JP5517322B1 - Three-part dialysis agent containing acetic acid and acetate - Google Patents
Three-part dialysis agent containing acetic acid and acetate Download PDFInfo
- Publication number
- JP5517322B1 JP5517322B1 JP2013207382A JP2013207382A JP5517322B1 JP 5517322 B1 JP5517322 B1 JP 5517322B1 JP 2013207382 A JP2013207382 A JP 2013207382A JP 2013207382 A JP2013207382 A JP 2013207382A JP 5517322 B1 JP5517322 B1 JP 5517322B1
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- JP
- Japan
- Prior art keywords
- agent
- acetate
- acetic acid
- dialysis
- sodium
- Prior art date
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims abstract description 653
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 447
- 238000000502 dialysis Methods 0.000 title claims abstract description 189
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 title claims abstract description 138
- 238000002360 preparation method Methods 0.000 claims abstract description 62
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims abstract description 61
- 239000003792 electrolyte Substances 0.000 claims abstract description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 44
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 44
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 22
- 239000011780 sodium chloride Substances 0.000 claims abstract description 22
- 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 claims abstract description 21
- 239000011734 sodium Substances 0.000 claims abstract description 21
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 21
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims description 93
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 67
- 239000001632 sodium acetate Substances 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 64
- 239000002994 raw material Substances 0.000 claims description 58
- 235000017281 sodium acetate Nutrition 0.000 claims description 58
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 54
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 47
- 239000008103 glucose Substances 0.000 claims description 47
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 44
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 44
- 235000002639 sodium chloride Nutrition 0.000 claims description 37
- -1 organic acid salt Chemical class 0.000 claims description 30
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 23
- 238000004806 packaging method and process Methods 0.000 claims description 23
- 229910052783 alkali metal Inorganic materials 0.000 claims description 22
- 239000001110 calcium chloride Substances 0.000 claims description 22
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 22
- 235000011148 calcium chloride Nutrition 0.000 claims description 22
- 239000001103 potassium chloride Substances 0.000 claims description 22
- 235000011164 potassium chloride Nutrition 0.000 claims description 22
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 21
- 235000011147 magnesium chloride Nutrition 0.000 claims description 21
- 150000001340 alkali metals Chemical class 0.000 claims description 18
- 235000015165 citric acid Nutrition 0.000 claims description 18
- 239000000385 dialysis solution Substances 0.000 claims description 17
- 150000007524 organic acids Chemical class 0.000 claims description 9
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical group [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 235000017454 sodium diacetate Nutrition 0.000 claims description 8
- 239000002274 desiccant Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 230000035699 permeability Effects 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 claims description 4
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 claims description 4
- 239000000174 gluconic acid Substances 0.000 claims description 4
- 235000012208 gluconic acid Nutrition 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 229960001790 sodium citrate Drugs 0.000 claims description 4
- 235000011083 sodium citrates Nutrition 0.000 claims description 4
- 239000000176 sodium gluconate Substances 0.000 claims description 4
- 235000012207 sodium gluconate Nutrition 0.000 claims description 4
- 229940005574 sodium gluconate Drugs 0.000 claims description 4
- 235000011088 sodium lactate Nutrition 0.000 claims description 4
- 239000001540 sodium lactate Substances 0.000 claims description 4
- 229940005581 sodium lactate Drugs 0.000 claims description 4
- 239000001394 sodium malate Substances 0.000 claims description 4
- 229940074404 sodium succinate Drugs 0.000 claims description 4
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 claims description 4
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 3
- LFQRKUIOSYPVFY-UHFFFAOYSA-L dipotassium diacetate Chemical compound [K+].[K+].CC([O-])=O.CC([O-])=O LFQRKUIOSYPVFY-UHFFFAOYSA-L 0.000 claims description 3
- 235000012209 glucono delta-lactone Nutrition 0.000 claims description 3
- 239000000182 glucono-delta-lactone Substances 0.000 claims description 3
- 229960003681 gluconolactone Drugs 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 235000011044 succinic acid Nutrition 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 33
- 230000002829 reductive effect Effects 0.000 abstract description 10
- 229910001414 potassium ion Inorganic materials 0.000 abstract description 9
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 8
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 abstract description 8
- 229910001424 calcium ion Inorganic materials 0.000 abstract description 8
- 229910001425 magnesium ion Inorganic materials 0.000 abstract description 8
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 abstract description 7
- 229910021655 trace metal ion Inorganic materials 0.000 abstract description 5
- 229960000583 acetic acid Drugs 0.000 description 208
- 239000007788 liquid Substances 0.000 description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 35
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 34
- 239000011575 calcium Substances 0.000 description 34
- 229960005069 calcium Drugs 0.000 description 34
- 229910052791 calcium Inorganic materials 0.000 description 34
- 150000002500 ions Chemical class 0.000 description 23
- 238000000034 method Methods 0.000 description 23
- 238000002156 mixing Methods 0.000 description 22
- 229960002816 potassium chloride Drugs 0.000 description 20
- 229960002713 calcium chloride Drugs 0.000 description 19
- 229960002337 magnesium chloride Drugs 0.000 description 18
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 16
- 229910001415 sodium ion Inorganic materials 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 15
- 230000007797 corrosion Effects 0.000 description 14
- 238000005260 corrosion Methods 0.000 description 14
- 230000007423 decrease Effects 0.000 description 13
- 238000001035 drying Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000004698 Polyethylene Substances 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 150000004677 hydrates Chemical class 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 229920000573 polyethylene Polymers 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
- 229960003975 potassium Drugs 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- 229910052742 iron Inorganic materials 0.000 description 8
- 239000011777 magnesium Substances 0.000 description 8
- 229910052749 magnesium Inorganic materials 0.000 description 8
- 229940091250 magnesium supplement Drugs 0.000 description 8
- WMFHUUKYIUOHRA-UHFFFAOYSA-N (3-phenoxyphenyl)methanamine;hydrochloride Chemical compound Cl.NCC1=CC=CC(OC=2C=CC=CC=2)=C1 WMFHUUKYIUOHRA-UHFFFAOYSA-N 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 238000002835 absorbance Methods 0.000 description 6
- 159000000021 acetate salts Chemical class 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 159000000003 magnesium salts Chemical class 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 159000000007 calcium salts Chemical class 0.000 description 5
- 150000003841 chloride salts Chemical class 0.000 description 5
- 238000013329 compounding Methods 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 235000011167 hydrochloric acid Nutrition 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 208000010444 Acidosis Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 3
- 239000001354 calcium citrate Substances 0.000 description 3
- 229960004256 calcium citrate Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 159000000001 potassium salts Chemical class 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 235000013337 tricalcium citrate Nutrition 0.000 description 3
- 238000007740 vapor deposition Methods 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 206010027417 Metabolic acidosis Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000005475 Vascular calcification Diseases 0.000 description 1
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- 208000026545 acidosis disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
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- 230000037396 body weight Effects 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
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- 239000004227 calcium gluconate Substances 0.000 description 1
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- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
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- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- PBUBJNYXWIDFMU-UHFFFAOYSA-L calcium;butanedioate Chemical compound [Ca+2].[O-]C(=O)CCC([O-])=O PBUBJNYXWIDFMU-UHFFFAOYSA-L 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- CVOQYKPWIVSMDC-UHFFFAOYSA-L dipotassium;butanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC([O-])=O CVOQYKPWIVSMDC-UHFFFAOYSA-L 0.000 description 1
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- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 238000012812 general test Methods 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000003673 groundwater Substances 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- RJGBSYZFOCAGQY-UHFFFAOYSA-N hydroxymethylfurfural Natural products COC1=CC=C(C=O)O1 RJGBSYZFOCAGQY-UHFFFAOYSA-N 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
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- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 235000002538 magnesium citrate Nutrition 0.000 description 1
- 239000004337 magnesium citrate Substances 0.000 description 1
- 229960005336 magnesium citrate Drugs 0.000 description 1
- 239000001755 magnesium gluconate Substances 0.000 description 1
- 235000015778 magnesium gluconate Nutrition 0.000 description 1
- 229960003035 magnesium gluconate Drugs 0.000 description 1
- OVGXLJDWSLQDRT-UHFFFAOYSA-L magnesium lactate Chemical compound [Mg+2].CC(O)C([O-])=O.CC(O)C([O-])=O OVGXLJDWSLQDRT-UHFFFAOYSA-L 0.000 description 1
- 239000000626 magnesium lactate Substances 0.000 description 1
- 235000015229 magnesium lactate Nutrition 0.000 description 1
- 229960004658 magnesium lactate Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- IAKLPCRFBAZVRW-XRDLMGPZSA-L magnesium;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoate;hydrate Chemical compound O.[Mg+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O IAKLPCRFBAZVRW-XRDLMGPZSA-L 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-M malate ion Chemical compound [O-]C(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-M 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 235000003715 nutritional status Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 229960004109 potassium acetate Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- PHZLMBHDXVLRIX-UHFFFAOYSA-M potassium lactate Chemical compound [K+].CC(O)C([O-])=O PHZLMBHDXVLRIX-UHFFFAOYSA-M 0.000 description 1
- 235000011085 potassium lactate Nutrition 0.000 description 1
- 239000001521 potassium lactate Substances 0.000 description 1
- 229960001304 potassium lactate Drugs 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- OKUCEQDKBKYEJY-UHFFFAOYSA-N tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate Chemical compound CNC1CCN(C(=O)OC(C)(C)C)C1 OKUCEQDKBKYEJY-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
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Abstract
【課題】本発明の目的は、透析液中の総酢酸イオン含量を低い値に設定可能で、しかも保存安定性に優れ、酢酸臭を低減でき、更に、必要に応じて、カリウムイオン、カルシウムイオン、マグネシウムイオン等の微量金属イオン濃度は一定に維持しつつ、重炭酸イオン濃度を任意に変化させ得る透析液を調製することができる３剤型透析用剤を提供することである。
【解決手段】塩化ナトリウムを含むＳ剤と、重炭酸ナトリウムを含むＢ剤と、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分を含むＡ剤を含む３剤型透析用剤において、Ａ剤に、酢酸及び酢酸塩を含有させ、且つ酢酸：酢酸塩のモル比が１：０．５〜２を充足させることによって、総酢酸イオン濃度が２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満となるような重炭酸透析液が調製可能となり、当該Ａ剤中の成分の安定性が優れていることに加え、酢酸臭を低減できる更に、当該３剤型透析用剤によれば、透析液の調製時にＳ剤、Ｂ剤、及びＡ剤の添加量を調節することによって透析液中の重炭酸イオン濃度及び／又はナトリウム濃度を変化させることもできる。
【選択図】なしAn object of the present invention is to set the total acetate ion content in a dialysate to a low value, and to be excellent in storage stability, to reduce an acetic acid odor, and further, if necessary, potassium ion, calcium ion Another object of the present invention is to provide a three-part dialysis agent capable of preparing a dialysate capable of arbitrarily changing the bicarbonate ion concentration while keeping the concentration of trace metal ions such as magnesium ions constant.
SOLUTION: A three-agent dialysis agent comprising an agent S containing sodium chloride, an agent B containing sodium bicarbonate, and an agent A containing an electrolyte component other than sodium chloride and sodium bicarbonate. And acetate, and a molar ratio of acetic acid: acetate of 1: 0.5-2 is satisfied, so that the total acetate ion concentration is 2 mEq / L or more and less than 6 mEq / L. In addition to being excellent in stability of the components in the agent A, the acetic acid odor can be reduced. Furthermore, according to the agent for three-part dialysis, the agent S and agent B are prepared at the time of preparation of the dialysate. The bicarbonate ion concentration and / or the sodium concentration in the dialysate can also be changed by adjusting the amount of agent A added.
[Selection figure] None
Description
本発明は、酢酸及び酢酸塩を含む３剤型透析用剤に関する。より具体的には、本発明は、透析液中の総酢酸イオン濃度を６ｍＥｑ／Ｌ未満となるように調製可能で、しかも保存安定性に優れ、酢酸臭を低減でき、更に必要に応じて重炭酸イオン濃度を任意に変化させることができる透析液を調製することができる、３剤型透析用剤に関する。 The present invention relates to a three-part dialysis agent containing acetic acid and acetate. More specifically, the present invention can be prepared so that the total acetate ion concentration in the dialysate is less than 6 mEq / L, has excellent storage stability, can reduce the odor of acetic acid, and can be used as needed. The present invention relates to a three-part dialysis agent capable of preparing a dialysate capable of arbitrarily changing the carbonate ion concentration.
透析療法は、腎不全患者の治療法として確立されており、血中電解質成分濃度の調節、***性物質の除去、酸塩基平衡の是正等を目的として実施されている。この透析治療に用いられる透析液には複数の成分が含まれているが、治療の目的に合致し、かつ生体に対する負担の少ない成分が適切な濃度で配合されるべきである。 Dialysis therapy has been established as a treatment method for patients with renal failure, and is performed for the purpose of adjusting blood electrolyte component concentration, removing uremic substances, correcting acid-base balance, and the like. The dialysate used for this dialysis treatment contains a plurality of components, but components that meet the purpose of the treatment and have a low burden on the living body should be blended in an appropriate concentration.
近年、透析液には酸塩基平衡の是正のために炭酸水素ナトリウムを用いた重炭酸透析液が主流になっており、透析液を中性にするために酸を配合することも必須となっている。また、これらを同一の容器に共存して流通させると、容器内で炭酸ガスを発生して非常に不安定になるため、透析液の調製に使用される透析用剤としてＡ剤及びＢ剤の２剤に分けて製造し、使用時に混合することが一般的となっている。 In recent years, bicarbonate dialysis solutions using sodium bicarbonate have been the mainstream in dialysis fluids to correct acid-base balance, and it has become essential to add acid to neutralize the dialysis fluid. Yes. In addition, if these coexist in the same container, carbon dioxide is generated in the container and it becomes very unstable. Therefore, as a dialysis agent used for the preparation of dialysate, It is common to manufacture in two parts and mix at the time of use.
通常、Ａ剤には塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム、ｐＨ調節剤（酸および任意成分としてのバッファー成分）およびブドウ糖が含まれており、Ｂ剤には炭酸水素ナトリウムが含まれている。また、不溶性塩の析出を防ぐため、Ｂ剤には塩化カルシウムや塩化マグネシウムの配合が禁忌されている。 Usually, agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, pH regulator (acid and optional buffer component) and glucose, and agent B contains sodium bicarbonate. Yes. In order to prevent precipitation of insoluble salts, the B agent is contraindicated in calcium chloride and magnesium chloride.
従来、これらＡ剤及びＢ剤はポリエチレン容器に充填された液体として使用されていたが、輸送コストや病院内での作業性の悪さ（重量、保管スペ−ス、ポリエチレン容器の廃棄方法など）が問題となり、今日では、用時に水と混合される粉末状の透析用剤が実用化されている。 Conventionally, these A and B agents have been used as liquids filled in polyethylene containers, but transportation costs and poor workability in hospitals (weight, storage space, disposal methods of polyethylene containers, etc.) Today, a dialysis agent in powder form that is mixed with water at the time of use has been put into practical use.
粉末状の透析用剤は、当初は電解質及びｐＨ調節剤を含むＡ−１剤と、ブドウ糖のみからなるＡ−２剤、炭酸水素ナトリウムからなるＢ剤の３剤で構成されていたが、現在ではＡ−１剤とＡ−２剤が組み合わされ、Ａ剤及びＢ剤からなる２剤型が主流となっている。 The powdered dialysis agent was initially composed of three agents: A-1 containing electrolyte and pH adjuster, A-2 consisting of glucose only, and B consisting of sodium bicarbonate. Then, A-1 agent and A-2 agent are combined, and the 2 agent type which consists of A agent and B agent has become mainstream.
今日では、重炭酸透析用剤は、臨床において透析液として使用する際に以下のような組成並びに濃度となるように処方されている。 Today, bicarbonate dialysis agents are formulated to have the following composition and concentration when used as dialysate in clinical practice.
透析液は透析治療時に、液体型のＡ剤、又は粉末型のＡ剤を溶解して得られるＡ液、又は粉末型のＡ−１剤及びＡ−２剤を溶解して得られるＡ液と、液体型のＢ剤、又は粉末型のＢ剤を溶解して得られるＢ液を、希釈、混合して用いられているが、前述したように重炭酸透析液では、酸及び炭酸水素ナトリウムの共存によって、時間の経過とともに炭酸ガスが発生し、同時にｐＨも上昇して不溶性の炭酸カルシウム等を生成してしまうことがある。この現象によって、治療に有効なカルシウム濃度が減少したり、透析装置の配管やホースに結晶が付着したりすることが問題となっている。 The dialysis solution is a liquid A agent obtained by dissolving a liquid type A agent, a powder type A agent, or an A solution obtained by dissolving a powder type A-1 agent and an A-2 agent during dialysis treatment. The liquid B or the liquid B obtained by dissolving the powder B is diluted and mixed, but as mentioned above, the bicarbonate dialysate contains acid and sodium bicarbonate. Due to the coexistence, carbon dioxide gas is generated with the passage of time, and at the same time, the pH is increased and insoluble calcium carbonate or the like may be generated. Due to this phenomenon, there is a problem that the calcium concentration effective for the treatment is reduced or crystals are attached to the piping or hose of the dialysis machine.
一方、ｐＨ調節剤としては酢酸が長期に渡って使用されてきたが、近年になって酢酸の末梢血管拡張作用や心機能抑制作用、炎症性サイトカインの誘発、酢酸不耐症の患者への負担が問題視されていた。即ち、酢酸は、短時間で代謝されるために生体への蓄積はないが、心機能抑制、末梢血管拡張効果があり、結果的に血圧を低下させる作用を持っている。透析治療は体内の水分を除去するための治療でもあるため、透析中並びに透析後は水分除去による血圧低下が必然的に起こってしまう。それを防止するために除水コントロールや昇圧剤の投与等の対処療法が併用されることが多々ある。これらの作用による症状発現の有無は患者毎に異なることから、透析液に含まれる酢酸の濃度も起因しているとも考えられている。近年になって、このような状況を打開するためのひとつの手法として無酢酸（アセテートフリー）透析という方法が提唱されるようになった。 On the other hand, acetic acid has been used as a pH regulator for a long time, but in recent years, acetic acid has a peripheral vasodilatory effect and cardiac function inhibitory effect, induces inflammatory cytokines, and burdens on patients with acetic intolerance. Was regarded as a problem. That is, since acetic acid is metabolized in a short time, it does not accumulate in the living body, but has an effect of suppressing cardiac function and peripheral vasodilatation, and has the effect of lowering blood pressure as a result. Since dialysis treatment is also a treatment for removing water in the body, blood pressure reduction inevitably occurs during dialysis and after dialysis. In order to prevent this, coping therapy such as water removal control and administration of vasopressor is often used in combination. Since the presence or absence of symptoms due to these actions varies from patient to patient, it is also considered that the concentration of acetic acid contained in the dialysate is also caused. In recent years, acetic acid-free (acetate-free) dialysis has been proposed as one method for overcoming such a situation.
そこで今日では、酢酸の代わりにクエン酸をｐＨ調節剤として配合されたものが市販され、臨床使用されるようになってきている（例えば、特許文献１〜４参照）。しかしながら、クエン酸は強いキレート作用を持つために透析液中のカルシウムの一部分をキレートし、イオン化カルシウム濃度を下げてしまうこと、酢酸よりも強酸であるために濃厚液であるＡ液のｐＨが低くなり、溶解装置や透析装置の部品腐食の恐れがあること、逆にＡ液のｐＨを高くするために有機酸塩を多く配合すると、クエン酸カルシウムの結晶が析出して組成に影響を及ぼすこと等の問題点を有している。即ち、クエン酸は、アルカリ土類金属とキレートしやすいので、透析液成分中のカルシウムやマグネシウムとキレートする。この作用は特にカルシウムに対して強いのであるが、透析治療においてはカルシウム量の調節が非常に重要であるので、キレートによるイオン化カルシウム濃度の減少は患者のカルシウム収支に大きく影響するという欠点がある。例えば、クエン酸とカルシウムが透析液中でほぼ同濃度（イオン当量比）で含まれていた場合、３５％程度のカルシウムがキレートされ、その分だけ透析液中のイオン化カルシウム濃度が減少し、結果的に血中カルシウム濃度のコントロールが困難になってしまう。また、クエン酸も透析により体内に入るため、血中でクエン酸とカルシウムが結合することにより、難溶性のクエン酸カルシウムが生成して血管内に沈着する恐れがあり、またクエン酸とカルシウムが同時に血中に入った後のそれら成分の動態が明確でないことによって、透析患者において重要な体内のカルシウム管理が困難になることも懸念されている。更に、クエン酸によるイオン化カルシウム濃度の低下は心筋や血管平滑筋の弛緩を促し、低血圧を招く点、クエン酸の抗凝固作用により出血傾向の患者には使いにくい点でも問題がある。 Therefore, today, a combination of citric acid instead of acetic acid as a pH regulator is commercially available and clinically used (for example, see Patent Documents 1 to 4). However, since citric acid has a strong chelating action, it chelate a part of calcium in the dialysate, lowering the ionized calcium concentration, and because it is a stronger acid than acetic acid, the pH of the concentrated solution A is low. Therefore, there is a risk of corrosion of parts of the dissolution apparatus and dialysis machine. Conversely, if a large amount of organic acid salt is added to increase the pH of solution A, calcium citrate crystals precipitate and affect the composition. And so on. That is, citric acid is easily chelated with alkaline earth metals, so it chelates with calcium and magnesium in the dialysate components. Although this action is particularly strong against calcium, the adjustment of the amount of calcium is very important in dialysis treatment, and thus there is a drawback that the decrease in ionized calcium concentration by chelate greatly affects the patient's calcium balance. For example, when citric acid and calcium are contained in the dialysate at approximately the same concentration (ion equivalent ratio), about 35% of calcium is chelated, and the amount of ionized calcium in the dialysate decreases accordingly. This makes it difficult to control the blood calcium concentration. In addition, citric acid also enters the body by dialysis, so when citric acid and calcium are combined in the blood, there is a risk that sparingly soluble calcium citrate will be generated and deposited in blood vessels. At the same time, there is also a concern that the management of calcium in the body, which is important in dialysis patients, becomes difficult due to unclear kinetics of these components after entering the blood. In addition, a decrease in the concentration of ionized calcium by citric acid promotes relaxation of the myocardium and vascular smooth muscle, leading to hypotension, and there are problems in that it is difficult to use for patients who tend to bleed due to the anticoagulant action of citric acid.
