Zaida Maria Faria de Freitas

Modelos in vitro para determinação da absorção de fármacos e previsão da relação dissolução/absorção

Farmacos contidos em formas farmaceuticas solidas devem ter adequada solubilidade aquosa e permeabilidade intestinal para serem absorvidos apos administracao oral. A velocidade e a extensao com as quais um farmaco e absorvido podem variar devido as suas caracteristicas fisico-quimicas e fatores relacionados a desintegracao e dissolucao. Segundo o Sistema de Classificacao Biofarmaceutica (SCB), a dissolucao e a permeacao intestinal do farmaco podem limitar a absorcao e, consequentemente, a acao terapeutica. Este trabalho objetiva discutir dados da literatura referentes a previsao da relacao entre a dissolucao de farmacos e sua absorcao empregando sistemas in vitro. Para avaliar a permeacao in vitro sao discutidos modelos com tecidos e segmentos intestinais, vesiculas extraidas de membranas e cultura de celulas. Na literatura existem estudos de permeabilidade utilizando celulas Caco-2, TC-7, 2/4/A1, MDCK e MDCK-MDR1. As celulas Caco-2 sao extraidas de adenocarcinoma de colon humano que, em cultura celular, se diferenciam em enterocitos, podendo ser acopladas a sistemas de dissolucao. Estas tecnicas representam importante ferramenta para estudos de dissolucao/permeacao, porem, ainda sao limitadas e nao conseguem reproduzir adequadamente os mecanismos de transporte ativo.

Evaluation of octyl p-methoxycinnamate included in liposomes and cyclodextrins in anti-solar preparations: preparations, characterizations and in vitro penetration studies

Purpose Awareness of the harmful effects of ultraviolet radiation has led to the increasing use of sunscreens, thus, the development of safe and effective antisolar preparations is important. The inclusion of sunscreen molecules in different release systems, like liposomes (lipo) and cyclodextrins (CD) is therefore required. Methods The in vivo sun protection factor (SPF), water resistance, and in vitro transdermal penetration test of octyl p-methoxycinnamate (OMC) in different dispersions, such as OMC encapsulated in liposomes (lipo/OMC), OMC encapsulated in β-cyclodextrins (β-CD/OMC), OMC encapsulated in both release systems (lipo/OMC and β-CD/OMC), and an OMC-free formulation were determined. Results Although the formulation containing only the lipo/OMC system revealed high value of in vivo SPF (11.0 ± 1.3) and water resistance (SPF = 10.3 ± 2.2), the formulation containing both release systems (lipo/OMC + β-cyclodextrin/OMC) showed the best result in the in vivo SPF test (11.6 ± 1.6). In the penetration test, the formulation containing the lipo/OMC system had better performance, since a high amount of OMC in the epidermis (18.04 ± 1.17 μg) and a low amount of OMC in the dermis (9.4 ± 2.36 μg) were observed. These results suggest that liposomes interact with the cells of the stratum corneum, promoting retention of OMC in this layer. Conclusion According to our study, the lipo/OMC system is the most advantageous release system, due to its ability to both increase the amount of OMC in the epidermis and decrease the risk of percutaneous absorption.

Improving the topical delivery of zinc phthalocyanine using oleic acid as a penetration enhancer: in vitro permeation and retention

Topical photodynamic therapy with zinc phthalocyanine (ZnPc), second-generation photosensitizer, can be an alternative method for the treatment of skin cancer. However, ZnPc has poor penetration in the skin. This study was aimed at investigating whether the presence of oleic acid (chemical enhancer) in propylene glycol can improve the topical delivery of ZnPc. The topical (to the skin) and transdermal (across the skin) delivery of ZnPc were evaluated in vitro using suine ear skin mounted in Franz diffusion cell. Photosensitizer was quantified by fluorescence emission, which is a sensitive and selective method. At 5 and 10%, oleic acid increased the topical and transdermal delivery significantly. When the concentration of oleic acid was further increased (20–60% w/w), the topical delivery of ZnPc was still elevated, but its transdermal delivery was substantially reduced. It was concluded that oleic acid (in propylene glycol formulations) can promote the topical delivery of ZnPc, with reduced transdermal delivery. This approach can be effective for the treatment of skin cancer by topical photodynamic therapy.

