JP5894628B2 - Method for producing dialysis agent - Google Patents
Method for producing dialysis agent Download PDFInfo
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- JP5894628B2 JP5894628B2 JP2014104412A JP2014104412A JP5894628B2 JP 5894628 B2 JP5894628 B2 JP 5894628B2 JP 2014104412 A JP2014104412 A JP 2014104412A JP 2014104412 A JP2014104412 A JP 2014104412A JP 5894628 B2 JP5894628 B2 JP 5894628B2
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- Prior art keywords
- calcium chloride
- dialysis agent
- component
- water
- acetic acid
- Prior art date
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- 238000000502 dialysis Methods 0.000 title claims description 123
- 238000004519 manufacturing process Methods 0.000 title claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 143
- 239000003795 chemical substances by application Substances 0.000 claims description 133
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 125
- 239000001110 calcium chloride Substances 0.000 claims description 122
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 122
- 238000001035 drying Methods 0.000 claims description 52
- 239000003792 electrolyte Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 15
- 239000003002 pH adjusting agent Substances 0.000 claims description 13
- 238000011049 filling Methods 0.000 claims description 7
- 239000004615 ingredient Substances 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 162
- 229960002713 calcium chloride Drugs 0.000 description 112
- 235000011148 calcium chloride Nutrition 0.000 description 112
- 229960000583 acetic acid Drugs 0.000 description 68
- 239000000203 mixture Substances 0.000 description 53
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 42
- 239000012362 glacial acetic acid Substances 0.000 description 41
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 38
- 239000001632 sodium acetate Substances 0.000 description 37
- 235000017281 sodium acetate Nutrition 0.000 description 37
- 238000000034 method Methods 0.000 description 35
- 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 description 33
- 239000008103 glucose Substances 0.000 description 32
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 28
- 235000002639 sodium chloride Nutrition 0.000 description 27
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 25
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 239000013078 crystal Substances 0.000 description 18
- -1 organic acid salt Chemical class 0.000 description 18
- 239000000047 product Substances 0.000 description 14
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- NOEGNKMFWQHSLB-UHFFFAOYSA-N 5-hydroxymethylfurfural Chemical compound OCC1=CC=C(C=O)O1 NOEGNKMFWQHSLB-UHFFFAOYSA-N 0.000 description 12
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 12
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- RJGBSYZFOCAGQY-UHFFFAOYSA-N hydroxymethylfurfural Natural products COC1=CC=C(C=O)O1 RJGBSYZFOCAGQY-UHFFFAOYSA-N 0.000 description 12
- 239000001103 potassium chloride Substances 0.000 description 12
- 235000011164 potassium chloride Nutrition 0.000 description 12
- 239000002994 raw material Substances 0.000 description 12
- 239000008187 granular material Substances 0.000 description 11
- 229960002337 magnesium chloride Drugs 0.000 description 11
- 229910001629 magnesium chloride Inorganic materials 0.000 description 11
- 235000011147 magnesium chloride Nutrition 0.000 description 11
- 230000002776 aggregation Effects 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 238000013112 stability test Methods 0.000 description 10
- 239000011550 stock solution Substances 0.000 description 10
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 10
- 238000004220 aggregation Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229960004543 anhydrous citric acid Drugs 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 238000007596 consolidation process Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 229960002816 potassium chloride Drugs 0.000 description 7
- 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 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 5
- 239000000385 dialysis solution Substances 0.000 description 5
- 238000011156 evaluation Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010977 unit operation Methods 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 238000011899 heat drying method Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 description 4
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000000691 measurement method Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000005096 rolling process Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229960004106 citric acid Drugs 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229960002668 sodium chloride Drugs 0.000 description 3
- 238000007711 solidification Methods 0.000 description 3
- 230000008023 solidification Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical compound [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229960004249 sodium acetate Drugs 0.000 description 2
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 2
- 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 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 2
- 235000017454 sodium diacetate Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000001744 Sodium fumarate Substances 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 238000002615 hemofiltration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- PRWXGRGLHYDWPS-UHFFFAOYSA-L sodium malonate Chemical compound [Na+].[Na+].[O-]C(=O)CC([O-])=O PRWXGRGLHYDWPS-UHFFFAOYSA-L 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000003221 volumetric titration Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- External Artificial Organs (AREA)
Description
本発明は、透析用剤およびその製造方法に関する。 The present invention relates to a dialysis agent and a method for producing the same.
