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1.
Eur J Pharm Sci ; 97: 218-226, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27916693

RESUMO

Pyridoclax is an original oligopyridine lead, very promising in treatment of chemoresistant cancers. However, from solubility measurement and permeability evaluation, it appeared that this compound can be considered as a BCS II drug, with a poor water solubility. To overcome this unfavorable property, two strategies were proposed and compared: pyridoclax di-hydrochloride salt synthesis and formulation of pyridoclax-loaded nanoemulsions (PNEs) efficiently performed by transposing the spontaneous emulsification process previously developed by our team. Whereas the salt improved the thermodynamic solubility of the drug by a factor 4, the apparent solubility of the encapsulated pyridoclax was 1000-fold higher. Their stability was assessed upon dilution in various complex biomimetic media relevant for oral administration (SGF, FaSSIF-V2, FeSSIF-V2) or for the intravenous route (PBS). The solubility of the salt was affected by the nature of the medium, indicating that it could precipitate after administration, negatively impacting its bioavailability and its efficiency in vivo. On the contrary, in all media, PNEs remained stable in terms of granulometric properties (determined by DLS), ζ-potential and encapsulation efficiency (measured by HPLC). Thus, such nanomedicines appear as a valuable option to perform preclinical studies on the promising pyridoclax.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Piridinas/síntese química , Cloreto de Sódio/síntese química , Composição de Medicamentos , Emulsões , Nanopartículas/administração & dosagem , Piridinas/administração & dosagem , Cloreto de Sódio/administração & dosagem , Solubilidade
2.
Int J Pharm ; 498(1-2): 49-65, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26685727

RESUMO

The formulate-ability of six model active pharmaceutical ingredients (API), with different physico-chemical profiles, in a nanoemulsion designed to be intraveinously administrable was explored. Nanoemulsions were spontaneously generated at room temperature by pouring a phosphate buffer in an anhydrous mixture containing pharmaceutically acceptable triglycerides and non-ionic surfactants. After determination of the apparent solubility of each API in excipients and characterization of mixtures by DSC, API-loaded nanoemulsions were formulated and characterized in terms of granulometric properties, surface potential, drug recovery efficiency, pH, osmolarity, in vitro drug release, and stability. Except ciprofloxacin, a BCS class IV drug, all studied APIs were soluble in at least one excipient used, i.e. Labrasol. At 2 wt% API, all drug-loaded nanoemulsions present properties compatible with i.v. administration. The formulation should permit to increase apparent solubility of poorly water-soluble APIs, and also to prolong delivery of hydrophobic as well of more hydrophilic compounds. Herein, the relative affinity of the API for nanodroplets and the release medium would directly influence drug release profiles. Nanoemulsions were stable for 7 days. They could also been extemporaneously reconstituted before use. Such a versatile nanoemulsion would provide a valuable option as formulation strategy for improvement of drug properties.


Assuntos
Química Farmacêutica/métodos , Nanopartículas/química , Tensoativos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões , Glicerídeos/química , Glicerídeos/farmacocinética , Nanopartículas/metabolismo , Tensoativos/farmacocinética
3.
Int J Pharm ; 458(1): 197-207, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24084450

RESUMO

We report the development of folate-functionalized nanoparticles able to target folate receptors, and to deliver a poorly water soluble cytotoxic agent, a tripentone, in ovarian carcinoma. The stability under incubation of lipid nanoparticles formulated by a low-energy phase inversion temperature method was investigated. Thanks to the presence of Labrasol(®), a macrogolglyceride into the composition of the nanocarriers, the conjugation of different quantities of a folate derivate (folic acid-polyethylene glycol2000-distearylphosphatidylethanolamine) to nanoparticles was possible by a rapid, soft, very simple post-insertion process. As determined by dynamic light scattering, nanoparticles present a monodisperse diameter of about 100 nm, a spherical shape as attested by transmission electron micrographs, a weakly negative surface zeta potential, and are able to encapsulate the tripentone MR22388. The presence of folate receptors on SKOV3 human ovarian cancer cells was identified by fluorescent immunocytochemistry. Cellular uptake studies assessed by flow cytometry indicated that these nanoparticles reached the SKOV3 cells rapidly, and were internalized by a folate-receptor mediated endocytosis pathway. Moreover, nanoparticles allowed the rapid delivery of the antitumor agent tripentone into cells as shown in vitro by real-time cellular activity assay. Such folate-lipid nanoparticles are a potential carrier for targeted delivery of poorly water soluble compounds into ovarian carcinoma.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carcinoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Excipientes/administração & dosagem , Excipientes/química , Feminino , Ácido Fólico , Humanos , Lipídeos/administração & dosagem , Lipídeos/química , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Solubilidade
4.
J Pharm Sci ; 99(11): 4603-15, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20845459

RESUMO

Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been studied with chemometric techniques to emphasize the influence of the four major components (Solutol®, Labrasol®, Labrafac®, water) on their average diameter and their distribution in size. Typically, these NP present a monodisperse size lower than 200 nm, as determined by dynamic light scattering measurements. From the application of the partial least squares (PLS) regression technique to the experimental data collected during definition of the feasibility zone, it was established that NP present a core-shell structure where Labrasol® is well encapsulated and contributes to the structuring of the NP. Even if this solubility enhancer is regarded as a pure surfactant in the literature, it appears that the oil moieties of this macrogolglyceride mixture significantly influence its properties. Furthermore, results have shown that PLS technique can be also used for predictions of sizes for given relative proportions of components and it was established that from a mixture design, the quantitative mixture composition to use in order to reach a targeted size and a targeted polydispersity index (PDI) can be easily predicted. Hence, statistical models can be a useful tool to control and optimize the characteristics in size of NP.


