CN1312714A - 含有脂酶抑制剂和壳聚糖的药物组合物 - Google Patents

含有脂酶抑制剂和壳聚糖的药物组合物 Download PDF

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CN1312714A
CN1312714A CN99809508A CN99809508A CN1312714A CN 1312714 A CN1312714 A CN 1312714A CN 99809508 A CN99809508 A CN 99809508A CN 99809508 A CN99809508 A CN 99809508A CN 1312714 A CN1312714 A CN 1312714A
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orlistat
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雅克·巴伊
安德烈·弗勒里
保罗·豪德瓦
汉斯·伦斯费尔德
汉斯·斯特芬
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Abstract

本发明涉及含有胃肠道脂酶抑制剂、一种(或多种)选自壳聚糖、其衍生物及其盐的添加化合物,和辅助赋形剂的药物组合物。

Description

含有脂酶抑制剂和壳聚糖的药物组合物
本发明涉及含有胃肠道脂酶抑制剂、一种(或多种)选自壳聚糖、其衍生物及其盐的添加化合物、和辅助赋形剂的药物组合物。
胃肠道脂酶抑制剂的实例是orlistat，先前曾称之为四氢一制胰脂菌素或THL。它减少饮食中脂肪的吸收。其控制或预防肥胖和降血脂的应用在4598089号美国专利中作了描述。Orlistat是具有(3S,4S)-3-己基4-[(2S)-2-羟十三烷基]-2-氧杂环丁酮的N-甲酰基-L-亮氨酸酯。
油从肛门漏出(油性污染)是偶然能够在用脂酶抑制剂治疗的患者观察到的副作用。该现象反映出在低位大肠处一些未吸收的饮食脂肪与大量粪便块发生了物理分离。此副作用可以用本发明药物组合物来预防。
美国专利5447953已经证实：脂酶抑制剂与大量水溶性粗纤维联合，可以增加对脂肪吸收的抑制作用。
令人惊奇的是，已经发现：脂酶抑制剂与小量的壳聚糖或其衍生物或其盐联合应用，可以显著减少油泄漏现象。
本发明也涉及壳聚糖或其衍生物或其盐与胃肠道脂酶抑制剂(如orlistat)同时、分开或者按时间顺序间隔应用在治疗肥胖和高脂血症以及comorbidities(如Ⅱ型糖尿病)中的用途。
人工不吸收脂，大部分是糖聚酯，在食品工业上用于生产低脂食品，如低脂薯条、低脂烹调品、低脂色拉调味品和低脂冰激凌。摄入大量此类含有不吸收脂的食物可以引起油性泄漏。
本发明还涉及壳聚糖或其衍生物或其盐在治疗或预防服用胃肠道脂酶抑制剂如orlistat后或者在摄入含有不易吸收性或不-吸收性脂或油或不消化性油脂物质的食物后出现的肛门油性泄漏症状中的用途。
壳聚糖衍生自壳多糖，是通过完全或部分脱乙酰作用和部分解聚，由从天然界分离出的(1→4)-连接的2-乙胺基-2-脱氧-β-D-吡喃葡萄糖基(glucopyranosyl)残基构成的多糖。壳聚糖分子量104～105。壳聚糖在胃pH时是可溶解的，而在肠pH时不溶解或呈凝胶状。壳聚糖衍生物的实例是中链或长链N-烷基-或N-烷醇基-壳多糖。术语“中链N-烷基或N-烷醇基”指C8-13-N-烷基-或-N-烷醇基链，术语“长链N-烷基或N-烷醇基”指C14-18-N-烷基-或-N-烷醇基链。壳聚糖盐的实例是与乙酸、柠檬酸、甲酸和酒石酸形成的盐，以及与稀释的无机酸形成的盐。
壳聚糖(默克索引，第11版，#2052,1989)的同义词是聚-D-氨基葡萄糖；聚-[1→4]-β-D-氨基葡萄糖和脱乙酰化的壳多糖。具有下式结构的壳多糖脱乙酰化
而转变成具有下式结构的壳聚糖，
Figure A9980950800052
后者可以在热的浓缩NaOH溶液(40-50％)中形成。壳聚糖是从PronovaBiopolymer公司，135 Commerce Way,Suite 201,Portsmouth,NH03801商购得到的，例如分别具有内部粘度20cps、20～200cps和200～800cps的SEACURE142、242或342。
可用于本发明药物组合物的辅助赋形剂的实例是粘合剂、稀释剂和润滑剂，如AVICEL、聚乙烯吡咯烷酮(聚乙烯吡咯酮)、滑石粉和延胡索酸硬脂酸钠；甜味剂，如山梨醇、葡萄糖、蔗糖、糖精钠盐和环磺酸钠；调味剂，如西番莲果、香橼和梨莓树；鲜味剂，如柠檬酸、柠檬酸一钠、氯化钠和硫酸奎宁；泡腾剂，如碳酸氢盐和酒石酸；崩解剂，如羟乙酸淀粉钠；抗微生物剂，如对-羟苯甲酸甲基或丙基酯；去污剂和着色剂，如β-胡萝卜素。
