CN108440456B - 奥利司他与有机酸钙的共晶体及包含该共晶体的药物组合物 - Google Patents
奥利司他与有机酸钙的共晶体及包含该共晶体的药物组合物 Download PDFInfo
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- CN108440456B CN108440456B CN201810241971.3A CN201810241971A CN108440456B CN 108440456 B CN108440456 B CN 108440456B CN 201810241971 A CN201810241971 A CN 201810241971A CN 108440456 B CN108440456 B CN 108440456B
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Abstract
本发明属于医药技术领域,具体涉及一种奥利司他与钙补充剂类有机酸钙的共晶体及包含该共晶体的药物组合物。所述的共晶体由奥利司他与钙补充剂类有机酸钙制备而成。该共晶体具有较高的熔点,可降低原料药与制剂的制备过程中对干燥条件的要求,并可提高奥利司他抑制脂肪吸收的效果。此外,以所得的共晶作为原料制备的口服固体制剂,所得口服固体制剂中共晶体在水中的溶解度显著高于市售奥利司他胶囊中的Ⅱ型奥利司他,其起效快于后者。
Description
技术领域
本发明属于医药技术领域,具体涉及奥利司他与钙补充剂类有机酸钙的共晶体及包含该共晶体的药物组合物。
背景技术
奥利司他(orlistat)为由罗氏制药公司研发脂肪酶抑制剂类减肥药,商品名Xenical,上个世纪九十年代末率先在欧美上市,2001年在中国上市,并于2005年被中国食品药品监督管理局批准转为非处方药。其化学名为N-甲酰-L-亮氨酸(s)-1-[(2s,3s)-3-己基-4-氧基-2-环氧丙基甲基]十二酯,也称四氢脂抑素(Tetrahydrolipstatin,THL),是一种半合成的脂抑素衍生物,其化学结构式如下所示:
奥利司他以其Ⅱ晶型的胶囊剂与片剂供药用,也是目前国内外唯一一种不影响食欲、不作用于中枢神经系统的化学减肥药,安全性特征优越,Bray GA于《柳叶刀》杂志发表的一篇名为Management of Obesity的文章中将奥利司他描述为“最安全”(safest)的减肥药。市售制剂中的Ⅱ型奥利司他结晶为白色至灰白色结晶性粉末,基本不溶于水,易溶于氯仿,极易溶于甲醇与乙醇,且在生理pH值范围内无pKa值。目前,国内生产奥利司他有两种方法:一种是化学全合成,反应步骤多,收率低,环境兼容性差;另一种是微生物发酵得到奥利司他中间体,然后中间体经一步氢化合成奥利司他,第二种方法生产的奥利司他占主导地位。无论何种方法,都需要对最后一步化学反应所得的奥利司他进行干燥,以除去产品中水分与有机溶剂。而Ⅱ晶型奥利司他的熔点仅为43℃,从而需要对原料药及制剂成品干燥过程中对温度与时间予以严格的控制。此外,奥利司他只能抑制30%的脂肪吸收,Bray GA等人于发表在《柳叶刀》的一篇名为Management of Obesity的文章将奥利司他的减肥效果评定为“modest(中等)”,不及近期上市的食欲抑制剂类减肥药。鉴于奥利司他优越的安全性,有必要改善奥利司他所存在的不足,从而扩大其临床应用,借以应对日趋严峻的肥胖症发病形式。
