Development of enteric-coated fixed dose combinations of amorphous solid dispersions of ezetimibe and lovastatin: Investigation of formulation and process parameters.

Enteric-coated fixed-dose combinations of ezetimibe and lovastatin were prepared by fluid bed coating aiming to avoid the acidic conversion of lovastatin to its hydroxyacid derivative. In a two-step process, sucrose beads were layered with a glass solution of ezetimibe, lovastatin and Soluplus®, top-coated with an enteric layer. The impact of different bead size, enteric polymers (Eudragit L100® and Eudragit L100-55®) and coating time was investigated. Samples were evaluated by X-ray diffraction, scanning electron microscopy, laser diffraction and in vitro studies in 0.1M HCl and phosphate buffer pH 6.8. Results showed that smaller beads tend to agglomerate and release was jeopardized in acidic conditions, most likely due to irregular coating layer. Eudragit L100-55® required longer processing, but thinner coating layers provided lower drug release. Both polymers showed low drug release in acidic environment and fast release at pH 6.8. The off-line measurement of the coating thickness determined the ideal coating time as 15 and 30min for Eudragit L100-55® and Eudragit L100®-based samples, respectively. Both compounds were molecularly dispersed in Soluplus®, and Eudragit L100® formulations showed concave pores on the surface, presenting higher drug release in acidic conditions. Stability studies after 6 months showed unaltered physical properties and drug release.

New Perspectives for Fixed Dose Combinations of Poorly Water-Soluble Compounds: a Case Study with Ezetimibe and Lovastatin.

PURPOSE: Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively. METHODS: Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by 'in vitro' dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%). RESULTS: Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions. CONCLUSIONS: A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.

Development and evaluation of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) and polycaprolactone microparticles of nimodipine.

Polymeric microparticles containing the calcium channel blocker nimodipine were successfully obtained through simple emulsion/ organic solvent evaporating method. The extended release formulations, composed by the polymers poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV) and polycaprolactone (PCL), were submitted to characterization through X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), Fourier transform infrared analysis (FT-IR) and determination of the mean particle diameter. All formulations obtained revealed an amorphous characteristic, proven through XRPD and DSC results. Besides, no chemical interaction was observed between drug and polymer in polymeric microparticles. PHBV-NMP formulation showed a higher drug entrapment, a larger particle size, a thermal degradation behavior similar to that observed for nimodipine and a longer drug release time, being selected for in vivo evaluation. The PHBV-NMP polymeric microparticles were able to keep the pharmacological antihypertensive effect for a longer period of time, becoming a good alternative to control nimodipine release in hypertension treatment.

Determination of nimodipine in the presence of its degradation products and overall kinetics through a stability-indicating LC method.

The determination of nimodipine in the presence of its degradation products, formed through photolysis, acidic and alkaline hydrolysis, and the drug degradation kinetics under these conditions, was investigated through a validated liquid chromatography method. Separation was achieved using a Phenomenex Luna C18 column (250 × 4.6 mm i.d., 5 µm) with a mobile phase consisting of acetonitrile-methanol-water (55:11:34, v/v/v), at 0.5 mL/min and with ultraviolet detection at 235 nm. The method was considered to be specific, accurate, precise, robust and linear over the concentration range of 5.0 to 35.0 µg/mL. The drug followed a first-order reaction for both hydrolysis and photolysis in methanol, and zero-order for photolysis in acetonitrile and water. The calculated activation energies were 10.899 and 23.442 kcal/mol for alkaline and acidic hydrolysis, respectively. No degradation was observed under thermal and oxidative stress conditions.

High-performance column liquid chromatographic method for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in tablets and oral suspension.

An HPLC method was developed and validated for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in pharmaceutical formulations. The chromatographic separation was carried out on an RP-C18 column using a mobile phase gradient of methanol, 0.015 M phosphate buffer (pH 3.0), and 0.03 M phosphoric acid at a flow rate of 1.0 mL/min and UV detection at 230, 280, and 360 nm, respectively, for buclizine, tryptophan, pyridoxine, and cyanocobalamin. The method validation yielded good results with respect to linearity (r>0.999), specificity, precision, accuracy, and robustness. The RSD values for intraday and interday precision were below 1.82 and 0.63%, respectively, and recoveries ranged from 98.11 to 101.95%. The method was successfully applied for the QC analysis of buclizine, tryptophan, pyridoxine, and cyanocobalamin in tablets and oral suspension.

Development and validation of an RP-HPLC method to quantitate acyclovir in cross-linked chitosan microspheres produced by spray drying.

An accurate, simple, reproducible, and sensitive liquid chromatographic method is developed and validated to quantitate acyclovir (ACV) in cross-linked chitosan microspheres produced by spray drying. The analysis is carried out using a reversed-phase C18 column with UV-vis detection at 254 nm. The mobile phase is diluted with pure water and acetonitrile (95:5 v/v) at a flow-rate of 0.8 mL/min. The parameters used in the validation process are: linearity, range, quantitation limit, detection limit, accuracy, specificity precision, and ruggedness. The retention time of acyclovir is approximately 3.5 min with symmetrical peaks. The linearity in the range of 1-10 microg/mL presents a correlation coefficient of 0.9999. The chitosan and the tripolyphosphate in the formulation do not interfere with the analysis, and the recovery is quantitative. Results are satisfactory, and the method proves to be suitable to quantitate ACV in cross-linked chitosan microspheres.

Antispasmodic effects of Persea cordata bark fractions on guinea pig ileum.

The present study describes the antispasmodic activity of some fractions from the bark of Persea cordata, against guinea pig ileum contracted by acetylcholine and histamine. Hexane and dichloromethane fractions demonstrated the most promising biological effects, having similar potency to that of papaverine, a well-known antispasmodic agent.

Antioedematogenic effect of marrubiin obtained from Marrubium vulgare.

This paper describes the antioedematogenic profile of marrubiin (1), the main constituent of Marrubium vulgare, a medicinal plant used in folk medicine of several countries to treat different pathologies. Compound (1) was analyzed in a model of microvascular leakage in mice ears. The results show that it exhibits significant and dose-related antioedematogenic effects. The results obtained for ID50 values (mg/kg, i.p.) and maximal inhibition (%) for the different phlogistic agents used were as follows: histamine (HIS, 13.84 mg/kg and 73.7%); (BK, 18.82 mg/kg and 70.0%); carrageenan (CAR, 13.61 mg/kg and 63.0%). The other phlogistic agonists, such as prostaglandin E2 (PGE2), caused inhibition of less than 50%. In addition, (1) (100 mg/kg) significantly inhibited the OVO-induced allergic edema in actively sensitized animals (maximal inhibition 67.6+/-4%). Our results demonstrate that the systemic administration of marrubiin exerts a non-specific inhibitory effect on pro-inflammatory agent-induced microvascular extravasation of Evans blue in mouse ear.