AVICEL主要包括微晶纤维素。可购自FMC公司，药学部，MarketStreet 1735号，费城，PA 19103，如AVICEL RC-591或CL-611，它们是微晶纤维素(约92％)和羧甲基纤维素钠(约8％)的混合物，AVICEL PH 101或PH 105，分别是平均粒径为50或20μ的微晶纤维素；AVICEL CE-15是微晶纤维素和瓜尔胶的混合物。
下面的试验证明壳聚糖在减轻肛门油性泄漏中超过纤维素如AVICEL的优越性：
游离粪便油损耗的试验是基于这样的观察：由于小鼠不断地梳理其皮毛，因而将所有排出的游离粪便油涂抹其全身。这导致很容易看到皮毛被染成褐色(油腻的皮毛涂油)。对于体重20-25g的小鼠而言，在喂食含有7％脂肪的饲料使得每日脂肪摄入量为1g/日的同时，给予过量orlistat(300μmol/kg/日)，则可以引发游离油的排泄。饲料由捣碎的汉堡包、黄油、French fries和多纤维菜豆组成。
遵照下面的时间表处理：1-5天：用上述饲料和食物添加剂(增加壳聚糖或AVICEL的量)喂
   食各组小鼠，每组3只小鼠，对照组不喂食食物添加剂3-4天：加入orlistat(300μmol/kg/日)第5天：通过对油腻的皮毛涂油照相来作记录
每日用1-4的分值来对油腻的皮毛涂油进行评价：
1：涉及0-25％皮肤，2：涉及26-50％皮肤，3：涉及50-70％皮肤，4：涉及75-100％皮肤。
把3-5天每只小鼠的皮肤评分分值累加起来。(例如，3-5天涉及100％皮肤，那么分值是最大的，即4+4+4=12)。对照组的油腻皮毛涂油分值是6.3±1.6(均值±SE)。
在接受壳聚糖或AVICEL的7组小鼠中，油腻的皮毛涂油减少，其减少范围首先根据上述评分进行评价，然后用占对照组的％表示，最后在每一组动物内取平均值。结果见下表：摄入orlistat(300μmol/kg/日)的小鼠油腻皮毛涂油(占对照％)食物添加剂(g/100g饲料) 壳聚糖    AVICEL15                       n.d.    17±410                       n.d.    29±75                        n.d.    53±243                        6±3     n.d.1                        37±16   n.d.0.3                      53±5    n.d.0.1                      63±9    n.d.n.d.=未检测到
当饲料含有壳聚糖时，油腻皮毛涂油的范围减少。举例来说，与对照相比，仅含0.3重量％壳聚糖的饲料就能够与含有多达5重量％AVICEL的饲料取得同样53％的油腻皮毛涂油抑制效果。
本发明组合物的通常配比是：每一重量份胃肠道脂酶抑制剂如orlistat，1～50、优选为20～40重量份的壳聚糖或其衍生物或其盐，和10～200、优选20～80重量份的辅助添加剂。
本发明组合物也可以是含有胃肠道脂酶抑制剂和壳聚糖或其衍生物或其盐的市售包装盒形式，并随盒装有说明在治疗肥胖或高脂血症时同时、分开或按时间顺序间隔应用的说明书。
为了治疗或预防肥胖或高脂血症，含有10～500mg胃肠道脂酶抑制剂(如orlistat)和500mg～20g、优选2g～10g添加化合物如壳聚糖的本发明组合物可每日口服给药1次、2次或3次。
本发明组合物可以是饮用型制剂，如用粉、散剂、小丸、重组片剂或泡腾片配制的溶液或悬浮液；或者是咀嚼制剂，如片剂、胶囊或糖锭。组合物还可掺入到食物配制品中，如薄酥饼、饼干或面包中，或者组合物呈宜于吞咽的剂型，如片剂或胶囊。
用于治疗肥胖的本发明的优选组合物是主要含有orlistat作为活性成分和壳聚糖为添加化合物的咀嚼片，其剂量是：10～120mg orlistat和0.5～5g壳多糖，最优选咀嚼片主要含有约60mg orlistat和约2.5g壳聚糖。
用于治疗肥胖的本发明另一优选组合物是薄酥饼，主要由作为活性成分的orlistat和作为添加化合物的壳聚糖组成，其剂量是：10～200mgorlistat和1～10g壳多糖。最优选薄酥饼主要由约120mg orlistat和约5g壳聚糖组成。
预防口服orlistat后偶然发生的肛门油性泄漏症状的方法包括：每顿含脂主餐口服剂量为10～200mg orlistat和0.5～10g壳聚糖的orlistat和壳聚糖。最为便利的是，方法包括：每顿含脂主餐要口服orlistat和壳聚糖，其剂量是10～120mg orlistat和2～6g壳聚糖，特别是约60mg orlistat和约2.5g壳聚糖。
下面的非限定性实施例描述用传统工艺即可以制备的药物制剂：
实施例1
用于与orlistat同时、分开或按时间顺序间隔给药的壳聚糖散或小丸如下制备：
50g壳聚糖(SEACURE 342)HE 50g AVICEL RC-591混合，用去离子水揉和到适宜坚硬度(consistency)。将湿团块过筛，然后流化床干燥得到散粒。或者，湿团块挤压并球化，然后流化床干燥产生小丸。把数量5g或10g的散粒或小丸装入小囊中作为剂量单位。或者，把物料装入适宜容器中。用适宜小勺完成给药。
