CN101952241A - 治疗维生素b12缺乏的方法 - Google Patents
治疗维生素b12缺乏的方法 Download PDFInfo
- Publication number
- CN101952241A CN101952241A CN2008801197240A CN200880119724A CN101952241A CN 101952241 A CN101952241 A CN 101952241A CN 2008801197240 A CN2008801197240 A CN 2008801197240A CN 200880119724 A CN200880119724 A CN 200880119724A CN 101952241 A CN101952241 A CN 101952241A
- Authority
- CN
- China
- Prior art keywords
- vitamins
- pharmaceutical composition
- snac
- tablet
- treatment
- 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.)
- Granted
Links
- 235000019156 vitamin B Nutrition 0.000 title claims abstract description 74
- 239000011720 vitamin B Substances 0.000 title claims abstract description 74
- 238000011282 treatment Methods 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 230000004044 response Effects 0.000 claims abstract description 6
- UOENJXXSKABLJL-UHFFFAOYSA-M sodium;8-[(2-hydroxybenzoyl)amino]octanoate Chemical compound [Na+].OC1=CC=CC=C1C(=O)NCCCCCCCC([O-])=O UOENJXXSKABLJL-UHFFFAOYSA-M 0.000 claims description 45
- 239000004278 EU approved seasoning Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000003995 emulsifying agent Substances 0.000 claims description 9
- 235000011194 food seasoning agent Nutrition 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 229930003270 Vitamin B Natural products 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 13
- 241000124008 Mammalia Species 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 26
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 18
- 235000013343 vitamin Nutrition 0.000 description 9
- 239000011782 vitamin Substances 0.000 description 9
- 229930003231 vitamin Natural products 0.000 description 9
- 229940088594 vitamin Drugs 0.000 description 9
- OAYRYNVEFFWSHK-UHFFFAOYSA-N carsalam Chemical group C1=CC=C2OC(=O)NC(=O)C2=C1 OAYRYNVEFFWSHK-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 5
- 229950004289 carsalam Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102000011409 Transcobalamins Human genes 0.000 description 3
- 108010023603 Transcobalamins Proteins 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229940029329 intrinsic factor Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 229920003082 Povidone K 90 Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- -1 SNAC sodium salt Chemical class 0.000 description 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 210000001711 oxyntic cell Anatomy 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OAJLVMGLJZXSGX-SLAFOUTOSA-L (2s,3s,4r,5r)-2-(6-aminopurin-9-yl)-5-methanidyloxolane-3,4-diol;cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7 Chemical compound [Co+3].O[C@H]1[C@@H](O)[C@@H]([CH2-])O[C@@H]1N1C2=NC=NC(N)=C2N=C1.[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O OAJLVMGLJZXSGX-SLAFOUTOSA-L 0.000 description 1