奥利司他的低熔点以及差强人意的减肥效果直接限制其应用,而熔点与溶解性往往与物质的晶型有关。现有技术中关于奥利司他晶型的研究有:国际专利WO2005026140公开了Ⅰ型与Ⅱ型奥利司他的制备方法,以及两种晶型的特征参数图谱,如X射线衍射(XRD)图谱、差示扫描量热(DSC)图谱与红外分析(IR)图谱。另有,国际专利WO2010084502公开了一种奥利司他结晶形式及其XRD与IR特征参数,该结晶是将固体奥利司他在极性溶剂与非极性有机溶剂的混合体系中重结晶而得,所述的溶剂混合体系优选了丙酮-庚烷体系,但该专利中未公开混合体系中各种溶剂所占比例,亦未公开所得奥利司他结晶形式的其他结构特征 (是否为溶剂合物)与药理活性参数。此外,国际专利WO2003047531同样公开了奥利司他的Ⅰ型与Ⅱ型结晶形式,以及这两种结晶形式的XRD图谱、热重分析(TGA)图谱与DSC图谱、结晶的制备方法和含有此两种结晶形式的固体制剂,但未公开活性资料,未披露此两种结晶形式与国际专利WO2005026140公开的奥利司他Ⅰ型及Ⅱ型相比有何优势。
Kristensen M等人的临床试验(Nutrition&Metabolism,2007Feb 7:14:13)指出,超重或肥胖者服用奥利司他的同时摄入适量来自牛奶的膳食钙,能显著提高其粪便内脂肪的排泄量,然而亦出现腹泻的现象,调整其对牛奶的顺应性后腹泻有所减轻。由于不同品牌的牛奶钙含量以及消费者肠道对不同品牌牛奶的适应性均不尽相同,而随餐服用牛奶也会在顺应性在存在诸多限制,因此有必要通过药物化学与药剂学手段将奥利司他与钙整合进单一的药物制剂中,从而提高脂肪排泄量,并同时改善用药的顺应性。
共晶是指药物活性成分(Active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API与CCF在纯态在室温下均为固体,并且各组分间存在固定的化学计量比。API形成共晶后,可以在熔点、引湿性、稳定性、溶解度和溶出度、生物利用度、生物利用度、释放度、机械性能等诸多方面均会有所改善,因此共晶理论在新药研究领域有着广阔的应用前景。
目前没有关于利用奥利司他与钙补充剂类有机酸钙制备共晶形成物,以克服奥利司他存在熔点低的缺点,同时提高其抑制脂肪吸收的效果的报道。
发明内容
为解决现有技术中存在的技术问题,本发明的目的在于提供一种奥利司他与钙补充剂类有机酸钙的共晶体及包含该共晶体的药物组合物。所述的共晶体具有较高的熔点,可降低原料药与制剂的制备过程中对干燥条件的要求,并可提高奥利司他抑制脂肪吸收的效果。
本发明通过如下技术方案以实现上述目的:
一方面,本发明以熔点与熔程为指标,考察了采用常规的共晶制备方法将多种常见的钙补充剂类有机酸钙与奥利司他制备成共晶体的可能性,所述的共晶制备方法是药物化学领域所已知的方法,例如但不限于黄雨婷等人在《药物共晶筛选技术的研究进展》(国际药学研究杂志,2016,43(4):682-286)以及高缘等人在《药物共晶研究进展》(化学进展,2010, 05:829-836)中披露的有关奥利司他的制备方法,通过引用被并入本文。作为潜在共晶形成物接受考察的钙补充剂类有机酸钙包括:葡萄糖酸钙、乳酸钙、枸橼酸钙、维生素C钙、酮亮氨酸钙、酮苯丙氨酸钙、消旋异亮氨酸钙、门冬氨酸钙、果糖酸钙。其中,葡萄糖酸钙、维生素C钙、枸橼酸钙、门冬氨酸钙可在不同的溶剂中采用降温析晶法与奥利司他形成熔程窄(<1℃)的晶体状物质,说明形成了单一的纯净物。
另一方面,本发明分别采用核磁共振(1H-NMR)、粉末X-射线衍射(XPRD)、示差扫描量热法(DSC)、热重分析(TGA)对奥利司他与上述共晶形成物所形成的共晶进行了结构表征,从而进一步证实了共晶的形成。
基于此,本发明提供一种奥利司他与钙补充剂类有机酸钙共晶体,所述的钙补充剂类有机酸钙选自:葡萄糖酸钙、维生素C钙、枸橼酸钙、门冬氨酸钙。
进一步地,所述的奥利司他与葡萄糖酸钙以1:5的摩尔比形成共晶体。
进一步地,所述的奥利司他与维生素C钙以1:4的摩尔比形成共晶体。
