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Fenofibrate microsphere preparation and pharmacokinetic study

Author: HuHaiBo
Tutor: XuQunWei
School: Nanjing Medical University
Course: Pharmacology
Keywords: fenofibrate fenofibrate acid microparticle preparation freeze-dry curve bioavailability
CLC: R96
Type: Master's thesis
Year: 2009
Downloads: 149
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Abstract

Fenofibrate is a lipid-regulating agent, produces reductions in total cholesterol and total triglycerides. Fenofibrate reduces hypercholesterolemia, hypertriglyceridema and combined hyperlipidemia familial. Fenofibrate also reduces hyperlipoidemia associated with diabetes, hypertension or other angiocardiopathy. The side effects of fenofibrate are hydrodipsia, greasy, belching and Serum alanine aminotransferase and blood urea nitrogen mild rise, temporary. The side effects of fenofibrate can return to normal after drug withdrawal. The chemical name for fenofibrate is 2-[4-(4-chlorob -enzoyl)phenoxy]-2-methylpropanoic acid isopropyl ester, the molecular weight is 360.83, the chemical structure of fenofibrate is shown in Fig.1; fenofibrate is insoluble in water. The melting point is 79°C to 82°C. Fenofibrate was first available in a pharmaceutical dosage form (Lipidil?) consisting of a hard gelatin capsule containing fenofibrate and pharmaceutically acceptable excipients such as lactose, pregelatinized starch and magnesium stearate. Conventional tablet, chewable tablet, collocystis, release pellet and modified release capsule are available domestic agents. Fig.1 The chemical structure of fenofibrateBioavailability of poorly-water-soluble hydrophobic drugs is limited by their solubility and dissolution rate. The dissolution rate of these drugs can be improved by decreasing particle size, and increasing the surface area by creating micro-particles or nano-particles. However, the fine drug particles have high tendency to agglomerate due to van der Waals attraction or hydrophobicity. Fenofibrate have a visible absorp -tion characteristics, its bioavailability is optimized when taken with meals. The bioavailability of micronized fenofibrate increased a little at fasting condition. The experiment invent a fenofibrate agent which stabilized by phospholipid directed to improved pharmacokinetic profile and reduced fed/fasted variability. The absorption of this composition is 80% greater than the same amount of the composition by fed a high fat meal.According to American Pharmacopeia(USP 30), the contents of fenofibrate and fenofibrate acid were determined by HPLC and study on the methodology. The calibration curve of fenofibrate exhibits an excellent linear(r=0.9998); Intra-day precision and inter-day precision RSD<2%. The calibration curve of fenofibrate acid exhibities an excellent linear(r=1); The mean recover was 100.32±0.48%; Intra-day precision RSD<4.52% and inter-day precision RSD<4.75%.The best craft produce was investigated by single factor experiments. The best prescription was fenofibrate 10g, lecithin 3g, tertiary butyl alcohol 2ml, mannitol 10g and 90ml water; Emulsion experimental factor was shearing at 90℃, 15000rpm, 10min.High pressure homogenization experimental factors was homogeny -izing at 80 centi-degree, 1000bar,six times. The produce was freezing dried after quick freezing by dry ice. The produces showed that the dried powder have smooth, compact and bright appearance and small particle diameter (750nm).Cryodesiccation was employed to dry microparticle fenofibrate. Mannitol, glucose, etc. were used as protective agents. Mannitol was the best protective agent according to the result of appearance and particle size. It’s showed that 10% mannitol solution led to best appearance and size protection. The best solution for fenofibrate cryodesiccated powder was investigated by single factor. The result showed that 0.1M HCL supersound 30min can reach requisition. The particle diameter was distributed between 400 ~1100nm.The best microparticle fenofibrate capsule prescription was cryodesiccated powder 250g, PVPP 20g, SDS 3g, talcous 7g; cohesive was 10%PVP; microaggr -egate was poured to capsule after made through 30 mesh grit and oven dry at 60℃. Dissolution condition was 1000ml, 0.1M SDS solution, 37℃, 120rpm. The stability was established by high temperature (40℃; 60℃); high moist (RH75%; RH92.5%); highlight(4500±500Lx). The result showed that microparticle fenofibrate capsule is sensitive to high temperature, high moist and highlight.Microparticle fenofibrate oral administration absorption was compared with micro-powder capsule by rat at fed/fasted condition. After oral administration of two capsules, the relevant bioavailability F1 and F2 were 134.22%±28.46% and 286.02%±81.65% at fed and fasted condition, respectively. The one way ANOVA result of micro-powder fenofibrate at fed/fasted condition indicated that AUC(0-t) showed significant difference(P<0.05); The one way ANOVA result of microparticle fenofibrate at fed/fasted condition indicated that AUC(0-t) did not showed significant difference(P>0.05).

Fenofibrate microsphere preparation and pharmacokinetic study

Abstract

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