透析用剤は、透析液を作製するための薬剤である。透析液は、血液透析、血液濾過、腹膜透析などにより、本来腎臓が行う機能に代わって体液の老廃物を取り去り、場合によっては血液中に必要な成分を補うために用いられるもので、体液に近い電解質組成を有する水溶液である。透析液としては、アルカリ化成分として炭酸水素ナトリウム（重炭酸ナトリウム）を用いる透析液が生理的に好ましく、主流となっている。このような透析液を得るための透析用剤は、通常、炭酸水素ナトリウムの他に、糖質成分として無水結晶ブドウ糖と、電解質成分として塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等と、ｐＨ調整成分として有機酸、有機酸塩等とを含む。透析用剤は、従来液剤であったが、容積と重量が大きく、貯留、運搬や使用時の取扱に不便をきたすという問題があったので、近年では固形剤に移行してきている。 The dialysis agent is a drug for preparing a dialysis solution. Dialysis fluid is used to remove body fluid wastes in place of the functions that the kidneys originally perform by hemodialysis, hemofiltration, peritoneal dialysis, etc., and in some cases is used to supplement the necessary components in the blood. It is an aqueous solution having a close electrolyte composition. As the dialysate, a dialysate using sodium hydrogen carbonate (sodium bicarbonate) as an alkalizing component is physiologically preferable and has become the mainstream. The dialysis agent for obtaining such a dialysate usually has anhydrous crystalline glucose as a saccharide component, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like as an electrolyte component, pH, As an adjustment component, an organic acid, an organic acid salt and the like are included. The dialysis agent is a conventional liquid agent, but its volume and weight are large, and there is a problem that it is inconvenient for storage, transportation and handling during use.
現在の透析用剤は、一般的には、カルシウムイオンおよびマグネシウムイオン等を含む電解質成分、無水結晶ブドウ糖およびｐＨ調整成分を含む「Ａ剤」と、炭酸水素ナトリウムを含む「Ｂ剤」との２剤構成となっている。現在使用されている電解質濃度および無水結晶ブドウ糖濃度の範囲は、例えば、以下の通りである（その他にｐＨ調整成分を含む）。
Ｎａ＋：１０３．０〜１４３．０ｍＥｑ／Ｌ
Ｋ＋：１．０〜４．０ｍＥｑ／Ｌ
Ｃａ＋＋：１．２５〜３．５０ｍＥｑ／Ｌ
Ｍｇ＋＋：０．２５〜１．５０ｍＥｑ／Ｌ
Ｃｌ−：１０７．０〜１１５．５ｍＥｑ／Ｌ
無水結晶ブドウ糖：０〜２５０ｍｇ／ｄＬ
The present dialysis agents are generally classified into two types of “agent A” containing an electrolyte component containing calcium ions, magnesium ions, etc., anhydrous crystalline glucose and a pH adjusting component, and “agent B” containing sodium bicarbonate. It is a drug composition. The ranges of electrolyte concentration and anhydrous crystalline glucose concentration currently used are, for example, as follows (including pH adjusting components).
Na + : 103.0 to 143.0 mEq / L
K + : 1.0 to 4.0 mEq / L
Ca ++ : 1.25 to 3.50 mEq / L
Mg ++ : 0.25-1.50mEq / L
Cl − : 107.0 to 115.5 mEq / L
Anhydrous crystalline glucose: 0-250 mg / dL
透析用剤の固形剤化の手段として、顆粒剤化があり、顆粒剤のＡ剤の造粒方法として、主に乾式造粒法、押出造粒法、転動撹拌流動層造粒法、撹拌造粒法等の造粒方法が行われている。 There is granulation as a means for solidifying the dialysis agent, and the granulation method of granule A is mainly dry granulation method, extrusion granulation method, tumbling stirring fluidized bed granulation method, stirring A granulation method such as a granulation method is performed.
乾式造粒法は、例えば、乾式造粒装置内で塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウムおよび酢酸ナトリウム等の有機酸塩の各電解質化合物を混合、圧縮、粉砕し造粒してＡ剤を得る造粒方法である。 The dry granulation method is, for example, mixing, compressing, grinding and granulating each electrolyte compound of organic acid salt such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate in a dry granulation apparatus. Is a granulation method.
