CN1152680C - 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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CN1152680C
CN1152680C CNB998095087A CN99809508A CN1152680C CN 1152680 C CN1152680 C CN 1152680C CN B998095087 A CNB998095087 A CN B998095087A CN 99809508 A CN99809508 A CN 99809508A CN 1152680 C CN1152680 C CN 1152680C
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雅克·巴伊
安德烈·弗勒里
保罗·豪德瓦
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汉斯·伦斯费尔德
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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奥利司他(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。奥利司他是具有(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(如奥利司他)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奥利司他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
Figure C9980950800051
而转变成具有下式结构的壳聚糖，
Figure C9980950800052
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SEACURE 142、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AVCEL、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PH105，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，给予过量奥利司他(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：加入奥利司他(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：
摄入奥利司他(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            AVICEL
15                      n.d.              17±4
10                      n.d.              29±7
5                       n.d.              53±24
3                       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奥利司他，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(如奥利司他)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奥利司他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奥利司他和0.5～5g壳多糖，最优选咀嚼片主要含有约60mg奥利司他和约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奥利司他和作为添加化合物的壳聚糖组成，其剂量是：10～200mg奥利司他和1～10g壳多糖。最优选薄酥饼主要由约120mg奥利司他和约5g壳聚糖组成。
预防口服奥利司他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奥利司他和0.5～10g壳聚糖的奥利司他和壳聚糖。最为便利的是，方法包括：每顿含脂主餐要口服奥利司他和壳聚糖，其剂量是10～120mg奥利司他和2～6g壳聚糖，特别是约60mg奥利司他和约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
用于与奥利司他同时、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2
奥利司他                        0.12g
低粘度壳聚糖(SEACURE 142)       5g
山梨醇                          7.11g
AVICEL CL 611                   1.20g
β-胡萝素                       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)                     0.13g
AVICEL 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即可得到口服悬浮液。
                        实施例3
散粒或小丸：
奥利司他                             0.120g
壳聚糖(SEACURE 242)                  5.0g
AVICEL PH101                         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：
奥利司他                             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
奥利司他、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：
奥利司他                             0.060g
壳聚糖(SEACURE 242)                  2.5g
山梨醇                               1.84g
AVICEL CE-15                         1.0g
滑石粉                               0.480g
硬脂酰基延胡索酸钠                   0.120g
                                  总量 6.0g
奥利司他、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
与奥利司他同时、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                         5g
奥利司他                       120mg
过程与实施例6相同，除外首先将奥利司他溶于大豆油中，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
与奥利司他同时、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                        2g
奥利司他                              120mg
与实施例9的步骤相同，除外奥利司他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 (19)

