Mitotane liposomes for potential treatment of adrenal cortical carcinoma: ex vivo intestinal permeation and in vivo bioavailability

Abstract

The adrenal cortical carcinoma (ACC) treatment, for which mitotane (o,p′-DDD) is the drug of choice, still remains a challenge both because of the well-known solubility problems of the drug, and its serious side effects. Mitotane is currently administered as oral tablets. The loading of mitotane into nanocarriers has been suggested as a way to circumvent the low solubility of the drug and its limited oral bioavailability. In this work, we have developed liposomes containing mitotane to enhance its intestinal absorption and oral bioavailability. Liposomes were produced by spray-drying of a mixture of phospholipids and the developed formulation was optimized by studying the degree of crystallinity, spray-drying conditions, phospholipid/mitotane ratio, and influence of mannitol in the hydrating ethanolic solution. An optimal liposomal formulation was produced with a phospholipid:mitotane combination (3.34:1), exhibiting a mean hydrodynamic diameter around 1 μm and spherical shape. The produced mitotane liposomes were re-suspended by hydrating the spray-dried powders in a stirred tank, and tested their intestinal permeability (ex vivo) and relative bioavailability (in vivo), against a free drug solution (with or without Trigliceril^®CM). Our results support the conclusion that the loading of mitotane in liposomes enhanced its intestinal absorption and relative bioavailability.

Keywords:

• mitotane
• liposomes
• adrenal cortical carcinoma
• spray-drying
• intestinal absorption
• bioavailability

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors acknowledge the sponsorship of the Fundação de Amparo à Pesquisa do Estado de São Paulo [FAPESP – Processo #2011/20801-2, #2012/21219-5], Fundação de Apoio a Pesquisa e à Inovação Tecnológica do Estado de Sergipe (Fapitec), and Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq, #443238/2014-6, #470388/2014-5]. This work was also financed through the project M-ERA-NET-0004/2015-PAIRED and UIDB/04469/2020 (strategic fund), from the Portuguese Science and Technology Foundation, Ministry of Science and Education (FCT/MEC) through national funds, co-financed by FEDER, under the Partnership Agreement PT2020.