また、クエン酸は固体であるために通常の取り扱いにおいては扱いやすいが、濃厚液は強酸性であるため、粉末状態で保管していても部分的な吸湿があった場合には塩化水素ガスが発生し易くなり、溶解装置等の部分的な金属腐食や樹脂劣化等を生じさせることもある。例えば、特許文献１は、クエン酸を用いることにより不溶性化合物の生成防止や炭酸カルシウムの沈殿抑制、ブドウ糖の分解を防止できる無酢酸の粉末型透析用剤について記載しているが、これはクエン酸をｐＨ２．２〜２．９という限定された範囲で用いることによって達成されるものである。この限定されたｐＨ範囲では溶解装置や透析装置の腐食の恐れがある点で問題があり、また、クエン酸の強いキレート作用によりイオン化カルシウム濃度が下がって上記のように治療効果に影響を与える恐れもある。 In addition, citric acid is solid and easy to handle in normal handling, but concentrated liquids are strongly acidic, so if there is partial moisture absorption even when stored in powder form, hydrogen chloride gas is generated. It tends to occur and may cause partial metal corrosion such as a melting device, resin degradation, and the like. For example, Patent Document 1 describes an acetic acid-free powder-type dialysis agent that can prevent the formation of insoluble compounds, suppress the precipitation of calcium carbonate, and prevent the decomposition of glucose by using citric acid. Is achieved in a limited range of pH 2.2 to 2.9. In this limited pH range, there is a problem in that there is a risk of corrosion of the dissolution apparatus and dialysis apparatus, and the ionized calcium concentration decreases due to the strong chelating action of citric acid, which may affect the therapeutic effect as described above. There is also.
そのため、酢酸以外の酸成分としてクエン酸を用いることは最適とは言えず、またクエン酸以外の有機酸として乳酸やリンゴ酸、フマル酸、グルコン酸等の生体に安全な物質の使用も考えられるが、慢性的な使用における透析後の体内での挙動については明確になっていないことから極力使用量を減らすこと、更にはこれら酸成分による透析液調製装置や透析装置への影響も考慮することが重要である。 For this reason, it is not optimal to use citric acid as an acid component other than acetic acid, and the use of biologically safe substances such as lactic acid, malic acid, fumaric acid and gluconic acid as organic acids other than citric acid is also conceivable. However, since the behavior in the body after dialysis in chronic use is not clear, reduce the amount of use as much as possible, and also consider the effects of these acid components on the dialysate preparation device and dialyzer is important.
一方、前述するように、クエン酸等は強いキレート作用からイオン化カルシウム濃度を下げてしまうことが懸念されるが、厳密に言えば酢酸もイオン化カルシウム濃度を下げている。おそらく酢酸の代謝が速いことで、臨床上の問題は軽視されてきたが、実際には、ｐＨ調節剤として塩酸を用いたものよりも透析液とした時のイオン化カルシウムの濃度は低くなり、酢酸の含量が増えるにつれ、更にイオン化カルシウム濃度は下がる。一般的には知られていないことであるが、酢酸の含量が多いと、クエン酸ほどではないものの透析液中のイオン化カルシウム濃度を下げる要因となることは確かである。このようなことからも酢酸含量は少ない方が望ましいことは明らかである。 On the other hand, as described above, citric acid and the like are concerned that the ionized calcium concentration is lowered due to the strong chelating action, but strictly speaking, acetic acid also lowers the ionized calcium concentration. Although the clinical problem has been neglected, probably due to the rapid metabolism of acetic acid, the concentration of ionized calcium in the dialysate is actually lower than that using hydrochloric acid as a pH regulator. As the content of increases, the ionized calcium concentration further decreases. Although it is not generally known, it is certain that a high acetic acid content is a factor that lowers the ionized calcium concentration in the dialysate, although not as much as citric acid. From these facts, it is clear that a lower acetic acid content is desirable.
これまで国内において販売されている酢酸含有の透析用Ａ剤は、液体、固体を問わず、総酢酸含量はすべて８ｍＥｑ／Ｌ以上、かつ酢酸１に対して酢酸ナトリウムの比率が２．２以上となっており、それ未満のものは使用されていない。この条件においてはＡ液のｐＨが４．７以上となることから、液体製剤の製造面からみると、透析液調製装置が腐食されにくく、取り扱いやすいというメリットがある。 The dialysis agent A containing acetic acid that has been sold in the country so far, regardless of whether it is liquid or solid, has a total acetic acid content of 8 mEq / L or more and a ratio of sodium acetate to acetic acid 1 of 2.2 or more. Nothing less than that is used. Under these conditions, the pH of the solution A is 4.7 or more, and therefore, from the viewpoint of production of the liquid preparation, there is an advantage that the dialysate preparation device is hardly corroded and is easy to handle.
国内で８ｍＥｑ／Ｌ以上の処方になっている理由は過去のアセテート透析液（重炭酸ナトリウムを使用せず酢酸ナトリウムが３０ｍＥｑ／Ｌ以上配合されている）から重炭酸透析液に変わった際に、重炭酸のメリットとアセテートのメリット、すなわち直接血液の重炭酸イオンを是正するものと、アセテートの代謝を経てゆっくりと重炭酸イオンを是正することのメリットを兼ね備えた処方としたためである。 The reason that the prescription is 8 mEq / L or more in Japan is that when the previous acetate dialysate (sodium acetate is not used and sodium acetate is blended more than 30 mEq / L) is changed to bicarbonate dialysate, This is because the merit of bicarbonate and the merit of acetate, that is, the one that directly corrects the bicarbonate ion of blood, and the merit of slowly correcting the bicarbonate ion through the metabolism of acetate are used.
一方、海外では液体製剤（Ａ液）が主として販売されている。国内においては、酢酸ナトリウムはアルカリ化剤の一部として用いられているが、海外においてはＢ剤の炭酸水素ナトリウムのみがアルカリ化剤として用いられているため、酢酸ナトリウムは使用されていない。故に、酢酸成分としては主として通常４ｍＥｑ／Ｌ以下となる量の酢酸のみをｐＨ調節剤として用いている。 On the other hand, liquid preparations (liquid A) are mainly sold overseas. In Japan, sodium acetate is used as a part of the alkalizing agent, but since only sodium B sodium carbonate is used as the alkalizing agent overseas, sodium acetate is not used. Therefore, as the acetic acid component, only acetic acid in an amount of usually 4 mEq / L or less is usually used as the pH regulator.
しかしながら、上記のように酢酸ナトリウムが含まれない場合には、Ａ液のｐＨは３以下となり、透析液調製装置や透析装置の金属部材の腐食や皮膚への強い刺激等の悪影響をもたらす。近年、Ａ液（Ａ剤粉末を溶解して調製したものも含む）のｐＨが３以下のものが市販されたことにより、透析液調製装置メーカーも腐食に強い耐酸性の素材を部品として用いることによって対応しているが、それら素材は高価であるために経済的に好ましくない。 However, when sodium acetate is not contained as described above, the pH of the solution A is 3 or less, which causes adverse effects such as corrosion of the dialysate preparation device and the metal members of the dialyzer, and strong irritation to the skin. In recent years, liquids of A liquid (including those prepared by dissolving A agent powder) with a pH of 3 or less have been marketed, so that dialysate preparation equipment manufacturers also use acid-resistant materials that are resistant to corrosion as parts. However, since these materials are expensive, it is not economically preferable.
また、酢酸を含む透析液では、液体といえども大量に取り扱う透析施設においては、非常に酢酸臭が強く不快であることより、製造時や使用時に出来るだけ透析用剤が開放系にならないような工夫も必要となってくる。 Also, in dialysate containing acetic acid, in dialysis facilities that handle a large amount even though it is a liquid, the dialysis agent does not become as open as possible during production and use because it is very unpleasant with the smell of acetic acid. Ingenuity is also required.
次に国内では透析用剤の粉末化の流れから粉末製剤が主流になり、粉末化に対応した重炭酸透析用剤に関する特許も数多く開示されている。例えば、特許文献５には、粉末状の透析用Ａ剤においては酢酸に対し酢酸ナトリウムの比率（モル比）が１．５６〜３．２９、好ましくは２．４９〜３．２９配合すると、酢酸ナトリウムが酢酸を吸着しやすく、揮発しにくいことから、粉末製剤の製造がより容易になることが記載されている。しかしながら、特許文献５が開示する技術でも、最終的に調製される透析液中の総酢酸イオン含量は８ｍＥｑ／Ｌ以上が想定されている。 Next, in Japan, powder preparations have become mainstream due to the flow of dialysis agents, and many patents relating to bicarbonate dialysis agents corresponding to pulverization have been disclosed. For example, in Patent Document 5, in a powdered dialysis agent A, the ratio (molar ratio) of sodium acetate to acetic acid is 1.56 to 3.29, preferably 2.49 to 3.29. It is described that the powder preparation is easier because sodium is easy to adsorb acetic acid and hardly volatilizes. However, even with the technique disclosed in Patent Document 5, the total acetate ion content in the finally prepared dialysate is assumed to be 8 mEq / L or more.
この他にも酢酸に対し酢酸ナトリウムが２倍超５倍以下で配合されるのが通例であり、例えば市販品のリンパックＴＡ−１は２．２倍（酢酸２．５ｍＥｑ／Ｌ：酢酸ナトリウム５．５ｍＥｑ／Ｌ）、キンダリー２Ｅは３倍（酢酸２ｍＥｑ／Ｌ：酢酸ナトリウム６ｍＥｑ／Ｌ）、ハイソルブＦは４．５倍（酢酸２ｍＥｑ／Ｌ：酢酸ナトリウム９ｍＥｑ／Ｌ）、ハイソルブＤは５倍（酢酸２ｍＥｑ／Ｌ：酢酸ナトリウム１０ｍＥｑ／Ｌ）となっている。過去の処方の変遷は別にしても酢酸に対する酢酸ナトリウムの比率が２倍以下のものが開示されていないのは酢酸臭の問題があったからである。すなわち３倍、４倍と酢酸ナトリウムの比率が上がるほど、粉末製剤としての酢酸臭は低減される。逆に２倍に近づくか、２倍以下になると耐え難いほどの酢酸臭が生じ、実用できるものではなくなる。 In addition to this, sodium acetate is usually blended in an amount of more than 2 times and not more than 5 times with respect to acetic acid. For example, commercially available Rinpac TA-1 is 2.2 times (acetic acid 2.5 mEq / L: sodium acetate. 5.5 mEq / L), kindery 2E is 3 times (acetic acid 2 mEq / L: sodium acetate 6 mEq / L), highsolve F is 4.5 times (acetic acid 2 mEq / L: sodium acetate 9 mEq / L), highsolve D is 5 times (Acetic acid 2 mEq / L: Sodium acetate 10 mEq / L). The reason why the ratio of sodium acetate to acetic acid is less than 2 times is not disclosed, apart from changes in past formulations, because of the problem of acetic acid odor. That is, the acetic acid odor as a powder formulation is reduced as the ratio of sodium acetate increases 3 times or 4 times. On the other hand, if it approaches 2 times or less than 2 times, an acetic acid odor that cannot be tolerated is produced, which is not practical.
このように国内外合わせても、酢酸を使用する透析液においては総酢酸イオン含量が４ｍＥｑ／Ｌ以下又は８ｍＥｑ／Ｌ以上のものが使用されるに止まっており、固体状Ａ剤を水に溶解して得られたＡ液（濃縮液）のｐＨが４程度となるように設定され、且つ透析液中の総酢酸イオン含量が４〜８ｍＥｑ／Ｌになるように設定されている透析用剤は存在していない。 As described above, even in domestic and overseas dialysates using acetic acid, only those with a total acetate ion content of 4 mEq / L or less or 8 mEq / L or more are used, and the solid A agent is dissolved in water. The dialysis agent set so that the pH of the liquid A (concentrated solution) obtained in this way is about 4 and the total acetate ion content in the dialysis solution is 4 to 8 mEq / L. Does not exist.
唯一、特許文献６において、酢酸と酢酸ナトリウムを使用し、透析液中の総酢酸イオン含量が最大で５ｍＥｑ／Ｌが望ましいことが開示されている。しかしながら、特許文献６には、基本濃縮物（炭酸水素ナトリウム、塩化ナトリウム及び酢酸ナトリウム）と個別濃縮物（ナトリウム、カリウム、カルシウム、マグネシウム、塩酸／又は酢酸、ブドウ糖）が開示されており、基本濃縮物と個別濃縮物を合わせた最終透析液では、アセテート／ナトリウムのモル比は０．０３以下とある。即ち、透析液中のナトリウム含量が一般的に設定されている１４０ｍＥｑ／Ｌであれば、透析液中の総酢酸イオン含量が４．２ｍＥｑ／Ｌ以下に相当する。更に基本濃縮物に配合する酢酸ナトリウムは、アセテート／ナトリウムとして０．０３未満とあり、これからも、透析液中の酢酸イオン含量が４ｍＥｑ／Ｌ程度未満であることが示されている。つまり、特許文献６は、その実態としては、総酢酸イオン含量が４ｍＥｑ／Ｌ程度未満となる透析液の製造に有効となる透析用剤が開示されているに止まっている。 Only Patent Document 6 discloses that acetic acid and sodium acetate are used, and the total acetate ion content in the dialysate is preferably 5 mEq / L at the maximum. However, Patent Document 6 discloses a basic concentrate (sodium hydrogen carbonate, sodium chloride and sodium acetate) and an individual concentrate (sodium, potassium, calcium, magnesium, hydrochloric acid / or acetic acid, glucose). In the final dialysate that combines the product and the individual concentrate, the molar ratio of acetate / sodium is 0.03 or less. That is, if the sodium content in the dialysate is generally set to 140 mEq / L, the total acetate ion content in the dialysate corresponds to 4.2 mEq / L or less. Further, sodium acetate to be blended in the basic concentrate is less than 0.03 as acetate / sodium, and it has been shown that the acetate ion content in the dialysate is less than about 4 mEq / L. That is, Patent Document 6 merely discloses a dialysis agent that is effective for producing a dialysis fluid having a total acetate ion content of less than about 4 mEq / L.
更に、特許文献６の透析用剤は、患者個々に選択できる多様な個別濃縮物の提供を可能にするものであり、その酢酸ナトリウムの配合目的は、基本濃縮物の低温時における安定性、保存性の向上である。即ち基本濃縮物中の少量の酢酸ナトリウムは炭酸水素ナトリウムの溶解性を高め、その沈殿物生成を抑制するとある。 Furthermore, the dialysis agent of Patent Document 6 makes it possible to provide various individual concentrates that can be selected for each patient, and the purpose of blending sodium acetate is the stability and storage of the basic concentrate at low temperatures. It is an improvement of sex. That is, a small amount of sodium acetate in the basic concentrate increases the solubility of sodium bicarbonate and suppresses the formation of precipitates.
つまり、特許文献６の透析用剤は、個々の患者に応じた多様な処方透析（カルシウム、マグネシウム、カリウム等）を可能にするものであって、かなり複雑なシステムを要するものであり、酢酸と酢酸塩がそれぞれ異なる製剤に配合されるように設計されているため、一般的なＡ剤及びＢ剤からなる２剤型、又はＡ−１剤、Ａ−２剤、Ｂ剤からなる３剤型透析用剤とは、その剤型、透析液の調製法の点で異なっている。また、特許文献６では、透析用剤の酢酸臭を低減するための技術的手段については一切検討されていない。更に、特許文献６の透析用剤では、個別濃縮液とするものは塩酸もしくは酢酸を含み、且つ塩基性成分を含まないために、ｐＨが３以下という強い酸性に晒されることになるため、透析液製造装置の腐食の問題、ブドウ糖等の安定性においても決して良好な製剤であるとは言えない。 That is, the dialysis agent of Patent Document 6 enables various prescription dialysis (calcium, magnesium, potassium, etc.) according to individual patients, and requires a rather complicated system. Since the acetate salt is designed to be blended into different preparations, it is a general two-agent type consisting of agent A and B, or a three-agent type consisting of agent A-1, agent A-2 and agent B. It differs from the dialysis agent in terms of its dosage form and the method of preparing the dialysis solution. Moreover, in patent document 6, the technical means for reducing the acetic acid odor of the dialysis agent is not examined at all. Furthermore, in the dialysis agent of Patent Document 6, since the individual concentrate contains hydrochloric acid or acetic acid and does not contain a basic component, it is exposed to strong acidity with a pH of 3 or less. It cannot be said that it is a good formulation in terms of the corrosion problem of liquid production equipment and the stability of glucose and the like.
以上のように、一般的な２剤型透析用剤として汎用されているＡ剤（電解質、酸、ブドウ糖等）、Ｂ剤（炭酸水素ナトリウム）の組み合わせにおいては、透析液中の総酢酸イオン含量が４〜８ｍＥｑ／Ｌとなるものは存在せず、ましてや粉末状の透析用剤については強い酢酸臭のために実用的なものはなかった。また従来の３剤型透析用剤として汎用されているＡ−１剤（電解質・酸）、Ａ−２剤（ブドウ糖）、Ｂ剤（炭酸水素ナトリウム）の組み合わせにおいても、上記問題点は全く同様であった。 As described above, in the combination of agent A (electrolyte, acid, glucose, etc.) and agent B (sodium bicarbonate), which are widely used as general two-part dialysis agents, the total acetate ion content in the dialysate However, no powdery dialysis agent was practical because of the strong odor of acetic acid. In addition, the above-mentioned problem is exactly the same in the combination of the A-1 agent (electrolyte / acid), the A-2 agent (glucose), and the B agent (sodium bicarbonate), which are widely used as conventional three-part dialysis agents Met.
実際、国内、海外合わせても、透析液中の総酢酸イオン含量が８ｍＥｑ／Ｌ未満となるように設定された粉末状の透析用剤を実際の実用化に成功した事例は皆無である。これは粉末状の透析用剤として流動性や安定性、酢酸臭の点で臨床使用に耐え得る製品化が困難であるためと考えられる。例えば、酢酸は、刺激臭がある点において環境への影響が大きい。臨床における透析液調製は一般に臨床工学技士が行うこととなるが、刺激臭に伴う不快感が生じるという点で問題がある。従って、このような問題点についても十分に考慮しつつ、最適な処方を見出す必要がある。 In fact, even in Japan and overseas, there have been no examples of successful practical application of powdered dialysis agents set so that the total acetate ion content in the dialysate is less than 8 mEq / L. This is probably because it is difficult to produce a powdery dialysis agent that can withstand clinical use in terms of fluidity, stability, and acetic acid odor. For example, acetic acid has a large environmental impact in that it has an irritating odor. The clinical dialysate preparation is generally performed by a clinical engineer, but there is a problem in that discomfort associated with an irritating odor occurs. Therefore, it is necessary to find an optimal prescription while fully considering such problems.
近年、透析液中の総酢酸イオン含量が低いほど生理的に望ましく、６ｍＥｑ／Ｌ未満または４ｍＥｑ／Ｌ未満が望ましいとも学会等で報告されており、低い総酢酸イオン含量に設定できる透析用剤の開発が益々強く求められている。このように総酢酸イオン含量を低く抑えることにより、酢酸は他の有機酸よりも代謝速度が速く、また含量も従来品より少ないため、透析中に患者の血中酢酸濃度を殆ど上げることがなく、透析時の血圧低下などの症状発現を抑制でき、安全性が格段に向上すると考えられている。但し、学会等で報告されている総酢酸イオン含量が低い透析液は、総酢酸イオン含量が８ｍＥｑ／Ｌに設定された透析用Ａ剤の酢酸及び酢酸ナトリウムの添加量を単にそれぞれ１/２に変更して調製しているため、透析液のｐＨが必然的に高くなるという欠点がある。このような高ｐＨの透析液では、継続的な使用は患者の血管石灰化を招くことが懸念され、更に透析液調製装置や透析装置へのカルシウム沈着の問題もある。 In recent years, the lower the total acetate ion content in the dialysate is physiologically desirable, the less than 6 mEq / L or less than 4 mEq / L has been reported by academic societies, etc., and dialysis agents that can be set to a low total acetate ion content have been reported. Development is increasingly sought after. By keeping the total acetate ion content low in this way, acetic acid has a faster metabolic rate than other organic acids and has a lower content than conventional products, so the patient's blood acetic acid concentration is hardly increased during dialysis. It is thought that the onset of symptoms such as a decrease in blood pressure during dialysis can be suppressed, and the safety is greatly improved. However, dialysates with low total acetate ion content reported at academic societies etc. simply reduce the addition amount of acetic acid and sodium acetate of dialysis agent A with total acetate ion content set to 8 mEq / L to 1/2 respectively. Since it is prepared by changing, there is a drawback that the pH of the dialysate is inevitably high. In such a high pH dialysate, there is a concern that continuous use may lead to vascular calcification of the patient, and there is also a problem of calcium deposition on the dialysate preparation device and the dialyzer.