1.用于治疗或者预防肥胖和高脂血症以及糖尿病的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、或C8-13-N-烷基-或-N-烷醇基链-或C14-18-N-烷基-或-N-烷醇基链-壳聚糖化合物和其盐的添加化合物，和辅助赋形剂，其中所述的组合物含有每一重量份胃肠道脂酶抑制剂1～50重量份的壳聚糖或C8-13-N-烷基-或-N-烷醇基链-或C14-18-N-烷基-或-N-烷醇基链-壳聚糖化合物或其盐，条件是该壳聚糖化合物是非硫酸化的。
2.按照权利要求1所述的组合物，含有500mg～20g添加化合物和10mg～500mg胃肠道脂酶抑制剂。
3.按照权利要求2所述的组合物，含有2g～10g添加化合物。
4.按照权利要求1所述的组合物，其中胃肠道脂酶抑制剂是奥利司他。
5.按照权利要求2所述的组合物，其中胃肠道脂酶抑制剂是奥利司他。
6.按照权利要求3所述的组合物，其中胃肠道脂酶抑制剂是奥利司他。
7.按照权利要求1所述的组合物，其中添加化合物是壳聚糖。
8.按照权利要求2所述的组合物，其中添加化合物是壳聚糖。
9.按照权利要求3所述的组合物，其中添加化合物是壳聚糖。
10.按照权利要求4所述的组合物，其中添加化合物是壳聚糖。
11.按照权利要求5所述的组合物，其中添加化合物是壳聚糖。
12.按照权利要求6所述的组合物，其中添加化合物是壳聚糖。
13.壳聚糖、或C8-13-N-烷基-或-N-烷醇基链-或C14-18-N-烷基-或-N-烷醇基链-壳聚糖化合物或其盐在制备治疗或预防口服胃肠道脂酶抑制剂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的药物中的应用。
14.按照权利要求13所述的应用，其中的胃肠道脂酶抑制剂是奥利司他。
15.按照权利要求4-12中任一项所述的组合物，是用于治疗肥胖的咀嚼片，主要由作为活性成分的奥利司他和作为添加化合物的壳聚糖组成，其剂量是10～120mg奥利司他和0.5～5g壳聚糖。
16.按照权利要求15所述的咀嚼片，其中剂量为约60mg奥利司他和约2.5g壳聚糖。
17.按照权利要求4-12中任一项所述的组合物，是治疗肥胖的薄酥饼，主要由作为活性成分的奥利司他和作为添加化合物的壳聚糖组成，其剂量是10～200mg奥利司他和1～10g壳聚糖。
18.按照权利要求17所述的薄酥饼，其中剂量为约120mg奥利司他和约5g壳聚糖。
19.壳聚糖、或C8-13-N-烷基-或-N-烷醇基链-或C14-18-N-烷基-或-N-烷醇基链-壳聚糖化合物或其盐和奥利司他在制备预防口服奥利司他后偶然发生的肛门油性泄漏症状的药物中的用途。
CNB998095087A 1998-08-14 1999-08-06 含有脂酶抑制剂和壳聚糖的药物组合物 Expired - Lifetime CN1152680C (zh)

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Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6299868B1 (en) 1999-07-14 2001-10-09 Geltex Pharmaceuticals, Inc. Fat-binding polymers
US6264937B1 (en) * 1998-01-09 2001-07-24 Geltex Pharmaceuticals, Inc. Fat-binding polymers
US7048917B1 (en) 1998-01-09 2006-05-23 Genzyme Corporation Fat-binding polymers
CA2340052C (en) * 1998-08-14 2007-05-29 F. Hoffmann-La Roche Ag Pharmaceutical compositions containing lipase inhibitors and chitosan
CA2342625A1 (en) 1998-09-08 2000-03-16 Smithkline Beecham Corporation Lipstatin derivative-soluble fiber tablets
AR025587A1 (es) 1999-09-13 2002-12-04 Hoffmann La Roche Formulaciones en dispersion que contienen inhibidores de lipasa
AR025609A1 (es) * 1999-09-13 2002-12-04 Hoffmann La Roche Formulaciones lipidas solidas
US6235305B1 (en) * 1999-10-29 2001-05-22 2Pro Chemical Essentially nonabsorbable lipase inhibitor derivatives, pharmaceutical compositions and methods of use therefor
EP1132389A1 (en) 2000-03-06 2001-09-12 Vernalis Research Limited New aza-indolyl derivatives for the treatment of obesity
FI20000780A (fi) * 2000-04-03 2001-10-04 Novasso Oy Peroraalinen lääkemuoto lääkeaineen hallituksi vapauttamiseksi
EP1142572A1 (de) * 2000-04-04 2001-10-10 Volker Dr. Helmstädter Oxetanon-enthaltende Präparate zur Behandlung von Darmerkrankungen
JP4549486B2 (ja) * 2000-04-26 2010-09-22 アピ株式会社 抗肥満薬及びその製造方法
JP4149803B2 (ja) * 2000-06-27 2008-09-17 エフ．ホフマン−ラ ロシュ アーゲー 組成物の調製方法
BR0112800A (pt) 2000-07-28 2003-07-01 Hoffmann La Roche Utilização de um inibidor de lìpases e de um sequestrante de ácido de bìlis farmaceuticamente aceitáveis e processo para a prevenção e tratamento de enfermidades associadas com altos nìveis de colesterol de plasma
JP4265911B2 (ja) * 2000-07-28 2009-05-20 エフ．ホフマン−ラ ロシュ アーゲー 新規医薬組成物
CN1323661C (zh) 2000-08-09 2007-07-04 霍夫曼-拉罗奇有限公司 脂酶抑制剂的用途
US6900226B2 (en) 2000-09-06 2005-05-31 Hoffman-La Roche Inc. Neuropeptide Y antagonists
US6251421B1 (en) * 2000-09-25 2001-06-26 Sarfaraz K. Niazi Pharmaceutical composition containing psyllium fiber and a lipase inhibitor
KR100545435B1 (ko) 2000-10-16 2006-01-24 에프. 호프만-라 로슈 아게 인돌린 유도체 및 5-ｈｔ2 수용체 리간드로서의 이들의 용도
GB0030710D0 (en) 2000-12-15 2001-01-31 Hoffmann La Roche Piperazine derivatives
KR100539143B1 (ko) 2000-12-27 2005-12-26 에프. 호프만-라 로슈 아게 인돌 유도체 및 그의 5-ｈｔ2ｂ 및 5-ｈｔ2ｃ 수용체리간드로서의 용도
GB0106177D0 (en) 2001-03-13 2001-05-02 Hoffmann La Roche Piperazine derivatives