- NJEKDCUDSORUJA-UHFFFAOYSA-N 8-[(2-hydroxybenzoyl)amino]octanoic acid Chemical compound OC(=O)CCCCCCCNC(=O)C1=CC=CC=C1O NJEKDCUDSORUJA-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 235000007466 Corylus avellana Nutrition 0.000 description 1
- 240000003211 Corylus maxima Species 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000006835 Lamins Human genes 0.000 description 1
- 108010047294 Lamins Proteins 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UMYZHWLYICNGRQ-UHFFFAOYSA-N ethanol;heptane Chemical compound CCO.CCCCCCC UMYZHWLYICNGRQ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000005053 lamin Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000015250 liver sausages Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 1
- 235000007672 methylcobalamin Nutrition 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
一种用于治疗对口服维生素B12治疗没有响应的哺乳动物维生素B12缺乏的方法和组合物,其包括制备一种用于口服给药的,含有维生素B12和至少一种选自N-[8-(2-羟基苯甲酰基)氨基]辛酸及其可药用盐的物质的药物组合物,然后向受试者施用该药物组合物以有效治疗所述的维生素B12缺乏。
Description
发明领域
本发明通常涉及治疗维生素B12缺乏的方法和用于此类治疗的药物组合物。
发明背景
维生素B12对脑和神经系统的正常机能和血的生成而言是重要的。它参与身体每个细胞的新陈代谢,尤其是影响DNA合成和调节脂肪酸合成及能量产生。它的作用仍未被人们所完全了解。
氰钴胺是维生素B12的最稳定和广泛使用的形式。其与血浆蛋白质结合并贮存于肝脏中。维生素B12经胆汁排泄并进行某种肝肠循环。吸收的维生素B12经特定的B12结合蛋白、运钴胺素蛋白I和II转运到各个组织中。肝脏是储存维生素B12的主要器官。
维生素B12缺乏有可能导致各种严重的和不可逆性损伤,特别是对脑和神经系统。已开发出治疗维生素B12缺乏的含维生素B12的口服片剂。然而,许多患有维生素B12缺乏的患者对口服维生素B12的治疗没有响应。因此需要开发一种用于这些患者的治疗。
本发明的简单概要
本发明一方面涉及一种用于治疗受试者维生素B12缺乏的方法,其包含以下步骤(a)制备一种口服给药的药物组合物,该组合物含有(1)维生素B12和(2)至少一种选自N-[8-(2-羟基苯甲酰基)氨基]辛酸及其可药用盐的物质;和(b)向受试者施用该药物组合物以有效治疗上述的维生素B12缺乏。
本发明另一方面涉及一种用于治疗受试者维生素B12缺乏的药物组合物,其包含(1)维生素B12和(2)至少一种选自N-[8-(2-羟基苯甲酰基)氨基]辛酸及其可药用盐的物质;其中所述受试者对现有的口服维生素B12治疗没有响应。
在允许的范围内将本文所引用的专利和出版物的内容以及这些专利和出版物中所引用文献的内容收入本文作为参考。
附图的简要说明
图1为一个以时间为函数的血清维生素B12浓度曲线图。
详细说明
本文所用术语“SNAC”意思是钠-N-水杨酰-8-氨基辛酸盐、一钠8-(N-水杨酰氨基)辛酸盐、N-(水杨酰)-8-氨基辛酸一钠盐、一钠N-{8-(2-苯氧基苯甲酰基)氨基}辛酸盐、E414一钠盐或钠8-[(2-羟基苯甲酰基)氨基]辛酸盐。其具有结构
“N-[8-(2-羟基苯甲酰基)氨基]辛酸”的实验式为C15H21NO4。
术语“维生素B12”是指任意一种被称作钴胺素的含钴的化合物,其非限制性地包括氰钴胺、羟钴胺素、甲基钴胺素、和5-脱氧腺苷钴胺素(deoxyadenosyIcoba lamin)。
术语“治疗(ment)”或“治疗(ing)”意思是对哺乳动物的疾病或病症的任何治疗,其包括:预防或防护疾病或病症,即使临床症状不再发展;抑制疾病或病症,即阻止或抑制临床症状的发展;和/或缓解疾病或病症,即使临床症状消退。术语“哺乳动物”包括人类受试者。
术语“载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂、增溶剂”如Raymond C.Rowe,Paul J.Sheskey和PaulJ.Weller《药用赋形剂手册》(Handbook of PharmaceuticalExcipients)(第四版)所定义,将其内容引入本文作为参考。
术语“内因子蛋白”意思是由胃壁细胞产生的一种糖蛋白。其对回肠末端上维生素B12的后吸收是必要的。