一方、本願の出願人は、微量金属イオン濃度を一定に維持しつつ、患者の病態に応じて、重炭酸イオン濃度を任意に変化させることができる透析液を調製するための３剤型透析用剤、及び当該透析液の調製装置について開発している（特許文献７参照）。このように、重炭酸イオン濃度を任意に変化させることができる３剤型透析用剤であって、且つ透析液中の総酢酸イオン含量を低い値に設定可能であり、しかもＡ剤の保存安定性に優れ、酢酸臭を低減できる製剤技術を開発できれば、透析患者のみならず、透析療法の従事者に福音をもたらすことになる。 On the other hand, the applicant of the present application is for a three-drug dialysis for preparing a dialysate capable of arbitrarily changing the bicarbonate ion concentration according to the patient's condition while maintaining the trace metal ion concentration constant. An agent and an apparatus for preparing the dialysate have been developed (see Patent Document 7). In this way, it is a three-part dialysis agent that can arbitrarily change the bicarbonate ion concentration, and the total acetate ion content in the dialysate can be set to a low value, and the storage stability of agent A is stable. If we can develop a pharmaceutical technology that can reduce acetic acid odor, it will bring the gospel to dialysis patients as well as dialysis patients.
本発明の目的は、透析液中の総酢酸イオン含量を低い値に設定可能で、しかも保存安定性に優れ、酢酸臭を低減でき、更に、必要に応じて、カリウムイオン、カルシウムイオン、マグネシウムイオン等の微量金属イオン濃度は一定に維持しつつ、重炭酸イオン濃度を任意に変化させ得る透析液を調製することができる３剤型透析用剤を提供することである。 The object of the present invention is that the total acetate ion content in the dialysate can be set to a low value, is excellent in storage stability, can reduce acetic acid odor, and further, potassium ion, calcium ion, magnesium ion as required It is intended to provide a three-part dialysis agent capable of preparing a dialysate capable of arbitrarily changing the bicarbonate ion concentration while maintaining a constant trace metal ion concentration.
本発明者らは、上記課題を解決すべく鋭意研究を重ねた結果、塩化ナトリウムを含むＳ剤と、重炭酸ナトリウムを含むＢ剤と、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分を含むＡ剤を含む３剤型透析用剤において、Ａ剤に、酢酸及び酢酸塩を含有させ、且つ酢酸：酢酸塩のモル比が１：０．５〜２を充足させることによって、総酢酸イオン濃度が２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満となるような重炭酸透析液が調製可能となり、当該Ａ剤中の成分の安定性が優れていることに加え、酢酸臭を低減できることを見出した。更に、当該３剤型透析用剤によれば、Ｓ剤とＡ剤を同時に溶解し、一般的な２剤型透析剤として使用できることはもちろんであるが、更に特許文献７のように透析液の調製時にＳ剤、Ｂ剤、及びＡ剤の添加量を調節することによって透析液中の重炭酸イオン濃度及び／又はナトリウム濃度を変化させ得ることも可能になる。本発明は、かかる知見に基づいて、更に検討を重ねることにより完成したものである。 As a result of intensive studies to solve the above problems, the present inventors have found that an S agent containing sodium chloride, a B agent containing sodium bicarbonate, and an A agent containing an electrolyte component other than sodium chloride and sodium bicarbonate. In the three-drug type dialysis agent containing A, the agent A contains acetic acid and acetate, and the molar ratio of acetic acid: acetate is 1: 0.5 to 2 so that the total acetate ion concentration is 2 mEq. It has been found that a bicarbonate dialysis solution can be prepared so as to be at least / L and less than 6 mEq / L, and in addition to the excellent stability of the components in the agent A, the acetic acid odor can be reduced. Furthermore, according to the three-agent dialysis agent, the S agent and the A agent can be dissolved at the same time and used as a general two-agent dialysis agent. It is also possible to change the bicarbonate ion concentration and / or the sodium concentration in the dialysate by adjusting the amount of S agent, B agent, and A agent added during preparation. The present invention has been completed by further studies based on this finding.
即ち、本発明は、下記に掲げる態様の発明を提供する。
項１． 塩化ナトリウムを含むＳ剤と、重炭酸ナトリウムを含むＢ剤と、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分を含むＡ剤を含む、透析液を調製するための３剤型の透析用剤であり、
前記Ａ剤が、酢酸及び酢酸塩を含み、且つ酢酸：酢酸塩のモル比が１：０．５〜２であり、
総酢酸イオンが２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満である透析液の調製に使用される、３剤型透析用剤。
項２． 前記Ａ剤における酢酸：酢酸塩のモル比が１：１〜１．５である、項１に記載の３剤型透析用剤。
項３． 総酢酸イオンが２ｍＥｑ／Ｌ以上５ｍＥｑ／Ｌ以下である透析液の調製に使用される、項１又は２に記載の３剤型透析用剤。
項４． 前記Ａ剤を、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した水溶液の状態にした際に、ｐＨが３．９〜４．７を示す、項１〜３のいずれかに記載の３剤型透析用剤。
項５． 酢酸塩が酢酸ナトリウムである、項１〜４のいずれかに記載の３剤型透析用剤。
項６． 前記Ａ剤が、更に、酢酸、酢酸塩、塩化ナトリウム及び重炭酸ナトリウム以外の生理的に利用可能な電解質成分を含む、項１〜５のいずれかに記載の３剤型透析用剤。
項７． 前記電解質として、塩化カリウム、塩化マグネシウム、及び塩化カルシウムを含む、項６に記載の３剤型透析用剤。
項８． 前記Ａ剤が、更に、ブドウ糖を含む、項１〜７のいずれかに記載の３剤型透析用剤。
項９． 前記Ａ剤が、前記電解質として、更に酢酸塩以外の有機酸塩を含む、及び／又はｐＨ調節剤として酢酸以外の有機酸を含む項６〜８のいずれかに記載の３剤型透析用剤。
項１０． 前記Ａ剤が固体状である、項１〜９のいずれかに記載の３剤型透析用剤。
項１１． 前記Ａ剤が固体状であり、且つ前記塩化マグネシウム及び／又は塩化カルシウムが、乾燥物若しくは無水物である、項７に記載の３剤型透析用剤。
項１２． 前記酢酸及び酢酸塩が混合物として含まれる、項１０又は１１に記載の３剤型透析用剤。
項１３． 前記酢酸及び酢酸塩の少なくとも一部が二酢酸アルカリ金属塩の形態で含まれる、項１０〜１２のいずれかに記載の３剤型透析用剤。
項１４． 前記二酢酸アルカリ金属塩が、二酢酸ナトリウム及び／又は二酢酸カリウムである、項１３に記載の３剤型透析用剤。
項１５． 前記有機酸塩が、乳酸ナトリウム、グルコン酸ナトリウム、クエン酸ナトリウム、リンゴ酸ナトリウム、及びコハク酸ナトリウムよりなる群から選択される少なくとも１種である、項９に記載の３剤型透析用剤。
項１６． 前記有機酸が、乳酸、グルコン酸、グルコノデルタラクトン、クエン酸、リンゴ酸、及びコハク酸よりなる群から選択される少なくとも１種である、項９に記載の３剤型透析用剤。
項１７． 前記Ａ剤が、酢酸及び酢酸塩の混合物を含む第１原料と、酢酸及び酢酸塩以外の生理的に利用可能な電解質を含む組成物を含む第２原料を含み、
前記Ａ剤中の酢酸塩の全てが前記第１原料に含まれ、又は透析用Ａ剤中の酢酸塩の一部が前記第２原料にも含まれ、且つ
ブドウ糖が前記第２原料の組成物に含まれる、及び／又は第１原料と第２原料とは別にブドウ糖を含む第３原料が含まれる、
項１０〜１６のいずれかに記載の３剤型透析用剤。
項１８． 前記第２原料に、電解質として、塩化カリウム、塩化マグネシウム、及び塩化カルシウムを含む、項１７に記載の３剤型透析用剤。
項１９． 前記第２原料に、電解質として、更に酢酸塩以外の有機酸塩が含まれる、項１７又は１８に記載の３剤型透析用剤。
項２０． 前記Ｓ剤、Ｂ剤、及びＡ剤が、透湿度が０．５ｇ／ｍ2・２４ｈ以下の包装容器に収容されてなる、項１０〜１９のいずれかに記載の３剤型透析用剤。
項２１． 前記Ｓ剤、Ｂ剤、及びＡ剤が、包装容器に、乾燥剤と共に収容されてなる、項１０〜２０のいずれかに記載の３剤型透析用剤。
項２２． 用時にＳ剤、Ｂ剤、及びＡ剤の添加量を調節することによって透析液中の重炭酸イオン濃度及び／又はナトリウム濃度を変化させて使用される、項１〜２１のいずれか記載の３剤型透析用剤。
That is, this invention provides the invention of the aspect hung up below.
Item 1. It is a three-part dialysis agent for preparing dialysate, which contains S agent containing sodium chloride, B agent containing sodium bicarbonate, and A agent containing electrolyte components other than sodium chloride and sodium bicarbonate. ,
The agent A contains acetic acid and acetate, and the molar ratio of acetic acid: acetate is 1: 0.5-2,
A three-part dialysis agent used for preparing a dialysate having a total acetate ion of 2 mEq / L or more and less than 6 mEq / L.
Item 2. Item 3. The three-part dialysis agent according to Item 1, wherein the molar ratio of acetic acid: acetate in Agent A is 1: 1 to 1.5.
Item 3. Item 3. The three-part dialysis agent according to Item 1 or 2, which is used for preparing a dialysate having a total acetate ion of 2 mEq / L or more and 5 mEq / L or less.
Item 4. Any of the items 1 to 3, wherein the pH of the agent A is 3.9 to 4.7 when the solution is concentrated to 175 times the concentration of each component in the dialysate to be finally prepared. A three-part dialysis agent according to claim 1.
Item 5. Item 5. The three-part dialysis agent according to any one of Items 1 to 4, wherein the acetate is sodium acetate.
Item 6. Item 6. The agent for three-part dialysis according to any one of Items 1 to 5, wherein the agent A further contains a physiologically usable electrolyte component other than acetic acid, acetate, sodium chloride and sodium bicarbonate.
Item 7. Item 7. The three-part dialysis agent according to Item 6, comprising potassium chloride, magnesium chloride, and calcium chloride as the electrolyte.
Item 8. Item 8. The three-agent dialysis agent according to any one of Items 1 to 7, wherein the agent A further comprises glucose.
Item 9. Item 9. The agent for three-part dialysis according to any one of Items 6 to 8, wherein the agent A further contains an organic acid salt other than acetate as the electrolyte, and / or an organic acid other than acetic acid as a pH regulator. .
Item 10. Item 10. The three-part dialysis agent according to any one of Items 1 to 9, wherein the agent A is solid.
Item 11. Item 8. The three-part dialysis agent according to Item 7, wherein the agent A is solid and the magnesium chloride and / or calcium chloride is a dried product or an anhydride.
Item 12. Item 13. The three-part dialysis agent according to Item 10 or 11, wherein the acetic acid and acetate are included as a mixture.
Item 13. Item 13. The three-part dialysis agent according to any one of Items 10 to 12, wherein at least a part of the acetic acid and the acetate is contained in the form of an alkali metal diacetate.
Item 14. Item 14. The three-part dialysis agent according to Item 13, wherein the alkali metal diacetate is sodium diacetate and / or potassium diacetate.
Item 15. Item 10. The three-part dialysis agent according to Item 9, wherein the organic acid salt is at least one selected from the group consisting of sodium lactate, sodium gluconate, sodium citrate, sodium malate, and sodium succinate.
Item 16. Item 10. The three-part dialysis agent according to Item 9, wherein the organic acid is at least one selected from the group consisting of lactic acid, gluconic acid, glucono delta lactone, citric acid, malic acid, and succinic acid.
Item 17. The agent A includes a first raw material containing a mixture of acetic acid and acetate, and a second raw material containing a composition containing a physiologically usable electrolyte other than acetic acid and acetate,
Composition of the second raw material, wherein all of the acetate in the agent A is contained in the first raw material, or part of the acetate in the agent A for dialysis is also contained in the second raw material. And / or a third raw material containing glucose separately from the first raw material and the second raw material,
Item 15. A three-part dialysis agent according to any one of Items 10 to 16.
Item 18. Item 18. The three-part dialysis agent according to Item 17, wherein the second raw material contains potassium chloride, magnesium chloride, and calcium chloride as an electrolyte.
Item 19. Item 19. The three-part dialysis agent according to Item 17 or 18, wherein the second raw material further contains an organic acid salt other than acetate as an electrolyte.
Item 20. Item 20. The three-part dialysis agent according to any one of Items 10 to 19, wherein the agent S, agent B, and agent A are accommodated in a packaging container having a moisture permeability of 0.5 g / m 2 · 24 h or less.
Item 21. Item 21. The three-part dialysis agent according to any one of Items 10 to 20, wherein the agent S, agent B, and agent A are contained in a packaging container together with a desiccant.
Item 22. Item 3. The item according to any one of Items 1 to 21, which is used by changing the bicarbonate ion concentration and / or the sodium concentration in the dialysate by adjusting the amount of S agent, B agent, and A agent added during use. Drug type dialysis agent.
本発明の３剤型透析用剤は、総酢酸イオン濃度が６ｍＥｑ／Ｌ未満になるように重炭酸透析液を調製できるので、透析時の血圧低下等の症状発現を抑制でき、安全性を格段に向上させることが可能になっており、更には透析液中でイオン化カルシウム濃度が低下するのを効果的に抑制することもできる。また、本発明の３剤型透析用剤におけるＡ剤は、ブドウ糖等の他の含有成分の安定性の向上、及び酢酸臭の低減が図られており、更には透析液調製装置や透析装置の腐食も抑制できるので、品質の向上、医療現場での使用環境の改善等が図られ、医療現場での操作性が格段に向上している。 Since the bicarbonate dialysis solution can be prepared so that the total acetate ion concentration is less than 6 mEq / L, the three-drug dialysis agent of the present invention can suppress the onset of symptoms such as a decrease in blood pressure during dialysis. In addition, it is possible to effectively suppress the decrease in the ionized calcium concentration in the dialysate. In addition, the agent A in the three-part dialysis agent of the present invention is intended to improve the stability of other components such as glucose and reduce the odor of acetic acid. Corrosion can also be suppressed, improving the quality, improving the use environment at the medical site, and so on, and improving the operability at the medical site.
とりわけ、本発明の３剤型透析用剤におけるＡ剤について、透析液中の総酢酸イオン濃度が２〜５ｍＥｑ／Ｌとなるように設定し、且つ酢酸：酢酸塩のモル比を１：１〜１．５程度に設定することにより、固体状Ａ剤を水に溶解して得られたＡ液（濃縮液）のｐＨ又は液体状Ａ剤のｐＨを４．４付近にすることができ、より一層、臨床的に安全で、且つ製造及び品質的にも安定性に優れた３剤型透析用剤を提供することが可能になる。 In particular, for agent A in the three-part dialysis agent of the present invention, the total acetate ion concentration in the dialysate is set to 2 to 5 mEq / L, and the molar ratio of acetic acid: acetate is 1: 1 to 1. By setting it to about 1.5, the pH of the liquid A (concentrated liquid) obtained by dissolving the solid A agent in water or the pH of the liquid A agent can be made around 4.4. Further, it is possible to provide a three-part dialysis agent that is clinically safe and excellent in stability in terms of production and quality.
このように、本発明によれば、総酢酸イオン濃度が６ｍＥｑ／Ｌ未満になるように重炭酸透析液を調製でき、従来の透析用剤よりも、臨床的に有用で且つ保存性やハンドリングの点でも優れた３剤型透析用剤を提供できる。 Thus, according to the present invention, a bicarbonate dialysis solution can be prepared so that the total acetate ion concentration is less than 6 mEq / L, which is clinically more useful and more storable and easier to handle than conventional dialysis agents. A three-part dialysis agent that is also superior in terms of points can be provided.
また、本発明によれば、特許文献７のように透析液の調製時に必要に応じて、Ｓ剤、Ｂ剤、及びＡ剤の添加量を調節することによって透析液中の重炭酸イオン濃度及び／又はナトリウム濃度を自在に変化させることもできる。例えば、本発明によれば、透析液中のカリウムイオン、カルシウムイオン、マグネシウムイオン等の微量金属イオン濃度を一定に維持しつつ、重炭酸イオン濃度を自在に変化させるとともにｐＨを至適範囲に制御できるので、患者の病態に適合した代謝性アシドーシスの是正が可能になる。そのため、本発明は、透析患者の死亡や入院リスクを低減させることができ、今後の透析治療において極めて有用である。 In addition, according to the present invention, as in Patent Document 7, the concentration of bicarbonate ions in the dialysate and the concentration of the S agent, the B agent, and the A agent are adjusted as necessary when preparing the dialysate. In addition, the sodium concentration can be freely changed. For example, according to the present invention, the concentration of trace ions such as potassium ions, calcium ions, magnesium ions, etc. in the dialysate is kept constant, the bicarbonate ion concentration is freely changed, and the pH is controlled within the optimum range. As a result, it is possible to correct metabolic acidosis that matches the patient's condition. Therefore, this invention can reduce the death and hospitalization risk of a dialysis patient, and is very useful in future dialysis treatment.
本明細書において、数値範囲を示す「〜」の表示は、その左側に付している数値以上且つその右側に付している数値以下であることを示し、例えば数値範囲「Ｘ〜Ｙ」の表記はＸ以上Ｙ以下であることを意味する。 In the present specification, the indication of “˜” indicating a numerical range indicates that the numerical value is greater than or equal to the numerical value attached to the left side and less than or equal to the numerical value attached to the right side thereof. The notation means X or more and Y or less.
本発明は、重炭酸透析液を調製するための３剤型透析用剤であり、塩化ナトリウムを含むＳ剤と、重炭酸ナトリウムを含むＢ剤と、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分を含むＡ剤を含み、当該Ａ剤が、酢酸及び酢酸塩を含み、且つ酢酸：酢酸塩のモル比が１：０．５〜２であり、総酢酸イオンが２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満である透析液の調製に使用されることを特徴とする。以下、本発明の３剤型透析用剤について詳述する。 The present invention is a three-part dialysis agent for preparing a bicarbonate dialysate, comprising an S agent containing sodium chloride, a B agent containing sodium bicarbonate, and an electrolyte component other than sodium chloride and sodium bicarbonate. The A agent contains an acetic acid and an acetate, the molar ratio of acetic acid: acetate is 1: 0.5-2, and the total acetate ion is 2 mEq / L or more and less than 6 mEq / L. It is used for the preparation of a certain dialysate. Hereinafter, the three-part dialysis agent of the present invention will be described in detail.
Ｓ剤
Ｓ剤には、塩化ナトリウムが含まれる。Ｓ剤には、塩化ナトリウム以外の電解質成分が含まれていないことが望ましく、含有成分が実質的に塩化ナトリウムのみからなるものが好適である。Ｓ剤は、固形状又は水溶液のいずれの形態で提供されてもよいが、輸送や保管の容易性の観点から、固形状であることが望ましい。固形状のＳ剤の形状としては、具体的には、粉末剤、顆粒剤等が挙げられる。本明細書において、固形状のＳ剤を「固形Ｓ剤」、水溶液のＳ剤を「液状Ｓ剤」と表記することもある。
S agent S agent contains sodium chloride. It is desirable that the S agent does not contain any electrolyte component other than sodium chloride, and it is preferable that the component contains substantially only sodium chloride. The agent S may be provided in a solid form or an aqueous solution form, but is preferably in a solid form from the viewpoint of ease of transportation and storage. Specific examples of the shape of the solid S agent include powders and granules. In the present specification, the solid S agent is sometimes referred to as “solid S agent”, and the aqueous S agent is sometimes referred to as “liquid S agent”.
液状Ｓ剤を採用する場合、液状Ｓ剤に含まれる塩化ナトリウムの含量については、例えば８〜３２ｇ／１００ｍｌ、好ましくは２６〜３２ｇ／１００ｍｌ、更に好ましくは３０〜３１ｇ／１００ｍｌが挙げられる。 When the liquid S agent is employed, the content of sodium chloride contained in the liquid S agent is, for example, 8 to 32 g / 100 ml, preferably 26 to 32 g / 100 ml, and more preferably 30 to 31 g / 100 ml.
Ｓ剤を流通時に収容する包装容器については、特に制限されないが、例えば、Ａ剤を収容する包装容器と同様のものが挙げられる。 Although it does not restrict | limit especially about the packaging container which accommodates S agent at the time of distribution, For example, the same thing as the packaging container which accommodates A agent is mentioned.
Ｂ剤
Ｂ剤には、重炭酸ナトリウムが含まれる。Ｂ剤には、重炭酸ナトリウム以外の電解質成分が含まれていないことが望ましく、含有成分が実質的に重炭酸ナトリウムのみからなるものが好適である。Ｂ剤も、Ｓ剤と同様に、固形状又は水溶液のいずれの形態で提供されてもよいが、輸送や保管の容易性の観点から、固形状であることが望ましい。固形状のＢ剤の形状としては、具体的には、粉末剤、顆粒剤等が挙げられる。本明細書において、固形状のＢ剤を「固形Ｂ剤」、水溶液のＢ剤を「液状Ｂ剤」と表記することもある。
Agent B Agent B includes sodium bicarbonate. It is desirable that the B agent does not contain an electrolyte component other than sodium bicarbonate, and it is preferable that the component B consists essentially of sodium bicarbonate. Similarly to the S agent, the B agent may be provided in any form of a solid or an aqueous solution, but it is preferably a solid from the viewpoint of ease of transportation and storage. Specific examples of the shape of the solid B agent include powders and granules. In the present specification, the solid B agent may be referred to as “solid B agent”, and the aqueous B agent may be referred to as “liquid B agent”.
