Preparation of silymarin nanocrystals using a novel high pressure crystallization technique and evaluation of its dissolution and absorption properties

Ttsuo Nkmur, Kori Aie,Kohei ThrHirofumi Tkeuchi

aGifu Pharmaceutical University,1-25-4 Daigaku-nishi,Gifu 501-1196,Japan

bFANCL Corporation,12-13 Kamisinano Totsuka-ku,Yokohama,Kanagawa 244-0806,Japan

Preparation of silymarin nanocrystals using a novel high pressure crystallization technique and evaluation of its dissolution and absorption properties

Risako Onoderaa,*,Tomohiro Hayashia,Tatsuo Nakamurab, Kaori Aibeb,Kohei Taharaa,Hirofumi Takeuchia

aGifu Pharmaceutical University,1-25-4 Daigaku-nishi,Gifu 501-1196,Japan

bFANCL Corporation,12-13 Kamisinano Totsuka-ku,Yokohama,Kanagawa 244-0806,Japan

A R T I C L E I N F O

Article history:

Available online 25 November 2015

PureNano®

Silymarin

Hydroxypropyl cyclodextrin

Crystallization

Oral bioavailability of drug is limited by the factors such as the membrane permeability,the solubility,the dissolution rate and so on[1].In case of a poorly water-soluble drug,its solubility and dissolution rate is a critical factor for its oral bioavailability. Among various techniques for enhancing solubility or dissolution properties,physical modifcation of drug products such as reducing the particle size is one of common approaches[2]. In previous studies,we have succeeded in preparation of nanocrystal suspensions of poorly water-soluble drugs by using a high pressure crystallizer(PureNano®).

Cyclodextrins(CyDs)are cyclic oligosaccharides consisting of six to eight glucose units linked by α-1,4-glycosidic linkage.The potential use of natural CyDs and their synthetic derivatives have been extensively studied to improve certain properties of the drugs,such as solubility,stability,and/ or bioavailability.One of the most useful applications of CyDs in dosage form design is enhancing the solubility of poorly water-soluble drugs by complex formation.

In the present study,we tried to prepare drug nanoparticles of a poorly water-soluble drug by high pressure crystallization method using CyDs or erythritol as additives in freezedrying process.Silymarin(SLM)is a functional food ingredient that has very low aqueous solubility(solubility in water: 50 μg/mL).In the present method,the model drug was dissolved in organic solvent,which was mixed with the aqueous phase under a high pressure.The obtained dispersions were freeze-dried for further physicochemical characterization of the obtained powdered nanoparticles.

The nanocrystal of SLM produced with this high pressure crystallization process exhibited a narrow size distribution.The particle size of SLM crystals powdered with erythritol or hydroxypropyl-β-CyD(HP-β-CyD)was observed about 230 nmafter hydration.When measuring the concentration of SLM in the dissolution test,SLM/HP-β-CyD showed the maximum supersaturated concentration of SLM(100 μg/mL).The plasma concentration profles in absorption test in rats with various SLM nanoparticles samples prepared with this high pressure crystallization process were shown in Fig.1.The SLM/HP-β-CyD nanoparticles exhibited signifcantly increasedAUC0-6hand Cmax compared with other SLM nanoparticles.Such a highAUC value was not observed with SLM/erythritol nanoparticle,where erythritol was used as a stabilizer instead of HP-β-CyD,and with physical mixture of SLM and HP-β-CyD.From these results,a combination of the high pressure crystallization method and use of HP-β-CyD is useful for the effective production of drug nanoparticles of SLM showing enhanced dissolution rate and absorbability.

Fig.1–Blood concentration profle after oral administration of various SLM nanoparticles in rats.

R E F E R E N C E S

[1]Langguth P,Hanafy A,Frenzel D,et al.Nanosuspension formulations for low soluble drugs:pharmacokinetic evaluation using spironolactone as model compound.Drug Dev Ind Pharm 2005;31:319–329.

[2]Liversidge G,Cundy K.Particle size reduction for improvement of oral bioavailability of hydrophobic drugs:I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs.Int J Pharm 1995;125:91–97.

*E-mail address:onodera@gifu-pu.ac.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.11.031

1818-0876/©2016 Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).