进一步地,所述的奥利司他与枸橼酸钙以2:7的摩尔比形成共晶体。
进一步地,所述的奥利司他与门冬氨酸钙以1:4的摩尔比形成共晶体。
更进一步的,所述1:5奥利司他与葡萄糖酸钙共晶体的XRPD图谱在12.14°、15.07°、 17.00°、19.18°、19.62°、21.86°、22.39°、22.78°、24.81°、29.16°2θ±0.2°2θ处有特征吸收。
更进一步的,所述1:4奥利司他与维生素C钙共晶体的XRPD图谱在4.64°、9.49°、14.42°、 16.27°、16.78°、19.01°、19.40°、20.27°、21.70°、22.90°2θ±0.2°2θ处有特征吸收。
更进一步的,所述2:7奥利司他与枸橼酸钙共晶体的XRPD图谱在10.56°、11.56°、12.46°、 13.62°、13.93°、18.24°、19.02°、19.79°、20.53°、21.21°2θ±0.2°2θ处有特征吸收。
更进一步的,所述1:4奥利司他与门冬氨酸钙共晶体的XRPD图谱在4.16°、8.37°、14.71°、16.24°、18.30°、19.25°、20.24°、20.48°、20.94°2θ±0.2°2θ处有特征吸收。
此外,本发明还涉及一种含有所述共晶体的药物组合物,该药物组合物为口服固体制剂,以奥利司他葡萄糖酸钙共晶体、奥利司他维生素C钙共晶体、奥利司他枸橼酸钙共晶体、奥利司他门冬氨酸钙中的至少一种作为有效成分,配以药学可接受的添加剂制备而成。所述的添加剂基本不改变奥利司他与钙补充剂类有机酸钙形成的共晶体,也不会与药物组合物中的任何成分发生任何作用而与所用的奥利司他钙补充剂类有机酸钙共晶体不相容。
所述的口服固体制剂通过药物制剂领域中已知的方法来制备,例如,参见崔福德主编,《药剂学》(第7版)(人民卫生出版社出版)。具体地,可以将1:5奥利司他葡萄糖酸钙共晶、 1:4奥利司他维生素C钙共晶、2:7奥利司他枸橼酸钙或1:4奥利司他门冬氨酸钙共晶与至少一种药学上可接受的赋形剂相混合,所述赋形剂可以为柠檬酸或磷酸二钙,或者为(a)填充剂或增量剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,纤维素衍生物、淀粉、海藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和金合欢树胶;(c)崩解剂,例如,琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、交联羧甲纤维素钠、复合硅酸盐和碳酸钠;(d)溶液缓凝剂,例如,石蜡;(e)吸收促进剂,例如季铵化合物;(f)润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯、硬脂酸镁等;(g)吸附剂,例如高岭土和皂粘土;和(h)润滑剂,例如,滑石粉,硬脂酸钙、硬脂酸镁、固体聚二醇、月桂基硫酸钠或它们的混合物。
进一步地,所述的口服固体制剂为本领域常用的制剂,如颗粒剂、胶囊剂、片剂、丸剂。
与现有技术相比,本发明的优势在于:
第一、本发明所提供的奥利司他与钙补充剂类有机酸钙的共晶体的熔点显著高于市售奥利司他胶囊中的Ⅱ型奥利司他,从而可在奥利司他原料药制备与制剂制备过程中升高干燥温度,提高干燥效率,缩短干燥时间,降低干燥能耗。
第二、本发明所提供的奥利司他与钙补充剂类有机酸钙的共晶体在水中的溶解度显著高于市售奥利司他胶囊中的Ⅱ型奥利司他,从而能在胃酸环境下更充分地溶解,从而提高其对脂肪酶的抑制作用。
第三、动物试验结果显示。本发明所提供的奥利司他与钙补充剂类有机酸钙的共晶体对营养性饲料所诱导的大鼠体重增加的抑制效果显著优于市售奥利司他胶囊中的Ⅱ型奥利司他。