液状Ｂ剤を採用する場合、液状Ｂ剤に含まれる重炭酸ナトリウムの含量は、最終的に得られる透析液において所望の重炭酸イオン濃度を充足させ得る量であればよいが、例えば７〜１２ｇ／１００ｍｌ、好ましくは８〜１２ｇ／１００ｍｌ、更に好ましくは９〜１１ｇ／１００ｍｌが挙げられる。 When the liquid B agent is used, the content of sodium bicarbonate contained in the liquid B agent may be an amount that can satisfy the desired bicarbonate ion concentration in the finally obtained dialysate, for example, 7 to 12 g. / 100 ml, preferably 8 to 12 g / 100 ml, more preferably 9 to 11 g / 100 ml.
Ｂ剤を流通時に収容する包装容器については、特に制限されないが、例えば、Ａ剤を収容する包装容器と同様のものが挙げられる。 Although it does not restrict | limit especially about the packaging container which accommodates B agent at the time of distribution, For example, the same thing as the packaging container which accommodates A agent is mentioned.
Ａ剤
Ａ剤には、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分が含まれる。また、当該Ａ剤には、電解質成分として、少なくとも酢酸及び酢酸塩が含まれ、且つ酢酸：酢酸塩のモル比が１：０．５〜２である。
Agent A Agent A contains electrolyte components other than sodium chloride and sodium bicarbonate. In addition, the agent A contains at least acetic acid and acetate as an electrolyte component, and the molar ratio of acetic acid: acetate is 1: 0.5-2.
Ａ剤に含まれる酢酸は氷酢酸であってもよい。また、Ａ剤に含まれる酢酸塩としては、透析液の成分として許容されるものである限り、特に制限されないが、例えば、酢酸ナトリウム、酢酸カリウム、酢酸カルシウム、酢酸マグネシウム等が挙げられる。これらの酢酸塩の中でも、長年の使用実績による安全性、コストの観点から、好ましくは酢酸ナトリウムが挙げられる。また、これらの酢酸塩は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 The acetic acid contained in the agent A may be glacial acetic acid. The acetate contained in the agent A is not particularly limited as long as it is acceptable as a component of the dialysate, and examples thereof include sodium acetate, potassium acetate, calcium acetate, and magnesium acetate. Among these acetates, sodium acetate is preferably used from the viewpoint of safety and cost due to many years of use. Moreover, these acetates may be used individually by 1 type, and may be used in combination of 2 or more type.
また、Ａ剤が固体状である場合、含まれる酢酸及び酢酸塩は、その少なくとも一部が二酢酸アルカリ金属塩の形態であってもよい。二酢酸アルカリ金属塩とは、酢酸アルカリ金属塩１モルと酢酸１モルが複合化した複合体（ＭＨ（Ｃ2Ｈ3Ｏ2）2；Ｍはアルカリ金属原子を示す）であり、二酢酸アルカリ金属塩１モルからは、酢酸塩（酢酸アルカリ金属塩）１モルと酢酸１モルが供給されることになる。二酢酸アルカリ金属塩としては、具体的には、二酢酸ナトリウム、二酢酸カリウム等が挙げられる。これらの二酢酸アルカリ金属塩は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。二酢酸アルカリ金属塩の中でも、好ましくは二酢酸ナトリウムが挙げられる。 Further, when the agent A is in a solid form, at least a part of the acetic acid and acetate contained therein may be in the form of an alkali metal diacetate salt. The alkali metal diacetate is a complex (MH (C 2 H 3 O 2 ) 2 ; M represents an alkali metal atom) in which 1 mol of an alkali metal acetate and 1 mol of acetic acid are complexed. From 1 mol of the metal salt, 1 mol of acetate (alkali metal acetate) and 1 mol of acetic acid are supplied. Specific examples of the alkali metal diacetate include sodium diacetate and potassium diacetate. These alkali metal diacetates may be used individually by 1 type, and may be used in combination of 2 or more type. Among the alkali metal diacetates, sodium diacetate is preferable.
Ａ剤は、酢酸及び酢酸塩を、酢酸：酢酸塩のモル比が１：０．５〜２を充足するように含有する。このようなモル比を充足することによって、透析液中の総酢酸イオン濃度を６ｍＥｑ／Ｌ未満に設定しても、固体状Ａ剤を水に溶解して得られたＡ液（濃縮液）のｐＨ又は液体状Ａ剤のｐＨを３．９〜４．７程度に調製することができ、透析液調製装置や透析装置の腐食を抑制することが可能になる。更に、このようなモル比を充足することによって、Ａ剤の保存安定性を高め、更には酢酸臭の低減を図ることも可能になる。 Agent A contains acetic acid and acetate so that the molar ratio of acetic acid: acetate satisfies 1: 0.5-2. By satisfying such a molar ratio, even if the total acetate ion concentration in the dialysate is set to less than 6 mEq / L, the liquid A obtained by dissolving the solid A agent in water (concentrated solution) The pH or pH of the liquid A agent can be adjusted to about 3.9 to 4.7, and corrosion of the dialysate preparation device and the dialyzer can be suppressed. Furthermore, by satisfying such a molar ratio, it becomes possible to improve the storage stability of the agent A and further reduce the acetic acid odor.
Ａ剤における酢酸と酢酸塩の比率としては、透析用Ａ剤の保存安定性の向上、酢酸臭の低減、及び透析液調製装置や透析装置の腐食を抑制等の作用をより一層効果的に発揮させるという観点から、酢酸：酢酸塩のモル比が、好ましくは１：０．７５〜１．７５、より好ましくは１：０．７５〜１．５、更に好ましくは１：１〜１．５、特に好ましくは１：１〜１．２５が挙げられる。ここで、前述するように、二酢酸アルカリ金属塩は、酢酸１モルと酢酸アルカリ金属塩１モルの複合体であるので、酢酸及び酢酸塩の少なくとも一部として二酢酸アルカリ金属塩を使用する場合であれば、二酢酸アルカリ金属塩１モルに由来する酢酸と酢酸塩は、各々１モルとして計算される。即ち、例えば、酢酸及び酢酸塩が二酢酸アルカリ金属塩のみからなる場合には、酢酸：酢酸塩のモル比は１：１になる。また、例えば、酢酸及び酢酸塩が、二酢酸アルカリ金属塩Ｘモル、酢酸Ｙモル、及び酢酸塩Ｚモルからなる場合には、酢酸：酢酸塩のモル比は１：（Ｘ＋Ｚ）／（Ｘ＋Ｙ）になる。 The ratio of acetic acid to acetate in agent A is more effective in improving the storage stability of agent A for dialysis, reducing the odor of acetic acid, and inhibiting corrosion of the dialysate preparation device and dialysis device. From the viewpoint of achieving the above, the molar ratio of acetic acid: acetate is preferably 1: 0.75 to 1.75, more preferably 1: 0.75 to 1.5, still more preferably 1: 1 to 1.5, Particularly preferred is 1: 1 to 1.25. Here, as described above, since the alkali metal diacetate is a complex of 1 mole of acetic acid and 1 mole of alkali metal acetate, when the alkali metal diacetate is used as at least a part of acetic acid and acetate, Then, acetic acid and acetate derived from 1 mol of alkali metal diacetate are each calculated as 1 mol. That is, for example, when acetic acid and acetate consist only of alkali metal diacetate, the molar ratio of acetic acid: acetate is 1: 1. Further, for example, when acetic acid and acetate are composed of X mol of alkali metal diacetate, Y mol of acetic acid, and Z mol of acetate, the molar ratio of acetic acid: acetate is 1: (X + Z) / (X + Y) become.
Ａ剤に含まれる酢酸と酢酸塩の含量については、固体状又は液体状であるかに応じて適宜設定すればよいが、通常、最終的に調製される透析液中の総酢酸イオン含量が２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満、好ましくは２ｍＥｑ／Ｌ以上５．５ｍＥｑ／Ｌ以下、更に好ましくは２ｍＥｑ／Ｌ以上５ｍＥｑ／Ｌ以下となるように設定される。このように、本発明の透析用Ａ剤によれば、従来の透析用剤では実現できていないレベルにまで透析液中の総酢酸イオン含量を低く設定できるので、透析時に酢酸イオンによって誘発される血圧低下等の症状発現を抑制でき、安全性を格段に向上させることが可能になる。 The content of acetic acid and acetate contained in the agent A may be appropriately set depending on whether it is solid or liquid. Usually, the total acetate ion content in the finally prepared dialysate is 2 mEq. / L or more and less than 6 mEq / L, preferably 2 mEq / L or more and 5.5 mEq / L or less, more preferably 2 mEq / L or more and 5 mEq / L or less. Thus, according to the dialysis agent A of the present invention, the total acetate ion content in the dialysate can be set to a level that cannot be achieved with conventional dialysis agents, and therefore induced by acetate ions during dialysis. Symptoms such as a decrease in blood pressure can be suppressed and safety can be significantly improved.
また、Ａ剤には、酢酸及び酢酸塩以外に、マグネシウムイオン、カルシウムイオン、ナトリウムイオン、カリウムイオン、塩化物イオン、クエン酸イオン、乳酸イオン、グルコン酸イオン、コハク酸イオン、リンゴ酸イオン等の供給源になる電解質成分が１種又は２種以上含まれていてもよい。Ａ剤に含まれる電解質成分（酢酸及び酢酸塩以外）として、少なくとも塩化物イオン、マグネシウムイオン及びカルシウムイオンの供給源になるものが含まれていることが好ましく、これらに加えてカリウムイオンの供給源になるものが更に含まれていることがより好ましい。 In addition to the acetic acid and acetate, the agent A includes magnesium ion, calcium ion, sodium ion, potassium ion, chloride ion, citrate ion, lactate ion, gluconate ion, succinate ion, malate ion, etc. 1 type, or 2 or more types of electrolyte components used as a supply source may be contained. The electrolyte component (other than acetic acid and acetate) contained in the agent A preferably contains at least chloride ion, magnesium ion and calcium ion supply sources, and in addition to these, potassium ion supply sources It is more preferable that the following is further included.
マグネシウムイオンの供給源としては、マグネシウム塩が挙げられる。Ａ剤に使用されるマグネシウム塩については、透析液の成分として許容されるものである限り、特に制限されないが、例えば、塩化マグネシウム、乳酸マグネシウム、クエン酸マグネシウム、グルコン酸マグネシウム、コハク酸マグネシウム、リンゴ酸マグネシウム等が挙げられる。これらのマグネシウム塩の中でも、塩化マグネシウムは、水に対する溶解度が高いため、マグネシウムの供給源として好適に使用される。これらのマグネシウム塩は、水和物の形態であってもよく、また水和物を乾燥により脱水させた形態であってもよい。また、これらのマグネシウム塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 A magnesium salt is mentioned as a supply source of magnesium ions. Although it does not restrict | limit especially about the magnesium salt used for A agent, as long as it is accept | permitted as a component of a dialysate, For example, magnesium chloride, magnesium lactate, magnesium citrate, magnesium gluconate, magnesium succinate, apple Examples include magnesium acid. Among these magnesium salts, magnesium chloride is preferably used as a magnesium supply source because of its high solubility in water. These magnesium salts may be in the form of hydrates or may be in the form of dehydrated hydrates by drying. Moreover, these magnesium salts may be used individually by 1 type, and may be used in combination of 2 or more type.
カルシウムイオンの供給源としては、カルシウム塩が挙げられる。Ａ剤に使用されるカルシウム塩としては、透析液の成分として許容されるものである限り、特に制限されないが、例えば、塩化カルシウム、乳酸カルシウム、クエン酸カルシウム、グルコン酸カルシウム、コハク酸カルシウム、リンゴ酸カルシウム等が挙げられる。これらのカルシウム塩の中でも、塩化カルシウムは、水に対する溶解度が高いため、カルシウムの供給源として好適に使用される。これらのカルシウム塩は、水和物の形態であってもよく、また水和物を乾燥により脱水させた形態であってもよい。また、これらのカルシウム塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 A calcium salt is mentioned as a supply source of calcium ions. The calcium salt used in the agent A is not particularly limited as long as it is acceptable as a component of the dialysate. For example, calcium chloride, calcium lactate, calcium citrate, calcium gluconate, calcium succinate, apple An acid calcium etc. are mentioned. Among these calcium salts, calcium chloride is preferably used as a calcium supply source because of its high solubility in water. These calcium salts may be in the form of hydrates or in the form of dehydrated hydrates by drying. Moreover, these calcium salts may be used individually by 1 type, and may be used in combination of 2 or more type.
ナトリウムイオンの供給源としては、ナトリウム塩が挙げられる。酢酸塩として酢酸ナトリウムを使用する場合には、当該酢酸ナトリウムがナトリウムイオンの供給源となるが、酢酸ナトリウム以外のナトリウム塩も使用することによって、ナトリウムイオンを補充し、透析液に所望のナトリウムイオン濃度を備えさせることができる。ナトリウム塩は、透析液の成分として許容されるものである限り、特に制限されないが、例えば、乳酸ナトリウム、クエン酸ナトリウム、グルコン酸ナトリウム、コハク酸ナトリウム、リンゴ酸ナトリウム等が挙げられる。これらのナトリウム塩は、水和物の形態であってもよい。また、これらのナトリウム塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 A sodium salt is mentioned as a supply source of sodium ions. When sodium acetate is used as the acetate salt, the sodium acetate is a source of sodium ions. However, by using a sodium salt other than sodium acetate, sodium ions are supplemented, and the dialysate is filled with desired sodium ions. A concentration can be provided. The sodium salt is not particularly limited as long as it is acceptable as a component of the dialysate, and examples thereof include sodium lactate, sodium citrate, sodium gluconate, sodium succinate, and sodium malate. These sodium salts may be in the form of hydrates. Moreover, these sodium salts may be used individually by 1 type, and may be used in combination of 2 or more type.
カリウムイオンの供給源としては、カリウム塩が挙げられる。Ａ剤に配合されるカリウム塩についても、透析液の成分として許容されるものである限り、特に制限されないが、例えば、塩化カリウム、乳酸カリウム、クエン酸カリウム、グルコン酸カリウム、コハク酸カリウム、リンゴ酸カリウム等が挙げられる。これらのカリウム塩の中でも、塩化カリウムは、塩化物イオンが最も生理的な物質であるため、カリウムの供給源として好適に使用される。これらのカリウム塩は、水和物の形態であってもよい。また、これらのカリウム塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。 A potassium salt is mentioned as a supply source of potassium ions. The potassium salt blended with the agent A is not particularly limited as long as it is acceptable as a component of the dialysate. For example, potassium chloride, potassium lactate, potassium citrate, potassium gluconate, potassium succinate, apple A potassium acid etc. are mentioned. Among these potassium salts, potassium chloride is suitably used as a potassium source because chloride ions are the most physiological substance. These potassium salts may be in the form of hydrates. Moreover, these potassium salts may be used individually by 1 type, and may be used in combination of 2 or more type.
塩化物イオンの供給源としては、塩化物塩が挙げられる。Ａ剤に配合される塩化物塩についても、透析液の成分として許容されるものである限り、特に制限されないが、塩化カルシウム、塩化マグネシウム、塩化カリウム等が挙げられる。これらの塩化物塩は、水に対する溶解度が高く、しかもカリウム、マグネシウム、又はカリウムの供給源としての役割も果たし得るので、好適に使用される。これらの塩化物塩は、水和物の形態であってもよい。また、これらの塩化物塩は、１種を単独で使用してもよく、２種以上を組み合わせて使用してもよい。また、ｐＨ調節剤としての役割も果たす塩酸を塩化物イオンの供給源として用いることもできる。 Examples of the source of chloride ions include chloride salts. The chloride salt added to the agent A is not particularly limited as long as it is acceptable as a component of the dialysate, and examples thereof include calcium chloride, magnesium chloride, and potassium chloride. These chloride salts are preferably used because they have high solubility in water and can also serve as a source of potassium, magnesium, or potassium. These chloride salts may be in the form of hydrates. Moreover, these chloride salts may be used individually by 1 type, and may be used in combination of 2 or more type. Hydrochloric acid, which also serves as a pH regulator, can also be used as a chloride ion source.
前述するように、Ａ剤に配合される各電解質成分は水和物の形態であってもよいが、より一層効果的に酢酸臭の低減、及び保存安定性の向上を図るという観点から、無水物の形態であることが好ましい。 As described above, each electrolyte component blended with the agent A may be in the form of a hydrate, but from the viewpoint of more effectively reducing acetic acid odor and improving storage stability, It is preferably in the form of a product.
Ａ剤に配合される電解質成分の種類と組み合わせについては、最終的に調製される透析液に含有させる各イオンの組成に応じて適宜設定されるが、Ａ剤に含まれる電解質成分（酢酸及び酢酸塩以外）の好適な例として、塩化マグネシウム、塩化カルシウム、及び塩化カリウムの組み合わせが挙げられる。また、電解質成分として、塩化マグネシウム、塩化カルシウム、及び塩化カリウムを組み合わせて使用する場合、更に有機酸塩（酢酸塩以外）を含んでいてもよい。このような有機酸塩としては、例えば、乳酸ナトリウム、グルコン酸ナトリウム、クエン酸ナトリウム、リンゴ酸ナトリウム、コハク酸ナトリウム等が挙げられる。これらの有機酸塩は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。 About the kind and combination of the electrolyte component mix | blended with A agent, although it sets suitably according to the composition of each ion contained in the dialysate finally prepared, the electrolyte component (Acetic acid and acetic acid contained in A agent) Preferable examples of other than salts include a combination of magnesium chloride, calcium chloride, and potassium chloride. Moreover, when using it combining magnesium chloride, calcium chloride, and potassium chloride as an electrolyte component, organic acid salt (other than acetate) may further be included. Examples of such organic acid salts include sodium lactate, sodium gluconate, sodium citrate, sodium malate, and sodium succinate. These organic acid salts may be used alone or in combination of two or more.
Ａ剤に含まれる各電解質成分の含有量は、最終的に調製される透析液に備えさせる各イオン濃度に応じて適宜設定される。具体的には、Ａ剤に含まれる電解質成分の含有量（酢酸及び酢酸塩以外）は、酢酸塩の種類とその含有量、Ｓ剤及びＢ剤に含有する電解質成分の量等を勘案し、最終的に調製される透析液が下記表２に示す各イオン濃度を満たすように、適宜設定すればよい。 The content of each electrolyte component contained in the agent A is appropriately set according to each ion concentration provided in the finally prepared dialysate. Specifically, the content of the electrolyte component contained in the agent A (other than acetic acid and acetate) takes into account the type and content of the acetate, the amount of the electrolyte component contained in the agent S and agent B, etc. What is necessary is just to set suitably so that the dialysate finally prepared may satisfy | fill each ion concentration shown in following Table 2. FIG.
なお、前記表２に示す各イオン濃度は、酢酸塩に由来する各イオンを含むものであり、Ａ剤に含まれる各電解質成分の量は、酢酸塩から供給されるイオンの量も勘案して決定される。また、Ａ剤に含まれるナトリウムの供給源となる電解質成分（酢酸ナトリウム以外）量については、透析用Ｂ剤中の炭酸水素ナトリウムから供給されるナトリウム量と、酢酸塩として酢酸ナトリウムを使用する場合には酢酸ナトリウムから供給されるナトリウム量を勘案した上で、前記表２に示すナトリウムイオン濃度を充足するように決定される。 In addition, each ion concentration shown in the said Table 2 contains each ion derived from acetate, The amount of each electrolyte component contained in A agent considers the quantity of the ion supplied from acetate. It is determined. Moreover, about the amount of electrolyte components (other than sodium acetate) used as the supply source of sodium contained in A agent, the amount of sodium supplied from sodium bicarbonate in dialysis agent B and sodium acetate as the acetate salt Is determined so as to satisfy the sodium ion concentration shown in Table 2 in consideration of the amount of sodium supplied from sodium acetate.
例えば、Ａ剤が、酢酸及び酢酸ナトリウムを含み、且つ他の電解質成分として塩化カリウム、塩化マグネシウム、及び塩化カルシウムを含む場合、透析液に含まれる各イオン濃度を前記表１に示す範囲を充足させるには、酢酸と酢酸ナトリウム合計モル数１モル当たり、塩化カリウムが０．０８〜１．５モル、好ましくは０．３〜１．２５モル；塩化マグネシウムが０〜０．５モル、好ましくは０．０５〜０．３８モル；塩化カルシウムが０．１３〜１．１３モル、好ましくは０．２５〜０．８８モルを満たす比率に設定すればよい。 For example, when the agent A contains acetic acid and sodium acetate and contains potassium chloride, magnesium chloride, and calcium chloride as other electrolyte components, each ion concentration contained in the dialysate is satisfied within the range shown in Table 1 above. In addition, potassium chloride is 0.08 to 1.5 mol, preferably 0.3 to 1.25 mol; magnesium chloride is 0 to 0.5 mol, preferably 0, per mol of acetic acid and sodium acetate. 0.05 to 0.38 mol; the ratio of calcium chloride may be set to 0.13 to 1.13 mol, preferably 0.25 to 0.88 mol.
また、Ａ剤には、前述する電解質成分の他に、患者の血糖値の維持の目的で、ブドウ糖を含んでいてもよい。Ａ剤中のブドウ糖の含有量は、最終的に調製される透析液に備えさせるブドウ糖濃度に応じて適宜設定される。具体的には、透析用Ａ剤中のブドウ糖の含有量は、最終的に調製される透析液におけるブドウ糖濃度が０〜２．５ｇ／Ｌ、好ましくは１．０〜２．０ｇ／Ｌとなるように適宜設定すればよい。 In addition to the electrolyte component described above, the agent A may contain glucose for the purpose of maintaining the blood glucose level of the patient. The content of glucose in agent A is appropriately set according to the glucose concentration provided in the dialysate finally prepared. Specifically, the glucose content in the dialysis agent A is such that the glucose concentration in the dialysate to be finally prepared is 0 to 2.5 g / L, preferably 1.0 to 2.0 g / L. What is necessary is just to set suitably.
