Exploratory Study on Lercanidipine Hydrochloride Polymorphism: pH-Dependent Solubility Behavior and Simulation of its Impact on Pharmacokinetics.

This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 µm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.

Ilex paraguariensis Pellets from a Spray-Dried Extract: Development, Characterization, and Stability.

Several studies have shown the potential use of Ilex paraguariensis in developing products with the aim to protect biological systems against oxidative stress-mediated damages. In the same way, technological studies have demonstrated the feasibility of obtaining dry products, by spray-drying process, from aqueous extracts of I. paraguariensis in laboratory. The present work was designed to develop pellets by extrusion/spheronization process, from an I. paraguariensis spray-dried powder. The pellets were characterized with respect to their chemical, physical, and technological properties, and the thermal and the photostability of the main polyphenol constituents were investigated. The pellets exhibited adequate size, shape, and high process yield (78.7%), as well as a good recovery of the total polyphenols (>95%) and a good dissolution in water (89.44 to 100.05%). The polyphenols were stable against light when conditioned in amber glass bottles; unstable against heat when the samples were conditioned either in open glass bottles or in hermetically sealed glass bottles and demonstrated to be hygroscopic and sensible to the temperature, especially when stored in permeable flasks. These findings pointed to the relevance of reducing the residual moisture content of pellets as well as of conditioning them in opaque humidity tight packages under low temperatures. The feasibility of obtaining pellets from an I. paraguariensis spray-dried powder using extrusion/spheronization technique was, for the first time, demonstrated. This finding represents a novelty for the herbal products in both pharmaceutical and food fields.

Development of papain containing pellets produced by extrusion-spheronization: an operational stage approach.

The performance of the standardized extrusion-spheronization technique, operational conditions, formulation parameters and storage of the final product over the bioactivity of papain containing pellets has been evaluated to obtain an insight into the potential of the technique for the manufacture of solid protein formulations. The pellets produced were assayed in terms of biological activity - monitored at each operational stage using N-benzoyl-dl-arginine ρ-nitroanilide as a substrate, and according to the physical properties - evaluated by means of size distribution, apparent density and friability. The produced pellets presented adequate physical and mechanical properties. Monitoring biological activity at each production stage revealed that the most critical steps corresponded to drying and storage, with bioactivity decay ranging from 5 to 30% and 5 to 20% for each process. Dry mixing and extrusion did not hold any influence over papain activity, while wet massing decreased the bioactivity by approximately 0-5% and the spheronization 0-2%. The results varied as a function of the experimental conditions and formulation components. In conclusion, the extrusion--spheronization technique was suitable to produce solid multiparticulate dosage forms for papain, considering the possibility to originate pellets with relatively low bioactivity decay. However, weak points of the technique corresponded to the wet massing and drying stages as well as storage.

Bromelain immobilization in cellulose triacetate nanofiber membranes from sugarcane bagasse by electrospinning technique.

Cellulose triacetate (CTAB) synthesized by cellulose extracted from sugarcane bagasse, and commercial cellulose acetate (CA) were used to produce nanofiber membranes contained bromelain by electrospinning technique. About 1.3 g of cellulose acetate per gram of bagasse were obtained, and both CTAB and CA was characterized by analysis of Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC). The nanofiber membranes were produced by electrospinning process testing the following conditions: voltage 25 kV, flow rate 4 mL/h and distance 10 cm, using acetone/ dimethylformamide (DMF) (85:15 m/ m) to 15% cellulose triacetate (70% CA + 30% CTAB) or CA solutions. Scanning Electron Microscopy (SEM) was used to nanofiber membranes characterization. Bromelain was immobilized on the nanofiber membranes by crosslinking with glutaraldehyde and directly in the electrospinning step, the highest activity recovery was about 675% and in vitro controlled release tests were performed to semi-quantitatively evaluate the release of the enzyme bromelain thus demonstrating complete release process in 3 days.

Binary and ternary inclusion complexes of finasteride in HPbetaCD and polymers: preparation and characterization.

The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HPbetaCD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed.

Preparation of gastro-resistant pellets containing chitosan microspheres for improvement of oral didanosine bioavailability.

The purpose of this work was to introduce a new concept of coated pellets containing chitosan microspheres loaded with didadosine for oral administration, aiming at reducing the frequency of administration and improving the bioavailability by a suitable release profile. Chitosan microspheres were produced under fluidized bed, followed by extrusion and spheronization to obtain pellets with a mean diameter of about 1 mm. The pellets were then coated with Kollidon® VA64 and Kollicoat® MAE100P in water dispersion to depict a sustained release profile. Conventional hard gelatine capsules were loaded with these pellets and tested in vitro for their release profile of didadosine. Dissolution testing confirmed that chitosan microsphere pellets provides appropriate sustained release up to 2 h behavior for didanosine.