                        实施例2orlistat                    0.12g低粘度壳聚糖(SEACURE 142)    5g山梨醇                       7.11gAVICEL CL 611                1.20gβ-胡萝卜素                  0.06g柠檬酸                       0.10g对-羟苯甲酸甲基酯            0.15g对-羟苯甲酸丙基酯     0.03g调味剂(西番莲果)      0.13gAVICEL PH105          8.00g柠檬酸一钠            1.00g糖精钠                0.10g
                总量23g
向上述粉中加入自来水至100ml口可得到口服悬浮液。
                 实施例3散粒或小丸：orlistat              0.120g壳聚糖(SEACURE 242)   5.0gAVICEL PH 101         4.88g
将上述组分混合，用去离子水揉和，使具有适宜的坚硬度。湿团块过筛，低于35℃的温度下流化床干燥，得到散粒。或者，湿团块挤出并球化，然后进行流化床干燥，产生小丸。把数量为10g的散粒或小丸装入小囊作为剂量单位。或者，把物料盛入适当容器中。用适合的小勺完成给药。
                        实施例4泡腾片：Orlistat                    0.120g蔗糖粉                      1.669g低粘度壳聚糖(SEACURE 142)   2.5g环磺酸钠                    0.115g糖精钠盐                    0.004g碳酸氢钠                    0.7g酒石酸(结晶)                1.12g氯化钠(研磨的)   0.04g硫酸奎宁         0.007g调味剂           0.025g
            总量6.3g
Orlistat、蔗糖、壳聚糖、环磺酸钠和糖精钠混合并过筛。用乙醇和去离子水的混合物揉合，粒化并在低于35℃的温度下流化床干燥，得到混合物A。碳酸氢钠、酒石酸、氯化钠、硫酸奎宁和调味剂混合并过筛，得到混合物B。A和B混合，压成重6.3g、直径30mm的泡腾片。
                   实施例5咀嚼片：Orlistat               0.060g壳聚糖(SEACURE 242)    2.5g山梨醇                 1.84gAVICEL CE-15           1.0g滑石粉                 0.480g硬脂酰基延胡索酸钠     0.120g
                  总量6.0g
Orlistat、壳聚糖、山梨醇和AVICEL CE-15混合并过筛。滑石粉和硬脂酰基延胡索酸钠过筛并与前一步得到的混合物混合，然后压成6.0g直径2cm的咀嚼片。
实施例6
与orlistat同时、分开或按时间顺序间隔服用的壳聚糖薄酥饼如下制备：
玉米粉(5g)和5g壳聚糖混合。加入大豆油(2g)并将混合物混合15分钟。加入水以形成湿的团块，然后进行挤出。在35℃烘箱中烘干湿的薄饼，接下来予以包装。
         实施例7薄酥饼：壳聚糖                        5g大豆油                        2g玉米粉                        5gorlistat                      120mg
过程与实施例6相同，除外首先将orlistat溶于大豆油中，然后再加入到混合物中。用水形成湿块后挤出，于35℃干燥薄酥饼。
实施例8
薄酥饼：组分比例和过程与实施例7相同，除外用溶化的三棕榈酸甘油酯代替大豆油。
实施例9
与orlistat同时、分开或按时间顺序间隔服用的壳聚糖薄酥饼如下制备：
壳聚糖(5g)和5g麦芽糖糊精混合。熔化的三棕榈酸甘油酯(2g)加入到混合物中。用水湿润团块，然后挤出湿块。在35℃干燥薄酥饼。
                         实施例10薄酥饼：壳聚糖                         5g麦芽糖糊精                     5g三棕榈酸甘油酯                 2gorlistat                       120mg
与实施例9的步骤相同，除外orlistat溶解在熔化的三棕榈酸甘油酯中，然后再加入到混合物中。在35℃干燥薄酥饼。