押出造粒法は、例えば、塩化ナトリウム粉末に塩化ナトリウム以外の各電解質水溶液を加えて練合し、得られた造粒物を押出造粒装置のスクリーン面に押しつけ、成形造粒してＡ剤を得る造粒方法である。 In the extrusion granulation method, for example, each electrolyte aqueous solution other than sodium chloride is added to sodium chloride powder and kneaded, and the resulting granulated product is pressed against the screen surface of the extrusion granulator, and then molded and granulated to prepare agent A. Is a granulation method.
転動撹拌流動層造粒法は、例えば、塩化ナトリウムを転動撹拌流動層造粒装置内で転動および流動させ、この転動流動中の塩化ナトリウムに塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウム等の有機酸塩の混合物水溶液を噴霧することにより、転動撹拌流動層造粒装置内で転動流動中の塩化ナトリウム粒子の表面を塩化カリウム、塩化カルシウム、塩化マグネシウム、酢酸ナトリウム等の有機酸塩を含有する混合物の微粒子によって略均一に覆ってＡ剤を得る造粒方法である。 In the rolling stirring fluidized bed granulation method, for example, sodium chloride is rolled and fluidized in a rolling stirring fluidized bed granulator, and potassium chloride, calcium chloride, magnesium chloride, acetic acid is added to the sodium chloride in the rolling fluid. By spraying an aqueous solution of a mixture of organic acid salts such as sodium, the surface of sodium chloride particles that are rolling and flowing in a tumbling stirred fluidized bed granulator is coated with organic substances such as potassium chloride, calcium chloride, magnesium chloride, and sodium acetate. This is a granulation method in which the agent A is obtained by substantially uniformly covering fine particles of a mixture containing an acid salt.
撹拌造粒法は、例えば、撹拌造粒装置中の塩化ナトリウムに塩化カリウム、塩化カルシウムおよび塩化マグネシウムの懸濁液を入れ撹拌混合し、得られた混合物に酢酸ナトリウム等の有機酸塩を混合し、乾燥してＡ剤を得る造粒方法である。 In the stirring granulation method, for example, a suspension of potassium chloride, calcium chloride and magnesium chloride is added to sodium chloride in a stirring granulator, and the mixture is stirred and mixed. Then, an organic acid salt such as sodium acetate is mixed in the resulting mixture. This is a granulation method for drying to obtain agent A.
しかし、顆粒剤に成形することにより、単位操作が複雑になり生産性が低下し、単位操作が増えることにより異物の混入の可能性が増大するという問題点がある。また、顆粒剤に成形することにより、品種切換（各成分の濃度変更）による品種ごとの製造条件の確立が必要になる。さらに、品種切換（各成分の濃度変更）時に生産設備に残る原料を除去しなければならず、製品ロスおよび時間ロスが生じ、生産性が低下するという問題点がある。 However, molding into a granule has a problem in that the unit operation becomes complicated and the productivity is lowered, and the unit operation increases, so that the possibility of contamination is increased. In addition, by forming into granules, it is necessary to establish production conditions for each product type by changing product types (changing the concentration of each component). Furthermore, there is a problem that the raw material remaining in the production facility must be removed at the time of product type change (concentration change of each component), resulting in a product loss and a time loss and a decrease in productivity.
一方、顆粒剤に成形しない透析用剤の製造方法としては、以下の方法が検討されている。例えば、特許文献１には、重炭酸ナトリウムが塩化カルシウムや塩化マグネシウム等と化学反応し、炭酸塩を析出する等の反応を防止するため、直接接触させると化学反応を起こす物質の間に、化学的に安定している塩化ナトリウム層を緩衝層として用いることにより、１包装にした、透析液の調剤に利用する薬剤が記載されている。 On the other hand, as a method for producing a dialysis agent that is not formed into granules, the following methods have been studied. For example, in Patent Document 1, in order to prevent a reaction in which sodium bicarbonate chemically reacts with calcium chloride, magnesium chloride or the like and precipitates a carbonate, a chemical reaction occurs between substances that cause a chemical reaction when directly contacted. There is described a medicine that is used for the preparation of dialysis fluid in one package by using a stable sodium chloride layer as a buffer layer.
特許文献２には、ブトウ糖および炭酸水素ナトリウムを含有する粉末透析用剤において、粉末透析用剤全体、もしくはブドウ糖、塩化ナトリウムおよび炭酸水素ナトリウムの少なくとも１成分を乾燥することにより、保存時の着色を抑制し、長期にわたって安定に保存可能とすることが記載されている。 In Patent Document 2, in powder dialysis agents containing butter sugar and sodium bicarbonate, the whole powder dialysis agent or at least one component of glucose, sodium chloride and sodium bicarbonate is dried to preserve coloring during storage. And can be stored stably over a long period of time.
