CN1147291C - 用于口服制剂的含有藻酸的肠溶包衣 - Google Patents
用于口服制剂的含有藻酸的肠溶包衣Info
- Publication number
- CN1147291C CN1147291C CNB971959986A CN97195998A CN1147291C CN 1147291 C CN1147291 C CN 1147291C CN B971959986 A CNB971959986 A CN B971959986A CN 97195998 A CN97195998 A CN 97195998A CN 1147291 C CN1147291 C CN 1147291C
- Authority
- CN
- China
- Prior art keywords
- oral formulations
- alginic acid
- enteric coating
- binding agent
- coating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000009505 enteric coating Methods 0.000 title claims abstract description 30
- 239000002702 enteric coating Substances 0.000 title claims abstract description 30
- 235000010443 alginic acid Nutrition 0.000 title claims abstract description 29
- 229920000615 alginic acid Polymers 0.000 title claims abstract description 29
- 239000000783 alginic acid Substances 0.000 title claims abstract description 28
- 229960001126 alginic acid Drugs 0.000 title claims abstract description 28
- 150000004781 alginic acids Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 70
- 239000011230 binding agent Substances 0.000 claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 3
- 238000009472 formulation Methods 0.000 claims description 25
- 239000002775 capsule Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 17
- 239000011248 coating agent Substances 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 230000000844 anti-bacterial effect Effects 0.000 claims description 9
- 229920000159 gelatin Polymers 0.000 claims description 8
- 235000019322 gelatine Nutrition 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 7
- 239000001828 Gelatine Substances 0.000 claims description 6
- 229920000161 Locust bean gum Polymers 0.000 claims description 5
- 235000010420 locust bean gum Nutrition 0.000 claims description 5
- 239000000711 locust bean gum Substances 0.000 claims description 5
- 239000006187 pill Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 235000013373 food additive Nutrition 0.000 claims description 2
- 239000002778 food additive Substances 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 241000196324 Embryophyta Species 0.000 claims 1
- 239000007864 aqueous solution Substances 0.000 claims 1
- 235000013305 food Nutrition 0.000 claims 1
- 239000003232 water-soluble binding agent Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 8
- 239000013588 oral product Substances 0.000 abstract 1
- 229940023486 oral product Drugs 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 239000013543 active substance Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 229920001817 Agar Polymers 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 241000186660 Lactobacillus Species 0.000 description 6