在一个优选的实施方案中,所述的治疗是针对现有口服维生素B12治疗没有响应的受试者的。优选地是,使用片剂用于该治疗。此类片剂在每片中含有各自约0.01mg至约25mg的维生素B12和约1mg至约600mg的SNAC,优选约0.02mg至约25mg维生素B12并且更优选约0.1mg至约20mg维生素B12,和最优选约0.5mg至10mg的维生素B12和约10mg至约200mg的SNAC。
维生素B12与SNAC在每片中优选的重量比为约2∶1至约1∶700,更优选约1∶2至约1∶600或约1∶3至约1∶20,和最优选约1∶4至约1∶10。
在一个优选的实施方案中,所述的药物组合物是片剂的形式。优选地是,每片含有约0.01mg至约25mg维生素B12和约50mg至约600mg SNAC。更优选地是,每片含约0.02mg至约20mg维生素B12。更优选地是,每片含约0.1mg至约10mg维生素B12。最优选地是,每片含约15至20mg维生素B12和约50至100mg SNAC,或约0.1至1.5mg维生素B12和约25至150mg SNAC。
在另一优选的实施方案中,所述片剂还进一步含有载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂、增溶剂或其组合中的至少一种。
在另一优选的实施方案中,该片剂任选地含有约1至25mg的Capmul PG-8和任选地含有约0.5至10mg的聚维酮。优选地是,CapmulPG-8为约2至20mg和聚维酮为约1至8mg的量。优选地是,CapmulPG-8为约5至15mg和聚维酮为约1.5至5mg的量。更优选地是,Capmul PG-8为约5至10mg和聚维酮为约1.5至5mg的量。
不受任何特殊操作原理的约束,人们认为维生素B12的胃肠吸收依赖于存在充足的由胃壁细胞分泌的内因子蛋白。平均饮食可供给约10mcg/天蛋白结合型的维生素B12,其为正常消化后可以吸收的。在通过胃部转运时,维生素B12与内因子结合;分离发生在回肠末端,且通过受体引导过程维生素B12进入到粘膜细胞以供吸收。然后通过运钴胺素结合蛋白将其传送。通过简单扩散可吸收少量(总摄入量的约1%),但该机制只有在非常大剂量的条件下才能满足。还认为SNAC可使B12绕开其通常的受体引导过程。
以本发明具体实例的形式给出了下面的实施例。然而,应当可以理解本发明并不限于实施例中所述的具体细节。除非另作规定,实施例以及说明书其余部分中的所有份数和百分数是以重量计的。
此外,说明书或下文所述段落或本发明各方面的权利要求中所述数字的范围,如其表示一组特定的性质、计量单位、条件、身体状况、或百分数,意指逐字地以引用的方式清楚地引入本文中,另外,任何在该范围内的数字,包括含在所列举的任何范围内的任何数字或范围的子集也同样描述。当被用作变量的修饰语,或与变量相连时,术语“约”是指本文所公开的数字或范围是可变通的且本领域技术人员使用范围以外或不同于单个值的浓度、数量、含量、碳原子数、以及性质来实践本发明,将能达到预期的结果,即对患有维生素B12缺乏的、对现有口服维生素B12片剂以及用于该治疗的药物组合物没有响应的受试者的有效治疗。
实施例1.N-[8-(2-羟基苯甲酰基)氨基]辛酸和SNAC的制备
N-[8-(2-羟基苯甲酰基)氨基]辛酸和SNAC的制备方法包含以下步骤:起始原料为水杨酰胺,将其转化成Carsalam形式。第二步包含Carsalam的烷基化。倒数第二步是水解作用,以裂解烷基链末端的乙基保护基和开启形成游离酸SNAC的杂环。最后一步,通过与化学当量过量1%的氢氧化钠碱反应,形成SNAC游离酸的钠盐。冷却后,通过离心分离沉淀的产物并在包装前真空干燥。该合成方案的过程质量控制如表I所示。
表I.SNAC生产过程的过程质量控制.
步骤 | 反应 | 预期产物 | 规格 | 过程质量控制 |
1 | Carsalam | carsalam | <10%水杨酰胺 | HPLC |
2 | 烷基化 | 烷化的carsalam | <8%carsalam | HPLC |
3 | 水解 | SNAC游离酸 | <0.5% | LOD |
4 | 钠盐 | SNAC钠盐 | 95-105% | HPLC |
实施例2.维生素B12片剂的制备。
检查片剂的模和冲头以确保其为清洁的,和其表面被撒上硬脂酸镁粉末。将维生素B12、SNAC、载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂、增溶剂过#35筛,并将其转移到一个密封的容器内。称量50mg维生素B12并将其与11g载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂和/或增溶剂进行充分混合。制成100片维生素B12片,每片含0.5mg维生素B12和110mg载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂和/或增溶剂。这些片被用来作对照物使用。
实施例3.维生素B12和SNAC片的制备
称量50mg维生素B12,1g SNAC,并将其与10g的载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂和/或增溶剂进行充分混合。制成100片维生素B12片,每片含0.5mg维生素B12,10mg SNAC和100mg载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂和/或增溶剂。重复该过程来分别制备含1.0mg、0.8mg、0.6mg、0.4mg和0.2维生素B12的各批片剂。就释放的SNAC成分而言,这些片剂具有如下规格:
试验 | 规格 | 分析方法 |
外观 | 带粉红调的白色至淡褐色粉末 | AM001 |
FTIR钠的鉴别试验 | 确定存在钠与参考标准一致 | USP<191>USP<197K> |
熔化范围/温度 | 193-203℃,其范围不超过5℃ | USP<741> |
含水量 | NMT 3.0% | USP<921>方法I |
重金属 | <20ppm | USP<231>方法II |
钠含量 | 6.9%至8.4% | AM017 |
残留溶剂乙醇庚烷 | 小于4000ppm小于500ppm | AM008AM008 |