特許文献３には、濃透析酸溶液の調製中の使用のため、ならびに使用準備が完了した透析液にする水および重炭酸塩含有濃縮物との混合のための透析酸前駆組成物であって、前記透析酸前駆組成物は、塩化ナトリウム、少なくとも１種の乾燥酸および少なくとも１種のマグネシウム塩、ならびに任意にカリウム塩、カルシウム塩およびグルコースを含む粉末成分からなり、前記少なくとも１種のマグネシウム塩および前記任意のグルコースは、前記透析酸前駆組成物中の無水成分として存在し、前記透析酸前駆組成物は、水蒸気透過率が３８℃／９０％ＲＨで０．３ｇ／ｍ２／日未満である耐湿性容器中に密封されている透析酸前駆組成物が記載されている。 Patent Document 3 discloses a dialysis acid precursor composition for use in the preparation of a concentrated dialysis acid solution and for mixing with water and bicarbonate-containing concentrates to make the dialysate ready for use. The dialysis acid precursor composition comprises sodium chloride, at least one dry acid and at least one magnesium salt, and optionally a powder component comprising potassium salt, calcium salt and glucose, and the at least one magnesium salt And the optional glucose is present as an anhydrous component in the dialysate precursor composition, the dialysate precursor composition having a water vapor transmission rate of less than 0.3 g / m 2 / day at 38 ° C./90% RH. A dialysate precursor composition is described that is sealed in a moisture resistant container.
特許文献１の方法では、自由度の高い水分に対する対策がとられることがなく薬剤を容器に充填しているので、薬剤の固結、凝集が発生し、迅速な溶解が困難となるという問題点がある。 In the method of Patent Document 1, since the medicine is filled in the container without taking measures against moisture having a high degree of freedom, the medicine is consolidated and agglomerated, and rapid dissolution becomes difficult. There is.
特許文献２の方法のように、粉末透析用剤全体を乾燥させる場合、ブドウ糖が分解しないように乾燥するため、減圧乾燥（例えば、乾燥条件：真空乾燥、２５℃、１６５時間程度）、凍結乾燥（例えば、乾燥条件：予備凍結−４５℃、１２時間、一次乾燥０℃、７２時間、二次乾燥２５℃、１２時間程度）という大型設備で長時間乾燥する必要があり、生産性が悪く現実的ではない。さらに、上記のような低温度の乾燥条件では、塩化カルシウム二水和物の結晶水の水分を乾燥させることはできない。そして、透析用剤の主要成分である、ブドウ糖、塩化ナトリウム、炭酸水素ナトリウムを乾燥させる場合、微量成分である塩化カルシウムを乾燥するより、１製剤あたり乾燥処理が必要な成分の重量が多く、生産効率が悪く現実的ではない。 When the whole powder dialysis agent is dried as in the method of Patent Document 2, drying is performed so that glucose does not decompose, and therefore, drying under reduced pressure (for example, drying conditions: vacuum drying, 25 ° C., about 165 hours), freeze drying (For example, drying conditions: preliminary freezing-45 ° C., 12 hours, primary drying 0 ° C., 72 hours, secondary drying 25 ° C., about 12 hours) It is necessary to dry for a long time, and the productivity is poor and the reality Not right. Furthermore, the moisture of the crystal water of calcium chloride dihydrate cannot be dried under the low temperature drying conditions as described above. And when drying glucose, sodium chloride, and sodium hydrogen carbonate, which are the main components of dialysis agents, the weight of the components that need to be dried per formulation is higher than that of calcium chloride, which is a trace component, and it is produced. Inefficient and impractical.
特許文献３の組成物では、無水のマグネシウム塩として無水塩化マグネシウムが用いられているが、単なる加熱乾燥だけでは無水塩化マグネシウムを製造することができず、無水塩化マグネシウムを使用した透析剤を製造するのはコストがかかるという問題点がある。また、無水塩化マグネシウムは吸湿速度が速く、大量の無水塩化マグネシウムの水分含有率を維持しながら輸送・保管することは難しい。さらに、水分含有率が安定した塩化マグネシウムを保持できないと透析剤のマグネシウム含有量の精度が安定しないという問題が生じる。 In the composition of Patent Document 3, anhydrous magnesium chloride is used as an anhydrous magnesium salt. However, anhydrous magnesium chloride cannot be produced by mere heating and drying, and a dialysate using anhydrous magnesium chloride is produced. There is a problem that it is expensive. In addition, anhydrous magnesium chloride has a high moisture absorption rate and is difficult to transport and store while maintaining the moisture content of a large amount of anhydrous magnesium chloride. Furthermore, if magnesium chloride having a stable moisture content cannot be maintained, there arises a problem that the accuracy of the magnesium content of the dialysate is not stable.