附图说明
图1为Ⅱ型奥利司他的1H-NMR图谱。
图2为奥利司他与葡萄糖酸钙共晶体的1H-NMR图谱。
图3为奥利司他与维生素C钙共晶体的1H-NMR图谱。
图4为奥利司他与枸橼酸钙共晶体的1H-NMR图谱。
图5为奥利司他与门冬氨酸钙共晶体的1H-NMR图谱。
图6为奥利司他与葡萄糖酸钙共晶体的XRPD图。
图7为奥利司他与维生素C钙的XRPD图谱。
图8为奥利司他与枸橼酸钙共晶体的XRPD图谱。
图9为奥利司他与门冬氨酸钙共晶体的XRPD图谱。
图10为奥利司他与葡萄糖酸钙共晶体的DSC图谱。
图11为奥利司他与维生素C钙共晶体的DSC图谱。
图12为奥利司他与枸橼酸钙共晶体的DSC图谱。
图13为奥利司他与葡萄糖酸钙共晶体的DSC图谱。
具体实施方式
以下通过具体实施方式进一步描述本发明,但本发明不仅仅限于以下实施例。
实施例1奥利司他与钙补充剂类有机酸钙共晶体的制备方法研究
(1)奥利司他与葡萄糖酸钙共晶体的制备研究
取Ⅱ型奥利司他0.497g(1.003×10-3mol),置于超声水浴(40℃)内的100mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得A液,搅拌下留置于超声水浴(40℃)中。另取葡萄糖酸钙一水合物(分子式:Ca[C6H11O7]2·H2O,分子量448.40)4.483g(含钙离子9.998×10-3mol,葡萄糖酸根离子19.996×10-3mol),置于超声水浴(40℃)内的500mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得B液,搅拌下留置于超声水浴(40℃)中。将A液缓慢移至B液中,若析出固体,则补加甲醇/水混合溶剂(30:1,v/v)。加完后超声水浴(40℃)下搅拌4h小时,而后室温下静置过夜。过滤析出的固体后,60℃下干燥至恒重,得白色针状结晶2.417g,产率87.9%。
(2)奥利司他与维生素C钙共晶体的制备研究
取Ⅱ型奥利司他0.501g(1.011×10-3mol),置于超声水浴(40℃)内的100mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得A液,搅拌下留置于超声水浴(40℃)中。另取维生素C钙二水合物(分子式:Ca[C6H7O6]2·2H2O,分子量426.35)4.278g(含钙离子10.034×10-3mol,含抗坏血酸根离子20.068×10-3mol),置于超声水浴(40℃)内的500mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1, v/v),直至固体完全溶解,得B液,搅拌下留置于超声水浴(40℃)中。将A液缓慢移至B 液中,若析出固体,则补加甲醇/水混合溶剂(30:1,v/v)。加完后超声水浴(40℃)下搅拌 4h小时,而后室温下静置过夜。过滤析出的固体后,60℃下干燥至恒重,得白色针状结晶 1.814g,产率81.5%。
(3)奥利司他与枸橼酸钙共晶体的制备研究
取Ⅱ型奥利司他0.489g(0.986×10-3mol),置于超声水浴(40℃)内的100mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得A液,搅拌下留置于超声水浴(40℃)中。另取枸橼酸钙四水合物(分子式:Ca3[C6H5O7]2·4H2O,分子量570.50)5.698g(含钙离子29.964×10-3mol,含枸橼酸根19.976×10-3mol),置于超声水浴(40℃)内的500mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得B液,搅拌下留置于超声水浴(40℃)中。将A液缓慢移至B液中,若析出固体,则补加甲醇/水混合溶剂(30:1,v/v)。加完后超声水浴(40℃)下搅拌4h小时,而后室温下静置过夜。过滤析出的固体后,60℃下干燥至恒重,得白色针状结晶1.946g,产率79.2%。
