Development of microemulsion of mitotane for improvement of oral bioavailability

Autor: Imane Ajana, David Attivi, Béatrice Demoré, Stéphane Gibaud, Alain Astier
Přispěvatelé: Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL)
Rok vydání: 2010
Předmět:
Male
MESH: Emulsions
Administration
Oral
MESH: Rabbits
Pharmaceutical Science
02 engineering and technology
Pharmacology
030226 pharmacology & pharmacy
MESH: Adrenocortical Carcinoma
Drug Delivery Systems
0302 clinical medicine
MESH: Mitotane
Drug Discovery
Adrenocortical Carcinoma
Adrenocortical carcinoma
MESH: Animals
Mitotane
Microemulsion
Solubility
MESH: Biological Availability
media_common
Chemistry
MESH: Surface-Active Agents
MESH: Antineoplastic Agents
Hormonal
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
021001 nanoscience & nanotechnology
3. Good health
Jejunum
MESH: Administration
Oral
Drug delivery
Emulsions
Rabbits
0210 nano-technology
medicine.drug
Drug
Antineoplastic Agents
Hormonal
MESH: Rats
Drug Compounding
MESH: Intestinal Absorption
media_common.quotation_subject
MESH: Drug Delivery Systems
Biological Availability
Surface-Active Agents
03 medical and health sciences
Pharmacokinetics
medicine
Animals
Humans
MESH: Particle Size
Particle Size
Rats
Wistar
MESH: Humans
Chromatography
Organic Chemistry
MESH: Rats
Wistar
medicine.disease
MESH: Male
Rats
Bioavailability
MESH: Solubility
Intestinal Absorption
MESH: Jejunum
MESH: Drug Compounding
Zdroj: Drug Development and Industrial Pharmacy
Drug Development and Industrial Pharmacy, Taylor & Francis, 2010, 36 (4), pp.421-7. ⟨10.3109/03639040903225083⟩
ISSN: 1520-5762
0363-9045
DOI: 10.3109/03639040903225083
Popis: International audience; BACKGROUND: Mitotane (o,p'-DDD) is considered to be the drug of choice in the treatment of nonresectable and metastasized adrenocortical carcinoma. However, mitotane has poor solubility in the gastrointestinal tract and very low bioavailability. Consequently, to achieve therapeutic plasma level, high cumulative doses (4-6 g/day) of mitotane were usually used during 3-5 months. To shorten this equilibration time and reduce gastrointestinal side effects, a self-microemulsifying drug delivery system (SMEDDS) of mitotane has been developed. METHOD: First time, the solubility of mitotane was determined in various oils and surfactants; then, the influence of oils, surfactants, and cosurfactants on the formation of SMEDDS was investigated by constructing ternary phase diagrams. SMEDDS was characterized by morphological observations and droplet size measurements. Intestinal drug permeation of SMEDDS of mitotane (3 mM) was assessed in an Ussing-type apparatus and the bioavailability was determined in a rabbit model. RESULTS: The optimum formulation consisted of a mixture of Capryol, Tween, and Cremophor EL (33:33:33). The formulation was found to pass through the intestinal barrier much faster than a solution of mitotane (14.85 +/- 0.8 versus 3.03 +/- 0.2 micromol/cm(2)). Moreover, after oral administration in rabbits, the relative bioavailability was 3.4, compared with that of the conventional form (Lysodren). CONCLUSION: This SMEDDS can now be considered as a very good candidate to optimize the administration of mitotane.
Databáze: OpenAIRE
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