本発明の目的は、電解質成分として少なくとも塩化カルシウムを含み、各含有成分が単一の固体成分として容器に充填された透析用剤において、薬剤の固結、凝集が抑制され、低コストで得られる透析用剤を提供することにある。 An object of the present invention is to obtain at low cost by suppressing caking and aggregation of a drug in a dialysis agent containing at least calcium chloride as an electrolyte component, and each component contained in a container as a single solid component. It is to provide a dialysis agent.
また、本発明の目的は、電解質成分として少なくとも塩化カルシウムを含み、各含有成分が単一の固体成分として容器に充填された透析用剤において、薬剤の固結、凝集を抑制する透析用剤が低コストで得られる透析用剤の製造方法を提供することにある。 Another object of the present invention is to provide a dialysis agent containing at least calcium chloride as an electrolyte component and containing each component as a single solid component in a container. It is providing the manufacturing method of the dialysis agent obtained at low cost.
本発明は、少なくとも塩化カルシウムを含む電解質成分と、ｐＨ調整剤とを含有し、前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が、１６３％未満２％以上であり、前記塩化カルシウムの水分含有率が１％〜２２％の範囲であり、前記塩化カルシウムは他の成分とは別に乾燥されており、各含有成分が単一の固体成分として容器に充填されている透析用剤である。 The present invention comprises an electrolyte component containing at least calcium chloride and a pH adjuster, and the ratio of the water content of the calcium chloride to the water content of the entire dialysis agent is less than 163% and 2% or more, The water content of calcium chloride is in the range of 1% to 22%, the calcium chloride is dried separately from other components, and each component is filled in a container as a single solid component. It is an agent.
また、前記透析用剤において、前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が、８２％未満２％以上であることが好ましい。 In the dialysis agent, it is preferable that the ratio of the water removal amount of the calcium chloride and the water content of the entire dialysis agent is less than 82% and 2% or more.
また、前記透析用剤において、前記塩化カルシウムの水分含有率が１４％〜２２％の範囲であることが好ましく、１４％〜１６％の範囲であることがさらに好ましい。 In the dialysis agent, the moisture content of the calcium chloride is preferably in the range of 14% to 22%, and more preferably in the range of 14% to 16%.
また、本発明は、少なくとも塩化カルシウムを含む電解質成分と、ｐＨ調整剤とを含有する透析用剤の製造方法であって、前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上となり、前記塩化カルシウムの水分含有率が１％〜２２％の範囲となるように塩化カルシウムを他の成分とは別に乾燥する乾燥処理工程と、各含有成分を単一の固体成分として容器に充填する充填工程と、を含む透析用剤の製造方法である。 The present invention is also a method for producing a dialysis agent comprising an electrolyte component containing at least calcium chloride and a pH adjuster, wherein the ratio of the water content of the calcium chloride to the total water content of the dialysis agent is A drying treatment step of drying calcium chloride separately from other components so that the water content of the calcium chloride is in the range of 1% to 22%, and less than 16% and 2% or more; And a filling step of filling the container as a solid component.
また、前記透析用剤の製造方法における前記乾燥処理工程において、前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が８２％未満２％以上となるように塩化カルシウムを乾燥することが好ましい。 Further, in the drying treatment step in the method for producing a dialysis agent, the calcium chloride is dried so that a ratio of a water removal amount of the calcium chloride and a water content of the entire dialysis agent is less than 82% and 2% or more. Is preferred.
また、前記透析用剤の製造方法における前記乾燥処理工程において、前記塩化カルシウムの水分含有率が１４％〜２２％の範囲となるように塩化カルシウムを乾燥することが好ましく、１４％〜１６％の範囲となるように塩化カルシウムを乾燥することがさらに好ましい。 Moreover, in the said drying process process in the manufacturing method of the said dialysis agent, it is preferable to dry calcium chloride so that the moisture content of the said calcium chloride may be in the range of 14%-22%, 14%-16% More preferably, the calcium chloride is dried so as to be in the range.