SNAC钠盐检测(以此形式) | 90.0-110.0%w/w | AM016 |
实施例4.用于大鼠试验的片剂制备
如下文所述制备四种不同成分的片剂:
(1)称量8.8mg维生素B12、35mg SNAC,将其充分混合并制成用于大鼠定量给药的片剂;(2)称量8.8mg维生素B12、35mg SNAC和5mg Capmul PG-8,将其充分混合并制成片剂;(3)称量8.8mg维生素B12,35mg SNAC和0.9mg聚维酮,将其充分混合并制成片剂。分别重复这四个过程以生产出更多的片剂。
实施例5.Sprague-Dawley大鼠的给药
雄性Sprague-Dawley大鼠(325-350g)进行静脉内单独维生素B12给药(0.5mg/kg),或单独或与200mg/kg的SNAC联合口服给予实施例4所制备的50mg/kg维生素B12剂量片剂。在给药后第0、3、10、20、30、60、120、240和360分钟采集血样。用RIA分析血浆样品的B12。将服用B12-SNAC的组合后得到的独立PK度量模型与服用单独的B12后所得的PK度量模型进行比较。该试验结果如表1所示。
表1.维生素B12吸收的比较实验结果
实施例6.用于人类受试者试验的片剂制备
用氰钴胺、SNAC、Kollidon 90F、无水Emcompress USP/EP和硬脂酸镁,NF/BP/EP/JP来制备片剂。每片含有的成分如下:
成分 | mg/片 |
氰钴胺,USP(粒内) | 5.00 |
SNAC(粒内) | 100.00 |
Kollidon 90F,NF/EP/JP(Providone K90;粒内) | 2.00 |
无水Emcompress USP/EP(磷酸氢钙,无水,粒内) | 70.00 |
无水Emcompress USP/EP(磷酸氢钙,无水,粒外(extragranular)) | 21.00 |
硬脂酸镁,NF/BP/EP/JP(粒外) | 2.00 |
总重 | 200.00 |
实施例7.人类受试者的给药
使16名健康的男性受试者随机接受如下治疗中的一种:
(1)治疗B:在禁食状态下以片剂形式给予单次口服剂量的氰钴胺/SNAC(5mg氰钴胺/100mg SNAC)。(6名受试者);
(2)治疗C:在禁食状态下以片剂形式仅给予单次口服剂量的氰钴胺(5mg氰钴胺,VitaLabs,商品)。(6名受试者)。
(3)治疗D:在禁食状态下给予单次静脉注射剂量的氰钴胺(1mg氰钴胺)。(4名受试者)。给每名受试者注射1mg/mL(1000μg/mL)溶液中的1mL静脉注射液由此得到1mg的氰钴胺总量。
给药前使受试者禁食一整夜,并且在给药前和给药后至少一小时内不摄入液体(包括水)。用50mL淡水以单次剂量片剂形式给予口服型氰钴胺/SNAC片。按照下列时间点抽取25份血样用于氰钴胺分析:给药前30分钟内和给药后第2、5、10、20、30、40、50分钟,和第1、1.5、2、3、4、5、6、7、8、9、10、11、12、14、16、20及24小时。
按照独立药代动力学模型分析每人氰钴胺浓度得到药代动力学度量(Pharmacokinetic metrics)。采用描述性统计来概括该结果。
服用1片5mg B12/100mg SNAC的片剂后,平均B12峰浓度为12847±6613pg/mL并且其发生在给药后1小时内(平均tmax 0.50±0.21小时)。平均AUClast(0-24)值为54618±16392hr*pg/mL。变动系数的百分数(%CV)Cmax为51.5%,AUC为30.0%。
服用单次口服剂量的单独氰钴胺(5mg氰钴胺,VitaLabs,商品)后,平均B12峰浓度为1239±450pg/mL并且其发生在给药后3至10小时之内(平均tmax 6.8±3.2小时)。平均AUClast(0-24)值为23131±8343hr*pg/mL。变动系数的百分数(%CV)Cmax为36.3%,AUC为36.1%。
在禁食状态下给予单次静脉注射剂量氰钴胺(1mg氰钴胺)(4名受试者)后,平均B12峰浓度为221287±80248pg/mL,平均AUClast(0-24)值为215391±44602hr*pg/mL。变动系数的百分数(%CV)Cmax为36.3%,AUC为20.7%。
1片5mg单独维生素B12、1片5mg维生素B12/100mg SNAC、以及2片5mg维生素B12/100mg SNAC的片剂平均生物利用度分别为2.15±0.77%,5.07±1.52,和5.92±3.05%。(注:先前在单臂试验中(inapilotarm)给予2片5mg维生素B12/100mg SNAC,其被指定为治疗A)。
1片5mg单独维生素B12、1片5mg维生素B12/100mg SNAC,和2片5mg维生素B12/100mg SNAC片剂的平均tmax分别为6.8±3.2小时、0.50±0.21小时、及0.54±0.32小时。
在给予治疗期间没有观察到不良反应。所有的制剂都显示是安全和有良好耐受性的。
令人惊讶地发现,通过氰钴胺/SNAC联合给药可显著地增强B12吸收的程度,该程度以Cmax和AUC来测量。1片5mg B12/100mg SNAC的片剂比5mg B12商品化制剂的维生素B12的生物利用度大~240%。可能是由于这两种口服制剂的吸收部位不同,服用B12商品化口服制剂后与服用B12/SNAC的联合后相比B12平均峰浓度的发生明显较晚。这与文献数据所描述的在缺少载体的情况下发生在胃肠道末端部位的B12肠道吸收相一致。
在前文的说明书中已对本发明的原理、优选的实施方案、以及操作方式进行了描述。然而,本文所要保护的发明不应被理解为是对所公开的特殊方式进行的限制,因为这些应视为对其进行的说明而非对其进行的限制。在不偏离本发明的精神下,本领域技术人员可以进行变型和变化。
Claims (20)
1.一种用于治疗受试者维生素B12缺乏的方法,其包含以下步骤
(a)制备一种口服给药的药物组合物,该组合物包含(1)维生素B12和(2)至少一种选自N-[8-(2-羟基苯甲酰基)氨基]辛酸及其可药用盐的物质;和
(b)向所述受试者施用所述药物组合物以有效地治疗所述的维生素B12缺乏。