(4)奥利司他与门冬氨酸钙共晶体的制备研究
取Ⅱ型奥利司他0.496(1.001×10-3mol),置于超声水浴(40℃)内的100mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得A液,搅拌下留置于超声水浴(40℃)中。另取门冬氨酸钙(分子式:Ca[C4H6NO4]2,分子量304.27)3.059g(含钙离子10.054×10-3mol,含门冬氨酸根20.108×10-3mol),置于超声水浴(40℃)内的500mL三颈瓶中,搅拌下向其中缓慢滴加甲醇/水混合溶剂(30:1,v/v),直至固体完全溶解,得B液,搅拌下留置于超声水浴(40℃)中。将A液缓慢移至B液中,若析出固体,则补加甲醇/水混合溶剂(30:1,v/v)。加完后超声水浴(40℃)下搅拌4h小时,而后室温下静置过夜。过滤析出的固体后,60℃下干燥至恒重,得白色针状结晶1.407g,产率 69.7%。
实施例2奥利司他与钙补充剂类有机酸钙共晶体熔点的测定
根据《中国药典》2015年版收载的熔点自动测定仪法对实例1中分别制的奥利司他·葡萄糖酸钙共晶体、奥利司他·维生素C钙共晶体、奥利司他·枸橼酸钙共晶体、与奥利司他门冬氨酸钙共晶体进行熔点与熔程的测定,结果如表1所示。
表1奥利司他与钙补充剂类有机酸钙共晶体的熔点测定结果
共晶形成物(CCF) | 奥利司他:CCF(分子数比/摩尔比) | 共晶熔点(℃) | 共晶熔程(℃) |
葡萄糖酸钙 | 1:5 | 253.52 | <1 |
维生素C钙 | 1:4 | 170.91 | <1 |
枸橼酸钙 | 2:7 | 220.27 | <1 |
门冬氨酸钙 | 1:4 | 259.43 | <1 |
表1中的奥利司他:CFF(分子数比/摩尔比)系通过实施例2中的1H-NMR测定而得。
结果显示,本发明制得的奥利司他与葡萄糖酸钙共晶体、奥利司他与维生素C钙共晶体、奥利司他与枸橼酸钙共晶体、奥利司他与门冬氨酸钙共晶体均具有狭窄的熔程(<1℃),表明制得的共晶纯度高,为单一的纯净物。并且制得的共晶体熔点均显著高于市售奥利司他胶囊中的Ⅱ型奥利司他的熔点(43℃)。
实施例3奥利司他与补钙剂类有机酸钙共晶体中奥利司他与共晶形成物(CCF)的分子数比/摩尔比的测定
采用核磁共振(1H-NMR,溶液质子NMR)测定实施例1中所制得奥利司他与钙补充剂类有机酸钙共晶体中奥利司他与共晶形成物(CFF)的分子数比/摩尔比。
方法:在装备有自动取样器并由DRX400控制台控制的Bruker-400MHz波长谱仪上记录1H-NMR谱。将样品溶解在d6-DMSO中用于分析。使用标准的Bruker负载实验,利用以Topsin v1.3(补丁级别8)运行的ICON-NMR v4.0.4(构造1)来获取数据。
结果:奥利司他的1H-NMR图谱如图1所示,所有峰的积分面积是0.88~0.94ppm范围内峰积分面积的4.33倍。
实施例1中制得的奥利司他与葡萄糖酸钙共晶体的1H-NMR图谱如图2所示,所有峰的积分面积是0.88~0.94ppm范围内峰积分面积的9.335倍。依下式计算奥利司他与葡萄糖酸钙的分子数比/摩尔比(x:y)
经计算,x:y≈1:5。
实施例1中制得的奥利司他与维生素C钙共晶体的1H-NMR图谱如图3所示,所有峰的积分面积是0.88~0.94范围内峰积分面积的6.995倍。依下式计算奥利司他与维生素C钙的分子数比/摩尔比(x:y)