- 239000008272 agar Substances 0.000 description 6
- 229940039696 lactobacillus Drugs 0.000 description 6
- 239000004006 olive oil Substances 0.000 description 6
- 235000008390 olive oil Nutrition 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002002 slurry Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229950010118 cellacefate Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/065—Microorganisms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Jellies, Jams, And Syrups (AREA)
Abstract
在口服产品上形成肠溶包衣的含有藻酸颗粒和粘合剂液体混合物的组合物，和在此基础上具有肠溶包衣的口服制剂。
Description
本发明涉及在口服制剂上形成肠溶包衣的组合物，如片剂、胶囊或丸剂形式的制剂。
肠溶包衣意指防止在胃中对所含活性物质产生不利影响的包衣。
例如，肠溶包衣用于
(1)防止胃液与活性物质产生反应或破坏活性物质，
(2)防止活性物质在到达肠之前被稀释，
(3)确保活性物质在制剂通过胃之后才释放，和
(4)防止制剂中所含有的活细菌因胃中的低pH值而被杀死。
肠溶包衣也用于避免口服制剂中所含有的物质对胃粘膜产生刺激或损伤，抵制或防止在胃中形成或释放具有令人不快气味或味道的物质。最后，此包衣可用于防止摄入口服制剂时的恶心或呕吐。
由一层或多层脂肪酸，如硬脂酸和棕榈酸、蜡、虫胶和/或乙酸邻苯二甲酸纤维素制成肠溶包衣是已知的。
已知的肠溶包衣组合物形成时需要使用丙酮或含氯化合物形式的有机溶剂的肠溶包衣组合物有实质性缺陷。
关于乙酸邻苯二甲酸纤维素，还要求它们一定不能用于包衣食料和食品添加剂，因为在EU未被批准在食料中使用，参见“Fortegnelseover tils&tnings-stoffer til levenedmidler”，Positivlisten，Levnedsmiddl-styrelsen，1995年12月，公开号231，ISSN0903-9783，ISSN0108-1667。
另一已知的包衣组分是丙烯酸树脂，其可以商标为Eudragit的商品买到，但是，该包衣组分通常也未被批准用于形成食料包衣。
日本专利公开号05-32543披露了肠溶包衣的胶囊，其由含药物的内容物和壳组成，该内容物和壳包括具体的物质，如分散在含基质材料的琼脂中的藻酸。该内容物和壳是通过将具体物质和含材料的琼脂的混合物加热到约100℃，然后冷却该混合物，再将该混合物通过铸模转变成胶囊而制备的。
US-A-4 661 162披露了肠溶组合物，其包括肠溶聚合物，如羧甲基乙基纤维素及多阴离子聚合物，如藻酸，其可溶于呀渗透到pH值小于或等于2的液体中。
现已惊奇地发现一种已知的物质(已被批准用作食料添加剂)与粘合剂混合时可用于在口服制剂上形成有效的包衣材料。
因此，通过在片剂、胶囊丸剂等形式的制剂上形成藻酸颗粒和粘合剂的液体混合物层来进行，获得耐受胃液影响的但在中性或碱性条件下溶解的包衣。这是由于藻酸在酸中是不溶的而在碱性或中性介质中是溶解的，这是因为以本身已知的方式形成藻酸盐。
藻酸和粘合剂混合物中的藻酸颗粒的平均颗粒大小最大为2μm时，获得最好的保护作用，但根据被进行肠溶包衣的制剂的种类，可使用更大或更小的颗粒。
使用大小变化的藻酸颗粒混合物可获得特别好的保护作用。
作为藻酸颗粒的粘合剂，可使用各种各样的治疗和/或滋养可接受的粘合剂。该粘合剂优选溶解在液体介质中，并且可用于药物和食料的粘合剂的例子包括豆角胶、明胶、植物性亲水胶和动物蛋白。
藻酸颗粒和粘合剂的液体混合物优选是含水的，并且水优选超过混合物重量的95％。根据粘合剂、藻酸颗粒的大小和包衣组合物的应用领域，藻酸与粘合剂的比可在宽的有限范围内变化。
一般来说，使用重量比4∶1到0.5∶1的藻酸和粘合剂。
使用藻酸和粘合剂(如豆角胶)的含水混合物时，后者优选溶解在一部分水中，藻酸则在剩余的水中浆化，然后浆状物可任意选择地进行处理如在均化器处理以便获得所需的颗粒大小。最后，混合两部分，并且可任意选择地进行进一步均化以便使藻酸分布在所述的第一部分中。
藻酸和粘合剂的液体混合物也可含有各种添加剂。例如，可使用油(如橄榄油)形式的软化剂和防粘剂如硬脂酸镁和脂肪。
使用本发明的包衣组合物在口服制剂上形成肠溶包衣可通过本身是已知的方法来进行，如在流化床或包衣锅中将藻酸和粘合剂的液体混合物直接喷雾在制剂上。
本发明也涉及具有肠溶包衣的制剂，所述肠溶包衣是使用本发明的包衣组合物制备的。
本发明还涉及制备包衣的口服制剂的方法，其中用本发明的包衣组合物喷雾口服制剂，然后蒸发水。
用本发明肠溶包衣包裹的口服制剂特别适于含有活的有机体，如冻干的细菌。
另外，本发明涉及在含有活的有机体的口服制剂上制备肠溶包衣的方法，该方法不使用毒性有机溶剂，并且温度不超过约30℃。
包衣含有活的有机体(如冻干的细菌)的口服制剂时，细菌不暴露在使其损害或易死亡的外界影响之下是重要的。
因此，在口服制剂上制备肠溶包衣时可避免使用毒性有机溶剂和高温。本发明在口服制剂上制备肠溶包衣时，温度优选不超过约30℃。而且，不使用毒性的有机溶剂。