2.如权利要求1所述的方法,其中所述受试者对现有的口服维生素B12治疗没有响应。
3.如权利要求1所述的方法,其中所述药物组合物包括片剂。
4.如权利要求3所述的方法,其中所述的片剂包含约0.01mg至约25mg的维生素B12和约1mg至约600mg的SNAC。
5.如权利要求3所述的方法,其中所述片剂包含约0.02mg至约25mg的维生素B12。
6.如权利要求3所述的方法,其中所述片剂包含约0.1mg至约20mg的维生素B12。
7.如权利要求3所述的方法,其中所述的片剂包含约0.5mg维生素B12和约17.5mg SNAC。
8.如权利要求1所述的方法,其中所述药物组合物中的维生素B12与SNAC的重量之比为约2∶1至约1∶700。
9.如权利要求8所述的方法,其中所述的重量之比为约1∶2至约1∶600。
10.如权利要求8所述的方法,其中所述的重量之比为约1∶3至约1∶20。
11.如权利要求8所述的方法,其中所述的重量之比为约1∶4。
12.如权利要求8所述的方法,其中所述的重量之比为约1∶500至约1∶700。
13.如权利要求3所述的方法,其中所述的药物组合物进一步包含载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂、增溶剂或其组合中的至少一种。
14.一种用于治疗受试者维生素B12缺乏的药物组合物,其包含(1)维生素B12和(2)至少一种选自N-[8-(2-羟基苯甲酰基)氨基]辛酸及其可药用盐的物质;其中所述受试者对口服维生素B12治疗没有响应。
15.如权利要求14所述的药物组合物,其中所述的药物组合物包括一种片剂。
16.如权利要求15所述的药物组合物,其中所述的片剂包含约0.01mg至约25mg维生素B12和约50mg至约600mg SNAC。
17.如权利要求15所述的药物组合物,其中所述的片剂包含约0.02mg至约20mg维生素B12。
18.如权利要求15所述的药物组合物,其中所述的片剂包含约0.1mg至约10mg维生素B12。
19.如权利要求15所述的药物组合物,其中所述的片剂包含约1至15mg维生素B12和约50至200mg SNAC。
20.如权利要求14所述的药物组合物,其进一步包含载体、赋形剂、乳化剂、稳定剂、甜味剂、调味剂、稀释剂、着色剂、增溶剂或其组合中的至少一种。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98489807P | 2007-11-02 | 2007-11-02 | |
US60/984,898 | 2007-11-02 | ||
US2010808P | 2008-01-09 | 2008-01-09 | |
US61/020,108 | 2008-01-09 | ||
US8356608P | 2008-07-25 | 2008-07-25 | |
US61/083,566 | 2008-07-25 | ||
PCT/US2008/082064 WO2009059188A1 (en) | 2007-11-02 | 2008-10-31 | Method of treating vitamin b12 deficiency |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101952241A true CN101952241A (zh) | 2011-01-19 |
CN101952241B CN101952241B (zh) | 2014-06-11 |
Family
ID=40591491
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200880119724.0A Expired - Fee Related CN101952241B (zh) | 2007-11-02 | 2008-10-31 | 治疗维生素b12缺乏的方法 |
Country Status (19)
Country | Link |
---|---|
US (3) | US8022048B2 (zh) |
EP (1) | EP2215047B1 (zh) |
JP (1) | JP5555634B2 (zh) |
KR (1) | KR101344369B1 (zh) |
CN (1) | CN101952241B (zh) |
AU (1) | AU2008318423B2 (zh) |
BR (1) | BRPI0817396C8 (zh) |
CA (1) | CA2704780C (zh) |
CL (1) | CL2010000434A1 (zh) |
CO (1) | CO6280475A2 (zh) |
DK (1) | DK2215047T3 (zh) |
ES (1) | ES2443817T3 (zh) |
HK (1) | HK1146480A1 (zh) |
MX (1) | MX2010004716A (zh) |
NZ (1) | NZ585080A (zh) |
PL (1) | PL2215047T3 (zh) |
PT (1) | PT2215047E (zh) |
RU (1) | RU2469728C2 (zh) |
WO (1) | WO2009059188A1 (zh) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2461803B1 (en) * | 2009-08-03 | 2018-10-17 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
EP3028709B1 (en) * | 2010-02-24 | 2019-08-28 | Emisphere Technologies, Inc | Oral b12 therapy |
DK3326620T3 (da) | 2010-12-16 | 2020-05-25 | Novo Nordisk As | Faste sammensætninger omfattende en glp-1-agonist og et salt af n-(8-(2- hydroxybenzoyl)amino)caprylsyre |
