Kinoshita Masahiro, Baba Kazuhiko, Nagayasu Atsushi, Yamabe Kanoo, Azuma Mami, Houchi Hitoshi, Minakuchi Kazuo
Pharmaceutical Research Laboratory, Taiho Pharmaceutical Co., Ltd., Hiraishi, Kawauchi-cho, Tokushima, Japan.
Drug Dev Ind Pharm. 2003 May;29(5):523-9. doi: 10.1081/ddc-120018641.
3-Bis(4-Methoxyphenyl)methylene-2-indolinone (TAS-301) is a poorly water-soluble drug showing low oral bioavailability in rats and dogs. Previously, we reported that when a physical mixture of TAS-301 and a porous calcium silicate, Florite RE (FLR), was heated at high temperature (250 degrees C), the drug melted and was adsorbed by the FLR in an amorphous state, and that the preparation (melt-adsorbed product) showed a significantly increased solubility and dissolution rate, and a significantly enhanced oral bioavailability of the drug. The aim of the present study was to elucidate important factors for preparing a melt-adsorbed product showing greater stability of drug in an amorphous state. We examined the effects of the kind of adsorbent, drug/adsorbent ratio, heating conditions, and drug particle size on converting drug crystal into an amorphous state, the stability of amorphous state, and chemical stability of the drug in the melt-adsorbed products under a high temperature and high humidity condition (60 degrees C/80% RH, open). FLR, light anhydrous silicic acid and two types of hydrated silicon dioxides were tested as adsorbents. For the batch method, TAS-301 was converted into an amorphous state by heating TAS-301/adsorbents physical mixtures above the melting point of TAS-301 for more than 2 min. The amorphous state was most stabilized when FLR was used as an adsorbent and drug/FLR ratio was 1:0.5 and more. For the continuous method using the twin screw extruder that enables significantly larger scale manufacturing than batch method, TAS-301 melt-adsorbed products were able to produce when only FLR was used as adsorbent. The heating temperature was needed to be set above the melting point of TAS-301 to convert it into an amorphous state as well as batch method. The amorphous state was stabilized when drug/FLR ratio was 1:2 and more. The micronization of the drug decreased the stability of the amorphous state. These results indicate the importance of optimizing the above factors in the preparation of melt-adsorbed product.
3-双（4-甲氧基苯基）亚甲基-2-吲哚酮（TAS-301）是一种水溶性差的药物，在大鼠和犬体内口服生物利用度较低。此前，我们报道过，当TAS-301与一种多孔硅酸钙（Florite RE，FLR）的物理混合物在高温（250℃）下加热时，药物会熔化并以无定形状态被FLR吸附，并且该制剂（熔融吸附产物）显示出溶解度和溶出速率显著增加，以及药物的口服生物利用度显著提高。本研究的目的是阐明制备在无定形状态下药物稳定性更高的熔融吸附产物的重要因素。我们研究了吸附剂种类、药物/吸附剂比例、加热条件和药物粒径对药物晶体转变为无定形状态、无定形状态的稳定性以及在高温高湿条件（60℃/80%RH，开放）下熔融吸附产物中药物化学稳定性的影响。测试了FLR、轻质无水硅酸和两种水合二氧化硅作为吸附剂。对于分批法，通过将TAS-301/吸附剂物理混合物加热至高于TAS-301的熔点2分钟以上，将TAS-301转变为无定形状态。当使用FLR作为吸附剂且药物/FLR比例为1:0.5及以上时，无定形状态最稳定。对于使用双螺杆挤出机的连续法，与分批法相比能够实现更大规模的生产，当仅使用FLR作为吸附剂时能够生产出TAS-301熔融吸附产物。与分批法一样，需要将加热温度设定在高于TAS-301的熔点以将其转变为无定形状态。当药物/FLR比例为1:2及以上时，无定形状态稳定。药物微粉化会降低无定形状态的稳定性。这些结果表明在制备熔融吸附产物时优化上述因素的重要性。