在本发明方法进一步的实施方案中，用肠溶包衣材料包裹的口服制剂由胶囊组成，优选是明胶胶囊。如果使用胶囊形式的制剂，还可在用肠溶包衣材料包裹之前得到活性物质的柔软制剂，因为制备胶囊时的物理条件不影响活性物质。将活性物质(如冻干形式的细菌)填充在空的胶囊中，相反地活性物质制成片剂或丸剂时，则压片和制丸。
对明胶胶囊进行肠溶包衣是特别有效的。
根据制剂的种类，构成几层肠溶包衣是理想的，其中每一层都通过粘合剂粘合细微粒化的藻酸颗粒来制备。
例如，需制备四层的包衣时，其中的一个中心层是用本发明的包衣组合物制备的。
提供由几个亚层组成的内层也是理想的。类似地，外层也可由几层构成。
参照下列实施例，更详细地描述本发明。
实施例
为了在含有冻干的乳酸菌的明胶胶囊上制备肠溶包衣，采用下列三种包衣组合物：
包衣组合物1
玉米醇溶蛋白F-4000 10％
乙醇96％ 79％
纯水 9％
硬脂酸镁 2％
通过下列方法制备包衣组合物1：在乙醇中将玉米醇溶蛋白F-4000制成淤浆，然后混合硬脂酸镁，最后与水搅拌混合。
包衣组合物2
藻酸钠 2.7％
纯水 97％
橄榄油 0.15％
硬脂酸镁 0.15％
通过下列方法制备包衣组合物2：在水中溶解藻酸钠，然后加入橄榄油和硬脂酸镁并通过均化器混合均匀。
包衣组合物3
藻酸 1.5％
豆角胶 0.8％
橄榄油 0.8％
纯水 96.9％
通过下列方法制备包衣组合物3：在38.4份的水中溶解0.8份的豆角胶，然后加入0.8份的橄榄油并用均化器乳化混合物。在58份的水中制备1.5份的藻酸淤浆并用均化器混合均匀，然后加入上述橄榄油乳液，用均化器将混合物混合均匀。
在明胶胶囊上按下表所描述的顺序和条件使用所述的包衣组合物。
表
| 制备方法 | 包衣组合物 | 液体的量，g | 喷嘴直径 | 喷嘴压力 | 喷雾速度 | 起始温度 | 干燥温度 | 干燥时间，分钟 | 胶囊中水的活性 |
| 预加热 | 0 | 0 | 30℃，15分钟 | 0.198，制备前 | |||||
| 预处理 | 乙醇96％ | 1500g | 0.8mm | 0.8巴 | 60g/分钟 | 30℃ | 30℃ | 0 | 0.162，制备后 |
| 第一层 | 12 | 50005000 | 0.8mm1.2mm | 0.8巴 | 60g/分钟 | 30℃ | 30℃ | 15分钟 | 0.218，制备后 |
| 第二层 | 3 | 5000 | 1.2mm | 0.8巴 | 60g/分钟 | 30℃ | 30℃ | 10分钟 | 0.218，制备后 |
| 第三层 | 12 | 10001000 | 0.8mm1.2mm | 0.8巴 | 60g/分钟 | 30℃ | 30℃ | 0 | |
| 第四层 | 1 | 700 | 0.8mm | 0.8巴 | 60g/分钟 | 30℃ | 30℃ | 15分钟 | |
| 冷却 | 0 | 不超过22℃ | 加热 | 不超过22℃ | 0.209，制备后 |
如上表所示，尽管使用含水的包衣组合物，胶囊中的水活性(通过“Novasina”湿润仪测得的)没有显著增加。这对于许多物质的稳定性和冻干细菌的存活来说是非常重要的。
根据欧洲药典试验制得的胶囊：在欧洲药典的衰变装置中，于37℃下，将6粒胶囊暴露于0.1N盐酸的影响之下2小时，必须显示无溶出或允许成分渗出的破坏的迹象。然后，用pH为6.8的磷酸盐缓冲液代替盐酸。60分钟后，胶囊必须溶解。
膜包衣的胶囊经得起该试验并且在磷酸盐中浸泡18分钟后全部溶解。
出于证明的目的，将本发明肠溶包衣的含有乳酸菌的制剂进行稳定性，即衰变试验，其中是根据欧洲药典第二版，478，1990所述的方法于36-38℃温度下，记录在用0.1N HCL处理两小时前后肠溶包衣胶囊中所包含的微生物的数目。
这些衰变试验的结果显示在下表中。
处理前
| 样品号 | 每克MRS琼脂在37℃温度，CO2环境中3天时的活的乳酸杆菌的数目 |
| 1a1b2a2b | 7.0×1075.8×107平均值：6.8×1077.3×1076.9×107 |
| 样品号 | 每克RCM琼脂在37℃温度，无氧环境中5天时的活的乳酸杆菌的数目 |
| 1a1b2a2b | 4.0×1083.9×108平均值：4.0×1083.8×1084.4×108 |
处理后
| 样品号 | 每克MRS琼脂在37℃温度，CO2环境中3天时的活的乳酸杆菌的数目 |
| 1a1b2a2b | 2.0×1071.4×107平均值：2.7×1073.0×1074.5×107 |
| 样品号 | 每克RCM琼脂在37℃温度，无氧环境中5天时的活的乳酸杆菌的数目 |
| 1a1b2a2b | 1.7×1071.5×107平均值：2.0×1072.2×1072.5×107 |
如上述结果所示，酸处理后仅仅使活的微生物略有下降。
Claims (12)
1、在口服制剂上形成肠溶包衣的组合物，其特征在于所述组合物包含大量分散于水性溶液中的藻酸颗粒和少量水溶性粘合剂，其中的粘合剂选自豆角胶、明胶、植物亲水胶和动物蛋白，该藻酸和粘合剂皆是允许作为包衣食物和/或食物添加剂使用的，其中所述藻酸颗粒和粘合剂以4∶1～0.5∶1的重量比存在。
2、权利要求1的组合物，其特征在于藻酸颗粒的平均颗粒大小最大为2μm。
3、权利要求1或2的组合物，其特征在于藻酸颗粒的大小是可变的。
4、一种具有肠溶包衣的口服制剂，其特征在于使用如权利要求1的组合物来制备肠溶包衣。
5、权利要求4的口服制剂，其特征在于含有活的细菌细菌。
6、权利要求5的口服制剂，其特征在于含有冻干的细菌。
7、权利要求4-6任一的口服制剂，其特征在于为片剂、胶囊或丸剂形式。
8、权利要求7的口服制剂，其特征在于为明胶胶囊。
9、制备包衣的口服制剂的方法，其特征在于：用权利要求1的包衣组合物喷雾口服制剂，然后蒸发水。
10、权利要求9的方法，其特征在于口服制剂含活的细菌。
11、权利要求9或10的方法，其特征在于口服制剂是胶囊形式。
12、权利要求11的方法，其特征在于口服制剂是明胶胶囊。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK0636/1996 | 1996-06-06 | ||
