CN1835758A - 高浓度甘草甜素制剂 - Google Patents
高浓度甘草甜素制剂 Download PDFInfo
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- CN1835758A CN1835758A CNA200480022998XA CN200480022998A CN1835758A CN 1835758 A CN1835758 A CN 1835758A CN A200480022998X A CNA200480022998X A CN A200480022998XA CN 200480022998 A CN200480022998 A CN 200480022998A CN 1835758 A CN1835758 A CN 1835758A
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- Prior art keywords
- glycyrrhizin
- cysteine
- glycine
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960004949 glycyrrhizic acid Drugs 0.000 title claims abstract description 35
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 35
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims abstract description 35
- 239000004378 Glycyrrhizin Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title abstract description 22
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 34
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 23
- 235000018417 cysteine Nutrition 0.000 claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 239000000654 additive Substances 0.000 claims abstract 2
- 230000000996 additive effect Effects 0.000 claims abstract 2
- 229960002433 cysteine Drugs 0.000 claims description 22
- 239000004471 Glycine Substances 0.000 claims description 15
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 13
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 13
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 10
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 abstract description 8
- 239000003381 stabilizer Substances 0.000 abstract description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 229960002449 glycine Drugs 0.000 abstract 2
- 235000013905 glycine and its sodium salt Nutrition 0.000 abstract 2
- LPLVUJXQOOQHMX-MOGLOQIBSA-N (2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-MOGLOQIBSA-N 0.000 abstract 1
- 229940000425 combination drug Drugs 0.000 abstract 1
- 238000013329 compounding Methods 0.000 abstract 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 24
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 21
- 235000010265 sodium sulphite Nutrition 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003708 ampul Substances 0.000 description 6
