CN1211077C - 组胺h2拮抗剂泡腾组合物 - Google Patents
组胺h2拮抗剂泡腾组合物 Download PDFInfo
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- CN1211077C CN1211077C CNB008167729A CN00816772A CN1211077C CN 1211077 C CN1211077 C CN 1211077C CN B008167729 A CNB008167729 A CN B008167729A CN 00816772 A CN00816772 A CN 00816772A CN 1211077 C CN1211077 C CN 1211077C
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- acidulant
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- acid
- antagonist
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- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 239000003485 histamine H2 receptor antagonist Substances 0.000 title claims abstract description 15
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims abstract description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 26
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000001361 adipic acid Substances 0.000 claims abstract description 21
- 235000011037 adipic acid Nutrition 0.000 claims abstract description 21
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 10
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims abstract description 5
- 239000001530 fumaric acid Substances 0.000 claims abstract description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960000620 ranitidine Drugs 0.000 claims description 21
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical group [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 claims description 21
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000001384 succinic acid Substances 0.000 claims description 8
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- 229960001380 cimetidine Drugs 0.000 claims description 4
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001596 famotidine Drugs 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- 229960004872 nizatidine Drugs 0.000 claims description 3
- SGXXNSQHWDMGGP-IZZDOVSWSA-N nizatidine Chemical compound [O-][N+](=O)\C=C(/NC)NCCSCC1=CSC(CN(C)C)=N1 SGXXNSQHWDMGGP-IZZDOVSWSA-N 0.000 claims description 3
- 230000007613 environmental effect Effects 0.000 claims 2
- 239000007787 solid Substances 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 229940014800 succinic anhydride Drugs 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 40