| DK0636/96 | 1996-06-06 | ||
| DK63696 | 1996-06-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1223573A CN1223573A (zh) | 1999-07-21 |
| CN1147291C true CN1147291C (zh) | 2004-04-28 |
Family
ID=8095832
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB971959986A Expired - Lifetime CN1147291C (zh) | 1996-06-06 | 1997-06-06 | 用于口服制剂的含有藻酸的肠溶包衣 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US6455052B1 (zh) |
| EP (1) | EP0952824B1 (zh) |
| JP (1) | JP2000514406A (zh) |
| KR (1) | KR20000016331A (zh) |
| CN (1) | CN1147291C (zh) |
| AT (1) | ATE277605T1 (zh) |
| AU (1) | AU717817B2 (zh) |
| BR (1) | BR9709535A (zh) |
| CA (1) | CA2257378C (zh) |
| DE (1) | DE69730991T2 (zh) |
| IL (1) | IL127378A (zh) |
| NO (1) | NO327294B1 (zh) |
| NZ (1) | NZ333182A (zh) |
| WO (1) | WO1997046224A1 (zh) |
Families Citing this family (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3142820B2 (ja) * | 1998-08-27 | 2001-03-07 | 株式会社エヌ・ティ・ティ・ドコモ | プッシュ型情報配信方法およびその中継装置 |
| JP3142821B2 (ja) * | 1998-08-27 | 2001-03-07 | 株式会社エヌ・ティ・ティ・ドコモ | 情報通信ネットワークの課金方法 |
| EA006132B1 (ru) * | 2000-10-20 | 2005-10-27 | Биовитрум Аб | 2-, 3-, 4- или 5-замещенные n-(1-(арил-, гетероарил- или арилалкил)сульфонил)индолы и их применение в терапии |
| NL1018991C2 (nl) * | 2001-09-20 | 2003-03-21 | Tno | Vochtwerende eetbare bekledingslaag voor voedingsmiddelen. |
| US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
| KR100491647B1 (ko) * | 2002-11-21 | 2005-05-27 | 한국화학연구원 | 알긴산 나트륨 피복층을 포함하는 벤즈 이미다졸 유도체의경구체제 및 그의 제조방법 |
| US7122370B2 (en) * | 2003-01-14 | 2006-10-17 | Randolph Stanley Porubcan | Formulations to increase in vivo survival of probiotic bacteria and extend their shelf-life |
| DE10336400A1 (de) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Gegen Missbrauch gesicherte Darreichungsform |
| DE102005005446A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Bruchfeste Darreichungsformen mit retardierter Freisetzung |
| DE10361596A1 (de) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
| GB0320522D0 (en) * | 2003-09-02 | 2003-10-01 | Glaxo Group Ltd | Formulation |
| EP1514553B1 (en) * | 2003-09-05 | 2008-02-27 | Chung, Myung-jun | Lactic acid bacteria powder double-coated using protein and polysaccharide and method preparing the same and a dosage form thereof |
| DE102004032049A1 (de) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Gegen Missbrauch gesicherte, orale Darreichungsform |
| WO2006012536A2 (en) | 2004-07-22 | 2006-02-02 | Ritter Andrew J | Methods and compositions for treating lactose intolerance |