- 239000003125 aqueous solvent Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
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- 229910052757 nitrogen Inorganic materials 0.000 description 4
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- 230000001954 sterilising effect Effects 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- -1 alkali metal salts Chemical class 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 208000019423 liver disease Diseases 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WBJOKIMCMNCILB-ZICUSWQYSA-N (2r,4as,6ar,6as,6br,10s,12as,14bs)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylic acid;2-aminoacetic acid;(2r)-2-amino-3-sulfanylpropanoic acid Chemical compound NCC(O)=O.SC[C@H](N)C(O)=O.C([C@@H]1C2=CC(=O)[C@H]34)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CCC1[C@]3(C)CC[C@H](O)C1(C)C WBJOKIMCMNCILB-ZICUSWQYSA-N 0.000 description 2
- 208000004262 Food Hypersensitivity Diseases 0.000 description 2
- 206010016946 Food allergy Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical compound NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 235000020932 food allergy Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 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 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- KPQJOKRSYYJJEL-VLQRKCJKSA-K [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O Chemical compound [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O KPQJOKRSYYJJEL-VLQRKCJKSA-K 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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 or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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Abstract
本发明涉及一种有效成分含量高、且稳定性和安全性优异的甘草甜素·氨基乙酸·半胱氨酸配合制剂。它通过不添加现有制品中作为稳定剂使用的亚硫酸钠，改善以高浓度配有有效成分时的稳定性。本发明的甘草甜素浓缩制剂是一种医药组合物，含有甘草甜素8～16mg/mL、半胱氨酸3～6mg/mL、氨基乙酸80～160mg/mL，且添加剂中不含亚硫酸盐类。
Description
技术领域
本发明涉及含有高浓度的可有效用于肝病用药或变态反应用药等的甘草甜素、半胱氨酸以及氨基乙酸(甘氨酸)的医药组合物。
背景技术
目前，人们已知甘草甜素类物质具有抗皮质酮的作用、脱胆固醇作用、抗变态反应作用、抗炎症作用、解毒作用、胃溃疡修复作用等各种药理作用，且由于其安全性已得到确认，所以，含有其作为有效成分的甘草甜素制剂广泛用作医治各种疾病的药剂。而且近年来，有报告表明，甘草甜素的大剂量静脉注射对慢性肝病效果很好，由此可重新评价甘草甜素制剂的有效性。