MX355361B (es) | 2011-04-12 | 2018-04-17 | Novo Nordisk As | Derivados de peptido 1 tipo glucagon (glp-1) doblemente acilados. |
US8805208B2 (en) * | 2012-02-03 | 2014-08-12 | Tyco Electronics Subsea Communications Llc | System and method for polarization de-multiplexing in a coherent optical receiver |
EP4331667A2 (en) | 2012-03-22 | 2024-03-06 | Novo Nordisk A/S | Compositions comprising a delivery agent and preparation thereof |
HUE042757T2 (hu) | 2012-03-22 | 2019-07-29 | Novo Nordisk As | Szállító szert tartalmazó készítmények és elõállításuk |
AU2013234496B2 (en) | 2012-03-22 | 2017-07-27 | Novo Nordisk A/S | Compositions of GLP-1 peptides and preparation thereof |
ES2871328T3 (es) | 2012-06-20 | 2021-10-28 | Novo Nordisk As | Formulación de comprimido que comprende un péptido y un agente de suministro |
US20170348417A1 (en) | 2013-04-11 | 2017-12-07 | Richard Louis Price | Treatment of attention deficit disorders and associated symptoms |
US20140309270A1 (en) | 2013-04-11 | 2014-10-16 | Richard Louis Price | Diagnosis and treatment of a form of autistic spectrum disorder |
US9211284B2 (en) | 2013-04-11 | 2015-12-15 | Richard Louis Price | Diagnosis and treatment of P.R.I.C.E. syndrome |
US10098848B2 (en) | 2013-04-11 | 2018-10-16 | Richard Louis Price | Inositol-containing comestible units and methods of treatment using the same |
US9603812B2 (en) | 2013-04-11 | 2017-03-28 | Richard Louis Price | Treatment of autistic spectrum disorder |
KR102393596B1 (ko) | 2016-04-22 | 2022-05-04 | 리셉터 홀딩스, 인크. | 속효성 식물-계 의약 화합물 및 영양 보충제 |
EA201892396A1 (ru) | 2016-12-02 | 2019-04-30 | Ресептор Лайф Сайенсиз, Инк. | Быстродействующие растительные лекарственные соединения и биологически активные добавки |
AU2018345812A1 (en) * | 2017-10-05 | 2020-05-14 | Spoke Sciences, Inc. | Herbal compositions with improved bioavailability |
EA202090890A1 (ru) * | 2017-10-05 | 2020-09-03 | Ресептор Холдингз, Инк. | Состав растительного и синтетического каннабиноида быстрого начала действия и пролонгированного действия |
IL275778B2 (en) | 2018-02-02 | 2023-12-01 | Novo Nordisk As | Solid compounds that make up glp-1 agonist n-8-2-hydroxybenzoyl salt |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5665379A (en) * | 1990-09-28 | 1997-09-09 | Pharmacia & Upjohn Aktiebolag | Lipid particle forming matrix, preparation and use thereof |
US5474978A (en) | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
US5650386A (en) * | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US6274564B1 (en) * | 1996-09-18 | 2001-08-14 | William J. Sarill | Compositions of cobalamin and related corrinoids, and uses thereof |