| DE102005005449A1 (de) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Verfahren zur Herstellung einer gegen Missbrauch gesicherten Darreichungsform |
| US8697126B2 (en) | 2005-05-18 | 2014-04-15 | Dsm Ip Assets B.V. | Compositions for enternal application of microorganisms |
| US8343548B2 (en) | 2006-08-08 | 2013-01-01 | Shin-Etsu Chemical Co., Ltd. | Solid dosage form comprising solid dispersion |
| US8343547B2 (en) | 2006-08-08 | 2013-01-01 | Shin-Etsu Chemical Co., Ltd. | Solid dosage form comprising solid dispersion |
| US8519120B2 (en) | 2006-08-08 | 2013-08-27 | Shin-Etsu Chemical Co., Ltd. | Methods for producing a low-substituted hydroxypropylcellulose powder |
| EP2334311B1 (en) * | 2008-09-17 | 2021-03-10 | Hunter Immunology Pty Ltd | Non-typeable haemophilus influenzae vaccines and their uses |
| BRPI1008280A2 (pt) | 2009-02-24 | 2015-08-25 | Ritter Pharmaceuticals Inc | Formulações prebióticas e métodos mde uso |
| KR101747156B1 (ko) | 2009-07-22 | 2017-06-27 | 그뤼넨탈 게엠베하 | 산화-안정화된 탬퍼-내성 용량형 |
| TW201105316A (en) | 2009-07-22 | 2011-02-16 | Gruenenthal Gmbh | Hot-melt extruded pharmaceutical dosage form |
| EP2563372A4 (en) | 2010-04-28 | 2013-10-02 | Ritter Pharmaceuticals Inc | PREBIOTIC FORMULATIONS AND METHODS OF USE |
| US8940858B2 (en) * | 2010-05-17 | 2015-01-27 | Northwestern University | Fibrous microcapsules and methods of assembly and use thereof |
| MX2013002377A (es) | 2010-09-02 | 2013-04-29 | Gruenenthal Gmbh | Forma de dosificacion resistente a manipulacion que comprende una sal inorganica. |
| EA201400172A1 (ru) | 2011-07-29 | 2014-06-30 | Грюненталь Гмбх | Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства |
| EA201400173A1 (ru) | 2011-07-29 | 2014-06-30 | Грюненталь Гмбх | Устойчивая к разрушению таблетка, которая обеспечивает немедленное высвобождение лекарственного средства |
| JP6282261B2 (ja) | 2012-04-18 | 2018-02-21 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | 不正使用防止および過量放出防止医薬剤形 |
| US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
| AU2014273227B2 (en) | 2013-05-29 | 2019-08-15 | Grunenthal Gmbh | Tamper-resistant dosage form containing one or more particles |
| CA2917136C (en) | 2013-07-12 | 2022-05-31 | Grunenthal Gmbh | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
| JP6480936B2 (ja) | 2013-11-26 | 2019-03-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | クライオミリングによる粉末状医薬組成物の調製 |
| EP3125905A4 (en) | 2014-04-04 | 2017-11-08 | Ritter Pharmaceuticals, Inc. | Methods and compositions for microbiome alteration |
