Renata Platcheck Raffin

Physicochemical Characterization of a Hydrophilic Model Drug-Loaded PHBV Microparticles Obtained by the Double Emulsion/Solvent Evaporation Technique

Microparticulas de poli(3-hidroxibutirato-co-3-hidroxivalerato) (PHBV) contendo um farmaco modelo hidrofilico, o cloridrato de metformina (MH), foram obtidas pela tecnica de emulsao multipla/evaporacao do solvente. Diversas formulacoes foram preparadas, com o objetivo de investigar a influencia de cada composicao sobre a eficiencia de encapsulacao (EE). O resultado mais elevado de EE (9,76%) foi verificado quando da simultânea alcalinizacao e adicao de NaCl na fase aquosa externa da formulacao. O estudo por MEV das microparticulas revelou morfologia esferica e superficie rugosa. As intensidades de difracao cristalina para as microparticulas contendo o MH foram menores do que aquelas observadas para a mistura fisica. Os resultados obtidos por IVTF sugerem que nenhuma ligacao quimica foi formada entre o polimero e o farmaco. A avaliacao por analise termica indica o surgimento de interacoes favoraveis entre MH e PHBV. O estudo de liberacao in vitro demonstrou a influencia do PHBV no perfil de dissolucao do MH. Poly(3-hydroxybutirate-co-3-hydroxyvalerate) (PHBV) microparticles containing a watersoluble model drug, metformin hydrochloride (MH), were obtained by a double emulsion/solvent evaporation technique. Several formulations were prepared in order to investigate the influence of each composition on the encapsulation efficiency (EE). The highest value of EE (9.76%) was obtained using simultaneously pH alkalinization and NaCl addition in the external water phase of the formulation. SEM study revealed a spherical morphology and a rough surface. The crystalline diffraction intensities for the MH-loaded microparticles were lower than that verified for the physical mixture. FTIR results suggested that no chemical bond between the polymer and the drug was formed. Also thermal analyses indicated a favorable interaction between MH and PHBV. In vitro drug release demonstrated the influence of the PHBV on the dissolution profile of MH.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% (w/v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Gastro-Resistant Microparticles Containing Sodium Pantoprazole: Stability Studies and In Vivo Anti-Ulcer Activity

The aim of the present work was to verify the in vivo capacity of pantoprazole-loaded microparticles to protect the gastric mucosa against ulcer formation and to evaluate their stability under accelerated conditions. Pantoprazole- loaded microparticles were prepared by spray-drying in pilot scale, using Eudragit ® S100 as polymer. Transparent glass vials containing drug-loaded microparticles were stored for 6 months at 40°C and 75% RH. Photostability was tested un- der UVA light. Ulcers were induced by the oral administration of absolute ethanol to rats. Sodium bicarbonate solution, pantoprazole solution and drug-loaded microparticles were tested. Regarding the drug content during the accelerate stabil- ity study, samples showed complete encapsulation efficiency and were considered stable. The microencapsulation of pan- toprazole reduced its photodegradation. The in vivo evaluation showed that the microparticles presented ulcer index lower than the solutions. Enteric microparticles had acceptable stability under accelerated conditions and were efficient in pro- tecting the stomach against ulceration caused by ethanol.

Increasing sodium pantoprazole photostability by microencapsulation: effect of the polymer and the preparation technique.

Pantoprazole sodium is a proton pump inhibitor, used in acid-related disorders, like peptic ulcers and gastroesophageal reflux. This drug is unstable in acid solution and in the presence of salts. The aim of this work was to study the photostability under UVC radiation of pantoprazole and to determine its kinetics. A methanol solution and the solid pantoprazole were evaluated by HPLC within 120 min and 10 days, respectively. The work was also dedicated to evaluate and compare the ability of microencapsulation in stabilizing pantoprazole after UVC radiation. Pantoprazole-loaded microparticles prepared by emulsification/solvent evaporation or spray drying were compared. Pantoprazole was encapsulated using Eudragit S100 or its blend with poly(epsilon-caprolactone) or HPMC. In methanol solution, pantoprazole was completely degraded after 120 min and presented zero-order kinetics with t1/2 of 6.48 min. In the solid form, after 10 days, pantoprazole concentration was reduced to 27% following zero-order kinetic. The microparticles prepared only with Eudragit S100 demonstrated an increase of the drug photostability. After 10 days of irradiation, 56 and 44% of the drug was stable when encapsulated by emulsification/solvent evaporation and spray drying, respectively. The use of polymer blends did not improve the pantoprazole photostability.

Enteric Controlled-Release Pantoprazole-Loaded Microparticles Prepared by Using Eudragit S100 and Poly(ε-caprolactone) Blend

Microparticles of poly(ε-caprolactone) and of its blend with Eudragit® S100 were prepared by emulsion/solvent evaporation technique to provide controlled release and gastro-resistance for an acid labile drug. This drug was sodium pantoprazole, a proton pump inhibitor. Both formulations were successfully prepared, but only the microparticles prepared with the blend were capable of stabilizing the drug in the acid medium. Furthermore, this formulation showed in vivo protection of stomachs against ulceration caused by ethanol in rats. These microparticles were tabletted, and the tablets demonstrated slower drug release and higher acid protection than the microparticles before tabletting.