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 28
- 239000005557 antagonist Substances 0.000 description 15
- 229960001340 histamine Drugs 0.000 description 14
- 235000015165 citric acid Nutrition 0.000 description 12
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 8
- 239000011975 tartaric acid Substances 0.000 description 8
- 235000002906 tartaric acid Nutrition 0.000 description 8
- 229960001520 ranitidine hydrochloride Drugs 0.000 description 7
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 7
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 6
- 239000001630 malic acid Substances 0.000 description 6
- 235000011090 malic acid Nutrition 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 235000012239 silicon dioxide Nutrition 0.000 description 5
- 108010011485 Aspartame Proteins 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 239000000605 aspartame Substances 0.000 description 4
- 235000010357 aspartame Nutrition 0.000 description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 4
- 229960003438 aspartame Drugs 0.000 description 4
- -1 carbonic acid hydrogen salt Chemical class 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229940085605 saccharin sodium Drugs 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- HXFCUMCLVYNZDM-UHFFFAOYSA-N 2-aminoacetic acid;sodium Chemical compound [Na].NCC(O)=O HXFCUMCLVYNZDM-UHFFFAOYSA-N 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940084489 cimetidine 200 mg Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical compound NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 229940083698 famotidine 10 mg Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 229940079390 nizatidine 75 mg Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940068679 ranitidine 75 mg Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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Abstract
与酸性材料不相容的组胺H2拮抗剂被加到泡腾组合物中并且在所述泡腾组合物中是稳定的，条件是在泡腾对中所使用的酸化剂是不含羟基基团的酸化剂并且这样的酸化剂基本上是所述配制物中酸化剂的全部量。优选地，所述组合物不含有含羟基基团的酸化剂。己二酸、琥珀酸、富马酸和琥珀酸酐可用作酸化剂。己二酸是优选的。
Description
本发明领域
本发明涉及包含与酸化剂不容的组胺H2拮抗剂的泡腾组合物，特别是涉及包含泡腾组胺H2拮抗剂的组合物，其中含有特定的酸化剂，发现这些特定的酸化剂与所述拮抗剂是相容的。