Technological development of Cecropia glaziovi extract pellets by extrusion-spheronization

Cecropia glaziovi Snethl., Urticaceae, is commonly used in South America and is one of the species included in the Brazilian Medicinal Plants Research Program. Pharmacological studies have led to reports of the potential of C. glaziovi as a hypotensive, antiasthmatic and anxiolytic agent. The strict requirements regarding the quality, safety and effectiveness of phytopharmaceutical products represent an enormous challenge in the search for products with a high level of uniformity, reproducibility and stability. The incorporation of dry extracts into multiparticulate dosage forms, such as pellets produced by extrusion/spheronization technology, is a suitable alternative to overcome the lack of technological properties of dry extracts, since they are associated with low flowability and high hygroscopicity. In this study, an optimized dry extract (ODE) of C. glaziovi was incorporated into pellets seeking to decrease the moisture sorption and increase the stability, safety and percentage of the extract in the final product. Pellets containing around 50% of ODE were considered the most technologically viable, offering a narrow particle size distribution, significant improvement in the flowability and compressibility properties, and decrease in the moisture compared with the ODE. In conclusion, pellets containing a high dose of the C. glaviovi extract were successfully prepared, achieving degrees of quality, physical stability and feasibility compatible with the desirable characteristics of a phytopharmaceutical.

Thermal characterization and cytotoxicity of complexes formed by papain and cyclodextrin.

Papain is a proteolytic enzyme with restricted applications due to its limited stability. Cyclodextrins are widely used in pharmaceutical formulations once they are able to form complexes with other molecules, improving their stability and bioavailability. The purpose of the present paper was to analyze complexes formed by papain/hydroxypropyl-beta-cyclodextrin and papain/beta-cyclodextrin by thermal analysis and cytotoxicity tests to verify their possible interactions and toxicological behavior. Complex solutions were prepared at different molar ratios and collected as a function of time to be lyophilized and analyzed. Results showed changes in endothermic events and cytotoxicity profiles. A complex formation for both complexes is observed; nevertheless, beta-cyclodextrin was able to change the enzyme characteristics more efficiently.

Avaliação da cinética de dissolução de ampicilina em comprimidos comercializados no Brasil / Dissolution kinetics of ampicillin from tablets available in Brazilian market

No presente estudo, foram avaliadas quatro especialidades farmacêuticas (A, B, C e D) contendo ampicilina, na forma de comprimidos, sendo que, do fabricante A, foram tomados dois lotes (A1 e A2). O perfil de dissolução dos produtos foi traçado utilizando-se as condições descritas na Farmacopéia Americana (USP 23, 1995), retirando-se alíquotas nos intervalos de: 1, 5, 10, 20, 30 e 45 minutos. Após a determinação da ordem do processo de dissolução, foram calculados os parâmetros cinéticos: eficiência de dissolução (ED), constante de velocidade de dissolução (k) e meia-vida de dissolução (t ANTPOT. 50 por cento). Os resultados indicaram que os produtos apresentam acentuada discrepância, porém, A2 e B mostraram-se semelhantes quanto ao processo de dissolução, não sendo evidenciadas diferenças significativas quanto ao valor de ED

Perfil de dissoluçäo do cloridrato de diltiazem a partir de formas farmaceuticas solidas de açäo prolongada comercializadas no Brasil / Dissolution profiles of diltiazem hydrochloride from solid prolonged release dosage forms available in the Brazilian market

Foram avaliadas duas especialidades farmaceuticas contendo cloridrato de diltiazem na dosagem de 120mg, sob a forma de capsulas e comprimidos de açäo prolongada, visando a comparacao do perfil de dissoluçäo do farmaco. Como meios de dissoluçäo, empregaram-se agua destilada e soluçäo aquosa com variaçäo gradual de pH. Os perfis obtidos indicaram diferença considerável entre os produtos pesquisados, o que pode decorrer das caracteristicas de formulaçäo dos mesmos. Tal fato poderia traduzir-se em comportamentos diferenciados em relaçäo a sua biodisponibilidade e bioequivalência.

Estudo comparativo do perfil de dissolução de comprimidos de cloreto de potássio comercializados no Brasil / Comparative study of dissolution profile of potassium chloride tablets marketed in Brazil

Avaliou-se a dissolução de comprimidos de cloreto de potássio de dois fabricantes (A e B), comercializados no mercado farmacêutico brasileiro. Foi adotada metodologia descrita pela Farmacopéia Americana 23ª edição, 1995. Além do teste de dissolução, conforme preconizado por esta Farmacopéia, traçou-se, sob as mesmas condições, o perfil de dissolução dos produtos. Foram analisados, de cada fabricante, dois lotes distintos (A1, A2 e B1, B2). A determinação das concentrações de potássio dissolvido foram realizadas em fotômetro de chama. Os resultados indicaram discrepância entre os dois produtos: o laboratório A teve seus dois lotes rejeitados, de acordo com o teste de dissolução da USP23(1995), enquanto que o laboratório B não apresentou este tipo de problema...