis pacientes, 5 mujeres (83,3%) y 1 hombre (16,7%); media de edad al presentar la primera luxación: 15,83 (7-30) ±8,47 años; rodilla afectada: 4 derechas (66,7%) y 2 izquierdas (33,3%); tiempo promedio desde la primera luxación hasta la cirugía: 10,08 (0,5-17) ±5,16 años; las evaluaciones prequirúrgicas y posquirúrgicas de las escalas Tegner-Lyshom y Kujala para el género y lado afectado no mostraron diferencias estadísticamente significativas (p>0,05). La mediana prequirúrgica de la escala Tegner-Lysholm fue 37,50 (6-78) ±26,66; posquirúrgica: 88,17 (77-99) ±7,73 (p = 0,028); mediana de la escala Kujala prequirúrgica: 36,67 (2-77) ±29,703; posquirúrgica: 84,83 (75-100) ±9,368 (p = 0,027). El seguimiento promedio fue 14,0 (12-18) ±2,44 meses; la aprensión posquirúrgica fue 100% negativa. El 100% respondió que se volverían a operar en caso de presentar nuevamente los síntomas. Discusión El AVMLR para el manejo de la ILFR en pacientes sin malformaciones óseas ni mala alineación ofrece buenos resultados clínicos. Nivel de evidencia clínica Nivel IV.

Background Patellofemoral lateral instability is a condition of multifactorial origin, and has multiple options for its treatment. Vastus medialis advancement with arthroscopic assisted lateral retinacle replication (AALRR) is performed when there is no alteration of alignment or bone structure. The purpose of this study is to evaluate the clinical and functional results of patients with patellofemoral lateral instability (PFLI) treated with AALRR. Material and methods A descriptive, cross-sectional study was conducted from September 2014 to January 2016 on patients with PFLI treated with AALRR. The results before surgery and 12months after surgery, were evaluated using the Tegner-Lysholm and Kujala scales. Results The study included 6 patients, 5women (83.3%), and 1man (16.7%). The median age at first dislocation was 15.83 (7-30) ±8.47years. The affected knees were 4right (66.7%) and 2left (33.3%). The mean time from first dislocation to surgery was 10.08 (0.5-17) ±5.16years. The pre- and post-surgical evaluations using the Tegner-Lysholm and Kujala scales for the affected gender and side showed no statistically significant differences (P>.05). The pre-surgical median of the Tegner-Lysholm scale was 37.50 (6-78) ±26.66, and post-surgical, 88.17 (77-99) ±7.73 (P=.028). The pre-surgical and post-surgical median of the Kujala scale was 36.67 (2-77) ±29.703, and 84.83 (75-100) ±9.368, respectively (P=.027). The mean follow-up was 14.0 (12-18) ±2.44months.; Post-surgical apprehension was 100% negative. All patients responded that they would have a further operation in case of presenting with the symptoms again. Discussion The AALRR for the management of PFLI in patients without bone malformations or misalignment offers good clinical results. Evidence level IV.

Bioadhesive and biocompatible films as wound dressing materials based on a novel dendronized chitosan loaded with ciprofloxacin.

The bioadhesive polymeric films as topical drug delivery systems are interesting alternatives to improve the pharmacotherapy and patient compliances. New derivate biomaterials based on weisocyanate- dendronized PVP- crosslinked chitosan and loaded with ciprofloxacin (CIP), as model drug, were used to prepare bioadhesive films. Relevant in vitro/in vivo attributes to define main physicochemical and biopharmaceutical characteristics for topical wound-healing applications were evaluated. A high proportion of CIP, uniformly dispersed along throughout the film, was loaded. An extended release of CIP and different behaviors of release profiles, depending on the presence of dendron, were observed. The films loaded with CIP were effective in inhibiting the growth of both Gram positive and Gram negative bacteria. In addition, biocompatibility and bioadhesion into conjuntival-sacs of the rabbits suggests that these films have good properties to be applied over skin wounds for topical applications, allowing a reduction of the frequency of administration and improving the residence time of the films.

Application of 1-Dimensional and 2-Dimensional Solid-State Nuclear Magnetic Resonance Spectroscopy to the Characterization of Morphine, Morphine Hydrochloride, and Their Hydrates.