经计算,x:y≈1:4。
实施例1中制得的奥利司他与枸橼酸钙共晶体的1H-NMR图谱如图4所示,所有峰的积分面积是0.88~0.94范围内峰积分面积的6.669倍,依下式计算奥利司他与枸橼酸钙的分子数比/摩尔比(x:y)
经计算,x:y≈1:3.5。
实施例1中制得的奥利司他与门冬氨酸钙共晶体的1H-NMR图谱如图5所示,所有峰的积分面积是0.88~0.94范围内峰积分面积的6.336倍,依下式计算奥利司他与枸橼酸钙的分子数比/摩尔比(x:y)
经计算,x:y≈1:4。
实施例4奥利司他与钙补充剂类有机酸钙共晶体的X-射线粉末衍射(XRPD)表征
方法:使用CuKα辐射(40kV,40mA)、θ-2θ测角仪、V4接收狭缝、Ge单色仪和Lynxeye检测器,在Bruker D8衍射仪上获得样品的X-射线粉末衍射图样。使用经认证的Corundum标准(NIST1976)对仪器进行性能检查,使用0.05°2θ的步长和0.5秒的步进时间,在0°至50°2θ的角度范围内在环境温度收集数据。使用接收的未经研磨的粉末,将在环境条件下运行的样品制备为平板样本。将约35mg样品轻轻堆积到切成经抛光的、零背景(510)的硅片中的腔内。使用Diffrac Plus EVA v11.0.02或v13.0.0.2,对所有样品进行分析。
结果:实施例1中所制得的奥利司他与葡萄糖酸钙共晶体的XRPD图见图6,其主要吸收峰如表2所示。
表2奥利司他与葡萄糖酸钙共晶体XRPD测定结果
实施例1中所制得的奥利司他与维生素C钙共晶体的XRPD图见图7,其主要吸收峰如表3所示。
表3奥利司他与维生素C钙共晶体XRPD测定结果
实施例1中所制得的奥利司他与枸橼酸钙共晶体的XRPD图见图8,其主要吸收峰如表 4所示。
表4奥利司他与枸橼酸钙共晶体XRPD测定结果
实施例1中所制得的奥利司他与门冬氨酸钙共晶体的XRPD图见图9,其主要吸收峰如表5所示。
表5奥利司他与门冬氨酸钙共晶体XRPD测定结果
实施例5奥利司他与补钙类有机酸钙共晶体的热分析-差示扫描量热(DSC)
方法:在装备有50个位置自动取样器的TA仪器Q2000上收集DSC数据。使用蓝宝石进行热容量的校准,并使用经认证的铟进行能量和温度的校准。通常情况下,在针孔铝盘中, 10℃/分钟将0.8~1.2mg的各个样品从25℃回执至350℃。在样品上倒挂50mL/分钟的干燥氮气流。仪器控制软件是Advantage(用于Q系列,v2.8.0.392)和Thermal Advantagev4.8.3。使用Universal Analysis v4.3A软件进行所有数据分析。
结果:奥利司他与葡萄糖酸钙共晶体、奥利司他与维生素C钙共晶体、奥利司他与枸橼酸钙共晶体与奥利司他与门冬氨酸钙共晶体的DSC图谱依次见图10-13。
实施例6含有奥利司他与补钙剂类有机酸钙共晶体的胶囊的制备方法
(1)处方
成分 | 投料量 |
共晶体 | 依奥利司他计12g |
微晶纤维素 | 8.5~9.2g |
羧甲淀粉钠 | 1.0~1.3g |
交联聚维酮 | 1.1~1.5g |
十二烷基硫酸钠 | 0.2~0.3g |
聚维酮K30 | 适量 |
共制成 | 100粒 |
所述共晶体包括:实施例1中制备得到的1:5奥利司他与葡萄糖酸钙共晶体、1:4奥利司他与维生素C钙共晶体、2:7奥利司他与枸橼酸钙共晶体与1:4奥利司他与门冬氨酸钙共晶体。
(2)胶囊制备
①混合:预先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠、微晶纤维素过80目筛,得细粉备用;然后按处方量称取十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠和微晶纤维素细粉以及共晶体;先将十二烷基硫酸钠、交联聚维酮、羧甲淀粉钠混合均匀,再加入微晶纤维素和共晶混合均匀,过80目筛两遍,即得混匀的粉末。
