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Int J Pharm ; 578: 119088, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001291


Docetaxel (DTX), a widely prescribed anticancer agent, is now associated with increased instances of multidrug resistance. Also, being a problematic BCS class IV drug, it poses challenges for the formulators. Henceforth, it was envisioned to synthesize an analogue of DTX with a biocompatible lipid, i.e., palmitic acid. The in-silico studies (molecular docking and simulation) inferred lesser binding of docetaxel palmitate (DTX-PL) with P-gp vis-à-vis DTX and paclitaxel, indicating it to be a poor substrate for P-gp efflux. Solid lipid nanoparticles (SLNs) of the conjugate were prepared using various lipids, viz. palmitic acid, stearic acid, cetyl palmitate and glyceryl monostearate. The characterization studies for the nanocarrier were performed for the surface charge, drug payload, micromeritics, release pattern of drug and surface morphology. From the cytotoxicity assays on resistant MCF-7 cells, it was established that the new analogue offered substantially decreased IC50 to that of DTX. Further, apoptosis assay also corroborated the results obtained in IC50 determination wherein, SA-SLNs showed the highest apoptotic index than free DTX. The conjugate not only enhanced the solubility but also offered lower plasma protein binding and improved pharmacokinetic and pharmacodynamic effect for DTX loaded SA-SLNs in apt animal models, and lower affinity to P-gp efflux. The studies provide preliminary evidence and a ray of hope for a better candidate in its nano version for safer and effective cancer chemotherapy.

Int J Pharm ; 560: 219-227, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30776407


The present investigation highlights the development of D-α-Tocopheryl polyethylene glycol 1000 succinate (Tocophersolan; TPGS) stabilized lipid nanocapsules for enhancing the oral bioavailability and permeability of curcumin (CUR). Lipid nanocapsules were optimized for different lipids, different concentrations of TPGS and different drug: lipid ratio and were further lyophilized. Subsequently, they were characterized by powder X-ray diffraction, Transmission electron microscopy and also evaluated for in vitro release study, Caco-2 cell uptake study, ex vivo intestinal permeability and in vivo pharmacokinetic performance. Optimized lipid nanocapsules exhibited desirable quality attributes (average particle size of 190 nm, polydispersity index of 0.240 and average % entrapment efficiency of 51.06 ±â€¯7.27) employing Maisine™ 35-1 as a lipid carrier, 0.05% TPGS and CUR: lipid ratio of 5:10 and showed sustained release biphasic pattern. They showcased excellent stability in simulated gastrointestinal fluids and storage stability. The CUR nanocapsules exhibited ∼14-fold higher Caco-2 cell uptake and ∼12.8-fold increased ex vivo intestinal permeability. Also, the AUC of CUR nanocapsules in Sprague Dawley rats was increased by ∼12 folds and MRT ∼2.47-folds as compared to aqueous CUR suspension. Thus, lipid nanocapsules possessed a positive impact on improving the permeability and oral bioavailability of CUR.

Curcumina/administração & dosagem , Excipientes/química , Lipídeos/química , Vitamina E/química , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Química Farmacêutica/métodos , Curcumina/farmacocinética , Portadores de Fármacos/química , Humanos , Absorção Intestinal , Masculino , Nanocápsulas , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Sprague-Dawley
Nanomedicine (Lond) ; 14(1): 57-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543141


AIM: To explore the potential of paclitaxel (PTX)-loaded anacardic acid conjugated hydrophobized gelatin nanoparticles. MATERIALS & METHODS: Nanoparticles prepared by nanoprecipitation technique were evaluated for various quality attributes (particle size, % entrapment efficiency) in vitro drug release, MCF-7 cell uptake, cell cytotoxicity, in vivo pharmacokinetics, antitumor efficacy and toxicity. RESULTS: The nanoparticles (250-300 nm, 74% entrapment efficiency) showed approximately 2.26-fold higher apoptosis index and approximately 5.86-fold reduction in IC50 value compared with PTX in MCF-7 cells. Also, approximately 3.51- and 1.36-fold increase in area under the curve compared with Intaxel® and Nanoxel™ (both from Fresenius Kabi, Gurugram, India) was achieved. Significant tumor burden reduction (∼60%) and reduced toxicity was observed compared with marketed formulations. CONCLUSION: The hydrophobized gelatin nanoparticles displayed promising therapeutic potential, paving a new path for efficient PTX delivery.

Ácidos Anacárdicos/química , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Gelatina/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Tamanho da Partícula , Ratos Sprague-Dawley , Propriedades de Superfície
J Control Release ; 248: 71-95, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28088572


BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many characteristics that are problematic for effective oral and per oral delivery. Some of the problems associated include low aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and significant positive food effect which leads to low and variable bioavailability. Also, most of the class IV drugs are substrate for P-glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism) which further potentiates the problem of poor therapeutic potential of these drugs. A decade back, extreme examples of class IV compounds were an exception rather than the rule, yet today many drug candidates under development pipeline fall into this category. Formulation and development of an efficacious delivery system for BCS class IV drugs are herculean tasks for any formulator. The inherent hurdles posed by these drugs hamper their translation to actual market. The importance of the formulation composition and design to successful drug development is especially illustrated by the BCS class IV case. To be clinically effective these drugs require the development of a proper delivery system for both oral and per oral delivery. Ideal oral dosage forms should produce both a reasonably high bioavailability and low inter and intra subject variability in absorption. Also, ideal systems for BCS class IV should produce a therapeutic concentration of the drug at reasonable dose volumes for intravenous administration. This article highlights the various techniques and upcoming strategies which can be employed for the development of highly notorious BCS class IV drugs. Some of the techniques employed are lipid based delivery systems, polymer based nanocarriers, crystal engineering (nanocrystals and co-crystals), liquisolid technology, self-emulsifying solid dispersions and miscellaneous techniques addressing the P-gp efflux problem. The review also focuses on the roadblocks in the clinical development of the aforementioned strategies such as problems in scale up, manufacturing under cGMP guidelines, appropriate quality control tests, validation of various processes and variable therein etc. It also brings to forefront the current lack of regulatory guidelines which poses difficulties during preclinical and clinical testing for submission of NDA and subsequent marketing. Today, the pharmaceutical industry has as its disposal a series of reliable and scalable formulation strategies for BCS Class IV drugs. However, due to lack of understanding of the basic physical chemistry behind these strategies formulation development is still driven by trial and error.

Sistemas de Liberação de Medicamentos/métodos , Preparações Farmacêuticas/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Emulsões/química , Humanos , Lipídeos/química , Nanoestruturas/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Farmacocinética , Polímeros/química , Solubilidade