Ａ剤は、所定の比率で酢酸及び酢酸塩を含有することにより、最終的に調製される透析液のｐＨも適度な範囲を備えるように調整されているが、更に必要に応じて、別途、ｐＨ調節剤を含んでいてもよい。Ａ剤に使用可能なｐＨ調節剤としては、透析液の成分として許容されるものである限り、特に制限されないが、例えば、塩酸、乳酸、グルコン酸等の液状の酸、クエン酸、コハク酸、フマル酸、リンゴ酸、グルコノデルタラクトン等の固形状の酸、及びこれらのナトリウム、カリウム、カルシウム、マグネシウム塩等が挙げられる。これらのｐＨ調節剤の中でも、有機酸が好適に使用される。ｐＨ調節剤は、１種単独で使用してもよく、また２種以上を組み合わせて使用してもよい。また、Ａ剤に、これらのｐＨ調節剤を含有させる場合、その含有量については、後述する、固体状Ａ剤を水に溶解して得られたＡ液又は液体状Ａ剤のｐＨ、並びに最終的に得られる透析液のｐＨを充足できるように適宜設定すればよい。 Agent A contains acetic acid and acetate at a predetermined ratio, so that the pH of the finally prepared dialysate is adjusted to have an appropriate range, but if necessary, separately, A pH regulator may be included. The pH adjuster that can be used for the agent A is not particularly limited as long as it is acceptable as a component of the dialysate. For example, liquid acids such as hydrochloric acid, lactic acid, and gluconic acid, citric acid, succinic acid, Examples thereof include solid acids such as fumaric acid, malic acid and glucono delta lactone, and sodium, potassium, calcium and magnesium salts thereof. Among these pH regulators, organic acids are preferably used. A pH regulator may be used individually by 1 type, and may be used in combination of 2 or more type. Moreover, when these A pH regulators are contained in A agent, about the content, the pH of A liquid obtained by melt | dissolving solid A agent in water mentioned later or liquid A agent, and the last are mentioned. What is necessary is just to set suitably so that pH of the dialysate obtained automatically can be satisfied.
Ａ剤の製剤形態については、特に制限されず、固体状又は液体状のいずれであってもよい。本明細書において、固形状の透析用Ａ剤を「固体状Ａ剤」、液体状の透析用Ａ剤を「液体状Ａ剤」と表記することもある。Ａ剤の製剤形態として、省スペース化、作業者の負担軽減という観点からは、好ましくは固体状Ａ剤が挙げられる。 The preparation form of the agent A is not particularly limited, and may be either solid or liquid. In the present specification, the solid dialysis agent A may be referred to as “solid A agent”, and the liquid dialysis agent A may be referred to as “liquid A agent”. As the preparation form of the agent A, from the viewpoint of saving space and reducing the burden on the worker, a solid agent A is preferably used.
固形状Ａ剤の形状については、特に制限されないが、例えば、粉末剤、顆粒剤等が挙げられる。また、固体状Ａ剤における各成分含量については、前述する透析液中の各イオン濃度を充足するように適宜設定すればよい。 The shape of the solid A agent is not particularly limited, and examples thereof include powders and granules. Moreover, what is necessary is just to set suitably about each component content in solid A agent so that each ion concentration in the dialysate mentioned above may be satisfied.
また、液体状Ａ剤における各成分含量については、特に制限されないが、実用性を考慮すると例えば、最終的に調製される透析液中の各成分濃度の１５０〜２００倍、好ましくは１７０〜１８０倍程度に濃縮されていればよい。 Further, the content of each component in the liquid A agent is not particularly limited, but considering practicality, for example, 150 to 200 times, preferably 170 to 180 times the concentration of each component in the finally prepared dialysate. It only needs to be concentrated to the extent.
Ａ剤は、酢酸及び酢酸塩が前述する比率を満たすことにより、固体状Ａ剤を水に溶解して得られたＡ液又は液体状Ａ剤のｐＨは４付近になるため、透析液調製装置や透析装置を腐食させることがなく、しかも臨床や製造現場における作業員や在宅透析における患者等の皮膚に触れた場合の安全性も確保されている。 Since the pH of the A liquid or the liquid A liquid obtained by dissolving the solid A liquid in water when the acetic acid and the acetate salt satisfy the above-mentioned ratio, the A liquid preparation device is a dialysate preparation device. In addition, the dialysis apparatus is not corroded, and safety is ensured when touching the skin of a worker in clinical or manufacturing sites or a patient in home dialysis.
固体状Ａ剤を水に溶解して得られたＡ液又は液体状Ａ剤のｐＨについて、より具体的には、Ａ剤を最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した水溶液の状態とした場合（以下、「１７５倍濃縮Ａ剤溶液」と表記する）に、そのｐＨが通常３．９〜４．７、好ましくは４．１〜４．４、更に好ましくは４．３程度になるものが挙げられる。ここで、１７５倍濃縮Ａ剤溶液のｐＨは、２５℃にて測定される値である。 About pH of A liquid obtained by melt | dissolving solid A agent in water or liquid A agent, More specifically, A agent is 175 times the concentration of each component in the dialysate finally prepared. When it is in the form of a concentrated aqueous solution (hereinafter referred to as “175-fold concentrated agent A solution”), its pH is usually 3.9 to 4.7, preferably 4.1 to 4.4, more preferably The thing which becomes about 4.3 is mentioned. Here, the pH of the 175-fold concentrated agent A solution is a value measured at 25 ° C.
Ａ剤がブドウ糖を含有させる場合には、前述するｐＨ範囲を満たすことによって、その安定性を確保することも可能になっている。ブドウ糖は、一般的にはｐＨ３前後が最も安定であるとされているが（食品成分の相互作用、発行者：野間省一、５−１５頁、編集者：並木満夫、松下雪郎、１９８０年５月１日発行）、Ａ剤中にブドウ糖が含まれる場合、酢酸：酢酸塩の比率が１：０．５〜２を満たし、且つ最終的に調製される透析液の総酢酸イオン濃度が６ｍＥｑ／Ｌ以下になるように設定されていることにより、Ａ剤中でブドウ糖が極めて安定に保持されることが確認されている。 When agent A contains glucose, the stability can be ensured by satisfying the pH range described above. Glucose is generally considered to be most stable at pH around 3 (interaction of food ingredients, publisher: Shoichi Noma, p. 5-15, editors: Mitsuo Namiki, Yukio Matsushita, 1980) (Issued on May 1), when glucose is contained in the agent A, the ratio of acetic acid: acetate satisfies 1: 0.5-2, and the total acetate ion concentration of the finally prepared dialysate is 6 mEq It has been confirmed that glucose is extremely stably maintained in the agent A by being set to be less than / L.
また、Ａ剤が、前述するｐＨ範囲を満たすことによって、酢酸臭を効果的に低減させることも可能になっている。液体状Ａ剤において、酢酸１モル当たり酢酸塩が２モルよりも多くなる場合には、酢酸臭が増大する傾向を示す。また、固体状Ａ剤においては、酢酸１モル当たり酢酸塩が０．５モルよりも少なく、ｐＨが前述する範囲を下回る場合には、酢酸臭が増大する傾向を示す。 Moreover, it is also possible for the A agent to effectively reduce the acetic acid odor by satisfying the pH range described above. In the liquid A agent, when the amount of acetate per mol of acetic acid is more than 2 mol, the acetic acid odor tends to increase. In the solid A agent, the acetic acid odor tends to increase when the amount of acetate is less than 0.5 mol per mol of acetic acid and the pH is lower than the above-mentioned range.
Ａ剤として、特に酢酸臭の低減、ブドウ糖の保存安定性等の作用をより一層向上させて発揮させるという観点から、好ましくは、酢酸及び酢酸塩のモル比が１：０．５〜２であり、透析液としたときの総酢酸イオンが２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満に設定されており、且つ１７５倍濃縮Ａ剤溶液のｐＨが３．９〜４．７であるＡ剤；より好ましくは酢酸及び酢酸塩のモル比が１：０．７５〜１．５（更に好ましくは１：１〜１．５）であり、透析液としたときの総酢酸イオンが２ｍＥｑ／Ｌ以上５．５ｍＥｑ／Ｌ以下に設定されており、且つ１７５倍濃縮Ａ剤溶液のｐＨが４．１〜４．４であるＡ剤；特に好ましくは酢酸及び酢酸塩のモル比が１：１〜１．２５であり、透析液としたときの総酢酸イオンが２ｍＥｑ／Ｌ以上５ｍＥｑ／Ｌ以下に設定されており、且つ１７５倍濃縮Ａ剤溶液のｐＨが４．３程度であるＡ剤が挙げられる。 The agent A preferably has a molar ratio of acetic acid and acetate of 1: 0.5 to 2, particularly from the viewpoint of further improving the effects such as reduction of odor of acetic acid and storage stability of glucose. The A agent in which the total acetate ion in the dialysate is set to 2 mEq / L or more and less than 6 mEq / L, and the pH of the 175-fold concentrated A agent solution is 3.9 to 4.7; more preferably The molar ratio of acetic acid and acetate is 1: 0.75 to 1.5 (more preferably 1: 1 to 1.5), and the total acetate ion in the dialysate is 2 mEq / L or more to 5.5 mEq / A agent which is set to L or less and the pH of the 175-fold concentrated agent A solution is 4.1 to 4.4; particularly preferably, the molar ratio of acetic acid and acetate is 1: 1 to 1.25 The total acetate ion when dialysate is 2 mEq / L or more and 5 mEq / L Is set below, pH of and 175-fold concentrated A solution can be cited A dosage is about 4.3.
Ａ剤が固体状Ａ剤である場合、その水分含量を低減させておくことによって、酢酸臭をより一層効果的に低減させ、保存安定性をより一層向上させることが可能になる。 When the A agent is a solid A agent, the acetic acid odor can be more effectively reduced and the storage stability can be further improved by reducing the water content.
Ａ剤の製造方法については、特に制限されず、その製剤形態に応じて適宜設定されるが、以下に、固体状Ａ剤と液体状Ａ剤に分けて、好適な製造方法について説明する。 The production method of the agent A is not particularly limited and is appropriately set according to the preparation form, but a suitable production method will be described below separately for the solid A agent and the liquid A agent.
固体状Ａ剤の好適な製造方法としては、酢酸と酢酸塩を混合する第１工程、及び第１工程で得られた混合物を他の配合成分と混合する第２工程を経て製造する方法が挙げられる。 As a suitable manufacturing method of solid A agent, the method of manufacturing through the 1st process which mixes an acetic acid and acetate, and the 2nd process which mixes the mixture obtained at the 1st process with other compounding ingredients is mentioned. It is done.
前記第１工程において、酢酸と酢酸塩の混合物（以下、第１原料と表記することもある）を予め調製することによって、最終的に得られる固体状Ａ剤の酢酸臭を大幅に軽減することが可能になる。とりわけ無水酢酸ナトリウムを用いた場合に、より効果的に酢酸臭の抑制が可能になるので、固体状Ａ剤の製造において、酢酸として氷酢酸を使用し、酢酸塩として無水酢酸ナトリウムを使用することが好ましい。 In the first step, by preparing in advance a mixture of acetic acid and acetate (hereinafter sometimes referred to as the first raw material), the acetic acid odor of the finally obtained solid A agent is greatly reduced. Is possible. In particular, when anhydrous sodium acetate is used, the odor of acetic acid can be more effectively suppressed. Therefore, in the production of the solid A agent, glacial acetic acid is used as acetic acid and anhydrous sodium acetate is used as the acetate salt. Is preferred.
また、固体状Ａ剤に含まれる酢酸塩の全量を第１工程における混合物の調製に供してもよく、また、固体状Ａ剤に含まれる酢酸塩の一部を第１工程における混合物の調製に供し、残部の酢酸塩は第２工程において混合してもよい。固体状Ａ剤に含まれる酢酸塩の内、第１工程に供される酢酸塩の量については、特に制限されないが、例えば、固体状Ａ剤に含まれる酢酸塩の総量１００重量部当たり、第１工程に供される酢酸塩の量が通常２０〜１００重量部、好ましくは５０〜１００重量部が挙げられる。 Further, the total amount of acetate contained in the solid A agent may be used for the preparation of the mixture in the first step, and a part of the acetate contained in the solid A agent may be used for the preparation of the mixture in the first step. The remaining acetate may be mixed in the second step. Of the acetates contained in the solid A agent, the amount of the acetate used in the first step is not particularly limited. For example, per 100 parts by weight of the total amount of acetate contained in the solid A agent, The amount of acetate used in one step is usually 20 to 100 parts by weight, preferably 50 to 100 parts by weight.
更に、固体状Ａ剤に含まれる酢酸の全量を第１工程における混合物の調製に供してもよく、また、固体状Ａ剤に含まれる酢酸の一部を第１工程における混合物の調製に供し、残部の酢酸は第２工程において混合してもよい。固体状Ａ剤に含まれる酢酸は第１工程に供される量が多い程、酢酸臭をより一層効果的に低減させることができ、固体状Ａ剤に含まれる酢酸全量が第１工程に供されることが好ましい。固体状Ａ剤に含まれる酢酸の内、第１工程に供される酢酸の量としては、具体的には、固体状Ａ剤に含まれる酢酸の総量１００重量部当たり、第１工程に供される酢酸の量が通常５０〜１００重量部、好ましくは７５〜１００重量部、更に好ましくは１００重量部が挙げられる。 Further, the total amount of acetic acid contained in the solid A agent may be used for the preparation of the mixture in the first step, and a part of acetic acid contained in the solid A agent is used for the preparation of the mixture in the first step. The remaining acetic acid may be mixed in the second step. As the amount of acetic acid contained in the solid A agent increases in the first step, the acetic acid odor can be reduced more effectively, and the total amount of acetic acid contained in the solid A agent is used in the first step. It is preferred that Of the acetic acid contained in the solid A agent, the amount of acetic acid provided in the first step is specifically, supplied to the first step per 100 parts by weight of the total amount of acetic acid contained in the solid A agent. The amount of acetic acid is usually 50 to 100 parts by weight, preferably 75 to 100 parts by weight, and more preferably 100 parts by weight.
第１工程において、酢酸と酢酸塩の混合方法については特に制限されないが、酢酸臭をより一層効果的に低減させるという観点からは、加熱混合、乾燥、送風、減圧処理等の低水分状態で混合する方法が好適である。 In the first step, the method for mixing acetic acid and acetate is not particularly limited, but from the viewpoint of more effectively reducing the odor of acetic acid, it is mixed in a low moisture state such as heat mixing, drying, blowing, and decompression treatment. Is preferred.
第１工程で得られる混合物は水分含量が少なく低湿度環境では、酢酸臭を僅かにしか発しないが、水分含量が多い場合や高湿度環境では強い酢酸臭を発する傾向があるので、製造工程における当該混合物の含有水分量や保管時の湿度を下げることによって、酢酸臭をより一層抑制することが可能になる。例えば、酢酸ナトリウムを５０〜１５０℃程度に加熱して含有水分量を十分に低くし、氷酢酸にはモレキュラーシーブスなどの水分吸着剤を添加することによって含有水分を除去することもできる。これらを６０％ＲＨ以下、好ましくは５０％ＲＨ以下、更に好ましくは４０％ＲＨ以下（ともに２５℃の場合）の条件下で混合することによって、酢酸臭の少ない混合物を得ることが可能となる。また、混合時に３０〜９０℃に加温したり、絶対湿度の低い、例えば１．５ｇ／ｍ3以下の乾燥空気を送風したり、減圧したりする等、余分な水分を除去する手段を用いることによって、或いは混合後、密閉容器内で一時的に保存、又は必要に応じて加温したりすることで更に酢酸臭の抑制効果を向上させることができる。 The mixture obtained in the first step has a low moisture content and emits only a slight acetic acid odor in a low humidity environment, but tends to emit a strong acetic acid odor in a high moisture environment or in a high humidity environment. By reducing the water content of the mixture and the humidity during storage, the odor of acetic acid can be further suppressed. For example, the water content can be removed by heating sodium acetate to about 50 to 150 ° C. to sufficiently reduce the water content and adding a water adsorbent such as molecular sieves to glacial acetic acid. By mixing these under the conditions of 60% RH or less, preferably 50% RH or less, more preferably 40% RH or less (both at 25 ° C.), a mixture with less acetic acid odor can be obtained. In addition, a means for removing excess water is used such as heating to 30 to 90 ° C. during mixing, blowing a dry air having a low absolute humidity, for example, 1.5 g / m 3 or less, or reducing the pressure. By this, or after mixing, the effect of suppressing the acetic acid odor can be further improved by temporarily storing in a sealed container or heating as necessary.
前記第２工程では、第１工程で得られた第１原料を他の配合成分と混合することにより、固体状Ａ剤を調製する。本第２工程における第１工程で得られた混合物と他の配合成分の混合は、単純混合であってもよく、また撹拌造粒、流動層造粒、転動流動層造粒、加圧造粒等の乾式及び湿式造粒法を用いて行ってもよい。 In the second step, the solid A agent is prepared by mixing the first raw material obtained in the first step with other blending components. Mixing of the mixture obtained in the first step in the second step and the other compounding components may be simple mixing, stirring granulation, fluidized bed granulation, rolling fluidized bed granulation, pressure granulation. You may carry out using dry and wet granulation methods, such as a grain.
前記第２工程において、混合される他の配合成分は、それぞれ個別に前記第１原料と混合されてもよく、また混合される他の配合成分の一部又は全部を含む組成物を予め調製し、当該組成物を前記第１原料と混合してもよい。好ましくは、酢酸と酢酸塩以外の電解質成分と必要に応じて酢酸塩を含む組成物（以下、第２原料と表記することもある）を予め調製し、これを前記第１原料と混合する方法が挙げられる。本発明の透析用Ａ剤に有機酸塩を含有させる場合には、当該有機酸塩は、前記第２原料中に含有させておくことが好ましい。また、本発明の透析用Ａ剤にブドウ糖を含有させる場合には、当該ブドウ糖は、前記第２原料に含有させてもよく、また第１原料及び第２原料とは別に、第３原料として前記第１原料及び第２原料と共に混合してもよい。更に、ブドウ糖は、一部を前記第２原料に含有させ、残部を第３原料として混合してもよい。更に、酢酸の一部を第２工程で混合する場合には、酢酸は、前記第２原料中に混合してもよいが、別途、前記第１原料及び第２原料、必要に応じて混合される第３原料とは別に、第４原料として混合してもよい。また、酢酸以外の有機酸についても、前記第２原料、第３原料、及び第４原料のいずれか少なくとも１つに含有させてもよく、またこれらとは別に、第５原料として混合してもよい。 In the second step, the other compounding components to be mixed may be individually mixed with the first raw material, and a composition containing a part or all of the other compounding components to be mixed is prepared in advance. The composition may be mixed with the first raw material. Preferably, a method for preparing in advance an electrolyte component other than acetic acid and acetate and, if necessary, a composition containing acetate (hereinafter sometimes referred to as a second raw material), and mixing this with the first raw material Is mentioned. When the organic acid salt is contained in the dialysis agent A of the present invention, the organic acid salt is preferably contained in the second raw material. Further, when glucose is included in the dialysis agent A of the present invention, the glucose may be contained in the second raw material, and separately from the first raw material and the second raw material, the third raw material is used as the third raw material. You may mix with a 1st raw material and a 2nd raw material. Furthermore, a part of glucose may be mixed in the second raw material, and the remaining part may be mixed as the third raw material. Furthermore, when a part of acetic acid is mixed in the second step, acetic acid may be mixed in the second raw material, but separately the first raw material and the second raw material are mixed as necessary. Apart from the third raw material, the fourth raw material may be mixed. Also, an organic acid other than acetic acid may be contained in at least one of the second raw material, the third raw material, and the fourth raw material, and separately from these, it may be mixed as a fifth raw material. Good.
また、前記第２原料として第２工程に供される組成物は、各電解質成分の混合物の状態であればよいが、造粒物の状態であることが好ましい。造粒物の状態の第２原料を製造する方法については、特に制限されないが、例えば、電解質成分として塩化カリウム、塩化カルシウム及び塩化マグネシウムを含む造粒物(第２原料)を製造する場合であれば、塩化カリウムに対して、塩化カルシウム及び塩化マグネシウムの少なくとも一部を水溶液として、必要に応じて残部を粉末として添加し、５０〜９０℃で加温混合後、必要に応じて他の配合成分（有機酸塩やブドウ糖等）を加えて、さらに加温混合することにより造粒物を形成する方法が挙げられる。また、当該造粒物の形成において、塩化カルシウム及び塩化マグネシウムの水溶液を添加する代わりに、粉末状の塩化カルシウム及び塩化マグネシウムを添加し、その前若しくは後に適量の水を添加してもよい。但し、どのような造粒操作を経たとしても造粒物は十分に乾燥されておくことが好ましい。また、無水物である塩化マグネシウム及び塩化カルシウムを使用してもよく、更にはそれらの水和物を乾燥により脱水したものを用いてもよい。 Moreover, the composition used for the second step as the second raw material may be in the state of a mixture of each electrolyte component, but is preferably in the state of a granulated product. The method for producing the second raw material in the state of the granulated product is not particularly limited, but for example, when producing a granulated product (second raw material) containing potassium chloride, calcium chloride and magnesium chloride as the electrolyte component. For example, at least a part of calcium chloride and magnesium chloride is added as an aqueous solution to potassium chloride, and the remainder is added as a powder as necessary. After heating and mixing at 50 to 90 ° C., other ingredients are added as necessary. Examples thereof include a method of forming a granulated product by adding (organic acid salt, glucose, etc.) and further heating and mixing. Further, in the formation of the granulated product, instead of adding an aqueous solution of calcium chloride and magnesium chloride, powdered calcium chloride and magnesium chloride may be added, and an appropriate amount of water may be added before or after that. However, it is preferable that the granulated product is sufficiently dried regardless of the granulation operation. Further, anhydrous magnesium chloride and calcium chloride may be used, and further, those obtained by dehydrating these hydrates by drying may be used.
