RESUMO
Quality by design (QbD) principles were implemented to understand the product and process variables of sonoprecipitation technique, for preparation of eprosartan mesylate (EM) nanosuspension. Quality risk management approach was utilized to identify and assess high-risk attributes affecting critical quality attributes (CQA's), prioritizing the number of experiments. The effect of critical material attributes (CMA's) and critical process parameters (CPP's) (soluplus concentration, drug concentration ultrasonication amplitude) on z-average particle size and PDI were investigated using a central composite face-centered design (CCF). Further, design space with criteria set of CMA's and CPP's was established to offer assurance of quality. The optimal formulation, identified using numerical optimization method, was further lyophilized and evaluated for redispersibility, solubility saturation, dissolution kinetic and in-vitro dissolution behavior. The EM nanoparticles were in an amorphous state as confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The stability study conducted for a span of 6â¯months attests physical and chemical stability of EM dry nanosuspension in an amorphous state when stored at 4⯰C. The enhanced solubility and in-vitro dissolution of EM nanosuspension may be attributed to the reduced particle size and alteration of the physical state from a crystalline to an amorphous state. Further, the optimized formulation was subjected to in-vitro and ex-vivo transport study using parallel artificial membrane permeability assay (PAMPA) and rat everted gut sac model respectively. The transport studies revealed successful permeation enhancement of EM nanoparticle when compared with EM API and physical mixture (PM). The absolute bioavailability of EM API was 7.1% and improved to 39.9% for EM nanosuspension, suggesting that nanoformulation had overcome solubility and permeability limited bioavailability which was observed with EM API.
Assuntos
Acrilatos , Anti-Hipertensivos , Imidazóis , Nanopartículas , Tiofenos , Acrilatos/administração & dosagem , Acrilatos/química , Acrilatos/farmacocinética , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Liberação Controlada de Fármacos , Imidazóis/administração & dosagem , Imidazóis/química , Imidazóis/farmacocinética , Mucosa Intestinal/metabolismo , Masculino , Membranas Artificiais , Nanopartículas/administração & dosagem , Nanopartículas/química , Permeabilidade , Ratos Wistar , Medição de Risco , Suspensões , Tiofenos/administração & dosagem , Tiofenos/química , Tiofenos/farmacocinéticaRESUMO
BACKGROUND: Transdermal drug delivery is an attractive approach for both local and systemic therapeutics of various diseases. Transdermal drug delivery systems show various advantages like reduction of local irritation, prevention of first-pass hepatic metabolism, and bioavailability enhancement of bioactive molecules over conventional drug delivery systems. OBJECTIVE: The main objective of the present research work was to develop and characterize (in-vitro and ex-vivo) econazole nitrate loaded transethosomes and their comparison with marketed cream of econazole nitrate [Ecoderm, Brown and Burk Pharmaceutical (Pvt.) Ltd., Bengaluru, India] for effective transdermal delivery. METHOD: Transethosomes loaded with econazole nitrate were developed by homogenization method and evaluated for entrapment (%), vesicular size, zeta potential, polydispersity index (PDI), and invitro drug release. Furthermore, optimized econazole nitrate loaded transethosomes were added to Carbopol 934 gel and this gel was evaluated for viscosity, pH, drug content, ex-vivo skin permeation and retention studies followed by in-vitro antifungal activity against C. albicans fungus. RESULTS: The optimized transethosomes loaded with econazole nitrate showed vesicle size of 159.3 ± 4.3 nm, entrapment efficiency about 78.3 ± 2.8%, acceptable colloidal properties like (zeta potential = -27.13 ± 0.33 mV, PDI = 0.244 ± 0.045), approximately 57.56 ± 2.33% drug release up to 24 h. Results of DSC analysis confirmed the encapsulation of econazole nitrate inside transethosomes. Optimized transethosomes showed drug release following zero order through diffusion mechanism. Transethosomal gel showed high drug content (92.35 ± 0.63%) and acceptable values of pH (5.68 ± 0.86) or viscosity (10390 ± 111 cPs). Transethosomal gel showed less ex-vivo skin penetration (17.53 ± 1.20%), high ex-vivo skin retention (38.75 ± 2.88%), and high in-vitro antifungal activity compared to the marketed cream of econazole nitrate. CONCLUSION: Therefore, it can be concluded that econazole nitrate loaded transethosomes are effective to deliver econazole nitrate transdermally in a controlled fashion for effective elimination of cutaneous candidiasis.