本发明背景
泡腾组合物通常含有赋形剂、活性组分和常常称作泡腾对(effervescent couples)的二氧化碳源。泡腾对通常由碱性碳酸氢盐或碳酸盐和酸组成。在水存在下，碱性碳酸氢盐或碳酸盐和酸产生二氧化碳。因此，泡腾组合物对于潮湿是特别敏感的。在整个制备过程中及其后都需要特别的步骤来保护原材料和最终制剂不受潮。在泡腾组合物的制备中，无水柠檬酸是最常用的酸化剂。然而，无水柠檬酸极易吸湿。碱金属碳酸氢盐和碳酸盐也是最常用的二氧化碳源。
泡腾组合物含有作为活性物质的组胺H2拮抗剂时，所述问题是化合。组胺H2拮抗剂与酸，特别是在泡腾组合物所采用的酸是不相容的。公开的EP专利说明书233853公开了在含有组胺H2拮抗剂的泡腾组合物使用柠檬酸表明组胺H2拮抗剂与泡腾组合物所包含酸的不相容性。在解决该问题的努力中，柠檬酸用单和二碱性柠檬酸盐代替。
美国专利4824664教导组胺H2拮抗剂与泡腾产品中包含的酸是不稳定的。他们努力克服由泡腾混合物制粒和特定比例单和二碱性柠檬酸盐混合物制粒期间产生的不稳定性。
美国专利5102665教导使用单碱性柠檬酸盐作为单一酸化剂来制备稳定的泡腾雷尼替丁。其中公开的泡腾体系先在乙醇中制粒，然后制备该组合物。
本发明概述
按照现有技术的上述教导，本领域技术人员会认识到组胺H2拮抗剂，特别是雷尼替丁与泡腾产品中使用酸的已知的不相容性，而不会制备这样的组合物。惊奇的和意想不到的是，本发明人现发现某些酸(即，不含羟基基团的酸)可加入到含有组胺H2拮抗剂的泡腾组合物中并且所得组合物是稳定的。换句话说，惊奇的和意想不到的是，在本发明泡腾组合物中的组胺H2拮抗剂是稳定的。
本发明详述
可用于制备本发明组胺H2拮抗剂泡腾组合物的酸化剂是不含羟基基团的酸化剂。例如己二酸、琥珀酸、富马酸或其水解形成不含羟基基团酸化剂的衍生物，如琥珀酸酐。
尽管含有少量羟基的酸化剂可以加入到本发明的泡腾组合物中，但本发明组合物中所采用的最理想的酸化剂基本上是不含羟基基团的所有酸化剂。最优选地，本发明的组合物无含有羟基基团的酸化剂。在某些情况中，含有非常少量羟基的酸化剂在本发明组合物中是可以容许的。
如上所述，本发明人发现柠檬酸(泡腾组合物中常用的含有羟基基团的酸化剂)加入到泡腾组合物中时与组胺H2拮抗剂不相容。而且，苹果酸及其它含有羟基基团的酸化剂甚至比柠檬酸更成问题。酒石酸也存在相容性问题，但比柠檬酸好些。
惊奇和意想不到的是，本发明人发现含有组胺H2拮抗剂的泡腾制剂中采用的作为泡腾对部分的含羟基基团酸化剂(如柠檬酸和酒石酸)被不含羟基基团的酸化剂(如己二酸或琥珀酸)替换时，其量相当于含羟基基团的酸化剂，所得泡腾产品具有可接受的味道、稳定性和泡腾性。因此，本发明通过组分的简单干混合而不需要碱金属单或二柠檬酸盐(加入的或通过湿法制粒在泡腾体系中产生的)也不需要含柠檬酸的泡腾对就能够制备含有组胺H2拮抗剂的泡腾产品。
本发明的组合物含有作为活性成分的组胺H2拮抗剂。组胺H2拮抗剂优选选自雷尼替丁、西咪替丁、法莫替丁和尼扎替丁及其可药用盐。更优选的是雷尼替丁和西咪替丁。雷尼替丁及其可药用盐是最优选的。
每剂量单位中，盐形式的雷尼替丁的量可为40-300mg，优选为50-150mg并且最优选50-75mg。
组合物中组胺H2拮抗剂通常存在量是使组合物含有现行政府卫生权力机构为处方(“Rx”)或非处方(“O.T.C”)使用而批准的组胺H2拮抗剂剂量。在美国，此剂量如下：
| OTC剂量 | Rx剂量 | |
| 雷尼替丁 | 75mg | 150-300mg |
| 西咪替丁 | 200mg | 300-800mg |
| 法莫替丁 | 10mg | 20-40mg |
| 尼扎替丁 | 75mg | 150-300mg |
本发明组合物采用的泡腾对包含碱性成分和酸化剂。碱性成分和酸化剂在水存在下反应产生二氧化碳(即，起泡)。如上所述，酸化剂应当主要含有一种或多种不含羟基基团的酸化剂。己二酸、琥珀酸、富马酸和琥珀酸酐是优选的。琥珀酸酐将水解形成琥珀酸。
作为泡腾对的碱性组分，可以采用碳酸氢钠、碳酸钠、碳酸钾、碳酸氢钾、碳酸钙、碳酸镁、碳酸甘氨酸钠及其混合物。
酸和碱性碳酸氢盐或碳酸盐的量各自为泡腾组合物的25-60％(w/w)，更优选30-50％(w/w)。酸和碱性碳酸盐或碳酸氢盐的当量比或化学计量的比例可以在1∶2-2∶1的范围中。
本发明的组合物可包括甜味剂如蔗糖、天冬甜素、环己烷氨基磺酸盐、丁磺氨-K、糖精酸或其盐以及它们的混合物。填充剂和助流剂也可使用，例如，二氧化硅。
为了说明本发明的优点，制备下列实施例的泡腾制剂。在所有实施例中使用的雷尼替丁盐酸盐的量等于75mg雷尼替丁(即，美国的OTC剂量)。酸化剂可以变化，如下列实施例2到6所示。
实施例1
制备下列原型粉末泡腾组胺H2拮抗剂组合物。尽管可采用任何组胺H2拮抗剂获得类似的结果，但在所有实施例中均使用雷尼替丁盐酸盐。
在双壳混合器(twin shell blender)中混合所有组分而获得均匀组合物来制备组合物。组合物组分如下：
组分 ％(WT/WT) 量(g/小药囊(sachet))
碳酸氢钠 45.25 2.29
碳酸钠(无水) 4.54 0.23