Glyceridic esters of p‐methoxycinnamic acid. A new sunscreen of the cinnamate class

Synopsis

Atividades antimicrobiana e fototóxica de extratos de frutos e raízes de Physalis angulata L.

Extracts and fractions of Physalis angulata L. prepared from fruits and roots were assayed to find out antimicrobial activity. Using the agar diffusion method all samples were tested against Staphylococcus aureus ATCC 6538. The ethanolic extract of the fruits displayed bacterial activity. Phototoxic property was estimated with guinea pigs when they were exposed to ultraviolet light, no erythemas were observed. These data encouraged us to look for different forms of extracts wich could be applied as a safe and effective antiseptic product.

In vivo and in vitro evaluation of octyl methoxycinnamate liposomes.

Solar radiation causes damage to human skin, and photoprotection is the main way to prevent these harmful effects. The development of sunscreen formulations containing nanosystems is of great interest in the pharmaceutical and cosmetic industries because of the many potential benefits. This study aimed to develop and evaluate an octyl methoxycinnamate (OMC) liposomal nanosystem (liposome/OMC) to obtain a sunscreen formulation with improved safety and efficacy by retaining OMC for longer on the stratum corneum. Methods The liposome/OMC nanostructure obtained was tested for enzymatic hydrolysis with lipase from Rhizomucor miehei and biodistribution with liposomes labeled with technetium-99m. The liposome/OMC formulation was then incorporated in a gel formulation and tested for ocular irritation using the hen’s egg test-chorio-allantoic membrane (HET-CAM) assay, in vitro and in vivo sun protection factor, in vitro release profile, skin biometrics, and in vivo tape stripping. Results The liposome/OMC nanosystem was not hydrolyzed from R. miehei by lipase. In the biodistribution assay, the liposome/OMC formulation labeled with technetium-99m had mainly deposited in the skin, while for OMC the main organ was the liver, showing that the liposome had higher affinity for the skin than OMC. The liposome/OMC formulation was classified as nonirritating in the HET-CAM test, indicating good histocompatibility. The formulation containing liposome/OMC had a higher in vivo solar photoprotection factor, but did not show increased water resistance. Inclusion in liposomes was able to slow down the release of OMC from the formulation, with a lower steady-state flux (3.9 ± 0.33 μg/cm2/hour) compared with the conventional formulation (6.3 ± 1.21 μg/cm2/hour). The stripping method showed increased uptake of OMC in the stratum corneum, giving an amount of 22.64 ± 7.55 μg/cm2 of OMC, which was higher than the amount found for the conventional formulation (14.57 ± 2.30 μg/cm2). Conclusion These results indicate that liposomes are superior carriers for OMC, and confer greater safety and efficacy to sunscreen formulations.

Nifedipine in semi-solid formulations for topical use in peripheral vascular disease: preparation, characterization, and permeation assay

Nifedipine (NFD) has been used for the treatment of cutaneous lesions caused by peripheral vascular disease and diabetic ulcers. NFD was formulated at 8% in three semi-solid formulations: Polaxamer 407 Lecithin Organogel (PLO), PLO plus Transcutol®, and an oil-in-water (o/w) emulsion. In vitro release and permeation tests were carried out using a synthetic (cellulose acetate) or natural membrane (pig ear skin), respectively, mounted in a Franz-type diffusion cell at 37°C in a constant water bath. As a receptor solution, isotonic phosphate buffer at pH 7.4 was used. All samples were analyzed by high-performance liquid chromatography by employing a previously validated method. The drug flow values were 6.126 ± 0.288, 4.030 ± 0.081, and 6.660 ± 0.254 μg/cm2/h for PLO, PLO plus Transcutol®, and o/w emulsion, respectively. The three formulations did not show significant differences in drug flow, considering p > 0.05. Furthermore, their penetration profiles in both the epidermis and dermis were statistically different. Thus, the incorporation of NFD in PLO, PLO plus Transcutol®, and o/w emulsion changed the drug thermodynamic activity, as expected. In addition, Transcutol® increased the solubility of NFD in the formulation and promoted its penetration in both the epidermis and dermis.