| AU2015261060A1 (en) | 2014-05-12 | 2016-11-03 | Grunenthal Gmbh | Tamper resistant immediate release capsule formulation comprising Tapentadol |
| WO2016035756A1 (ja) * | 2014-09-03 | 2016-03-10 | ライオン株式会社 | コーティング製剤及びその製造方法 |
| ITUB20152290A1 (it) * | 2015-07-17 | 2017-01-17 | Laboratori Baldacci Spa | Prodotto a base di ferro bisglicinato chelato e acido alginico e/o suoi sali idrosolubili, sue formulazioni ed suoi usi farmaceutici |
| US11865099B2 (en) | 2015-07-17 | 2024-01-09 | Laboratori Baldacci S.P.A. | Product based on iron bis-glycinate chelate and alginic acid and/or water-soluble salts thereof, formulations thereof, and pharmaceutical uses thereof |
| CA2998259A1 (en) | 2015-09-10 | 2017-03-16 | Grunenthal Gmbh | Protecting oral overdose with abuse deterrent immediate release formulations |
| IL298281A (en) | 2015-11-03 | 2023-01-01 | Brigham & Womens Hospital Inc | Medical microbiota for the treatment and/or prevention of food allergy |
| US20170296476A1 (en) * | 2016-04-15 | 2017-10-19 | Grünenthal GmbH | Modified release abuse deterrent dosage forms |
| US10618042B1 (en) | 2017-05-31 | 2020-04-14 | University Of South Florida | Mixed metal oxide extrudate catalyst |
| CA3088630A1 (en) | 2017-12-15 | 2019-06-20 | Solarea Bio, Inc. | Microbial compositions and methods for treating type 2 diabetes, obesity, and metabolic syndrome |
| FR3083545A1 (fr) | 2018-07-04 | 2020-01-10 | Institut National De La Recherche Agronomique | Utilisation d'une souche de roseburia intestinalis pour la prevention et le traitement de l'inflammation de l'intestin |
| US11980647B2 (en) | 2018-09-05 | 2024-05-14 | Solarea Bio, Inc. | Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause |
| CA3111795A1 (en) | 2018-09-05 | 2020-03-12 | Solarea Bio, Inc. | Methods and compositions for treating musculoskeletal diseases |
| EP3646857A1 (en) | 2018-11-01 | 2020-05-06 | Evonik Operations GmbH | Colonic delivery system for microorganisms |
| KR102682981B1 (ko) | 2018-11-05 | 2024-07-11 | 마블바이옴 인코포레이티드 | 엘라기탄닌을 포함하는 미생물 조성물 및 사용 방법 |
| EP3986163A2 (en) | 2019-06-19 | 2022-04-27 | Solarea Bio, Inc. | Microbial compositions and methods for producing upgraded probiotic assemblages |
| EP4376810A1 (en) * | 2021-07-29 | 2024-06-05 | Nutrition & Biosciences USA 1, LLC | Controlled release coating agent |
| AU2022391767A1 (en) | 2021-11-22 | 2024-07-04 | Solarea Bio, Inc. | Methods and compositions for treating musculoskeletal diseases, treating inflammation, and managing symptoms of menopause |