Assuntos
Antifúngicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Econazol/administração & dosagem , Acrilatos/administração & dosagem , Acrilatos/química , Administração Cutânea , Animais , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Econazol/química , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
Chronic repeated gavage dosing of high concentrations of ethyl acrylate (EA) causes forestomach tumors in rats and mice. For two decades, there has been general consensus that these tumors are unique to rodents because of: i) lack of carcinogenicity in other organs, ii) specificity to the forestomach (an organ unique to rodents which humans do not possess), iii) lack of carcinogenicity by other routes of exposure, and iv) obvious site of contact toxicity at carcinogenic doses. In 1986, EA was classified as possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC). However, by applying a MOA analyses and human relevance framework assessment, the weight-of-evidence supports a cytotoxic MOA with the following key events: i) bolus delivery of EA to forestomach lumen and subsequent absorption, ii) cytotoxicity likely due to saturation of enzymatic detoxification, iii) chronic regenerative hyperplasia, and iv) spontaneous mutation due to increased cell replication and cell population. Clonal expansion of initiated cells thus results in late onset tumorigenesis. The key events in this 'wound and healing' MOA provide high confidence in the MOA as assessed by evolved Bradford-Hill Criteria. The weight-of-evidence supported by the proposed MOA, combined with a unique tissue that does not exist in humans, indicates that EA is highly unlikely to pose a human cancer hazard.
Assuntos
Acrilatos/administração & dosagem , Acrilatos/toxicidade , Neoplasias Gástricas/induzido quimicamente , Acrilatos/química , Administração Oral , Animais , Humanos , Estrutura Molecular , RatosAssuntos
Acrilatos/toxicidade , Qualidade de Produtos para o Consumidor , Cosméticos/toxicidade , Metacrilatos/toxicidade , Acrilatos/administração & dosagem , Acrilatos/normas , Administração Cutânea , Animais , Cosméticos/administração & dosagem , Cosméticos/normas , Relação Dose-Resposta a Droga , Cobaias , Humanos , Exposição por Inalação , Metacrilatos/administração & dosagem , Metacrilatos/normas , Camundongos , Polímeros , Coelhos , Medição de Risco , Testes de ToxicidadeRESUMO
The available inhalation toxicity information for acrylic acid (AA) suggests that lesions to the nasal cavity, specifically olfactory degeneration, are the most sensitive end point for developing a reference concentration (RfC). Advances in physiologically based pharmacokinetic (PBPK) modeling, specifically the incorporation of computational fluid dynamic (CFD) models, now make it possible to estimate the flux of inhaled chemicals within the nasal cavity of experimental species, specifically rats. The focus of this investigation was to apply an existing CFD-PBPK hybrid model in the estimation of an RfC to determine the impact of incorporation of this new modeling technique into the risk assessment process. Information provided in the literature on the toxicity and mode of action for AA was used to determine the risk assessment approach. A comparison of the approach used for the current U.S. Environmental Protection Agency (U.S. EPA) RfC with the approach using the CFD-PBPK hybrid model was also conducted. The application of the CFD-PBPK hybrid model in a risk assessment for AA resulted in an RfC of 79 ppb, assuming a minute ventilation of 13.8 l/min (20 m(3)/day) in humans. This value differs substantially from the RfC of 0.37 ppb estimated for AA by the U.S. EPA before the PBPK modeling advances became available. The difference in these two RfCs arises from many factors, with the main difference being the species selected (mouse vs. rat). The choice to conduct the evaluation using the rat was based on the availability of dosimetry data in this species. Once these data are available in the mouse, an assessment should be conducted using this information. Additional differences included the methods used for estimating the target tissue concentration, the uncertainty factors (UFs) applied, and the application of duration and uncertainty adjustments to the internal target tissue dose rather than the external exposure concentration.
Assuntos
Acrilatos/toxicidade , Modelos Biológicos , Cavidade Nasal/efeitos dos fármacos , Acrilatos/administração & dosagem , Acrilatos/farmacocinética , Administração por Inalação , Animais , Simulação por Computador , Deslocamentos de Líquidos Corporais/fisiologia , Humanos , Camundongos , Cavidade Nasal/metabolismo , Cavidade Nasal/patologia , Nível de Efeito Adverso não Observado , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/metabolismo , Mucosa Olfatória/patologia , Ratos , Valores de Referência , Medição de Risco , Especificidade da EspécieRESUMO
An assessment of T-lymphocyte proliferation and lymph node weight is proposed as a predictive test for contact sensitizers of industrial origin. Data are presented showing increased T-lymphocyte proliferation following epicutaneous application of a variety of industrially important acrylate-like chemicals which appear to correlate well with their ability to sensitize in the guinea pig. These data were compared with those obtained after application of 2,4-dinitro-1-fluorobenzene (DNFB) a strong sensitizer, and 2,4-dinitrothiocyanatebenzene (DNTB) a nonsensitizer when given epicutaneously. It is suggested that this quantitative approach, in parallel with a simple one-dose immunization, may provide a better picture of sensitization potential than the longer multidose immunizations currently in use.