用于治疗肝病的医药品通常多为在较长一段时间内连续服用的药剂。现阶段市售的甘草甜素·氨基乙酸·半胱氨酸配合制剂(商品名：强力Neo-Minophagen C)是以甘草酸单铵2.65mg/mL(甘草甜素2mg/mL)、半胱氨酸盐酸盐1mg/mL(半胱氨酸0.77mg/mL)、氨基乙酸20mg/mL的配合比制成的注射制剂，尽管根据年龄、症状有适度增减，但对慢性肝病患者而言，采用一日一次、40～60mL(可加大剂量至100mL)向静脉内注射或静脉滴注。这类大量服用的方式，不仅会在服用时给患者带来痛苦，且经过连日的长期服用，还会导致注射部位的组织肥大的问题。此外，还存在作为该制剂的配合组分的甘草甜素会产生沉淀，或半胱氨酸盐酸盐易分解不稳定等问题(参照专利文献1)，在现有的注射用制剂中，添加用作稳定剂的亚硫酸盐(亚硫酸钠：0.8mg/mL，参照非专利文献1)。但有报告指出亚硫酸盐类是诱发哮喘的物质(参照非专利文献2)，而且还有报告指出亚硫酸盐类是引发变态反应的食品添加剂(参照非专利文献3和非专利文献4)，因此，含有高浓度亚硫酸盐类的制剂存在安全性问题。
专利文献1：日本特开2002-65808号公报，第2页，第0004段；
非专利文献1：“强力Neo-Minophagen C”药品说明书(株式会社MINOPHAGEN制药制作)；
非专利文献2：坂本龙雄，食品添加剂与哮喘(以亚硫酸盐为中心物质)气管变态反应，96Medical View公司，第151页，1996；
非专利文献3：河野阳一，食物变态反应的基础与临床(食物过敏性)变态反应领域：4(6)，第741～745页，1997；
非专利文献4：道端正孝，类固醇的自我管理我的办法临床与药物治疗：16(3)，第226～230页，1997。
发明内容
如上所述，由于人们希望哪怕只是稍微减轻些与服用甘草甜素·氨基乙酸·半胱氨酸配合制剂相关的、因静脉注射等大量服用时造成的疼痛以及注射部位的组织肥大等对患者的负担，因此，本发明人等对少量服用也能期待有药效、且稳定性和安全性好的高浓度制剂进行了深入研究。
本发明的课题在于提供以高于现有制品的浓度配合有效成分，且稳定性和安全性好的甘草甜素·氨基乙酸·半胱氨酸配合制剂。仅仅是使现有产品的配合组分为高浓度，会产生有效成分的分解或沉淀等，无法得到充分的稳定性。且因含有亚硫酸盐还会产生安全性问题。
本发明人为解决上述问题进行了深入的研究，结果发现：如果不添加现有制品中作为稳定剂使用的亚硫酸钠，就能改善以高浓度配有有效成分时的稳定性，可得到以比现有制剂更高浓度含有有效成分、且安全性优异的甘草甜素·氨基乙酸·半胱氨酸配合制剂。由此完成了本发明。
本发明的医药组合物是不添加现有制品中作为稳定剂使用的亚硫酸盐的组合物，由此，不仅不会产生以高浓度配合的甘草甜素的沉淀，而且降低了半胱氨酸含量的减少，提高了稳定性。
具体实施方式
本发明涉及一种高浓度甘草甜素·氨基乙酸·半胱氨酸配合制剂，其特征在于，在以甘草甜素或其可药用盐为有效成分的甘草甜素制剂中，除上述成分之外，还含有半胱氨酸和氨基乙酸，且不含亚硫酸盐类。
作为本发明医药组合物有效成分的甘草甜素可通过从甘草中提取得到，也可使用市售品。本发明的甘草甜素包括也被称为甘草酸，在本发明中为甘草甜素的可药用盐。作为可药用盐可举出其与酸或与碱的盐，例如甘草酸单铵等铵盐，甘草酸二钠、甘草酸三钠、甘草酸二钾等碱金属盐等。
此外，本发明的半胱氨酸及氨基乙酸(甘氨酸)还包括其可药用盐，例如，包括与盐酸、苹果酸等的酸加成盐，以及与钠等碱金属、碱土金属、铵、含氮有机碱等的碱加成盐这两种盐，半胱氨酸的优选盐可举出其盐酸盐。再者，半胱氨酸、氨基乙酸或其盐的水合物，例如半胱氨酸盐酸盐一水合物、氨基乙酸钠水合物等也作为本发明的半胱氨酸及氨基乙酸被含有。半胱氨酸存在旋光体，采用L型旋光体或外消旋体均可，优选采用L-半胱氨酸。
本发明医药组合物的优选配合量为上述现有制剂的4～8倍的有效成分含量，即：甘草甜素为8～16mg/mL、半胱氨酸盐酸盐为4～8mg/mL(作为半胱氨酸为3～6mg/mL)、氨基乙酸为80～160mg/mL。特别优选为以最高浓度含有效成分的制剂，即：含有甘草甜素16mg/mL、半胱氨酸盐酸盐8mg/mL、氨基乙酸160mg/mL的医药组合物。其中，上述各浓度(mg/mL)数值为按照日本药典第十四修订版通则18所规定的规格值表示，为四舍五入小数点后第一位的数值。
此外，本发明的医药组合物可通过与适当的药用载体或稀释剂组合形成最终的医药品，可采用常见的任意方法制成制剂。例如，注射制剂可采用水性溶剂或非水性溶剂等的溶液或悬浊液，上述水性溶剂或非水性溶剂可举出例如注射用蒸馏水、生理盐水、林格氏溶液(Ringer′s solution)、植物油、合成脂肪酸甘油酯、高级脂肪酸酯、丙二醇等。在为处方药时，还可作为与其它医药活性成分的配合制剂。
实施例1
添加亚硫酸钠造成的影响(1)
在溶解氧很少的水中溶解各成分，使得形成甘草酸单铵16mg/mL(以甘草甜素计)、半胱氨酸盐酸盐8mg/mL、氨基乙酸160mg/mL的配比，用氢氧化钠将pH值调至7.2～7.5。再添加作为稳定剂使用的亚硫酸钠，使其浓度分别为0mg/mL、2.4mg/mL、4.0mg/mL，然后用氮除去溶解氧，过滤杀菌，在安瓿中填充氮。将该安瓿在25℃下储藏4年，观察甘草甜素的沉淀状况，另将与上述安瓿不同的安瓿在40℃下储藏4个月以及在60℃下储藏14天，然后用HPLC对半胱氨酸进行定量。表1表明了如上所述处理后的本发明医药组合物因亚硫酸钠添加量的不同造成的不同稳定性的测定结果的一例。