| US20230190834A1 (en) | 2021-12-21 | 2023-06-22 | Solarea Bio, Inc. | Immunomodulatory compositions comprising microbial entities |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE338976B (zh) * | 1970-01-29 | 1971-09-27 | Foerenade Superfosfatfab Ab | |
| GB1509866A (en) * | 1975-06-10 | 1978-05-04 | Johnson & Johnson | Enteric coated digestive enzyme compositions |
| JPS59193831A (ja) * | 1983-04-18 | 1984-11-02 | Sankyo Co Ltd | 腸溶性製剤の製造法 |
| CN1033441A (zh) * | 1987-12-11 | 1989-06-21 | 福建省水产研究所 | 用褐藻胶制肠溶片剂的方法 |
| CN1034489A (zh) * | 1987-12-11 | 1989-08-09 | 福建省水产研究所 | 一种制作肠溶胶囊的方法 |
| US5733575A (en) * | 1994-10-07 | 1998-03-31 | Bpsi Holdings, Inc. | Enteric film coating compositions, method of coating therewith, and coated forms |
| US5674495A (en) * | 1995-02-27 | 1997-10-07 | Purdue Research Foundation | Alginate-based vaccine compositions |
| AU6122496A (en) * | 1995-06-20 | 1997-01-22 | Pharma-Vinci A/S | A method of preparing an oral preparation provided on the outer side with an enteric coating, as well as an oral preparation obtained by the method |
-
1997
- 1997-06-06 US US09/194,922 patent/US6455052B1/en not_active Expired - Lifetime
- 1997-06-06 JP JP10500114A patent/JP2000514406A/ja active Pending
- 1997-06-06 AT AT97924938T patent/ATE277605T1/de not_active IP Right Cessation
- 1997-06-06 WO PCT/DK1997/000252 patent/WO1997046224A1/en active IP Right Grant
- 1997-06-06 CA CA002257378A patent/CA2257378C/en not_active Expired - Lifetime
- 1997-06-06 KR KR1019980709904A patent/KR20000016331A/ko not_active Application Discontinuation
- 1997-06-06 CN CNB971959986A patent/CN1147291C/zh not_active Expired - Lifetime
- 1997-06-06 BR BR9709535-4A patent/BR9709535A/pt not_active IP Right Cessation
- 1997-06-06 NZ NZ333182A patent/NZ333182A/xx not_active IP Right Cessation
- 1997-06-06 IL IL12737897A patent/IL127378A/xx not_active IP Right Cessation
- 1997-06-06 EP EP97924938A patent/EP0952824B1/en not_active Expired - Lifetime
- 1997-06-06 DE DE69730991T patent/DE69730991T2/de not_active Expired - Lifetime
- 1997-06-06 AU AU30263/97A patent/AU717817B2/en not_active Expired
-
1998
- 1998-12-04 NO NO19985699A patent/NO327294B1/no not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN1223573A (zh) | 1999-07-21 |
| IL127378A (en) | 2003-07-31 |
| EP0952824B1 (en) | 2004-09-29 |
| JP2000514406A (ja) | 2000-10-31 |
| EP0952824A1 (en) | 1999-11-03 |
| IL127378A0 (en) | 1999-10-28 |
| ATE277605T1 (de) | 2004-10-15 |
| NO985699D0 (no) | 1998-12-04 |
| AU3026397A (en) | 1998-01-05 |
| NZ333182A (en) | 2000-03-27 |
| NO327294B1 (no) | 2009-06-02 |
| DE69730991T2 (de) | 2006-02-23 |
| NO985699L (no) | 1999-02-08 |