第２工程の好適な具体例として、第１原料（酢酸と酢酸塩の混合物）と、第２原料（酢酸と酢酸塩以外の電解質を含む組成物）と、必要に応じて第３原料（ブドウ糖）と、必要に応じて第４原料（酢酸）と、必要に応じて第５原料（酢酸以外の有機酸）を、低湿度下（６０％ＲＨ以下、好ましくは５０％ＲＨ以下、更に好ましくは４０％ＲＨ以下（ともに２５℃の場合））で混合する方法が挙げられる。第２工程における混合時には、前記第１工程と同様に、３０〜９０℃に加温したり、絶対湿度の低い乾燥空気を送風したり、減圧したりする等、余分な水分を除去する手段を用いることによって、より一層酢酸臭の抑制効果を高めることができる。また、製造される固体状Ａ剤の酢酸臭をより一層低減させるという観点から、第１原料、第２原料、並びに必要に応じて添加される第３原料等は、水分含量が低い状態にしておくことが好ましい。このように水分含量を低減させる方法としては、例えば、第２工程の混合に供される各原料を予め９０〜１４０℃で乾燥し、絶対湿度１．５ｇ／ｍ3以下の冷風により冷却する方法が挙げられる。 As a suitable specific example of the second step, a first raw material (a mixture of acetic acid and acetate), a second raw material (a composition containing an electrolyte other than acetic acid and acetate), and a third raw material (glucose as necessary) ), If necessary, the fourth raw material (acetic acid), and if necessary, the fifth raw material (organic acid other than acetic acid) under low humidity (60% RH or less, preferably 50% RH or less, more preferably 40% RH or less (both at 25 ° C.)). At the time of mixing in the second step, as in the first step, means for removing excess water, such as heating to 30 to 90 ° C., blowing dry air having a low absolute humidity, or reducing the pressure, etc. By using it, the effect of suppressing acetic acid odor can be further enhanced. In addition, from the viewpoint of further reducing the acetic acid odor of the solid A agent to be produced, the first raw material, the second raw material, and the third raw material added as necessary are in a state where the moisture content is low. It is preferable to keep it. As a method for reducing the water content in this way, for example, each raw material to be mixed in the second step is previously dried at 90 to 140 ° C. and cooled with cold air having an absolute humidity of 1.5 g / m 3 or less. Is mentioned.
また、前述するように、二酢酸アルカリ金属塩は、酢酸と酢酸塩の複合体であるので、前記第１原料となる酢酸と酢酸塩の混合物として二酢酸アルカリ金属塩を用いてもよい。また、二酢酸アルカリ金属塩は、市販品であっても、また公知の製法で得られたもの（例えば、酢酸とアルカリ金属水酸化物との反応物、酢酸とアルカリ金属炭酸塩との反応物、酢酸アルカリ金属に酢酸を含浸させたもの等）であってもよい。 Further, as described above, since the alkali metal diacetate is a complex of acetic acid and acetate, an alkali metal diacetate may be used as a mixture of acetic acid and acetate as the first raw material. The alkali metal diacetate may be a commercially available product or obtained by a known production method (for example, a reaction product of acetic acid and an alkali metal hydroxide, a reaction product of acetic acid and an alkali metal carbonate). Or an alkali metal acetate impregnated with acetic acid).
斯して製造される固体状Ａ剤は、必要に応じて乾燥処理に供した後に包装容器に収容して提供される。固体状Ａ剤の包装に使用される包装容器としては、例えば、フレキシブルバッグやハードボトルが使用される。当該包装容器として、具体的には、シリカ蒸着ラミネート袋やアルミ蒸着ラミネート袋、酸化アルミ蒸着ラミネート袋、アルミラミネート袋、ポリエチレン製ハードボトル等が挙げられる。とりわけ、アルミニウム箔等の金属箔が用いられている包装袋（アルミラミネート袋等）は、透湿度を低くでき、酢酸の揮発及び環境からの吸湿をより効果的に抑制できる。また、これらの包装容器の透湿度については、酢酸臭をより一層有効に低減させるという観点から、好ましくは０．５ｇ／ｍ2・２４ｈ（４０℃、９０％ＲＨ）以下、更に好ましくは０．２ｇ／ｍ2・２４ｈ（４０℃、９０％ＲＨ）以下が挙げられる。当該透湿度は、ＪＩＳ Ｚ０２０８ 防湿包装材料の透湿度試験方法（カップ法）に規定の測定方法に準拠して測定される値である。 The solid A agent thus produced is provided after being subjected to a drying treatment as necessary and then housed in a packaging container. As a packaging container used for packaging of the solid A agent, for example, a flexible bag or a hard bottle is used. Specific examples of the packaging container include a silica vapor deposition laminate bag, an aluminum vapor deposition laminate bag, an aluminum oxide vapor deposition laminate bag, an aluminum laminate bag, and a polyethylene hard bottle. In particular, a packaging bag (aluminum laminate bag or the like) in which a metal foil such as an aluminum foil is used can reduce moisture permeability, and can more effectively suppress acetic acid volatilization and moisture absorption from the environment. Further, the moisture permeability of these packaging containers is preferably 0.5 g / m 2 · 24 h (40 ° C., 90% RH) or less, and more preferably, from the viewpoint of more effectively reducing the odor of acetic acid. 2 g / m 2 · 24 h (40 ° C., 90% RH) or less. The said moisture permeability is a value measured based on the measuring method prescribed | regulated to the moisture permeability test method (cup method) of moisture-proof packaging material of JISZ0208.
更に、包装容器に収容される固体状Ａ剤の水分含量をより効果的に低減させるために、包装容器内には、固体状Ａ剤と共に、乾燥剤を収容してもよい。乾燥剤としては、特に制限されないが、例えば、ゼオライト、硫酸マグネシウム、硫酸ナトリウム、シリカゲル、アルミナ等が挙げられる。包装容器に乾燥剤を収容する場合、これら物質が容器を構成するプラスチックの一部（例えば、ポリエチレン層）に配合された容器を用いてもよいし、包装容器内に乾燥剤を収納できるスペース（別室）を設けてもよい。また乾燥剤を不織布等に入れた状態で、固体状Ａ剤に混入しないようにして包装容器に収容してもよい。 Furthermore, in order to more effectively reduce the moisture content of the solid A agent contained in the packaging container, a desiccant may be contained in the packaging container together with the solid A agent. Although it does not restrict | limit especially as a desiccant, For example, a zeolite, magnesium sulfate, sodium sulfate, a silica gel, an alumina etc. are mentioned. When a desiccant is stored in a packaging container, a container in which these substances are blended with a part of plastic (for example, a polyethylene layer) constituting the container may be used, or a space in which the desiccant can be stored in the packaging container ( A separate room may be provided. Alternatively, the desiccant may be contained in a non-woven fabric or the like so as not to be mixed with the solid A agent and contained in the packaging container.
液体状Ａ剤は、酢酸、酢酸塩、他の電解質、必要に応じてブドウ糖を所定量はかり取り、水に混合して溶解させることにより調製される。また、前述する固体状Ａ剤の所定量を水に溶解させることにより調製することもできる。また、各配合成分を水に溶解させた後に、必要に応じて濾過等の処理に供してもよい。 The liquid A agent is prepared by measuring a predetermined amount of acetic acid, acetate, other electrolytes, and if necessary, glucose, and mixing and dissolving in water. It can also be prepared by dissolving a predetermined amount of the aforementioned solid A agent in water. Moreover, after dissolving each compounding component in water, you may use for processes, such as filtration, as needed.
斯して調製された液体状Ａ剤は、包装容器に収容して提供される。液体状Ａ剤の包装に使用される包装容器としては、例えばポリエチレンボトル等のプラスチック容器が挙げられる。 The liquid A agent thus prepared is provided by being contained in a packaging container. As a packaging container used for packaging of liquid A agent, plastic containers, such as a polyethylene bottle, are mentioned, for example.
透析液の調製
前記Ｓ剤、Ｂ剤、Ａ剤、及び必要に応じて水を所望量添加・混合する工程を経て、透析液が調製される。
Preparation of dialysate The dialysate is prepared through the step of adding and mixing the S agent, the B agent, the A agent, and, if necessary, a desired amount of water.
発明の透析用剤を用いた透析液の調製において、水は、最終的に得られる透析液の各成分濃度を調整するために、必要に応じて添加される。本発明の３剤型透析用剤から透析液を調製する際に使用される水としては、薬学的に許容される程度に精製されたものであればよく、具体的には、日本薬局方に規定する精製水と品質的に合致するものであればよい。例えば、透析液の調製に使用される水としては、水道水や地下水を、活性炭処理や軟水化処理等で前処理した後に、逆浸透膜ろ過、蒸留、超ろ過等で精製処理したものが挙げられる。また、透析液を調製する際に使用される水は、市販されている精製水や蒸留水であってもよい。 In the preparation of a dialysate using the dialysis agent of the invention, water is added as necessary to adjust the concentration of each component of the finally obtained dialysate. The water used for preparing the dialysate from the three-part dialysis agent of the present invention may be any water that has been purified to a pharmaceutically acceptable level. Any material that matches the quality of the purified water specified may be used. For example, as water used for the preparation of dialysate, tap water or groundwater is pretreated with activated carbon treatment or water softening treatment, and then purified by reverse osmosis membrane filtration, distillation, ultrafiltration, or the like. It is done. The water used when preparing the dialysate may be commercially available purified water or distilled water.
また、本発明の３剤型透析用剤によって調製される透析液のｐＨについては、透析液として許容される範囲を充足する限り、特に制限されないが、透析患者の過剰なアシドーシス是正の危険性を避けるという観点から、好ましくは７．２〜７．６、更に好ましくは７．３〜７．５、特に好ましくは７．３〜７．４が挙げられる。本発明で使用されるＡ剤は、重炭酸の緩衝作用に加え、酢酸と酢酸塩の供給源が特定の組成を満たすことにより備わる酢酸−酢酸塩の緩衝作用で、前記範囲のｐＨの透析液を調製可能に設定されている。 In addition, the pH of the dialysate prepared by the three-part dialysis agent of the present invention is not particularly limited as long as it satisfies the allowable range as a dialysate, but there is a risk of correcting excessive acidosis in dialysis patients. From the viewpoint of avoidance, 7.2 to 7.6 is preferable, 7.3 to 7.5 is more preferable, and 7.3 to 7.4 is particularly preferable. The agent A used in the present invention is an acetic acid-acetate buffering action provided by satisfying a specific composition of the source of acetic acid and acetate in addition to the buffering action of bicarbonate. It is set to be ready for preparation.
本発明の３剤型透析用剤によって調製される透析液の重炭酸イオン濃度については、例えば、２０〜４０ｍＥｑ／Ｌ、好ましくは２５〜３５ｍＥｑ／Ｌ、更に好ましくは２７〜３３ｍＥｑ／Ｌの範囲内に設定される。また、本発明の３剤型透析用剤によって調製される透析液の総酢酸イオン濃度、その他のイオン濃度については、前述する通りである。 The bicarbonate ion concentration of the dialysate prepared by the three-part dialysis agent of the present invention is, for example, in the range of 20 to 40 mEq / L, preferably 25 to 35 mEq / L, and more preferably 27 to 33 mEq / L. Set to The total acetate ion concentration and other ion concentrations of the dialysate prepared by the three-part dialysis agent of the present invention are as described above.
本発明の３剤型透析用剤は、重炭酸イオンと共に他の各イオン濃度が経時的に一定に保持された透析液（イオン濃度一定型）を調製することもでき、またカリウム、カルシウム、マグネシウム等のイオン濃度を一定に維持しながら、重炭酸イオン濃度及び／又はナトリウムイオンを自在に変化させた透析液（イオン濃度変動型）を調製することもできる。 The three-part dialysis agent of the present invention can also prepare a dialysate (an ion concentration constant type) in which other ion concentrations are kept constant over time together with bicarbonate ions, and potassium, calcium and magnesium. It is also possible to prepare a dialysate (ion concentration variation type) in which the bicarbonate ion concentration and / or the sodium ion is freely changed while maintaining the ion concentration such as.
イオン濃度一定型の透析液の調製
イオン濃度一定型の透析液の調製は、最終的に得られる透析液の全量に対して、Ｓ剤、Ｂ剤、Ａ剤、及び必要に応じて添加する水の各添加量を一定にして、一括で、或いは断続的又は連続的にこれらを混合することにより行われる。また、イオン濃度一定型の透析液を調製する場合、前記Ｓ剤、Ｂ剤、及びＡ剤は、任意の順で混合すればよい。例えば、Ｓ剤とＡ剤を同時に溶解して予め濃厚Ａ液を調製することにより、当該濃厚Ａ液とＢ剤からなる一般的な２剤型透析剤として、イオン濃度一定型の透析液の調製に使用することもできる。
Preparation of dialysis fluid of constant ion concentration type The preparation of dialysis fluid of constant ion concentration type is based on the S agent, B agent, A agent, and water to be added as needed, with respect to the total amount of dialysate finally obtained. These are added at a constant amount, or by mixing them all at once or intermittently or continuously. Moreover, when preparing a dialysate of a constant ion concentration type, the S agent, B agent, and A agent may be mixed in any order. For example, by dissolving S agent and A agent at the same time and preparing concentrated A solution in advance, preparation of dialysate of constant ion concentration type as a general two-component dialysate composed of concentrated A solution and B agent Can also be used.
イオン濃度変動型の透析液の調製
イオン濃度変動型の透析液の調製は、Ｓ剤、Ｂ剤、及びＡ剤の添加量を適宜調節することによって行われる。例えば、最終的に得られる透析液の全量に対してＡ剤の添加量の割合を一定に維持しつつ、Ｂ剤の添加量を調節することにより、透析液中のカリウム、カルシウム、マグネシウム等の微量金属イオン濃度を一定に維持しながら、重炭酸イオン濃度を自在に変化させることもできる。また、最終的に得られる透析液の全量に対してＡ剤の添加量の割合を一定に維持しつつ、Ｓ剤の添加量を調節することにより、透析液中の微量金属イオン濃度を一定に維持しながら、ナトリウムイオン濃度を自在に変化させることもできる。更に、最終的に得られる透析液の全量に対してＡ剤の添加量の割合を一定に維持しつつ、Ｓ剤及びＢ剤の添加量を調節することにより、透析液中の微量金属イオン濃度を一定に維持しながら、重炭酸イオン濃度とナトリウムイオン濃度の双方を変化させたり、一方を一定に維持しつつ他方を変化させたりすることもできる。
Preparation of ion concentration fluctuation type dialysate The preparation of ion concentration fluctuation type dialysate is performed by appropriately adjusting the addition amounts of S agent, B agent, and A agent. For example, by maintaining the ratio of the added amount of agent A relative to the total amount of dialysate finally obtained, by adjusting the added amount of agent B, potassium, calcium, magnesium, etc. in the dialysate can be adjusted. The bicarbonate ion concentration can be freely changed while maintaining the trace metal ion concentration constant. In addition, the concentration of trace metal ions in the dialysate is kept constant by adjusting the amount of S agent added while maintaining the ratio of the amount of Agent A added to the total amount of dialysate finally obtained. While maintaining, the sodium ion concentration can be changed freely. Furthermore, the concentration of the trace amount of metal ions in the dialysate is adjusted by adjusting the addition amount of the S agent and the B agent while maintaining the ratio of the added amount of the A agent to the total amount of the dialysate finally obtained. It is also possible to change both the bicarbonate ion concentration and the sodium ion concentration while maintaining one constant, or to change the other while maintaining one constant.
具体的には、透析液中の重炭酸イオン濃度は、前述する範囲内で、患者の病態に応じて個々に設定することができ、例えば、一定値に設定してもよく、透析中に前述する範囲内で変化するように設定してもよい。ここでいう患者の病態には、患者の代謝性アシドーシスの程度や栄養状態、透析中における容態等が含まれる。 Specifically, the bicarbonate ion concentration in the dialysate can be set individually according to the patient's condition within the above-mentioned range, for example, it may be set to a constant value, It may be set so as to change within a range. The patient's pathology here includes the degree of metabolic acidosis, nutritional status, condition during dialysis, and the like.
透析液中の重炭酸イオンの濃度を透析中に変化させる例としては、例えば以下の(1)〜(8)の態様が挙げられる。
(1)透析処置の開始時から終了時にかけて重炭酸イオン濃度を低下させる。
(2)透析処置の開始時から終了時にかけて重炭酸イオン濃度を上昇させる。
(3)透析処置の開始時から途中まで重炭酸イオン濃度を低下させ、その後、終了時まで重炭酸イオン濃度を一定に維持する。
(4)透析処置の開始時から途中まで重炭酸イオン濃度を上昇させ、その後、終了時まで重炭酸イオン濃度を一定に維持する。
(5)透析処置の開始時から途中まで重炭酸イオン濃度を一定に維持し、その後、終了時まで重炭酸イオン濃度を上昇させる。
(6)透析処置の開始時から途中まで重炭酸イオン濃度を一定に維持し、その後、終了時まで重炭酸イオン濃度を低下させる。
(7)透析処置の開始時から途中まで重炭酸イオン濃度を低下させ、その後、終了時まで重炭酸イオン濃度を上昇させる。
(8)透析処置の開始時から途中まで重炭酸イオン濃度を上昇させ、その後、終了時まで重炭酸イオン濃度を低下させる。
これらの重炭酸イオン濃度を変動させる態様はあくまで例示であり、患者の病状や生理状態に応じて、上記(1)〜(8)以外の態様で、透析中に重炭酸イオン濃度を連続的に、段階的に、間欠的に、反復的に変化させ得ることはいうまでもない。
Examples of changing the bicarbonate ion concentration in the dialysate during dialysis include the following embodiments (1) to (8).
(1) Decrease bicarbonate ion concentration from the start to the end of dialysis treatment.
(2) Increase the bicarbonate ion concentration from the start to the end of the dialysis treatment.
(3) Decrease the bicarbonate ion concentration from the beginning to the middle of the dialysis treatment, and then maintain the bicarbonate ion concentration constant until the end.
(4) Increase the bicarbonate ion concentration from the beginning to the middle of the dialysis treatment, and then keep the bicarbonate ion concentration constant until the end.
(5) Maintain the bicarbonate ion concentration constant from the beginning to the middle of the dialysis treatment, and then increase the bicarbonate ion concentration until the end.
(6) The bicarbonate ion concentration is kept constant from the start to the middle of the dialysis treatment, and then the bicarbonate ion concentration is lowered until the end.
(7) Decrease the bicarbonate ion concentration from the start to the middle of the dialysis treatment, and then increase the bicarbonate ion concentration until the end.
(8) Increase the bicarbonate ion concentration from the start to the middle of the dialysis treatment, and then decrease the bicarbonate ion concentration until the end.
These modes of varying the bicarbonate ion concentration are merely examples, and the bicarbonate ion concentration is continuously increased during dialysis in modes other than the above (1) to (8), depending on the patient's medical condition and physiological state. Needless to say, it can be changed stepwise, intermittently and repetitively.
また、透析液中のナトリウムイオン濃度は、前述する範囲内で、個々の患者の病態や透析中における容態に応じて一定値に設定したり、前述する範囲内で透析中に変化するように設定してもよい。 In addition, the sodium ion concentration in the dialysate is set to a constant value according to the pathology of individual patients and conditions during dialysis within the range described above, or set to change during dialysis within the range described above. May be.
例えば、低血圧患者や糖尿病などの溢水状態になりやすい患者に対しては、現在広く使われている透析液のナトリウムイオン濃度（１４０ｍＥｑ／Ｌ）で十分な除水をする事が困難な場合がある。このような患者に対しては、ナトリウム濃度を１４５〜１６０ｍＥｑ／Ｌ程度とする高ナトリウム透析液を用いる場合がある。高ナトリウム透析により、血漿浸透圧を上げることで細胞内の水分を効率よく血中に引き出し、循環血漿量の増加させるために透析中の血圧低下防止に有用であると考えられるが、口渇により透析間の体重増加量の増大が問題となるため、透析開始当初のナトリウムイオン濃度を高く設定し、以後段階的にナトリウムイオン濃度を減少させていく方法や、高ナトリウム濃度と正ナトリウム濃度又は低ナトリウム濃度を一定時間ごとで交互に切り替える方法等、患者に応じたナトリウムイオン濃度に変動させることができ、且つ重炭酸イオン濃度も同時に変動させることもできることが、より患者にとって好ましい。 For example, for patients with low blood pressure and those who are prone to overflow such as diabetes, it may be difficult to remove water sufficiently with the sodium ion concentration (140 mEq / L) of the dialysate currently widely used. is there. For such patients, a high sodium dialysate having a sodium concentration of about 145 to 160 mEq / L may be used. High sodium dialysis is thought to be useful in preventing blood pressure drop during dialysis because it effectively draws intracellular water into the blood by increasing plasma osmotic pressure and increases circulating plasma volume. Since the increase in body weight gain during dialysis becomes a problem, a method in which the sodium ion concentration at the beginning of dialysis is set high and then the sodium ion concentration is decreased step by step, high sodium concentration and positive sodium concentration or low It is more preferable for the patient that the sodium ion concentration can be changed according to the patient and the bicarbonate ion concentration can be changed at the same time, such as a method of alternately switching the sodium concentration every predetermined time.
３剤型透析用剤を用いてイオン濃度変動型の透析液を調製するための条件については特許文献７において詳細に開示されており、本発明の３剤型透析用剤を用いてイオン濃度変動型の透析液を調製するための詳細条件は、特許文献７の開示内容を参考にして適宜設定すればよい。 The conditions for preparing an ion concentration variation-type dialysate using a three-agent dialysis agent are disclosed in detail in Patent Document 7, and the ion concentration variation using the three-agent dialysis agent of the present invention is disclosed. Detailed conditions for preparing the type of dialysate may be set as appropriate with reference to the disclosure of Patent Document 7.