表1
| 亚硫酸钠添加量(mg/mL) | |||||
| 0 | 2.4 | 4.0 | |||
| 制造时pH | 7.22 | 7.49 | 7.29 | ||
| 是否存在甘草甜素沉淀 | 25℃4年后 | - | + | + | |
| 半胱氨酸盐酸盐的含量(％) | 未杀菌时 | 97.3 | 101.6 | 98.9 | |
| 杀菌后 | 94.4 | 95.2 | 91.1 | ||
| 60℃ | 3天后 | 89.7 | 87.8 | 81.4 | |
| 7天后 | 81.2 | 71.3 | 64.2 | ||
| 14天后 | 77.8 | 66.5 | 53.9 | ||
| 40℃ | 2个月后 | 89.4 | 86.0 | 70.3 | |
| 4个月后 | 83.6 | 77.7 | 68.5 | ||
实施例2
添加亚硫酸钠造成的影响(2)
与上述实施例1同样，在溶解氧很少的水中溶解各成分，使得形成甘草酸单铵16mg/mL(以甘草甜素计)、半胱氨酸盐酸盐8mg/mL、氨基乙酸160mg/mL的配合比，用氢氧化钠将pH值调至7.2～7.5。再制作添加作为稳定及使用的亚硫酸钠，得到其含量为6.4mg/mL的制品和其添加量为零的制品，还制作了在上述配合的基础上，将半胱氨酸盐酸盐浓度稀释为6mg/mL及4mg/mL的制品。再用氮除去各制品中的溶解氧，过滤杀菌，然后在安瓿中填充氮。将该安瓿在60℃下储藏14天，然后在刚开始时、4天后、7天后、14天后用HPLC对半胱氨酸定量。表2表明了如上所述处理后的本发明医药组合物因亚硫酸钠添加量的不同对半胱氨酸盐酸盐稳定性造成的影响的测定结果的一例。
表2
| 半胱氨酸盐酸盐配合量(mg/mL) | 8 | 6 | 4 | |
| 添加量为零 | 开始 | 100.0 | 100.0 | 100.0 |
| 4天 | 93.5 | 97.5 | 94.3 | |
| 7天 | 88.6 | 94.5 | 89.5 | |
| 14天 | 82.8 | 82.4 | 88.7 | |
| 添加亚硫酸Na | 开始 | 100.0 | 100.0 | 100.0 |
| 4天 | 73.6 | 84.4 | 88.8 | |
| 7天 | 53.1 | 70.4 | 77.1 | |
| 14天 | 40.4 | 52.2 | 59.8 | |
产业上的可利用性
根据上述表1和表2所示结果可知，亚硫酸钠的浓度越高，半胱氨酸含量随时间的减少越显著。此外，添加有亚硫酸钠的制品会产生甘草甜素的沉淀，而未添加亚硫酸钠时，以高浓度配合甘草甜素也不会产生沉淀，且半胱氨酸含量的减少程度也很低，稳定性得到提高。由此，本发明的甘草甜素浓缩制剂与现有制剂相比，以高浓度含有有效成分，且稳定性和安全性优异，作为医药品非常有用。
Claims (5)
1.一种医药组合物，其特征在于，含有：甘草甜素8～16mg/mL、半胱氨酸3～6mg/mL和氨基乙酸80～160mg/mL。
2.如权利要求1所述的医药组合物，其特征在于，不含亚硫酸盐类。
3.如权利要求1或2所述的医药组合物，其特征在于，所述甘草甜素为甘草酸单铵。
4.如权利要求1～3任一项所述的医药组合物，其特征在于，所述半胱氨酸为半胱氨酸盐酸盐。
5.一种医药组合物，其特征在于，含有：甘草甜素16mg/mL、半胱氨酸盐酸盐8mg/mL和氨基乙酸160mg/mL，且添加剂中不含亚硫酸盐类。
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| JP5213137B2 (ja) * | 2006-12-06 | 2013-06-19 | コーネル リサーチ ファウンデーション， インコーポレイテッド | 中程度の持続時間の神経筋遮断剤およびそのアンタゴニスト |
| US8592451B2 (en) | 2009-03-17 | 2013-11-26 | Cornell University | Reversible nondepolarizing neuromuscular blockade agents and methods for their use |
| CN102573794B (zh) * | 2009-08-19 | 2017-03-15 | 康奈尔大学 | 供生理注射用的半胱氨酸 |
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| WO2002074238A2 (en) * | 2001-02-16 | 2002-09-26 | Lavipharm Laboratories Inc. | Water soluble and palatable complexes |
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| JP4463206B2 (ja) | 2010-05-19 |
| EP1676580A4 (en) | 2010-07-28 |
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