本発明では、電解質成分として少なくとも塩化カルシウムを含み、各含有成分が単一の固体成分として容器に充填された透析用剤において、ｐＨ調整剤を含有し、塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上であり、塩化カルシウムの水分含有率が１％〜２２％の範囲であることにより、薬剤の固結、凝集が抑制される、低コストで得られる透析用剤が提供される。 In the present invention, in a dialysis agent containing at least calcium chloride as an electrolyte component, and each containing component is filled in a container as a single solid component, a pH adjuster is contained, and the water removal amount of calcium chloride and the entire dialysis agent The ratio of the water content to less than 163% is 2% or more, and the moisture content of calcium chloride is in the range of 1% to 22%. A dialysis agent is provided.
また、本発明では、電解質成分として少なくとも塩化カルシウムを含み、各含有成分が単一の固体成分として容器に充填された透析用剤の製造方法において、ｐＨ調整剤を含有させ、塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上となり、塩化カルシウムの水分含有率が１％〜２２％の範囲となるように塩化カルシウムを乾燥することにより、薬剤の固結、凝集を抑制することができる透析用剤が低コストで得られる。 Further, in the present invention, in the method for producing a dialysis agent comprising at least calcium chloride as an electrolyte component, and each component contained in a container as a single solid component, a pH adjuster is contained, and the water removal amount of calcium chloride is reduced. Of calcium chloride by drying the calcium chloride so that the ratio of the water content of the dialysis agent to less than 163% is 2% or more and the moisture content of calcium chloride is in the range of 1% to 22%. Thus, a dialysis agent capable of suppressing aggregation can be obtained at a low cost.
本発明の実施の形態について以下説明する。本実施形態は本発明を実施する一例であって、本発明は本実施形態に限定されるものではない。 Embodiments of the present invention will be described below. This embodiment is an example for carrying out the present invention, and the present invention is not limited to this embodiment.
＜透析用剤＞
本発明の実施形態に係る透析用剤は、少なくとも塩化カルシウムを含む電解質成分と、ｐＨ調整剤とを含有し、各含有成分が単一の固体成分として容器に充填された透析用剤である。本実施形態に係る透析用剤において、塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上であり、塩化カルシウムの水分含有率が１％〜２２％の範囲である。本明細書において「各含有成分が単一の固体成分として容器に充填されている」とは、透析用剤に含まれる複数の成分が顆粒剤として成形されておらず、各含有成分が、「単一成分の結晶物」として容器に充填されている形態以外に、「単一成分の造粒物」として容器に充填されている形態、「単一成分の粉砕物」として容器に充填されている形態を含む。ここで、「単一成分」とは純度として９５％以上のことをいい、５％以下程度の不純物を含む場合も「単一成分」とする。また、本明細書における「単一成分」の中には、二酢酸ナトリウム等の上記酢酸混合物も含まれる。さらに、「各含有成分が単一の固体成分として容器に充填されている」とは、各「単一成分」が容器に充填される前に「単一成分」同士が混合される形態、例えば、各「単一成分」を容器に受けそれらを混合した後に所定量を容器に１回で充填する製造方法等も含まれる。
<Dialysis agent>
The dialysis agent according to an embodiment of the present invention is a dialysis agent containing an electrolyte component containing at least calcium chloride and a pH adjuster, and each of the components contained in a container as a single solid component. In the dialysis agent according to this embodiment, the ratio of the water content of calcium chloride to the water content of the entire dialysis agent is less than 163% and 2% or more, and the moisture content of calcium chloride is in the range of 1% to 22%. It is. In the present specification, "each container is filled in a container as a single solid component" means that a plurality of components contained in the dialysis agent are not formed as granules, In addition to the form filled in the container as “single-component crystal”, the form filled in the container as “single-component granulated product”, and filled in the container as “single-component pulverized product” Including forms. Here, the term “single component” means that the purity is 95% or more, and even when impurities of about 5% or less are included, the term “single component” is used. In addition, “single component” in the present specification includes the acetic acid mixture such as sodium diacetate. Furthermore, “each contained component is filled in a container as a single solid component” means that “single component” is mixed with each other before each “single component” is filled in the container, for example, Also included is a production method in which each “single component” is received in a container and mixed, and then a predetermined amount is filled into the container at a time.