Claims (11)

1．口服给药药物组合物，含有胃肠道脂酶抑制剂、一种(或多种)选自壳聚糖、其衍生物或其盐的添加化合物，和辅助赋形剂。
2．按照权利要求1所述的组合物，含有500mg～20g、优选2g～10g添加化合物和10mg～500mg胃肠道脂酶抑制剂。
3．按照权利要求1或2所述的组合物，其中胃肠道脂酶抑制剂是orlistat。
4．按照权利要求1、2或3所述的组合物，其中添加化合物是壳聚糖。
5．壳聚糖、其衍生物或其盐在治疗或预防口服胃肠道脂酶抑制剂如orlistat后或者在摄入了含有不易吸收或不吸收性脂或油或不消化性油脂物质的食物后偶然发生的肛门油性泄漏症状中的应用。
6．按照权利要求3或4所述的组合物，是用于治疗肥胖的咀嚼片，主要由作为活性成分的orlistat和作为添加化合物的壳聚糖组成，其剂量是10～120mg orlistat和0.5～5g壳聚糖。
7．按照权利要求6所述的咀嚼片，其中剂量为约60mg orlistat和约2.5g壳聚糖。
8．按照权利要求3或4所述的组合物，是治疗肥胖的薄酥饼，主要由作为活性成分的orlistat和作为添加化合物的壳聚糖组成，其剂量是10～200mg orlistat和1～10g壳聚糖。
9．按照权利要求8所述的薄酥饼，其中剂量为约120mg orlistat和约5g壳聚糖。
10．预防口服orlistat后偶然发生的肛门油性泄漏症状的方法，包括每顿含脂主餐口服orlistat和壳聚糖，其剂量为10～200mg orlistat和0.5～10g壳聚糖。
11．按照权利要求10所述方法，其中每顿含脂主餐口服orlistat和壳聚糖的剂量是10～120mg orlistat和2～6g壳聚糖，优选约60mg orlistat和约2.5g壳聚糖。
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