Powder Characteristics of Pantoprazole Delivery Systems Produced in Different Spray-Dryer Scales

ABSTRACT The purpose of this study is to investigate the physical characteristics of pantoprazole-loaded enteric microparticles produced in different spray dryers and operational conditions. In all conditions tested it was possible to obtain powders that presented spherical shape microparticles, with mean sizes from 6.7 to 24.5 µm. The size was affected mainly by initial feed concentration (2.2 or 6.6% w/w). The integrity of microparticles affected surface area (24 to 113 m2/g)and drug release (71 to 98%). All powders presented very poor flow. The powder that presented higher release was produced with 6.6% solution and a rotating disc atomizer.

Co-encapsulation of imiquimod and copaiba oil in novel nanostructured systems: promising formulations against skin carcinoma

In this study, two types of cutaneous-directed nanoparticles are proposed for the co-encapsulation of imiquimod (a drug approved for the treatment of basal cell carcinoma) and copaiba oil (oil that exhibits anti-proliferative properties). Nanostructured copaiba capsules (NCCImq) were prepared using the interfacial deposition method, and nanostructured Brazilian lipids (NBLImq) were prepared by high-pressure homogenization. The formulations exhibited average diameter, zeta potential, pH and drug content of approximately 200nm, -12mV, 6 and 1mgmL(-1), respectively. In addition, the formulations exhibited homogeneity regarding particle size, high encapsulation efficiency and stability. Both nanocarriers controlled imiquimod release, and NBLImq exhibited slower drug release (p < 0.05), likely due to increased interaction of the drug with the solid lipid (cupuaçu seed butter). The in vitro evaluation of the imiquimod-loaded nanocarriers was performed using healthy skin cells (keratinocytes, HaCaT); no alteration was observed, suggesting the biocompatibility of the nanocarriers. In addition, in vitro skin permeation/penetration using pig skin was performed, and NCCImq led to increased drug retention in the skin layers and reduced amounts of drug found in the receiver solution. Thus, NCCImq is considered the most promising nanoformulation for the treatment of skin carcinoma.

Soft agglomerates of pantoprazole gastro-resistant microparticles for oral administration and intestinal release

Soft agglomerates containing pantoprazole gastro-resistant microparticles were prepared for an oral delayed-release solid dosage form. A new technique was used to agglomerate the microparticles: enteric microparticles of pantoprazole, non-agglomerating per se, were blended with mannitol/lecithin spray-dried microparticles, i.e. excipient microparticles. The blend was agglomerated by tumbling or sieve vibration. In order to elucidate the agglomerate formation, the effect of factors such as the amount of lecithin in the excipient microparticles, the ratio between pantoprazole and excipient microparticles and the agglomeration method were investigated by factorial design. Twelve batches of agglomerates presenting differing yield, drug loading, morphology, mechanical and release properties were prepared. The concentration of lecithin in the excipient microparticles was crucial for the agglomeration process. The biopharmaceutical characteristics of pantoprazole microparticles, i.e. their delayed-release properties, were not affected by the agglomeration process.

Validação de metodologia analítica por cromatografia líquida para doseamento e estudo da estabilidade de pantoprazol sódico

Pantoprazole is a proton pump inhibitor used in the treatment of digestive ulcers, gastro-esophageal reflux disease and in the eradication of Helicobacter pylori. In this work, an analytical method was developed and validated for the quantification of sodium pantoprazole by HPLC. The method was specific, linear, precise and exact. In order to verify the stability of pantoprazole during dissolution assays, pantoprazole solution in phosphate buffer pH 7.4 was kept at room temperature and protected from light for 22 days. Pantoprazole presented less than 5% of degradation in 6 hours and the half live of the degradation was 124 h.

Pharmacokinetics evaluation of soft agglomerates for prompt delivery of enteric pantoprazole-loaded microparticles

Soft agglomerates containing pantoprazole-loaded microparticles were developed with the aim of prompt delivery of gastro-resistant particles. The objective was to evaluate the relative bioavailability in dogs after the oral administration of soft agglomerates. Gastro-resistant pantoprazole-loaded microparticles prepared by spray drying were mixed with mannitol/lecithin spray-dried powder and agglomerated by vibration. One single oral dose (40mg) was administered to dogs. Each dog received either a reference tablet or hard gelatin capsules containing the agglomerates. The plasma profiles were evaluated by non-compartmental and compartmental approaches, and the pharmacokinetic parameters were determined. The agglomerates presented 100% of drug particle loading and a production yield of 80.5%. The amount of drug absorbed after oral dosing was similar after reference or agglomerate administration, leading to a relative bioavailability of 108%. The absorption lag-time was significantly reduced after agglomerate administration (from 135.5+/-50.6 to 15.0+/-2.5min). The agglomerated gastro-resistant pantoprazole-loaded microparticles reduced time to peak plasma. The agglomerates were equivalent to the reference tablets in terms of extent but not in terms of rate of absorption, showing that this formulation is an alternative to single-unit oral dosing with enteric coating and with the advantage of reducing time to effect.