Nanoemulsion containing 8-methoxypsoralen for topical treatment of dermatoses: Development, characterization and ex vivo permeation in porcine skin

Graphical abstract Figure. No caption available. ABSTRACT Oral therapy with 8‐methoxypsoralen (8‐MOP) may cause major side effects, whereas the topical treatment might not be much effective due to the low penetration induced by typical formulations. Therefore, the objectives of this work are the development and characterization of a nanoemulsion (NE) containing 8‐MOP together with an ex vivo permeation study, monitored by a validated HPLC‐Fluo method, to determine the amount of drug retained in viable skin (epidermis (E) and dermis (D)) and in stratum corneum (SC). The optimized conditions for NE formulation were achieved by full factorial designs (25 and 32): 60 s and 60% of ultrasound time and potency, respectively; 10 mL of final volume; 2% v/v of oil phase (clove essential oil); and 10% m/v of Poloxamer 407. The NE showed mean droplet diameter of 24.98 ± 0.49 nm, polydispersity index (PDI) of 0.091 ± 0.23, pH values of 6.54 ± 0.06, refractive index of 1.3525 ± 0.0001 and apparent viscosity of 51.15 ± 3.66 mPa at 20 °C. Droplets with nanospherical diameters were also observed by transmission electron microscopy (TEM). Ex vivo permeation study showed that 8.5% of the applied 8‐MOP dose permeated through the biological membranes, with flux (J) of 1.35 &mgr;g cm−2 h−1. The drug retention in E + D and in SC was 10.15 ± 1.36 and 1.95 ± 0.71 &mgr;g cm−2, respectively. Retention in viable skin induced by the NE was almost two‐fold higher than a compounded cream (5.04 ± 0.30 &mgr;g cm−2). These results suggested that the developed NE is a promising alternative for 8‐MOP topical therapy when compared to commercial formulations.

Development and characterization of a nanoemulsion containing propranolol for topical delivery

Background Propranolol (PPN) is a therapeutic option for the treatment of infantile hemangiomas. This study aimed at the development of nanoemulsion (NE) containing 1% PPN, characterization of the system, and safety studies based on ex vivo permeation, cytotoxicity, and biodistribution in vivo. Methods The formulation was developed and characterized in relation to the droplet size, polydispersity index (PDI), pH, zeta potential, and electronic microscopy. Ex vivo permeation studies were used to evaluate the cutaneous retention of PPN in the epidermis and dermis. Cytotoxicity studies were performed in fibroblasts, macrophages, and keratinocytes. In vivo biodistribution assay of the formulations was performed by means of labeling with technetium-99m. Results NE1 exhibited droplet size of 26 nm, PDI <0.4, pH compatible with the skin, and zeta potential of −20 mV, which possibly contributes to the stability. Electron microscopy showed that the NE presented droplets of nanometric size and spherical shape. NE1 provided excellent stability for PPN. In the ex vivo cutaneous permeation assay, the NE provided satisfactory PPN retention particularly in the dermis, which is the site of drug action. In addition, NE1 promoted cutaneous permeation of the PPN in small amount. In vivo biodistribution showed that the radiolabeled formulation remained in the skin and a small amount reached the bloodstream. NE1 presented low cytotoxicity to fibroblasts, macrophages, and keratinocytes in the concentrations evaluated in the cytotoxicity assay. Conclusion We concluded that the formulation is safe for skin administration; however, cutaneous irritation studies should be performed to confirm the safety of the formulation before clinical studies in patients with infantile hemangiomas.