己二酸 43.86 2.22
蔗糖 2.17 0.11
二氧化硅 0.10 0.005
雷尼替丁盐酸盐 1.66 0.084
天冬甜素 0.40 0.02
甘氨酸(氨基乙酸) 1.98 0.10
糖精钠 0.04 0.002
总量 100.00 5.061
实施例2
制备实施例1所述的组合物，只是采用1.95g/小药囊的柠檬酸代替2.22g/小药囊的己二酸。
实施例3
制备实施例1所述的组合物，只是采用2.04g/小药囊的苹果酸代替2.22g/小药囊的己二酸。
实施例4
制备实施例1所述的组合物，只是采用2.29g/小药囊的酒石酸代替2.22g/小药囊的己二酸。
实施例5
制备实施例1所述的组合物，只是采用1.80g/小药囊的琥珀酸代替2.22g/小药囊的己二酸。
应当注意在实施例2到5中各自采用的酸化剂的量相当于实施例1中己二酸的用量。换句话说，在所有实施例中，采用酸化剂的化学计量当量。
实施例6
相当量的实施例1、2、3、4和5各个组合物储存在室温下并暴露在大气中。储存12天后测定各个组合物的物理外观。结果示于下表1中。
应当注意实施例1和5是本发明的实施例，而实施例2、3和4是所用酸化剂为含羟基基团酸化剂的实施例，因此不是本发明的实施例。
表1
| 实施例号 | 酸化剂 | 暴露12天后的物理外观 |
| 2 | 柠檬酸 | -大量结块并且不自由流动-没有变色 |
| 3 | 苹果酸 | -大量结块并且不自由流动-严重变色 |
| 4 | 酒石酸 | -有些结块，但自由流动-没有颜色变化 |
| 1 | 己二酸 | -无结块并且自由流动-没有颜色变化 |
| 5 | 琥珀酸 | -无结块并且自由流动-没有颜色变化 |
应当注意分别含有己二酸和琥珀酸的实施例1和5的组合物允许在大气中再暴露16天。换句话说，总共有四周。实施例1和5组合物均继续显示无结块、自由流动并且不显示变色。
实施例7
将相当量的实施例2、3、1和5组合物包装在小瓶中。封闭小瓶并在40℃温度下储存，然后观察。结果显示在下表2中。
表2
| 实施例号 | 酸化剂 | 指定储存期后的物理外观 |
| 2 | 柠檬酸 | -3天后大量结块并且轻微变色 |
| 3 | 苹果酸 | -3天后大量结块并且轻微变色 |
| 5 | 琥珀酸 | -四周后自由流动并有非常轻微的颜色变化，在10周后仍然自由流动 |
| 1 | 己二酸 | -四周后自由流动并且没有颜色变化，在13周后仍然自由流动并且没有颜色变化 |
实施例8
如上所述，现有技术教导雷尼替丁与酸不相容。为了评价这种不相容的程度，本发明人制备含有1∶1雷尼替丁和酸化剂的二元混合物。然后按下表3改变这些混合物的储存温度和相对湿度。
表3
| 在下列条件下储存后所剩雷尼替丁的百分数 | |||
| 1∶1混合物 | 30℃/60％RH | 35℃/75％RH | 40℃/75％RH |
| 雷尼替丁∶柠檬酸* | 85.7 | 70.3 | 28.4 |
| 雷尼替丁∶苹果酸** | 63.9 | 18.9 | 2.3 |
| 雷尼替丁∶酒石酸* | 97.7 | 67.9 | 37.6 |
| 雷尼替丁∶己二酸** | 100.1 | 84.5 | 63.9 |
*储存8周后进行的测定
**储存6周后进行的测定
表3中的数据是利用非常高比例的雷尼替丁与酸产生的。另外，进行湿度和温度的变化。这样做是为了加速可能发生的任何降解。
表3所数据十分清楚地表明即使在极端条件下评价雷尼替丁，雷尼替丁与己二酸(不含羟基基团的酸化剂)比与柠檬酸、苹果酸或酒石酸(含有羟基基团的酸化剂)稳定得多。这完全是意想不到的和令人惊异的。
实施例9
为了证明本发明泡腾组合物中采用的酸化剂优选基本上完全含有不含羟基基团的酸化剂，并且更具体来说，优选不含含有羟基基团的酸化剂，制备具有下列组分的组合物：
| 组分 | 量(g/小药囊) | ％(Wt/Wt) |
| 碳酸氢钠 | 2.29 | 43.36 |
| 无水碳酸钠 | 0.23 | 4.36 |
| 己二酸 | 2.22 | 42.04 |
| 酒石酸 | 0.22 | 4.17 |
| 蔗糖 | 0.11 | 2.08 |
| 二氧化硅 | 0.005 | 0.09 |
| 雷尼替丁盐酸盐 | 0.084 | 1.59 |
| 天冬甜素 | 0.02 | 0.38 |
| 甘氨酸 | 0.10 | 1.89 |
| 糖精钠 | 0.002 | 0.04 |
| 总量 | 5.281 | 100.00 |
通过在双壳混合器中将粉末干混合为均匀混合物来制备本实施例的组合物。
使用相同方法，制备与上文组合物相同的另一组合物，只是去掉组合物中的酒石酸。在40℃温度下储存两种组合物。在该温度下6周后，含有雷尼替丁盐酸盐、己二酸和酒石酸的组合物显示一些变色。没有酒石酸的相同组合物在40℃温度下6周后不显示变色，而且更重要的是，在40℃温度下储存13周后不显示变色。因此，由这些结果显而易见本发明组合物中采用的酸化剂应当优选基本上完全含有不含羟基基团的酸化剂并且最优选不含含有羟基基团的酸化剂。
尽管参照粉末和小药囊描述了本发明，但不限定剂量形式。也可生产片剂。下述实施例10举例描述本发明片剂的制备。
实施例10
组合物如下：