The detailed knowledge of the solid forms of a drug is a key element in pharmaceutical development. Morphine (MOR) is an opiate alkaloid widely used to treat severe acute and chronic pain. Much of the available information on its solid state dates from several decades ago. In order to obtain updated and reliable information, 1-dimensional (1D) and 2-dimensional solid-state nuclear magnetic resonance spectroscopy were used and complemented with powder X-ray diffraction, FTIR, and Raman spectroscopy and thermal analysis. 13C cross-polarization with magic angle spinning 1D spectra accomplish a complete identification of the related forms of MOR. Remarkably, 1H-13C heteronuclear correlation spectra together with FTIR results gave clear evidence that neither MOR nor its hydrate crystallizes as a zwitterion. Our results indicate that the hydrogen bonds in the anhydrate forms have a different nature or strength than in their respective hydrates. The unique information obtained would be useful for the characterization of MOR as a bulk drug, dosage forms, and future developments.

Interaction between DNA and Drugs Having Protonable Basic Groups: Characterization through Affinity Constants, Drug Release Kinetics, and Conformational Changes.

This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA-drug were in the order of 106. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA-drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs.

Preoperative Ultrasonographic Prediction of Hamstring Tendon Diameter for Anterior Cruciate Ligament Repair.

The incidence of anterior cruciate ligament (ACL) injuries is rising every year. The autologous hamstring tendon graft, using semitendinosus tendon (SMT) and gracilis tendon (GR), is a common repair technique in the management of ACL injuries due to its multiple advantages. Using a final graft with a minimum diameter of 8 mm is necessary to avoid graft failure. The aim of this study was to find a correlation between preoperative ultrasound (USG) measurement of the SMT and GR tendon diameters (SMTd and GRd) and their actual diameters measured during the grafting procedure. In the present study, 33 male patients aged between 16 and 43 years with ACL injury that required grafting were enrolled. Before the grafting procedure, we sonographically measured the SMTd, GRd, and calculated the hamstring tendon diameter (SMTd + GRd) as the sum of these two. During surgery, we obtained the SMTd, GRd, and SMTd + GRd; we also obtained the length of both tendons and the final graft diameter (FGd). We then compared the obtained values. Mean age was 25.6 ± 7.9 years in our study population. The mean SMTd, GRd, and SMTd + GRd obtained by USG versus transoperatively were 4.9 versus 4.7 mm, 4.3 versus 3.8 mm, and 9.3 versus 8.6 mm, respectively. The mean of FGd was 8.4 mm and the mean length of both tendons was 14.2 cm. The GRd obtained by USG positively correlated with SMTd, SMT tendon length, GRd, and SMTd + GRd (r = 0.460, 0.404, 0.411, and 0.508, respectively). USG-obtained GRd predicts a final tendon diameter < 8 mm (high risk of failure) with a sensitivity, specificity, positive predictive value, and negative predictive value of 100, 54, 28 and 100%, respectively, using 4.5 mm as cutoff. Of all obtained grafts, 85% were deemed adequate (≥ 8 mm) using transoperative measurement, while 91% were ≥ 8 mm using USG measurement. The USG measurement of hamstring tendons is a useful method to predict their transoperative diameter. GRd obtained by USG is the best predictor of transoperative GRd and SMTd + GRd.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization.

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release.

The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease.

Chagas disease is an important public health problem in Latin America, and its treatment by chemotherapy with benznidazole (BZ) or nifurtimox remains unsatisfactory. In order to design new alternative strategies to improve the current etiological treatments, in the present work, we comprehensively evaluated the in vitro and in vivo anti-Trypanosoma cruzi effects of clomipramine (CMP) (a parasite-trypanothione reductase-specific inhibitor) combined with BZ. In vitro studies, carried out using a checkerboard technique on trypomastigotes (T. cruzi strain Tulahuen), revealed a combination index (CI) of 0.375, indicative of a synergistic effect of the drug combination. This result was correlated with the data obtained in infected BALB/c mice. We observed that during the acute phase (15 days postinfection [dpi]), BZ at 25 mg/kg of body weight/day alone decreased the levels of parasitemia compared with those of the control group, but when BZ was administered with CMP, the drug combination completely suppressed the parasitemia due to the observed synergistic effect. Furthermore, in the chronic phase (90 dpi), mice treated with both drugs showed less heart damage as assessed by the histopathological analysis, index of myocardial inflammation, and levels of heart injury biochemical markers than mice treated with BZ alone at the reference dose (100 mg/kg/day). Collectively, these data support the notion that CMP combined with low doses of BZ diminishes cardiac damage and inflammation during the chronic phase of cardiomyopathy. The synergistic activity of BZ-CMP clearly suggests a potential drug combination for Chagas disease treatment, which would allow a reduction of the effective dose of BZ and an increase in therapeutic safety.

Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids.

OBJECTIVES: Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. METHODS: Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non-specific sedative effects. KEY FINDINGS: O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. CONCLUSION: This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects.

Extemporaneous benznidazole oral suspension prepared from commercially available tablets for treatment of Chagas disease in paediatric patients.

OBJECTIVE: To develop an extemporaneous 1% benznidazole (BNZ) suspension, with masked taste and adequate stability starting from available commercial tablets. The quality of compounding was evaluated through content uniformity measurement and physical and microbiological stability evaluation, under different storage conditions during 90 days. METHODS: Six batches of 1% BNZ suspension were prepared using safe excipients currently available in a galenic area of Hospital Pharmacy and then stored at 5 and 25 °C for 90 days. The BNZ content was determined by UV spectrophotometry. Physical stability was defined as the absence of colour, odour and/or flavour changes and the re-suspension of solid phase by a reasonable amount of simple 15-s shaking. The compliance with microbiological attributes of non-sterile pharmaceutical products was also evaluated. RESULTS: An oral liquid suspension, containing 1% of BNZ, was developed from commercially available BNZ tablets. The formulations stored for 90 days were easily re-dispersed after a simple 15-s shaking, ensuring the pouring of a liquid volume containing the desired dose of BNZ. All samples were within the acceptable range of BNZ concentration with minimal standard deviations. There were no detectable changes in colour, odour, viscosity, pH and microbial growth, complying with official quality requirements. The quality attributes were not affected by storage, room or refrigeration conditions or by the frequent opening or closing of the multidose containers. CONCLUSION: Paediatric oral liquid suspension containing 1.0% of BNZ was easily prepared starting from commercial tablets, being an interesting alternative for optimising the paediatric treatment of Chagas disease.

Formulation and quality control of semi-solid containing harmless bacteria by-products: chronic wounds pro-healing activity.

Chronic wounds are those that remain in a chronic inflammatory state and fail to follow normal healing process. Infection is one of the most important causes of chronicity. A frequent pathogen isolated from chronic infections is Pseudomonas aeruginosa; refractory to therapy and host immune attack in its biofilm phenotype. Lactobacillus plantarum cultures supernatants (LAPS) interfere with its pathogenic capacity. In addition, LAPS showed bacteriostatic and bactericide properties and is neither cytotoxic nor an inductor of necrosis-apoptosis. LAPSs chemical composition was determined; allowing us to propose a correlation between its constituents and their biological activity. This article shows a pharmaceutical dosage form designed by using LAPS as an API with pro-healing activity and its quality control. Pharmacotechnical and anti-microbial assays were adapted to demonstrate that the vehicle used does not modify LAPS activities. Selected formulation (F100) showed fair mechanical and technological properties. From the in vitro release assays was found an adequate release from the carrier matrix and maintains its anti-pathogenic activity for 6 months. We propose F100 for chronic wounds treatment. The use of harmless bacteria by-products, such as LAPS, to antagonize infectious pathogens that have ability to form biofilm is an efficient and economic approach to treat infected chronic wounds.

Ocular delivery of flurbiprofen based on Eudragit(®) E-flurbiprofen complex dispersed in aqueous solution: preparation, characterization, in vitro corneal penetration, and ocular irritation.

A novel ophthalmic formulation based on the ionic complexation between Eudragit E 100 (EU) and flurbiprofen (FB) is proposed. The selected complex composition, named EU-FBH50 Cl50 , had the basic groups of EU completely neutralized with equal molar amounts of FB and HCl. This complex, obtained in the solid state, exhibited a high aqueous compatibility producing a colloidal dispersion with a high positive electrokinetic potential, in which more than 99% of FB was ionically condensed with EU. In bicompartimental Franz cells, FB diffusion from the complex was very slow. However, dispersion in 0.9% NaCl increased the FB release through an ionic exchange, providing an optimal constant rate of delivery. Corneal FB permeation from 0.1% EU-FBH50 -Cl50 dispersed in 0.9% NaCl solution was substantially more effective compared with 0.1% FB solution, EU-FBH50 -Cl50 (Dex), or Tolerane(®) (a marketed formulation). This complex formulation was shown to be innocuous for rabbit ocular tissues because no irritant effects were evidenced.

Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100.

The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug.

Equilibrium and release properties of hyaluronic acid-drug complexes.

With the aim to provide more rational basis about the potentiality of hyaluronic acid (or hyaluronan) as drug carrier a set of ionic complexes of its acid form (HA) and its sodium salt (NaHA) with three model drugs (D) (atenolol, propranolol and lidocaine) were prepared. Besides NaHA subjected to hyalurodinase depolimerization (NaHA(d)) was also used. Transparent dispersions were obtained. They exhibited negative electrokinetic potential and a high degree of counterionic condensation with affinity constants (log Kcc) in the range of 5.8-6.1 for propranolol complexes (pK(a) 9.45) and 4.0-4.6 for lidocaine ones (pK(a) 7.92). Delivery rates of D from the complexes were measured in a Franz-type bicompartimental device. Loaded D were slowly released from the three types of complexes, even when a neutral salt was added to the dispersion placed in the donor compartment, revealing the high affinity between the protonated drugs and the ionisable groups of the polymer. Complex dispersions based on HA or on NaHA(d) exhibited lower viscosity than those of NaHA but their complexing ability remained unaltered. The results reported on equilibrium and release properties of Hyaluronan-model D complexes contribute to expand the use of HA and NaHA as drug carriers for different routes of administration.

Systemic exposure, tissue distribution, and disease evolution of a high solubility ciprofloxacin-aluminum complex in a murine model of septicemia induced by salmonella enterica serotype Enteritidis.

A new pharmaceutical derivative obtained by stoichiometric complexation of ciprofloxacin (CIP) with aluminum (CIP-complex) has been investigated and reported in this study. Such product has high solubility in the gastrointestinal pH range and was successful in the development of optimized formulations while maintaining its antimicrobial potency. The systemic exposure, tissue distribution, and the disease evolution after given CIP-complex were assessed. The systemic exposure and distribution in intestines, lungs, and kidneys after a single intragastric administration of CIP-complex and CIP given alone, used as reference, were performed in Balb-C mice at a dose of 5 mg CIP/kg. For the assessment of the disease evolution assay, mice were infected with a virulent strain of Salmonella enterica serotype Enteritidis and treated intragastrically once or twice daily during 5 consecutive days with solutions of CIP-complex or the reference. Clinical follow up and survival was measured during 15 days post inoculation and health state was scored during this period from 0 to 5. CIP-complex showed a 32% increase in C(max), an earlier T(max), and a smaller AUC(0-12) than the reference. Maximum tissue concentrations (0.5-1 h) were significantly higher in CIP-complex (447% in intestine, 93% in kidney, and 44% in lungs). In the infection model used in this study, survival in CIP-complex versus CIP groups was 40% versus 20% (twice-daily administration) and 30% versus 0% (once-daily administration). Health state of the survivors of CIP-complex group (5/5) was higher than CIP group (3/5). The greater effectiveness of CIP-complex is attributed to the higher levels of CIP in the intestine. Our results supported the fact that CIP-complex is a promising candidate to develop dose-efficient formulations of CIP for oral administration.

Equilibrium and release properties of aqueous dispersions of non-steroidal anti-inflammatory drugs complexed with polyelectrolyte eudragit e 100.

Equilibria and release properties of aqueous systems consisting of a set of five non-steroidal anti-inflammatory drugs (AH) complexed with the cationic polymethacrylate Eudragit E 100 (EU) are reported in this study. The composition (EU(AH)(50) (HCl)(50)) having fifty mole percent of each counterion (A(-) and Cl(-)) produces clear, stable aqueous dispersions in which a remarkably high proportion of AH (higher than 98%) is condensed with the PE under the form of ion pairs. This property expands the interval of pH in which AH are aqueous soluble. The set of AH contains members with and without an alpha methyl group (-(CH(3))CH-COOH: Flurbiprofen, Naproxen, Ketoprofen) and (-CH(2)-COOH: Diclofenac, Indomethacin). The proportion of ion pairs in the complexes was lower in the former group. Release of AH from the complexes toward a saline (NaCl 0.9%) solution was assayed in Franz cells. The five complexes behaved as drug carriers that exhibited a slow drug release with a remarkable zero order. In line with the percentages of counterionic condensation observed, release rates from -(CH(3))CH-COOH complexes were clearly higher than those of -CH(2)-COOH ones.