Assuntos
Lipídeos/química , Nanopartículas/química , Glicerídeos , Análise dos Mínimos Quadrados , Modelos Estatísticos , Nanopartículas/ultraestrutura , Compostos Orgânicos/química , Tamanho da Partícula , Solubilidade
5.
Eur J Pharm Biopharm ; 75(2): 117-27, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20144710

RESUMO

The objective of the present paper is to develop lipidic nanoparticles (NP) able to encapsulate drugs presenting limited solubility in both water and lipids, with high loading rates, and without using organic solvents. In this goal, a solubility enhancer, a macrogolglyceride (Labrasol), was incorporated in a formulation process based on a low-energy phase inversion temperature method. From electrical conductivity through the temperature scans, it appears that presence of Labrasol does not prevent the phase inversion, and it takes part in the microemulsion structuring, probably of bicontinuous type. After screening pseudo-ternary diagrams, the feasibility of NP was established. From results of a partial least square analysis, it appears that these NP present a core-shell structure where Labrasol is well encapsulated and contributes to the formation of the oily liquid core of the NP. The diameter of the NP, assessed by dynamic light scattering, remains kinetically stable. These NP, smaller than 200 nm, spherical in shape as attested by cryo-transmission electron micrographs, are able to encapsulate a tripentone, a new anticancer agent, with drug loading rates up to 6.5% (w/w). So highly drug-loaded lipidic nanocarriers were developed without using the slightest organic solvent trace, and making it easily possible dose adjustment.


Assuntos
Excipientes/química , Nanopartículas , Alcaloides de Pirrolizidina/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Estabilidade de Medicamentos , Emulsões , Glicerídeos , Análise dos Mínimos Quadrados , Lipídeos/química , Microscopia Eletrônica de Transmissão , Compostos Orgânicos/química , Tamanho da Partícula , Alcaloides de Pirrolizidina/química , Solubilidade , Temperatura
6.
Int J Pharm ; 320(1-2): 157-64, 2006 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-16723200

RESUMO

The purpose of the present work is to develop nanoparticles of a new antitubulin agent of the family of tripentones by means of a phase inversion process. Dynamic light scattering, transmission electron microscopy and zeta-potential measurements were used to characterize tripentone loaded nanoparticles. From interfacial tension measurements and from the study of the rheological interfacial properties of the tripentone at the Labrafac-Solutol interface, the fraction of tripentone initially present in Labrafac would stay in the oily core of nanocapsules. Moreover, the interpenetration of some tripentone molecules within the surfactant units helps to the stabilization of the formulated nanoparticles. The encapsulation efficiency was determined by high performance liquid chromatography (HPLC) and was found to be above 95%. In vitro release studies were carried out in blank nanoparticles containing phosphate buffer, pH 7.4, at 37 degrees C. The drug release kinetics was measured by HPLC. Antiproliferative activity studies on L1210 cells showed that the cytotoxic activity of tripentone was totally recovered after encapsulation of the antitubulin agent in lipid nanoparticles. This study shows that lipid nanocapsules could be a promising and effective carrier for tripentone delivery in the treatment of cancers.


Assuntos
Antineoplásicos/química , Portadores de Fármacos , Nanopartículas , Alcaloides de Pirrolizidina/química , Moduladores de Tubulina/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Coloides , Preparações de Ação Retardada , Estudos de Viabilidade , Concentração Inibidora 50 , Camundongos , Tamanho da Partícula , Polietilenoglicóis/química , Alcaloides de Pirrolizidina/farmacologia , Reologia , Solubilidade , Ácidos Esteáricos/química , Tensão Superficial , Fatores de Tempo , Triglicerídeos/química , Moduladores de Tubulina/farmacologia
7.
Colloids Surf B Biointerfaces ; 42(2): 97-106, 2005 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-15833660

RESUMO

In this paper, we compared the efficiency of polymer films, made of a poly(ethylene glycol) (PEG2,000)/poly(d,l-lactide) (PLA50) mixture, or a PEG2,000-PLA50 copolymer, to prevent adsorption of a model protein, the hen egg-white lysozyme (HEWL), at the air-water interface. This was achieved by analyzing the surface pressure/surface area curves, and the X-ray reflectivity data of the polymer films spread on a Langmuir trough, obtained in absence or in presence of the protein. For both the mixture and the copolymer, the amount of protein adsorbed at the air-water interface decreases when the density of the polymer surface coverage increases. It was shown that even in a condensed state, the polymer film made by the mixture can not totally prevent HEWL molecules to adsorb and penetrate the polymer mixed film, but however, protein molecules would not be directly exposed to the more hydrophobic phase, i.e. the air phase. It was also shown that the configuration adopted by the copolymer at the interface in its condensed state would prevent adsorption of HEWL molecules for several hours; this would be due in particular to the presence of PEG segments in the interfacial film.


Assuntos
Coloides/química , Ácido Láctico/química , Muramidase/química , Polietilenoglicóis/química , Polímeros/química , Adsorção , Ar , Animais , Fenômenos Biofísicos , Biofísica , Galinhas , Clara de Ovo , Cinética , Ácido Láctico/metabolismo , Microscopia de Força Atômica , Poliésteres , Polímeros/metabolismo , Pressão , Proteínas/química , Temperatura , Fatores de Tempo , Água/química , Raios X
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