②制粒与干燥:往混匀的粉末中缓慢加入含10%聚维酮K30的50%乙醇溶液,制软材, 20目挤压过筛制湿颗粒,湿颗粒置60℃鼓风干燥箱中烘干6小时,取出过20目筛整粒。
③颗粒含量测定:按质量标准中含量测定方法进行,测定干燥颗粒中奥利司他含量,计算理论装量。
④灌装胶囊:按计算出的理论装量,将干燥颗粒灌装入0号胶囊(主要由明胶、钛白粉、柠檬黄、亮蓝构成)中。
实施例7奥利司他与补钙剂类有机酸钙的共晶体在胃酸中的溶解度的测定
(1)药物
①对照药:Ⅱ型奥利司他,药用级別,大邦(湖南)生物制药有限公司提供。
②试验药:包括实施例1中制得的奥利司他与葡萄糖钙共晶体、奥利司他与维生素C 钙共晶体、奥利司他与枸橼酸钙共晶体、奥利司他与门冬氨酸钙共晶体。
(2)溶解度的测定方法
①Ⅱ型奥利司他溶解度的测定方法与结果
取10mgⅡ型奥利司他,置于500mL烧瓶中,加入300mL pH4.0的盐酸水溶液,37℃水浴上搅拌(60转/分钟)过夜,静置1小时后,滤出瓶底沉积的固体,30℃下干燥至恒重,约为9.97mg。依此计算,Ⅱ型奥利司他在pH4.0盐酸溶液中的溶解度约为3×10-4mg/mL。
②试验药溶解度的测定
取每种试验药各50mg,置于250mL烧瓶中,加入100mL pH4.0的盐酸水溶液,37℃水浴上保温40分钟,取50mL水相置于离心管中,4000转/分钟离心5分钟,取上清液40mL,蒸干后80℃下干燥至恒重,并根据最后的重量计算各共晶体的溶解度,结果如表6所示。
表6奥利司他与补钙剂类有机酸钙的共晶体在pH4.0盐酸溶液中的溶解度(mg/mL)
共晶形成物(CCF) | 溶解度(mg/mL) |
葡萄糖酸钙 | 0.35 |
维生素C钙 | 0.29 |
枸橼酸钙 | 0.41 |
门冬氨酸钙 | 0.26 |
实施例8奥利司他与补钙剂类有机酸钙的共晶体对营养性饲料所诱导的大鼠体重增加的抑制作用
(1)材料
①药物
Ⅰ、奥利司他胶囊(内含Ⅱ型奥利司他规格为0.12g,中山万汉制药有限公司生产,批号 01170806),临用前取胶囊内容物,用0.5%羧甲基纤维素钠(CMC-Na)溶液配成3g·L-1的灌胃液,按60mg·kg-1·d-1的剂量灌胃。
Ⅱ、试验药,包括实施例1中制得的奥利司他与葡萄糖钙共晶体、奥利司他与维生素C 钙共晶体、奥利司他与枸橼酸钙共晶体、奥利司他与门冬氨酸钙共晶体,临用前用0.5%羧甲基纤维素钠(CMC-Na)溶液配成100g·L-1的灌胃液,依奥利司他剂按60mg·kg-1·d-1的剂量灌胃。
②动物和饲料
Ⅰ、动物
雄性清洁级SD大鼠,由中山大学实验动物中心提供,动物使用许可证号SCXK(粤)2017-0036,体重75~85g。
Ⅱ、饲料
普通饲料与营养性饲料均有中山大学实验动物中心提供,其组成成分如表7所示:
表7普通饲料与营养性饲料的组成成分
③仪器
8893超声波清洗仪(Cole-Pamer公司,美国);TL-602L电子天平(Mettler公司,德国)。
(2)造模、分组及给药
依据《中药药效学研究与评价》中肥胖症药效学研究与评价方法,采用预防肥胖模型法。将试验动物按体重随机分为7组,每组10只,每只单笼饲喂,并允许其在笼内自由活动。各组饲喂与给药方法如表8所示。
表8各组动物的饲喂与给药方法
组别 | 饲料 | 药物 |
空白对照组 | 普通饲料 | CMC-Na溶液 |
模型组 | 营养性饲料 | CMC-Na溶液 |
奥利司他对照组 | 营养性饲料 | Ⅱ型奥利司他/CMC-Na溶液 |
试验Ⅰ组 | 营养性饲料 | 奥利司他与葡萄糖酸钙共晶体/CMC-Na溶液 |