US20030072804A1 (en) * 2001-03-19 2003-04-17 The Procter & Gamble Company Use of non-digestible polymeric foams to sequester ingested materials thereby inhibiting their absorption by the body
US20030091610A1 (en) * 2001-03-19 2003-05-15 The Procter & Gamble Company Use of non-digestible polymeric foams to sequester ingested materials thereby inhibiting their absorption by the body
BR0209957A (pt) 2001-05-21 2004-03-30 Hoffmann La Roche Composto, processo para a preparação de um composto, composição farmacêutica que compreende um composto, utilização desse composto e processo para o tratamento e profilaxia de artrite, diabetes, distúrbios alimentares e obesidade
CA2449814A1 (en) * 2001-06-05 2002-12-12 The Children's Hospital Of Philadelphia Methods and kits for diagnosing a pancreatic-based fat malabsorption disorder
US20030027786A1 (en) 2001-06-06 2003-02-06 Karsten Maeder Lipase inhibiting composition
US7041280B2 (en) * 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
US7049345B2 (en) * 2001-06-29 2006-05-23 Genzyme Corporation Fat-binding polymers
US6787558B2 (en) 2001-09-28 2004-09-07 Hoffmann-La Roche Inc. Quinoline derivatives
GB0202015D0 (en) 2002-01-29 2002-03-13 Hoffmann La Roche Piperazine Derivatives
ATE392897T1 (de) 2002-02-04 2008-05-15 Hoffmann La Roche Chinolinderivate als npy antagonisten
US20040091450A1 (en) * 2002-02-26 2004-05-13 The Procter & Gamble Company Use of non-digestible polymeric foams to sequester ingested materials thereby inhibiting their absorption by the body
CN100363362C (zh) 2002-02-28 2008-01-23 霍夫曼-拉罗奇有限公司 用作npy受体拮抗剂的噻唑衍生物
WO2003090742A1 (en) * 2002-04-26 2003-11-06 F. Hoffmann-La Roche Ag Pharmaceutical composition comprising a lipase inhibitor and glucomannan
JP2005535648A (ja) 2002-07-05 2005-11-24 エフ．ホフマン−ラ　ロシュ　アーゲー キナゾリン誘導体
MXPA05001328A (es) 2002-08-07 2005-04-28 Hoffmann La Roche Derivados de tiazol.
ES2209632B1 (es) * 2002-08-30 2005-08-01 Romildo Holding, N.V. Complemento dietetico, soluble, efervescente y alimenticio.
PL375878A1 (en) 2002-09-12 2005-12-12 F.Hoffmann-La Roche Ag N-substituted-1h-indol-5-propionic acid compounds as ppar agonists useful for the treatment of diabetes
DE10248575A1 (de) * 2002-10-17 2004-05-06 Christian-Albrechts-Universität Zu Kiel Chiltosanpellets
MXPA05005445A (es) 2002-11-25 2005-08-26 Hoffmann La Roche Derivados de indolilo.
US8372430B2 (en) * 2002-12-17 2013-02-12 The Procter & Gamble Company Compositions, methods, and kits useful for the alleviation of gastrointestinal effects
GB0310919D0 (en) * 2003-05-13 2003-06-18 West Pharm Serv Drug Res Ltd Pharmaceutical compositions
GB0314967D0 (en) 2003-06-26 2003-07-30 Hoffmann La Roche Piperazine derivatives
US20050008699A1 (en) * 2003-07-11 2005-01-13 Fred Wehling Effervescent glucosamine composition
RU2006107444A (ru) 2003-08-12 2007-09-20 Ф.Хоффманн-Ля Рош Аг (Ch) 2-амино-5-бензоилтиазолы в качестве антагонистов npy
EP1656374B1 (en) 2003-08-12 2009-03-11 F. Hoffmann-La Roche Ag Thiazole derivatives as npy antagonists
US20080075688A1 (en) * 2003-10-31 2008-03-27 The Procter & Gamble Company Use of non-digestible polymeric foams to sequester ingested materials thereby inhibiting their absorption by the body
JP2005154477A (ja) * 2003-11-20 2005-06-16 Tottori Univ 紫外線硬化型キトサン誘導体を用いた医療用接着剤および医療用被覆剤
CN100496468C (zh) * 2004-03-23 2009-06-10 利统股份有限公司 甲壳素包埋或包胶胶囊
US7465417B2 (en) * 2004-07-19 2008-12-16 Baxter International Inc. Parametric injection molding system and method
MXPA04010692A (es) * 2004-10-28 2006-05-02 Jorge Luis Rosado Loria Composicion para el tratamiento de la obesidad e hiperlipidemia.