本発明の３剤型透析用剤を用いた透析液の調製は、Ｂ剤、Ｓ剤、Ａ剤、及び必要に応じて添加される水を、所定の比率で混合できる透析液調製装置を利用して行うことができる。また、透析液中の重炭酸イオン濃度を経時的に変化させる場合には、Ｂ剤の添加量を制御する手段や、Ｓ剤とＢ剤の添加量の比率を制御する手段を有する透析液調製装置を利用すればよく、このような透析装置については特許文献７に示されており、公知である。 Preparation of dialysate using the three-part dialysis agent of the present invention utilizes a dialysate preparation device that can mix B agent, S agent, A agent, and water added as necessary at a predetermined ratio. Can be done. In addition, when changing the bicarbonate ion concentration in the dialysate over time, dialysate preparation having means for controlling the amount of B agent added and means for controlling the ratio of the amount of S agent and B agent added An apparatus may be used, and such a dialysis apparatus is disclosed in Patent Document 7 and is publicly known.
以下、実施例を挙げて本発明を具体的に説明する。但し、本発明は以下の実施例に限定して解釈されるものではない。 Hereinafter, the present invention will be specifically described with reference to examples. However, the present invention is not construed as being limited to the following examples.
試験例１
(1)液体状Ａ剤の調製
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、ブドウ糖１７．５０ｇ、氷酢酸（表３に示す所定量）、及び無水酢酸ナトリウム（表３に示す所定量）を水に溶かし、総量を１００ｍＬにした透析用液体状Ａ剤を調製した。当該透析用液体状Ａ剤は、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した水溶液（カリウムイオン濃度が３５０ｍＥｑ／Ｌ）の状態のものである。
Test example 1
(1) Preparation of liquid A agent 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, 17.50 g of glucose, glacial acetic acid (predetermined amount shown in Table 3), and Anhydrous sodium acetate (predetermined amount shown in Table 3) was dissolved in water to prepare a liquid A preparation for dialysis having a total amount of 100 mL. The liquid A agent for dialysis is in a state of an aqueous solution (potassium ion concentration is 350 mEq / L) concentrated to 175 times the concentration of each component in the dialysate to be finally prepared.
(2)液体状Ａ剤のｐＨ、揮発酢酸濃度、５−ＨＭＦ量、及び腐食性の評価
上記で得られた各液体状Ａ剤のｐＨを測定した。ｐＨはｐＨメーター（製造元：堀場製作所、型番：Ｆ−７３）を用いて液温２５℃で測定した。
(2) Evaluation of pH of liquid A agent, volatile acetic acid concentration, 5-HMF amount, and corrosiveness The pH of each liquid A agent obtained above was measured. The pH was measured at a liquid temperature of 25 ° C. using a pH meter (manufacturer: Horiba, model number: F-73).
上記で得られた各液体状Ａ剤の揮発酢酸濃度を、以下の方法で測定した。具体的には、揮発酢酸濃度については、三角フラスコに各液体状Ａ剤を収容し、１５分間静置後に液面上部に酢酸測定用の検知管をセットし、一定量の試料気体を検知管に通気させて、検知管式気体測定器（製造元：ＧＡＳＴＥＣ、型番：ＧＶ−１００Ｓ）で測定した。 The volatile acetic acid concentration of each liquid A agent obtained above was measured by the following method. Specifically, regarding the concentration of volatile acetic acid, each liquid A agent is accommodated in an Erlenmeyer flask, and after standing for 15 minutes, a detection tube for measuring acetic acid is set on the upper surface of the liquid, and a certain amount of sample gas is detected. And measured with a detector tube type gas measuring device (manufacturer: GASTEC, model number: GV-100S).
また、調製直後の各液体状Ａ剤について、ブドウ糖の分解物である５−ヒドロキシメチルフルフラール（以下５−ＨＭＦと記載）量を測定した。更に、ポリエチレン製ボトルに各液体状Ａ剤を収容し、４０℃且つ相対湿度７５％ＲＨで１カ月間保存後に５−ＨＭＦ量を測定した。５−ＨＭＦ量については、０．２μｍフィルターでろ過した液について分光光度計を用いて、５−ＨＭＦの吸収波長（波長２８４ｎｍ）の吸光度を測定した。 Moreover, about each liquid A agent immediately after preparation, the amount of 5-hydroxymethyl furfural (henceforth 5-HMF) which is a decomposition product of glucose was measured. Furthermore, each liquid A agent was accommodated in the polyethylene bottle, and the amount of 5-HMF was measured after storage for 1 month at 40 ° C. and a relative humidity of 75% RH. Regarding the amount of 5-HMF, the absorbance at the absorption wavelength (wavelength 284 nm) of 5-HMF was measured using a spectrophotometer for the liquid filtered with a 0.2 μm filter.
また、上記で得られた各液体状Ａ剤のステンレスに対する腐食性について、以下の方法で評価した。２００ｍＬ容の透明スチロール容器に各液体状Ａ剤１００ｍＬを入れ、更に４０ｍｍ×１００ｍｍのステンレス（ＳＵＳ３０４）プレートのほぼ半分の面積が各液体状Ａ剤に浸漬するように静置し、透明スチロール容器に蓋を載せ、室温で２カ月間放置した。保存２カ月後に、液体状Ａ剤中の鉄濃度を測定した。鉄濃度の測定は、第十六改正日本薬局方の「一般試験法 １.化学的試験法 １．１０鉄試験法」で規定されているＡ法に準じて行った。具体的な測定条件は、以下の通りである。液体状Ａ剤５ｍＬに鉄試験用酢酸・酢酸ナトリウム緩衝液５ｍＬ、Ｌ−アスコルビン酸溶液（１ｇ→１００ｍＬ）２ｍＬを加え混和し、３０分間放置した。次に、２、２’−ビピリジルのエタノール（９５）溶液（０．２５ｇ→５０ｍＬ）１ｍＬを加え、水で正確に５０ｍＬとし、混和し、３０分間放置し、試料溶液とした。標準溶液には日局鉄標準液（日局０．０１ｍｇ／ｍＬ）２ｍＬを用いた。試料溶液をブランク補正した後、試料溶液及び標準溶液について、分光光度計を用いて、吸収波長（波長５２２ｎｍ）の吸光度を測定し、鉄濃度を算出した。なお、腐食性の評価はｎ＝２で測定を行い、液体状Ａ剤中の鉄濃度の平均値を算出した。 Moreover, the corrosivity with respect to stainless of each liquid A agent obtained above was evaluated with the following method. Put 100 mL of each liquid A agent in a 200 mL transparent polystyrene container, and then leave it so that almost half of the 40 mm x 100 mm stainless steel (SUS304) plate is immersed in each liquid A agent. The lid was placed and left at room temperature for 2 months. Two months after storage, the iron concentration in the liquid A agent was measured. The iron concentration was measured according to the A method defined in “General Test Method 1. Chemical Test Method 1.10 Iron Test Method” of the 16th revision Japanese Pharmacopoeia. Specific measurement conditions are as follows. To 5 mL of liquid A agent, 5 mL of acetic acid / sodium acetate buffer for iron test and 2 mL of L-ascorbic acid solution (1 g → 100 mL) were added and mixed, and left for 30 minutes. Next, 1 mL of an ethanol (95) solution of 2,2′-bipyridyl (0.25 g → 50 mL) was added to make exactly 50 mL with water, mixed and allowed to stand for 30 minutes to obtain a sample solution. As the standard solution, 2 mL of a Japanese Pharmacopoeia standard solution (Japanese Pharmacopoeia 0.01 mg / mL) was used. After blank correction of the sample solution, the absorbance of the absorption wavelength (wavelength 522 nm) was measured for the sample solution and the standard solution using a spectrophotometer, and the iron concentration was calculated. In addition, evaluation of corrosiveness measured by n = 2, and computed the average value of the iron concentration in liquid A agent.
得られた結果を表４に示す。表４から明らかなように、酢酸：酢酸ナトリウムのモル比が１：０．５〜２の範囲内である液体状Ａ剤（実施例１〜４）は、ｐＨが３．９以上であり、臨床現場で安全に取り扱うことができ、透析液調製装置や透析装置の腐食の心配がないものであった。一方、酢酸：酢酸ナトリウムのモル比が１：０の液体状Ａ剤（比較例１）では、ｐＨが３未満の強い酸性を示し、取扱い上の十分な安全性が確保できていなかった。 Table 4 shows the obtained results. As apparent from Table 4, the liquid A agent (Examples 1 to 4) in which the molar ratio of acetic acid: sodium acetate is in the range of 1: 0.5 to 2 has a pH of 3.9 or more, It can be handled safely at the clinical site, and there is no worry about the corrosion of the dialysate preparation device and the dialyzer. On the other hand, the liquid A agent (comparative example 1) having an acetic acid: sodium acetate molar ratio of 1: 0 showed strong acidity with a pH of less than 3, and sufficient safety in handling could not be ensured.
酢酸：酢酸ナトリウムのモル比が１：０．５〜２の液体状Ａ剤（実施例１〜４）は、比較例２に比し揮発酢酸濃度が低くなっており、揮発酢酸濃度を格段に低減できていた。 The liquid A agent (Examples 1 to 4) having an acetic acid: sodium acetate molar ratio of 1: 0.5 to 2 has a lower volatile acetic acid concentration than that of Comparative Example 2, and the volatile acetic acid concentration is markedly higher. It was reduced.
また、酢酸：酢酸ナトリウムのモル比が１：０．５〜２の液体状Ａ剤（実施例１〜４）は、ブドウ糖の分解物である５−ＨＭＦ量が少なく、特に当該モル比が１：０．５〜１．５の場合（実施例１〜３）では５−ＨＭＦ量が格段に少なくなっており、ブドウ糖の分解が効果的に抑制できていた。従来の透析用Ａ剤（透析液中の総酢酸濃度８ｍＥｑ／Ｌ以上）においては、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した際に、輸送コストや病院内での作業性が改善できる反面、塩化ナトリウム及び重炭酸ナトリウム以外の電解質成分及びブドウ糖が高濃度に濃縮されているため、各電解質成分の影響を受けやすく、また酢酸及び酢酸塩の総量が増加すると更にその影響が強くなることによってブドウ糖の分解が促進される傾向を示すが（例えば、比較例２の結果を参照）、実施例１〜４の液体状Ａ剤では、最終的に調製される透析液中の酢酸イオン濃度が６ｍＥｑ／Ｌ未満となるように設定されており、酢酸及び酢酸塩の総量が少ないため、１７５倍に濃縮された液体状Ａ剤であっても、ブドウ糖の分解が効果的に抑制できていると考えられる。 The liquid A agent (Examples 1 to 4) having an acetic acid: sodium acetate molar ratio of 1: 0.5 to 2 has a small amount of 5-HMF, which is a degradation product of glucose, and the molar ratio is particularly 1. : In the case of 0.5 to 1.5 (Examples 1 to 3), the amount of 5-HMF was remarkably reduced, and the degradation of glucose could be effectively suppressed. In the conventional dialysis agent A (total acetic acid concentration in dialysate: 8 mEq / L or more), when concentrated to 175 times the concentration of each component in the final dialysate, However, the electrolyte components and glucose other than sodium chloride and sodium bicarbonate are concentrated at a high concentration, so that they are easily affected by each electrolyte component, and when the total amount of acetic acid and acetate increases. Although the influence of strengthening tends to promote the degradation of glucose (see, for example, the results of Comparative Example 2), in the liquid A preparations of Examples 1 to 4, the dialysate finally prepared The concentration of acetate ion in the solution is set to be less than 6 mEq / L, and since the total amount of acetic acid and acetate is small, the degradation of glucose is effective even with liquid A preparation concentrated 175 times. Restrained It is considered to come.
更に、酢酸：酢酸ナトリウムのモル比が１：０の液体状Ａ剤（比較例１）では、保存後の鉄濃度が高く、ステンレスプレートの腐食が進行していた。これに対して、当該モル比が１：０．５〜２の液体状Ａ剤（実施例１〜４）では、保存後の鉄濃度が低い値で維持されており、透析液調製装置や透析装置の腐食を抑制できるものであった。 Further, in the liquid A agent (Comparative Example 1) having a molar ratio of acetic acid: sodium acetate of 1: 0 (Comparative Example 1), the iron concentration after storage was high, and corrosion of the stainless steel plate was progressing. On the other hand, in the liquid A agent (Examples 1 to 4) having a molar ratio of 1: 0.5 to 2, the iron concentration after storage is maintained at a low value. The corrosion of the device could be suppressed.
(3) 重炭酸透析液の調製と評価
上記で得られた各透析用液体状Ａ剤２ｍＬを正確に量り、精製水を加えて３００ｍＬとし、ここに透析用Ｓ剤（塩化ナトリウム）（表５に示す所定量）、及び透析用Ｂ剤（炭酸水素ナトリウム）０．８８２ｇを添加し（透析液の重炭酸イオン濃度は３０ｍＥｑ／Ｌ）、精製水を加えて正確に３５０ｍＬとし、重炭酸透析液を調製した。得られた重炭酸透析液（実施例１〜４及び比較例１〜２の透析用液体状Ａ剤使用）には、いずれも、ナトリウムイオン１４０ｍＥｑ／Ｌ、カリウムイオン２ｍＥｑ／Ｌ、カルシウムイオン３ｍＥｑ／Ｌ、マグネシウムイオン１ｍＥｑ／Ｌが含まれている。得られた重炭酸透析液のｐＨ及びイオン化カルシウム濃度を測定した。ｐＨはｐＨメーター（製造元：堀場製作所、型番：Ｆ−７３）を用いて液温２５℃で測定し、またイオン化カルシウム濃度は血液ガス分析装置ｃｏｂａｓ ｂ１２１（製造元：ロシュ・ダイアグノスティックス）を用いて測定した。
(3) Preparation and evaluation of bicarbonate dialysis solution 2 mL of each liquid A agent for dialysis obtained above was accurately weighed, and purified water was added to make 300 mL, where S agent for dialysis (sodium chloride) (Table 5 ) And 0.882 g of dialysis agent B (sodium bicarbonate) are added (bicarbonate ion concentration of dialysate is 30 mEq / L), and purified water is added to make exactly 350 mL. Was prepared. In the obtained bicarbonate dialysate (use of liquid A agent for dialysis of Examples 1 to 4 and Comparative Examples 1 to 2), sodium ion 140 mEq / L, potassium ion 2 mEq / L, calcium ion 3 mEq / L and magnesium ion 1 mEq / L are included. The pH and ionized calcium concentration of the bicarbonate dialysis solution obtained were measured. The pH is measured using a pH meter (manufacturer: Horiba, model number: F-73) at a liquid temperature of 25 ° C., and the ionized calcium concentration is measured using a blood gas analyzer cobas b121 (manufacturer: Roche Diagnostics). Measured.
得られた重炭酸透析液における総酢酸イオン濃度、ｐＨ及びイオン化カルシウム濃度を表６に示す。実施例１〜４の透析用液体状Ａ剤を用いて調製した重炭酸透析液は、総酢酸イオン濃度が２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満であって、透析液として適したｐＨを保持しており、しかも比較例２に比して、イオン化カルシウム濃度を高く維持することができた。 Table 6 shows the total acetate ion concentration, pH, and ionized calcium concentration in the bicarbonate dialysate obtained. The bicarbonate dialysate prepared using the liquid A agent for dialysis of Examples 1 to 4 has a total acetate ion concentration of 2 mEq / L or more and less than 6 mEq / L, and maintains a pH suitable as a dialysate. And compared with the comparative example 2, the ionized calcium concentration was able to be maintained high.
試験例２
(1)固体状Ａ剤の調製
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、さらに水０．５３ｇを加え混合し、１５０℃で乾燥することにより、電解質組成物を得た。前期電解質組成物とブドウ糖１７．５０ｇ、酢酸（表７に示す所定量）、二酢酸ナトリウム（表７に示す所定量）、酢酸ナトリウム（表７に示す所定量）を撹拌混合し、透析用固体状Ａ剤を得た。
Test example 2
(1) Preparation of solid agent A 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, and 0.53 g of water were added and mixed, followed by drying at 150 ° C. An electrolyte composition was obtained. The dialysis solid was prepared by stirring and mixing the electrolyte composition, 17.50 g of glucose, acetic acid (predetermined amount shown in Table 7), sodium diacetate (predetermined amount shown in Table 7), and sodium acetate (predetermined amount shown in Table 7). A shaped agent A was obtained.
(2)固体状Ａ剤の評価
（１７５倍濃縮Ａ剤溶液のｐＨ）
上記で得られた各固体状Ａ剤を精製水に溶解し、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した水溶液の状態にして、１７５倍濃縮Ａ剤溶液を調製した。具体的には、上記で得られた各固体状Ａ剤全量を精製水に溶解して１００ｍＬとすることにより、１７５倍濃縮Ａ剤溶液を調製した。得られた１７５倍濃縮Ａ剤溶液について、ｐＨメーター（製造元：堀場製作所、型番：Ｆ−７３）を用いて液温２５℃でｐＨを測定した。
(2) Evaluation of solid A agent (pH of 175 times concentrated A agent solution)
Dissolve each solid A agent obtained above in purified water and prepare 175 times concentrated A agent solution in the state of an aqueous solution concentrated to 175 times the concentration of each component in the dialysate to be finally prepared did. Specifically, a 175-fold concentrated A agent solution was prepared by dissolving the total amount of each solid A agent obtained above in purified water to 100 mL. About the obtained 175 times concentrated A agent solution, pH was measured at the liquid temperature of 25 degreeC using the pH meter (manufacturer: Horiba, model number: F-73).
（揮発酢酸濃度及び５−ＨＭＦ量）
各固体状Ａ剤について、得られた各固体状Ａ剤全量を、ポリエチレン製の袋に収容した。更に、これを表８に示す包装袋に収容して密封し、２５℃且つ相対湿度６０％ＲＨ、及び４０℃且つ相対湿度７５％ＲＨで２カ月間保存した。
(Volatile acetic acid concentration and 5-HMF amount)
About each solid A agent, each obtained solid A agent whole quantity was accommodated in the bag made from polyethylene. Furthermore, this was stored in a packaging bag shown in Table 8, sealed, and stored for 2 months at 25 ° C. and a relative humidity of 60% RH, and at 40 ° C. and a relative humidity of 75% RH.
保存前、保存２週間後、及び保存１カ月後に、各固体状Ａ剤を収容したポリエチレン製袋内に検知管をセットし、一定量の試料気体を酢酸測定用の検知管に通気させて、検知管式気体測定器（製造元：ＧＡＳＴＥＣ、型番：ＧＶ−１００Ｓ）で揮発酢酸濃度を測定した。 Before storage, after 2 weeks of storage, and after 1 month of storage, set a detector tube in a polyethylene bag containing each solid A agent, and let a certain amount of sample gas pass through the detector tube for measuring acetic acid, The volatile acetic acid concentration was measured with a detector tube type gas meter (manufacturer: GASTEC, model number: GV-100S).
また、保存前、保存２週間後、及び保存１カ月後の各固体状Ａ剤を、上記で得られた各固体状Ａ剤全量を精製水に溶解して１００ｍＬとすることにより、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した１７５倍濃縮Ａ剤溶液を調製した。得られた１７５倍濃縮Ａ剤溶液の５−ＨＭＦ量を上記と同様の方法で測定した。 In addition, each solid A agent after storage, 2 weeks after storage, and 1 month after storage is dissolved in purified water to 100 mL by dissolving the total amount of each solid A agent obtained above. A 175-fold concentrated agent A solution concentrated to 175 times the concentration of each component in the prepared dialysate was prepared. The amount of 5-HMF of the obtained 175-fold concentrated agent A solution was measured by the same method as described above.
１７５倍濃縮Ａ剤溶液のｐＨの測定結果を表９、揮発酢酸濃度の測定結果を表１０及び１１、５−ＨＭＦ量の測定結果を表１２及び１３に示す。 Table 9 shows the measurement results of the pH of the 175-fold concentrated agent A solution, Tables 10 and 11 show the measurement results of the volatile acetic acid concentration, and Tables 12 and 13 show the measurement results of the 5-HMF amount.
酢酸：酢酸塩のモル比が１：０の透析用固体状Ａ剤（比較例３）から調製した１７５倍濃縮Ａ剤溶液では、ｐＨが２．２付近と低く、強い酸性であって、取扱い上の十分な安全性が確保できておらず、更には透析液調製装置や透析装置の腐食が懸念される処方になっていた。また、比較例３の透析用固体状Ａ剤では、揮発酢酸濃度も１０００ｐｐｍを超えており、臨床現場では許容できないレベルであった。また、５−ＨＭＦの吸収波長である２８４ｎｍでの吸光度が保存期間中において、他の実施例に比して高めであり、ブドウ糖が安定に保持できていなかった。更に、比較例４の透析用固体状Ａ剤においては、酢酸：酢酸塩のモル比が１：３にも拘らず、揮発酢酸濃度は９００ｐｐｍと高い値を示していた。 The 175-fold concentrated A agent solution prepared from the solid A agent for dialysis (Comparative Example 3) having an acetic acid: acetate molar ratio of 1: 0 has a low pH of around 2.2 and is strongly acidic. The above safety has not been ensured, and the dialysate preparation device and the dialyzer are corroded. Moreover, in the solid A agent for dialysis of Comparative Example 3, the concentration of volatile acetic acid exceeded 1000 ppm, which was an unacceptable level in clinical practice. Further, the absorbance at 284 nm, which is the absorption wavelength of 5-HMF, was higher than that of the other examples during the storage period, and glucose could not be stably maintained. Furthermore, in the solid A preparation for dialysis of Comparative Example 4, the volatile acetic acid concentration showed a high value of 900 ppm, even though the molar ratio of acetic acid: acetate was 1: 3.