试验Ⅱ组 | 营养性饲料 | 奥利司他与维生素C钙共晶体/CMC-Na溶液 |
试验Ⅲ组 | 营养性饲料 | 奥利司他与枸橼酸钙共晶体/CMC-Na溶液 |
试验Ⅳ组 | 营养性饲料 | 奥利司他与门冬氨酸钙共晶体/CMC-Na溶液 |
结合奥利司他胶囊的作用机制和用法用量,每天上午9时给予各组大鼠相应的饲料,晚上7时取走食物,每天定量给食(以多数动物吃完为原则每日调整饲料给予量)。各组均在上午9时和下午3时分两次按10m L·kg-1用对应的药物灌胃。连续处理7周,并于处理前与连续处理7周后称量动物体重。
(3)结果
各组动物在试验前后的体重变化情况如表9所示。
表9各组动物的体重变化情况
a与空白对照组相比P<0.001,t检验
b与模型组相比P<0.001,t检验
c与奥利司他组相比P<0.01,t检验
统计学检验结果显示,处于7周后,模型组大鼠的增重程度显著高于空白对照组,说明造模成功;奥利司他组大鼠的增重幅度显著低于模型组,说明奥利司他能显著抑制营养性饲料所诱发的大鼠体重增加;试验Ⅰ~Ⅳ组大鼠的增重幅度显著低于奥利司他组,说明奥利司他与葡萄糖酸钙共晶体、奥利司他与维生素C钙、奥利司他与枸橼酸钙共晶体、奥利司他与门冬氨酸钙共晶体对营养性饲料所诱发的大鼠体重增加的抑制效果显著优于奥利司他。
以上仅是本发明的优选实施方式,应当指出的是,上述优选实施方式不应视为对本发明的限制,本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说,在不脱离本发明的精神和范围内,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.一种奥利司他与钙补充剂类有机酸钙的共晶体,其特征在于,所述的有机酸钙选自葡萄糖酸钙、维生素C钙、枸橼酸钙、门冬氨酸钙中的任意一种;
所述的奥利司他与葡萄糖酸钙以1:5的摩尔比形成共晶;所述的奥利司他与维生素C钙以1:4的摩尔比形成共晶;所述的奥利司他与枸橼酸钙以2:7的摩尔比形成共晶;所述的奥利司他与门冬氨酸钙以1:4的摩尔比形成共晶;
所述的奥利司他与葡萄糖酸钙共晶体的X射线粉末衍射图谱在12.14°、15.07°、17.00°、19.18°、19.62°、21.86°、22.39°、22.78°、24.81°、29.16°2θ±0.2°2θ角处有特征吸收峰;
所述的奥利司他与维生素C钙共晶体的X射线粉末衍射图谱在4.64°、9.49°、14.42°、16.27°、16.78°、19.01°、19.40°、20.27°、21.70°、22.90°2θ±0.2°2θ角处有特征吸收峰;
所述的奥利司他与枸橼酸钙共晶体的X射线粉末衍射图谱在10.56°、11.56°、12.46°、13.62°、13.93°、18.24°、19.02°、19.79°、20.53°、21.21°2θ±0.2°2θ角处有特征吸收峰;
所述的奥利司他与门冬氨酸钙共晶体的X射线粉末衍射图谱在4.16°、8.37°、14.71°、16.24°、18.30°、19.25°、20.24°、20.48°、20.94°2θ±0.2°2θ角处有特征吸收峰。
2.一种药物组合物,其特征在于,所述的药物组合物包含权利要求1所述的至少一种共晶体。
3.根据权利要求2所述的药物组合物,其特征在于,所述的药物组合物为口服固体制剂,所述的口服固体制剂以权利要求1所述的至少一种共晶体作为有效成分,配以药学可接受的添加剂制备而成。
4.根据权利要求3所述的药物组合物,其特征在于,所述的口服固体制剂为颗粒剂、胶囊剂、片剂或丸剂。
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