透析用剤の溶解性悪化の要因の一つである固結、凝集は、気密容器内の自由度の高い水分が透析用剤の各成分の結晶に液架橋を形成することによる凝集と、凝集物の乾燥とを繰り返して粒子間に再結晶を起こして生じると考えられる。 Consolidation and agglomeration, which is one of the causes of deterioration in solubility of dialysis agents, are caused by the formation of liquid bridges in the crystal of each component of the dialysis agent due to highly flexible water in the airtight container. It is considered that the product is repeatedly dried and recrystallized between the particles.
また、透析用剤を気密容器内に充填した場合、気密容器内の自由度の高い水分がクエン酸と塩化ナトリウム（または塩化マグネシウム、塩化カルシウム）の反応の触媒となり、塩化水素を発生させると考えられる。そして、発生した塩化水素が無水結晶ブドウ糖を脱水し、５−ヒドロキシメチルフルフラール（５−ＨＭＦ）を産生する可能性がある。 In addition, when a dialysis agent is filled in an airtight container, water with a high degree of freedom in the airtight container acts as a catalyst for the reaction between citric acid and sodium chloride (or magnesium chloride, calcium chloride), generating hydrogen chloride. It is done. Then, the generated hydrogen chloride may dehydrate anhydrous crystalline glucose and produce 5-hydroxymethylfurfural (5-HMF).
一方、塩化カルシウムとして一般的に用いられる塩化カルシウム二水和物に含まれる水分は、潮解性物質の結晶水である。この塩化カルシウム二水和物の結晶水は、科学的に結合されている脱水しにくい水分である。そのため、結晶水の脱水は自由水の脱水よりも高いエネルギーが必要となる。したがって、塩化カルシウム二水和物等の水分をどの程度除水する必要があるのか把握することは、塩化カルシウムを乾燥する乾燥処理工程を含む透析用剤の製造方法で作製される透析用剤の塩化カルシウム乾燥工程の効率化、最適化を図ることになる。 On the other hand, the water contained in calcium chloride dihydrate generally used as calcium chloride is crystal water of a deliquescent substance. This crystal water of calcium chloride dihydrate is scientifically bound water that is difficult to dehydrate. Therefore, dehydration of crystal water requires higher energy than free water dehydration. Therefore, to understand how much water such as calcium chloride dihydrate needs to be dehydrated, the dialysis agent produced by the method for producing a dialysis agent including a drying treatment step for drying calcium chloride is used. This will improve the efficiency and optimization of the calcium chloride drying process.
塩化カルシウムには、吸水能力があり、例えば、１４７．０ｇの塩化カルシウム二水和物（水分含有率：２４．５％）を乾燥して、水分含有率が１％の乾燥塩化カルシウムにした場合は、３４．９１ｇの水分を喪失する。この喪失水分は、水分含有率が１％の乾燥塩化カルシウムが吸水できる能力としてみなすことができる。 Calcium chloride has a water absorption capability, for example, when 147.0 g of calcium chloride dihydrate (water content: 24.5%) is dried to form dry calcium chloride with a water content of 1%. Loses 34.91 g of water. This lost water can be regarded as the ability of dry calcium chloride having a water content of 1% to absorb water.
本明細書では、乾燥塩化カルシウムの吸水能力を、塩化カルシウムの初期の所持水分量（ｇ）（［塩化カルシウム二水和物の重量］×［塩化カルシウム二水和物の理論水分率（２４．５％）］）と、塩化カルシウムの乾燥後の所持水分量（ｇ）（［乾燥塩化カルシウムの重量］×［乾燥塩化カルシウムの実測水分率（％）］）との差で表し、「塩化カルシウムの除水量」と表現する。 In this specification, the water absorption capacity of dry calcium chloride is expressed as the initial water content (g) of calcium chloride ([weight of calcium chloride dihydrate] × [theoretical moisture content of calcium chloride dihydrate (24. 5%)]) and the water content (g) of calcium chloride after drying ([weight of dry calcium chloride] × [measured moisture content of dry calcium chloride (%)]) Is expressed as “water removal amount”.
一方、透析用剤の各原料に含まれている水分は、「付着水」と「結晶水」の２種類に大別される。そして、結晶水を持つ原料には、空気中の水分を取り込んで自発的に水溶液となる「潮解性」のある原料と、物質が空気中で結晶水を放出する「風解性」のある原料とがある。風解性のある原料の結晶水と、原料の付着水は、容易に空気中に放出されうる自由度の高い水分である。 On the other hand, the water contained in each raw material of the dialysis agent is roughly classified into two types, “adhesion water” and “crystal water”. The raw materials with crystal water include “deliquescent” raw materials that take in moisture in the air and spontaneously become aqueous solutions, and “decolonized” raw materials that release crystal water in the air. There is. The water of crystallizing raw material and the water adhering to the raw material having a high degree of freedom can be easily released into the air.