| 组分 | ％(Wt/Wt) | g/片 |
| 雷尼替丁盐酸盐 | 1.61 | 0.084 |
| 二氧化硅 | 0.1 | 0.005 |
| 碳酸钠(无水) | 4.41 | 0.23 |
| 碳酸氢钠 | 43.95 | 2.29 |
| 己二酸 | 42.6 | 2.22 |
| 天冬甜素 | 0.38 | 0.02 |
| 糖精钠 | 0.04 | 0.002 |
| 甘氨酸 | 1.92 | 0.10 |
| 蔗糖 | 2.11 | 0.11 |
| 苯甲酸钠 | 2.88 | 0.15 |
| 总量 | 100.00 | 5.211 |
上述配方制备50片
上述配方中包括的苯甲酸钠作为可溶性润滑剂。制备片剂的本领域技术人员会理解其它润滑剂也可使用。
雷尼替丁盐酸盐过40筛目的筛。二氧化硅过20筛目的筛。剩余的组分过30筛目的筛。将组分干混合并且所得混合物在F3单冲压片机上压制。如此产生的片剂在所有方面都是满意的。
应当理解上文所述的实施例仅仅是举例说明本发明并不打算限制本发明的任何方面。本领域技术人员在不脱离本发明的精神实质和范围的条件下可使用本领域常规技术修饰上述制剂。
Claims (12)
1.一种粉末组合物，它包含有效量组胺H2拮抗剂、酸化剂和碱性材料，所述碱性材料在水存在下与酸化剂反应形成二氧化碳，其中改进包括所述组合物不含有含羟基基团的酸化剂并且所述酸化剂是不含羟基基团的在环境条件下为固体的酸化剂。
2.根据权利要求1的组合物，其中所述不含羟基基团的酸化剂选自己二酸、琥珀酸、富马酸、琥珀酸酐及其混合物。
3.根据权利要求2的组合物，其中所述不含羟基基团的酸化剂是己二酸。
4.根据权利要求2的组合物，其中所述不含羟基基团的酸化剂是琥珀酸。
5.根据权利要求1的组合物，其中所述组胺H2拮抗剂选自雷尼替丁、西咪替丁、尼扎替丁、法莫替丁及其可药用盐。
6.根据权利要求1的组合物，其中所述组胺H2受体拮抗剂是雷尼替丁或其可药用盐。
7.一种片剂，它包含有效量组胺H2拮抗剂、酸化剂、碱性材料和润滑剂，所述碱性材料接触水时与酸化剂反应形成二氧化碳，所述片剂不含有含羟基基团的酸化剂，所述酸化剂是不含羟基基团的在环境条件下为固体的酸化剂。
8.根据权利要求7的片剂，其中所述组胺H2受体拮抗剂选自雷尼替丁、西咪替丁、尼扎替丁、法莫替丁及其可药用盐。
9.根据权利要求8的片剂，其中所述组胺H2受体拮抗剂是雷尼替丁或其可药用盐。
10.根据权利要求7的片剂，其中所述不含羟基基团的酸化剂选自己二酸、琥珀酸、富马酸、琥珀酸酐及其混合物。
11.根据权利要求10的片剂，其中所述不含羟基基团的酸化剂是己二酸。
12.根据权利要求10的片剂，其中所述不含羟基基团的酸化剂是琥珀酸。
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| US9717726B2 (en) * | 2013-03-14 | 2017-08-01 | Maregade Rx, LLC | Product and method for treating diarrhea |
| WO2015157729A1 (en) * | 2014-04-11 | 2015-10-15 | Wilmink Michael | Pharmaceutical formulations an comprising analgesic agent, a nonsteroidal anti-inflammatory agent, a gastric acid production suppressant and an anti-nauseant |
| CN105997922A (zh) * | 2016-06-12 | 2016-10-12 | 佛山市腾瑞医药科技有限公司 | 一种盐酸雷尼替丁泡腾片及其制备方法 |
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| ZA200203168B (en) | 2003-09-23 |
| JP2003515553A (ja) | 2003-05-07 |
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| PE20010909A1 (es) | 2001-11-11 |
| EP1237543A4 (en) | 2004-06-30 |
| KR100795259B1 (ko) | 2008-01-15 |
| CA2394902A1 (en) | 2001-06-07 |
| AU1766101A (en) | 2001-06-12 |
| ATE309783T1 (de) | 2005-12-15 |
| US6264984B1 (en) | 2001-07-24 |
| ES2252078T3 (es) | 2006-05-16 |
| DE60024132T2 (de) | 2006-08-03 |
| EP1237543A1 (en) | 2002-09-11 |
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