ITMI20050150A1 (it) * 2005-02-03 2006-08-04 Umberto Cornelli Prodotti alimentari
KR100895758B1 (ko) 2005-05-03 2009-04-30 에프. 호프만-라 로슈 아게 5-ｈｔ2 리간드로서 테트라사이클릭 아자피라지노인돌린
MX2008002061A (es) 2005-08-18 2008-04-16 Hoffmann La Roche Derivados de tiazolil piperidina utiles como moduladores del receptor h3.
KR20080076987A (ko) 2005-11-30 2008-08-20 에프. 호프만-라 로슈 아게 5-치환된 인돌-2-카복스아미드 유도체
ES2362929T3 (es) 2005-11-30 2011-07-15 F. Hoffmann-La Roche Ag Derivados de 1,1-dioxo-tiomorfolinil-indolil-metanona para uso como moduladores de h3.
CA2630314A1 (en) 2005-11-30 2007-06-07 F. Hoffmann-La Roche Ag 1,5-substituted indol-2-yl amide derivatives
ATE448230T1 (de) 2005-12-09 2009-11-15 Hoffmann La Roche Für die behandlung von obesitas geeignete tricyclische amidderivate
ATE449776T1 (de) 2005-12-15 2009-12-15 Hoffmann La Roche Pyrroloä2,3-cüpyridinderivate
ATE467632T1 (de) 2005-12-16 2010-05-15 Hoffmann La Roche Pyrroloä2,3-büpyridinderivate als modulatoren des h3-rezeptors
ITMI20060384A1 (it) * 2006-03-03 2007-09-04 Umberto Cornelli Composizioni comprendenti chitosano atte al trattamento terapeutico complessivo o alla prevenzione complessiva della sindrome metabolica
KR101252635B1 (ko) * 2006-04-20 2013-04-10 (주)아모레퍼시픽 리파아제 저해제 및 친유성 오일흡수제를 포함하는 약학조성물 및 이로부터 제조된 경구 투여용 제제
US7432255B2 (en) 2006-05-16 2008-10-07 Hoffmann-La Roche Inc. 1H-indol-5-yl-piperazin-1-yl-methanone derivatives
CA2652158A1 (en) 2006-05-30 2007-12-06 Matthias Heinrich Nettekoven Piperidinyl pyrimidine derivatives
US7514433B2 (en) 2006-08-03 2009-04-07 Hoffmann-La Roche Inc. 1H-indole-6-yl-piperazin-1-yl-methanone derivatives
US20080146559A1 (en) 2006-12-08 2008-06-19 Li Chen 4,5,6,7-Tetrahydro-Thieno [2,3-C] Pyridine Derivatives
TR200607613A2 (tr) * 2006-12-29 2008-07-21 NOBEL İLAÇ SAN.ve TiC.A.Ş. Lipaz inhibitörü içeren farmasötik formülasyonlar
EP2016946B1 (en) * 2007-07-18 2013-02-27 The Jordanian Pharmaceutical Manufacturing Co. Chitosan silicon dioxide coprecipitate composition for use as a therapeutically active agent
JP2010534217A (ja) 2007-07-25 2010-11-04 エフ．ホフマン−ラ ロシュ アーゲー ベンゾフラン−及びベンゾ［ｂ］チオフェン−２−カルボン酸アミド誘導体ならびにヒスタミン３受容体モジュレータとしてのその使用
WO2012070702A1 (ko) * 2010-11-25 2012-05-31 주식회사 삼양사 올리스태트 및 키토산 함유 조성물 및 그 제조방법
CN104546768B (zh) * 2014-12-30 2017-06-16 重庆植恩药业有限公司 含有脂肪酶抑制剂的咀嚼片组合物及其制备方法
CN105520947B (zh) * 2015-12-24 2018-05-01 广东药科大学 一种含有氨基葡萄糖的具有减肥功能的药物组合物
JOP20180128A1 (ar) * 2018-12-24 2020-06-24 Univ Of Petra صيغة دوائية صلبة قابلة للتشتت في الفم
GB202212379D0 (en) * 2022-08-25 2022-10-12 GlaxoSmithKline Consumer Healthcare UK IP Ltd Novel toothpaste tablet composition

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4223023A (en) * 1978-10-12 1980-09-16 Ivan Furda Nonabsorbable lipid binder
CA1247547A (en) * 1983-06-22 1988-12-28 Paul Hadvary Leucine derivatives
US5063210A (en) * 1989-04-20 1991-11-05 Lange Iii Louis G Use of sulfated polysaccharides to decrease cholesterol and fatty acid absorption
CA2098167C (en) * 1992-06-24 2006-12-19 Dorothea Isler Foodstuffs and feedstuffs containing a lipase inhibitor
CA2340052C (en) * 1998-08-14 2007-05-29 F. Hoffmann-La Roche Ag Pharmaceutical compositions containing lipase inhibitors and chitosan

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