| CA2257378C (en) | 2009-04-07 |
| AU717817B2 (en) | 2000-04-06 |
| WO1997046224A1 (en) | 1997-12-11 |
| CA2257378A1 (en) | 1997-12-11 |
| BR9709535A (pt) | 2000-01-11 |
| KR20000016331A (ko) | 2000-03-25 |
| US6455052B1 (en) | 2002-09-24 |
| DE69730991D1 (de) | 2004-11-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1147291C (zh) | 用于口服制剂的含有藻酸的肠溶包衣 | |
| EP0391518B1 (en) | Sustained-release pharmaceutical preparation | |
| CN1160062C (zh) | 包含奥美拉唑的药用制剂 | |
| JP2773959B2 (ja) | 大腸内放出性固形製剤 | |
| DE2838309C3 (de) | Pille für die orale Verabfolgung an Wiederkäuer | |
| CN1125057A (zh) | 反刍动物饲料添加剂组合物 | |
| CN1057671C (zh) | 用于动物饲料的包衣维生素ｃ制剂生产方法及其应用 | |
| CN1284533C (zh) | 具有高直链淀粉含量的乙酰化预凝胶化淀粉的用途 | |
| MX2007005279A (es) | Composiciones de bacteriofagos. | |
| US4808412A (en) | Rumen-stable compositions | |
| US20180000743A1 (en) | Modified Alginate Hydrogels for Therapeutic Agents, their Preparation and Methods Thereof | |
| KR880701543A (ko) | 동물의 장구간에 생물학적 활성물질을 방출하는데 유용한 미세과립형 제제 | |
| JPS63501403A (ja) | こぶ胃で安定なペレット | |
| JP2020516653A (ja) | プルランカプセル | |
| US5882715A (en) | Method of preparing an oral preparation provided on the outer side with an enteric coating, as well as an oral preparation obtained by the method | |
| DE2838308A1 (de) | Verfahren zur herstellung von pillen fuer die orale verabfolgung an wiederkaeuer | |
| CA2072459A1 (fr) | Compositions sous forme de pellets contenant des principes actifs non proteges vis-a-vis de la panse des ruminants associes a des principes actifs proteges contre la degradation dans la panse des ruminants | |
| EP0246310A1 (en) | COMPARED TO DEGREASING IN RUMPLE STABLE PELLETS. | |
| CA2033234C (fr) | Procede d'incorporation dans des pellets de principes actifs proteges contre la degradation dans la panse des ruminants | |
| RU2096452C1 (ru) | Способ приготовления микрокапсул из бактерий в жирной кислоте и микрокапсула, содержащая лиофилизированную бактериальную культуру | |
| DE2035739A1 (en) | Oral enzyme prepsn - consisting of granulate with gastric juices-resistant coating in tablet or capsule form | |
| EP1381285B1 (en) | A rumen bypass composition containing a bioactive substance and a method for its preparation | |
| CN1268342C (zh) | 药物组合物 | |
| Cárdenas-Triviño et al. | Microencapsulation of oxolinic acid with chitosan beads | |
| GB2279871A (en) | Active agent delivery systems |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1021328 Country of ref document: HK |
|
| CX01 | Expiry of patent term |
Granted publication date: 20040428 |
|
| CX01 | Expiry of patent term |