US5773647A (en) | 1997-02-07 | 1998-06-30 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6255294B1 (en) * | 1998-12-28 | 2001-07-03 | Allergy Limited | Cyanocobalamin (vitamin B12) treatment in allergic disease |
EP1535625B1 (en) | 1999-04-05 | 2014-01-08 | Novartis AG | Composition containing n-(5-chlorosalicyloyl)-8-aminocaprylic acid and salmon calcitonin |
CA2369591C (en) | 1999-04-05 | 2011-06-14 | Emisphere Technologies, Inc. | Disodium salts, monohydrate, and ethanol solvates |
ES2386263T3 (es) * | 2000-03-21 | 2012-08-14 | Emisphere Technologies, Inc. | Método de preparación de salicilamidas alquiladas mediante un producto intermedio de dicarboxilato |
US7049283B2 (en) | 2000-12-06 | 2006-05-23 | Novartis Ag | Pharmaceutical compositions for the oral delivery of pharmacologically active agents |
NZ529439A (en) | 2001-06-01 | 2005-11-25 | Novartis Ag | Method for orally administering parathyroid hormone (PTH) |
PT1420827E (pt) | 2001-08-17 | 2009-12-15 | Novartis Ag | 5-cnac como agente de administração oral de fragmentos da hormona paratiróide |
US20050054557A1 (en) | 2002-05-09 | 2005-03-10 | Goldberg Michael M. | Compositions for delivering parathyroid hormone and calcitonin |
TW200403052A (en) | 2002-07-17 | 2004-03-01 | Novartis Ag | Use of organic compounds |
AR040737A1 (es) | 2002-08-01 | 2005-04-20 | Novartis Ag | Administracion oral de calcitonina |
AU2003275329B2 (en) | 2002-09-13 | 2008-04-03 | Cydex Pharmaceuticals, Inc. | Capsules containing aqueous fill compositions stabilized with derivatized cyclodextrin |
CN100579955C (zh) | 2003-04-04 | 2010-01-13 | 帝斯曼知识产权资产管理有限公司 | N-烷氧基草酰丙氨酸酯的制备方法 |
US6938439B2 (en) | 2003-05-22 | 2005-09-06 | Cool Clean Technologies, Inc. | System for use of land fills and recyclable materials |
JP3924616B2 (ja) | 2003-06-30 | 2007-06-06 | 独立行政法人物質・材料研究機構 | 微小サイズの温度感知素子を用いる温度計測方法 |
EP1643978A1 (en) | 2003-07-04 | 2006-04-12 | Nycomed Danmark A/S | Parathyroid hormone (pth) containing pharmaceutical compositions for oral use |
MXPA06000446A (es) | 2003-07-11 | 2006-04-07 | Novartis Ag | Composiciones farmaceuticas de dosis oral que comprenden un agente de distribucion en forma micronizada. |
NZ544645A (en) | 2003-07-23 | 2009-04-30 | Novartis Ag | Use of calcitonin in osteoarthritis |
EP1773351B1 (en) * | 2004-05-06 | 2019-04-24 | Emisphere Technologies, Inc. | Crystalline polymorphic forms of monosodium n-[8-(2-hydroxybenzoyl)amino]caprylate |
MX2007001348A (es) * | 2004-08-02 | 2008-03-11 | Bebaas Inc | Composiciones de vitamina b12. |