これに対して、酢酸：酢酸塩のモル比が１：０．５〜２の範囲内である透析用固体状Ａ剤（実施例５〜８）から調製した１７５倍濃縮Ａ剤溶液では、ｐＨが３．９以上であり、臨床現場で安全に取り扱うことができ、透析液調製装置や透析装置の腐食の心配がないものであった。また、実施例５〜８の透析用固体状Ａ剤では、揮発酢酸濃度が比較例３及び４よりも低かった。更に、実施例５〜８の透析用固体状Ａ剤から調製した１７５倍濃縮Ａ剤溶液は、調製後の５−ＨＭＦの吸収波長である波長２８４ｎｍでの吸光度が、比較例３に比べると十分に低い値を示しており、ブドウ糖の分解が十分に抑制できていた。中でも、実施例６〜８（酢酸：酢酸塩＝１：１〜２）では、揮発酢酸濃度と波長２８４ｎｍでの吸光度が顕著に低い値を示していた。 On the other hand, in the 175-fold concentrated A agent solution prepared from the solid A agent for dialysis (Examples 5 to 8) in which the molar ratio of acetic acid: acetate is in the range of 1: 0.5 to 2, the pH is Is 3.9 or more, and can be handled safely at the clinical site, and there is no concern about the corrosion of the dialysate preparation device and the dialyzer. Moreover, in the solid A agent for dialysis of Examples 5 to 8, the volatile acetic acid concentration was lower than those of Comparative Examples 3 and 4. Furthermore, the 175-fold concentrated A agent solution prepared from the solid A agent for dialysis of Examples 5 to 8 has a sufficient absorbance at 284 nm, which is the absorption wavelength of 5-HMF after preparation, compared to Comparative Example 3. The glucose value was low, and the degradation of glucose was sufficiently suppressed. In particular, in Examples 6 to 8 (acetic acid: acetate salt = 1: 1 to 2), the volatile acetic acid concentration and the absorbance at a wavelength of 284 nm showed remarkably low values.
(3)透析液の調製
前記で調製した１７５倍濃縮Ａ剤溶液２ｍＬを正確に量り、精製水を加えて約３００ｍＬとし、ここに透析用Ｓ剤（塩化ナトリウム）（表１４に示す所定量）、及び透析用Ｂ剤（炭酸水素ナトリウム）０．８８２ｇを添加し（透析液の重炭酸イオン濃度は３０ｍＥｑ／Ｌ）、精製水を加えて正確に３５０ｍＬとし、重炭酸透析液を調製した。得られた重炭酸透析液（実施例５〜８及び比較例３〜４の固体状Ａ剤を使用）には、いずれも、ナトリウムイオン１４０ｍＥｑ／Ｌ、カリウムイオン２ｍＥｑ／Ｌ、カルシウムイオン３ｍＥｑ／Ｌ、マグネシウムイオン１ｍＥｑ／Ｌが含まれている。
(3) Preparation of dialysate Accurately measure 2 mL of the 175-fold concentrated agent A solution prepared above, and add purified water to make approximately 300 mL, where S agent for dialysis (sodium chloride) (predetermined amount shown in Table 14) In addition, 0.882 g of dialysis agent B (sodium bicarbonate) was added (bicarbonate ion concentration of the dialysate was 30 mEq / L), and purified water was added to make exactly 350 mL to prepare a bicarbonate dialysate. In the obtained bicarbonate dialysate (using the solid A agent of Examples 5 to 8 and Comparative Examples 3 to 4), sodium ion 140 mEq / L, potassium ion 2 mEq / L, calcium ion 3 mEq / L , 1 mEq / L of magnesium ion is included.
また、得られた重炭酸透析液（実施例５〜８及び比較例３〜４の固体状Ａ剤を使用）に含まれる総酢酸イオン濃度は表１５の通りであり、酢酸：酢酸ナトリウムのモル比が１：０．５〜２の固体状Ａ剤を使用して調製された重炭酸透析液は、総酢酸イオン濃度が２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満の範囲を充足できることが確認された。 Moreover, the total acetate ion concentration contained in the obtained bicarbonate dialysis solution (using the solid A agent of Examples 5 to 8 and Comparative Examples 3 to 4) is as shown in Table 15, and the molar ratio of acetic acid: sodium acetate It was confirmed that the bicarbonate dialysate prepared using the solid A agent having a ratio of 1: 0.5 to 2 can satisfy the total acetate ion concentration range of 2 mEq / L or more and less than 6 mEq / L.
試験例３
(1)固体状Ａ剤の調製
（実施例９）
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、さらに水０．５３ｇを加え混合し、１５０℃で乾燥することにより、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物とブドウ糖１７．５０ｇ、二酢酸ナトリウム３．４８ｇ、酢酸及び酢酸ナトリウム混合物１．４９ｇを撹拌混合し、透析用固体状Ａ剤を得た。得られた透析用固体状Ａ剤における酢酸：酢酸ナトリウムのモル比は１：１である。
Test example 3
(1) Preparation of solid A agent (Example 9)
An electrolyte composition was obtained by adding 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, 0.53 g of water and mixing, followed by drying at 150 ° C. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. The previous electrolyte composition and 17.50 g of glucose, 3.48 g of sodium diacetate, and 1.49 g of a mixture of acetic acid and sodium acetate were mixed with stirring to obtain a solid A agent for dialysis. The molar ratio of acetic acid: sodium acetate in the obtained solid A preparation for dialysis is 1: 1.
（実施例１０）
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、さらに水０．５３ｇを加え混合し、１５０℃で乾燥することにより、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物とブドウ糖１７．５０ｇ、二酢酸ナトリウム２．４９ｇ、酢酸及び酢酸ナトリウム混合物２．４９ｇを撹拌混合し、透析用固体状Ａ剤を得た。得られた透析用固体状Ａ剤における酢酸：酢酸ナトリウムのモル比は１：１である。
(Example 10)
An electrolyte composition was obtained by adding 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, 0.53 g of water and mixing, followed by drying at 150 ° C. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. The initial electrolyte composition and 17.50 g of glucose, 2.49 g of sodium diacetate, and 2.49 g of a mixture of acetic acid and sodium acetate were mixed with stirring to obtain a solid A agent for dialysis. The molar ratio of acetic acid: sodium acetate in the obtained solid A preparation for dialysis is 1: 1.
（実施例１１）
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、さらに水０．５３ｇを加え混合し、１５０℃で乾燥することにより、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物とブドウ糖１７．５０ｇ、二酢酸ナトリウム０．９９ｇ、酢酸及び酢酸ナトリウム混合物３．９８ｇを撹拌混合し、透析用固体状Ａ剤を得た。得られた透析用固体状Ａ剤における酢酸：酢酸ナトリウムのモル比は１：１である。
(Example 11)
An electrolyte composition was obtained by adding 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, 0.53 g of water and mixing, followed by drying at 150 ° C. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. The initial electrolyte composition and 17.50 g of glucose, 0.99 g of sodium diacetate, and 3.98 g of a mixture of acetic acid and sodium acetate were mixed with stirring to obtain a solid A agent for dialysis. The molar ratio of acetic acid: sodium acetate in the obtained solid A preparation for dialysis is 1: 1.
（実施例１２）
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇ、さらに水０．５３ｇを加え混合し、１５０℃で乾燥することにより、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物とブドウ糖１７．５０ｇ、酢酸及び酢酸ナトリウム混合物４．９７ｇを撹拌混合し、透析用固体状Ａ剤を得た。得られた透析用固体状Ａ剤における酢酸：酢酸ナトリウムのモル比は１：１である。
(Example 12)
An electrolyte composition was obtained by adding 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate, 1.78 g of magnesium chloride hydrate, 0.53 g of water and mixing, followed by drying at 150 ° C. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. The previous electrolyte composition, 17.50 g of glucose, and 4.97 g of a mixture of acetic acid and sodium acetate were mixed with stirring to obtain a solid A agent for dialysis. The molar ratio of acetic acid: sodium acetate in the obtained solid A preparation for dialysis is 1: 1.
各透析用固体状Ａ剤（実施例９〜１２）について、酢酸及び／又は酢酸塩として添加した成分の種類と添加量、酢酸及び酢酸ナトリウムのモル比を表１６に示す。 Table 16 shows the types and amounts of components added as acetic acid and / or acetate, and the molar ratio of acetic acid and sodium acetate for each of the solid A agents for dialysis (Examples 9 to 12).
(2)透析用固体状Ａ剤の長期及び加速安定性の評価
各透析用Ａ剤（実施例９〜１２）について、得られた各固体状Ａ剤全量を、ポリエチレン製の袋に収容した。更に、これを表８に示すＰＥＴ／ＡＬ／ＰＥ袋に収容して密封し、２５℃且つ相対湿度６０％ＲＨ、及び４０℃且つ相対湿度７５％ＲＨで２カ月間保存した。
(2) Evaluation of long-term and accelerated stability of dialysis solid agent A For each dialysis agent A (Examples 9 to 12), the total amount of each solid agent A obtained was accommodated in a polyethylene bag. Further, this was placed in a PET / AL / PE bag shown in Table 8 and sealed, and stored at 25 ° C. and a relative humidity of 60% RH, and at 40 ° C. and a relative humidity of 75% RH for 2 months.
保存前、保存２週間後及び１カ月後の各透析用Ａ剤について、試験例２と同様の方法で揮発酢酸濃度を測定した。また、保存前、保存２週間後及び１カ月後の各透析用Ａ剤全量を精製水に溶解して１００ｍＬとすることにより、最終的に調製される透析液中の各成分濃度の１７５倍に濃縮した１７５倍濃縮Ａ剤溶液を調製し、得られた１７５倍濃縮Ａ剤溶液のｐＨ及び５−ＨＭＦ量を試験例２と同様の方法で測定した。 The volatile acetic acid concentration was measured by the same method as in Test Example 2 for each dialysis agent A after storage, after 2 weeks of storage, and after 1 month. In addition, by dissolving the total amount of each dialysis agent A after storage, 2 weeks and 1 month after storage in purified water to 100 mL, the concentration of each component in the dialysate to be finally prepared is 175 times higher. A concentrated 175-fold concentrated agent A solution was prepared, and the pH and 5-HMF amount of the obtained 175-fold concentrated agent A solution were measured in the same manner as in Test Example 2.
得られた結果を表１７及び１８に示す。この結果から、実施例９〜１２の透析用固体状Ａ剤では、長期及び加速試験後であっても、酢酸の揮発とブドウ糖の分解を十分に抑制できており、優れた保存安定性を備えていた。 The results obtained are shown in Tables 17 and 18. From these results, the solid A preparation for dialysis of Examples 9 to 12 can sufficiently suppress the volatilization of acetic acid and the degradation of glucose even after a long period and after an accelerated test, and has excellent storage stability. It was.
試験例４
(1)固体状Ａ剤（実施例１３〜１５）の調製
塩化カリウム２．６１ｇ、塩化カルシウム水和物３．８６ｇ、塩化マグネシウム水和物１．７８ｇを加え混合し、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物８．２５ｇとブドウ糖１７．５０ｇ、酢酸及び酢酸塩の混合物（表１９に示す所定量）、酢酸ナトリウム（表１９に示す所定量）を撹拌混合し、透析用固体状Ａ剤を得た。
Test example 4
(1) Preparation of Solid A Agent (Examples 13 to 15) 2.61 g of potassium chloride, 3.86 g of calcium chloride hydrate and 1.78 g of magnesium chloride hydrate were added and mixed to obtain an electrolyte composition. . Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. A mixture of 8.25 g of the previous electrolyte composition, 17.50 g of glucose, a mixture of acetic acid and acetate (predetermined amount shown in Table 19) and sodium acetate (predetermined amount shown in Table 19) were stirred and mixed, and solid A preparation for dialysis was prepared. Obtained.
(2)固体状Ａ剤（実施例１６〜１８）の調製
塩化カリウム２．６１ｇ、無水塩化カルシウム２．９１ｇ、無水塩化マグネシウム０．８３ｇ、を加え混合し、電解質組成物を得た。また別に氷酢酸０．１０５ｋｇと無水酢酸ナトリウム０．１４４ｋｇを混合し、酢酸及び酢酸ナトリウムの混合物を得た。前期電解質組成物６．３５ｇとブドウ糖１７．５０ｇ、酢酸及び酢酸塩の混合物（表１９に示す所定量）、酢酸ナトリウム（表１９に示す所定量）を撹拌混合し、透析用固体状Ａ剤を得た。
(2) Preparation of Solid A Agent (Examples 16 to 18) 2.61 g of potassium chloride, 2.91 g of anhydrous calcium chloride, and 0.83 g of anhydrous magnesium chloride were added and mixed to obtain an electrolyte composition. Separately, 0.105 kg of glacial acetic acid and 0.144 kg of anhydrous sodium acetate were mixed to obtain a mixture of acetic acid and sodium acetate. 6.35 g of the previous electrolyte composition, 17.50 g of glucose, a mixture of acetic acid and acetate (predetermined amount shown in Table 19), and sodium acetate (predetermined amount shown in Table 19) were stirred and mixed to obtain a solid A agent for dialysis. Obtained.
(3)固体状Ａ剤の評価
（１７５倍濃縮Ａ剤溶液のｐＨ）
上記で得られた各固体状Ａ剤を用いて、前記試験例２と同様の方法で、１７５倍濃縮Ａ剤溶液のｐＨ、揮発酢酸濃度及び５−ＨＭＦ量について測定した。
(3) Evaluation of solid A agent (pH of 175 times concentrated A agent solution)
Using each solid A agent obtained above, the pH, volatile acetic acid concentration and 5-HMF amount of the 175-fold concentrated A agent solution were measured in the same manner as in Test Example 2.
１７５倍濃縮Ａ剤溶液のｐＨの測定結果を表２０、揮発酢酸濃度の測定結果を表２１、５−ＨＭＦ量の測定結果を表２２に示す。 Table 20 shows the measurement results of the pH of the 175-fold concentrated agent A solution, Table 21 shows the measurement results of the volatile acetic acid concentration, and Table 22 shows the measurement results of the 5-HMF amount.
酢酸：酢酸ナトリウムのモル比が１：１〜１．５の固体状Ａ剤（実施例１３〜１８）を使用して得られた１７５倍濃縮Ａ剤溶液では、いずれもｐＨが４以上であり、臨床現場で安全に取り扱うことができ、透析液調製装置や透析装置の腐食の心配がないものであった。塩化カルシウム及び塩化マグネシウムとして水和物を使用し、乾燥工程を含まない実施例１３〜１５では、乾燥工程を含む試験例２の比較例３、４に比して、保存前において揮発酢酸濃度が低くなっていた。また、塩化カルシウム及び塩化マグネシウムとして無水物を使用した実施例１６〜１８では、これらの水和物を使用し、乾燥工程を含まない実施例１３〜１５に比して、保存前及び４０℃且つ相対湿度７５％ＲＨの保存期間中も揮発酢酸量及び５−ＨＭＦの吸収波長である波長２８４ｎｍでの吸光度が低い値を示しており、配合する電解質成分として無水物を使用することによって、より一層効果的に透析用剤の安定性の向上及び酢酸臭の低減が図れることが明らかとなった。 In the 175-fold concentrated A agent solution obtained by using the solid A agent (Examples 13 to 18) having an acetic acid: sodium acetate molar ratio of 1: 1 to 1.5, the pH is 4 or more. Therefore, it can be handled safely at the clinical site, and there is no worry about corrosion of the dialysate preparation device and the dialyzer. In Examples 13 to 15 using hydrates as calcium chloride and magnesium chloride and not including a drying step, the concentration of volatile acetic acid before storage is higher than that of Comparative Examples 3 and 4 of Test Example 2 including the drying step. It was low. Moreover, in Examples 16-18 which used an anhydride as calcium chloride and magnesium chloride, compared with Examples 13-15 which use these hydrates and do not include a drying process, before storage and 40 degreeC and Even during storage at a relative humidity of 75% RH, the amount of volatile acetic acid and the absorbance at a wavelength of 284 nm, which is the absorption wavelength of 5-HMF, are low. By using an anhydride as the electrolyte component to be blended, It was revealed that the stability of the dialysis agent can be effectively improved and the acetic acid odor can be reduced.
Claims (20)
前記Ａ剤が、酢酸及び酢酸塩を含み、且つ酢酸：酢酸塩のモル比が１：０．５〜２であり、且つ前記酢酸塩が酢酸ナトリウム及び／又は酢酸カリウムであり、
総酢酸イオンが２ｍＥｑ／Ｌ以上６ｍＥｑ／Ｌ未満である透析液の調製に使用される、３剤型透析用剤。 And S agent comprising sodium chloride, and the B agent containing the sodium bicarbonate, sodium chloride and the electrolyte component other than sodium bicarbonate, as well as the A agent containing glucose, dialysis three dosage forms for the preparation of dialysis fluid Agent,
The agent A contains acetic acid and acetate, the molar ratio of acetic acid: acetate is 1: 0.5-2, and the acetate is sodium acetate and / or potassium acetate,
A three-part dialysis agent used for preparing a dialysate having a total acetate ion of 2 mEq / L or more and less than 6 mEq / L.
前記Ａ剤中の酢酸塩の全てが前記第１原料に含まれ、又は透析用Ａ剤中の酢酸塩の一部が前記第２原料にも含まれ、且つ
ブドウ糖が前記第２原料の組成物に含まれる、及び／又は第１原料と第２原料とは別にブドウ糖を含む第３原料が含まれる、
請求項８〜１４のいずれかに記載の３剤型透析用剤。 The agent A includes a first raw material containing a mixture of acetic acid and acetate, and a second raw material containing a composition containing a physiologically usable electrolyte other than acetic acid and acetate,
Composition of the second raw material, wherein all of the acetate in the agent A is contained in the first raw material, or part of the acetate in the agent A for dialysis is also contained in the second raw material. And / or a third raw material containing glucose separately from the first raw material and the second raw material,
The three-drug type dialysis agent according to any one of claims 8 to 14 .
The agent according to any one of claims 1 to 19 , wherein the bicarbonate ion concentration and / or the sodium concentration in the dialysate is changed by adjusting the addition amount of the agent S, agent B, and agent A during use. 3 agent type dialysis agent.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
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| JP2013207382A JP5517322B1 (en) | 2013-10-02 | 2013-10-02 | Three-part dialysis agent containing acetic acid and acetate |
| PCT/JP2014/076373 WO2015050189A1 (en) | 2013-10-02 | 2014-10-02 | Three-pack type dialysis agent containing acetic acid and acetic acid salt |
| MYPI2016701187A MY176214A (en) | 2013-10-02 | 2014-10-02 | Three-pack type dialysis agent containing acetic acid and acetic acid salt |
| SG11201602533QA SG11201602533QA (en) | 2013-10-02 | 2014-10-02 | Three-pack type dialysis agent containing acetic acid and acetic acid salt |
| MYPI2016701186A MY178249A (en) | 2013-10-02 | 2014-10-02 | Solid dialysis a agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same |
| KR1020167011118A KR102363179B1 (en) | 2013-10-02 | 2014-10-02 | Three-pack type dialysis agent containing acetic acid and acetic acid salt |
| PH12016500571A PH12016500571B1 (en) | 2013-10-02 | 2016-03-29 | Three-pack type dialysis agent containing acetic acid and acetic acid salt |
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| JP2013207382A JP5517322B1 (en) | 2013-10-02 | 2013-10-02 | Three-part dialysis agent containing acetic acid and acetate |
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| MY (2) | MY176214A (en) |
| PH (1) | PH12016500571B1 (en) |
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| WO (1) | WO2015050189A1 (en) |
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| WO2015050188A1 (en) * | 2013-10-02 | 2015-04-09 | 富田製薬株式会社 | Solid dialysis a agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same |
| WO2015072494A1 (en) | 2013-11-12 | 2015-05-21 | 扶桑薬品工業株式会社 | Novel sodium diacetate crystal and solid dialysis preparation comprising said crystal |
| JP2016112062A (en) * | 2014-12-11 | 2016-06-23 | 富田製薬株式会社 | Producing method of granules used in dialysis agent a |
| WO2016156502A1 (en) * | 2015-03-31 | 2016-10-06 | Gambro Lundia Ab | A package for an acidic dialysis fluid concentrate containing citrate and glucose |
| US9931453B2 (en) | 2012-10-10 | 2018-04-03 | Tomita Pharmaceutical Co., Ltd. | Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6467285B2 (en) * | 2015-05-13 | 2019-02-13 | 富田製薬株式会社 | Granules for agent A for dialysis and method for producing the same |
| CN109890370B (en) * | 2016-10-28 | 2021-06-29 | 富田制药株式会社 | Agent A for hemodialysis |
| JP6312957B1 (en) * | 2016-10-28 | 2018-04-18 | 富田製薬株式会社 | Agent A for hemodialysis |
| CN110522763A (en) * | 2019-10-08 | 2019-12-03 | 四川太平洋药业有限责任公司 | A kind of Multiple electrolytes injection and preparation process |
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| US9931453B2 (en) | 2012-10-10 | 2018-04-03 | Tomita Pharmaceutical Co., Ltd. | Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof |
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| JP2016112062A (en) * | 2014-12-11 | 2016-06-23 | 富田製薬株式会社 | Producing method of granules used in dialysis agent a |
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Also Published As
| Publication number | Publication date |
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| WO2015050189A1 (en) | 2015-04-09 |
| KR102363179B1 (en) | 2022-02-14 |
| SG11201602533QA (en) | 2016-05-30 |
| JP2015070908A (en) | 2015-04-16 |
| KR20160064181A (en) | 2016-06-07 |
| MY176214A (en) | 2020-07-24 |
| MY178249A (en) | 2020-10-07 |
| PH12016500571A1 (en) | 2016-06-20 |
| PH12016500571B1 (en) | 2016-06-20 |
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