JP2008509933A (ja) * | 2004-08-13 | 2008-04-03 | エミスフェアー・テクノロジーズ・インク | 送達剤のマイクロ粒子またはナノ粒子を含む医薬製剤 |
US20060116334A1 (en) * | 2004-12-01 | 2006-06-01 | Curt Hendrix | Folate based composition for treatment of the cardiovascular system |
GB0427600D0 (en) | 2004-12-16 | 2005-01-19 | Novartis Ag | Organic compounds |
GB0427603D0 (en) | 2004-12-16 | 2005-01-19 | Novartis Ag | Organic compounds |
AU2006312117A1 (en) * | 2005-11-04 | 2007-05-18 | Genta Incorporated | Pharmaceutical gallium compositions and methods |
-
2008
- 2008-10-31 ES ES08844673.7T patent/ES2443817T3/es active Active
- 2008-10-31 RU RU2010118423/15A patent/RU2469728C2/ru active
- 2008-10-31 DK DK08844673.7T patent/DK2215047T3/da active
- 2008-10-31 BR BRPI0817396A patent/BRPI0817396C8/pt not_active IP Right Cessation
- 2008-10-31 NZ NZ585080A patent/NZ585080A/en not_active IP Right Cessation
- 2008-10-31 JP JP2010532292A patent/JP5555634B2/ja not_active Expired - Fee Related
- 2008-10-31 EP EP08844673.7A patent/EP2215047B1/en active Active
- 2008-10-31 KR KR1020107010771A patent/KR101344369B1/ko active IP Right Grant
- 2008-10-31 MX MX2010004716A patent/MX2010004716A/es active IP Right Grant
- 2008-10-31 CA CA2704780A patent/CA2704780C/en active Active
- 2008-10-31 US US12/262,677 patent/US8022048B2/en not_active Expired - Fee Related
- 2008-10-31 AU AU2008318423A patent/AU2008318423B2/en not_active Ceased
- 2008-10-31 CN CN200880119724.0A patent/CN101952241B/zh not_active Expired - Fee Related
- 2008-10-31 PL PL08844673T patent/PL2215047T3/pl unknown
- 2008-10-31 WO PCT/US2008/082064 patent/WO2009059188A1/en active Application Filing
- 2008-10-31 PT PT88446737T patent/PT2215047E/pt unknown
-
2010
- 2010-04-30 CL CL2010000434A patent/CL2010000434A1/es unknown
- 2010-06-02 CO CO10066425A patent/CO6280475A2/es active IP Right Grant
-
2011
- 2011-01-21 HK HK11100634.9A patent/HK1146480A1/zh not_active IP Right Cessation
- 2011-08-09 US US13/206,090 patent/US8288360B2/en active Active
-
2012
- 2012-09-14 US US13/618,654 patent/US8557792B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101952241B (zh) | 治疗维生素b12缺乏的方法 | |
AU2015222754A1 (en) | Compositions and methods for the reduction or prevention of hepatic steatosis | |
KR20160065998A (ko) | 테트라하이드로바이오프테린 투여 방법, 관련 조성물 및 측정 방법 | |
US20200206247A1 (en) | Oral b12 therapy | |
US9669051B2 (en) | Dietary fiber compositions with metformin, sitagliptin, or a combination thereof for the treatment of metabolic disease | |
KR101324425B1 (ko) | 증가된 비스포스포네이트의 생체이용률을 가지는 경구투여 약제 | |
EP1471888A2 (en) | Oral trimethobenzamide formulations and methods |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140611 |