本明細書では、これらの自由度の高い水分である原料の付着水の重量と、風解性成分の結晶水の重量との和を「透析用剤全体の含水量」と表現する。 In the present specification, the sum of the weight of the adhering water of the raw material, which is water having a high degree of freedom, and the weight of the crystal water of the disintegrating component is expressed as “the total water content of the dialysis agent”.
まず、乾燥塩化カルシウムを除いた各成分実測含水率と、各成分理論水分率、各成分重量から全体付着水水分量（付着水量）を算出する。
各成分実測含水率（％）−各成分理論含水率（％）＝各成分付着水による含水率（％）
各成分重量（ｇ）×各成分付着水による含水率（％）＝各成分付着水水分量（ｇ）
各成分付着水水分量の合計（ｇ）＝全体付着水水分量（付着水量）（ｇ）
または、
付着水量（ｇ）＝（全成分合計重量（ｇ）−乾燥塩化カルシウム重量（ｇ））×全体付着水の水分含有率（％）
として求めてもよい。
そして、風解性成分理論水率と、風解性成分重量から風解性成分の結晶水の重量（結晶水量）を算出する。
結晶水量（ｇ）＝風解性成分重量（ｇ）×風解性成分の理論水分率（％）
First, the total amount of adhering water (adhering water amount) is calculated from the measured water content of each component excluding dry calcium chloride, the theoretical water content of each component, and the weight of each component.
Actual moisture content of each component (%)-Theoretical moisture content of each component (%) = Moisture content of each component adhering water (%)
Weight of each component (g) x Moisture content of each component adhering water (%) = Water content of each component adhering water (g)
Total amount of water adhering to each component (g) = Total amount of adhering water (adhering water) (g)
Or
Amount of water adhering (g) = (total weight of all components (g) −weight of dry calcium chloride (g)) × moisture content of total adhering water (%)
You may ask as.
Then, the weight (crystal water amount) of the crystallized water of the wind-dissolvable component is calculated from the wind-dissolvable component theoretical water rate and the wind-dissolvable component weight.
Amount of crystal water (g) = Weathering component weight (g) × Theoretical moisture content of wetting component (%)
このようにして求めた原料の「付着水量」と、「風解性成分の結晶水の重量（結晶水量）」との和から「透析用剤全体の含水量」を求める。そして、「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率をＣとする。
透析用剤全体の含水量（ｇ）＝付着水量（ｇ）＋結晶水量（ｇ）
Ｃ（％）＝［（透析用剤全体の含水量（ｇ））／（塩化カルシウムの除水量（ｇ））］×１００
The “water content of the dialysis agent as a whole” is determined from the sum of the “adhesion water amount” of the raw material thus obtained and “the weight of crystallized water of the disentangling component (crystal water amount)”. The ratio between the “water removal amount of calcium chloride” and the “water content of the entire dialysis agent” is C.
Total water content of dialysis agent (g) = amount of adhering water (g) + amount of crystal water (g)
C (%) = [(water content of the entire dialysis agent (g)) / (water removal amount of calcium chloride (g))] × 100
本発明者らは、「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率であるＣが所定の値以下であれば、顆粒剤ではない、各含有成分が単一の固体成分として容器に充填された透析用剤の固結、凝集が抑制されることを見出した。また、「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率であるＣが所定の値以下であれば、気密容器内の自由度の高い水分の存在を減少させ、塩化水素の発生を抑制し、５−ＨＭＦの産生が抑制されることを見出した。すなわち、透析用剤に含まれる原料のうちの一般に少量成分である塩化カルシウムに乾燥処理を施して、付着水だけではなく結晶水まで除去して、その乾燥塩化カルシウムに「乾燥剤」としての機能を持たせたものである。本願発明では、各含有成分が単一の固体成分として容器に充填された透析用剤において、「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率Ｃというパラメータと、固結、凝集の抑制との関係を見出したことに大きな意義がある。 The inventors of the present invention are not granules, and each contained component is a single component if C, which is the ratio of “water removal amount of calcium chloride” and “water content of the entire dialysis agent”, is not more than a predetermined value. It has been found that consolidation and aggregation of a dialysis agent filled in a container as a solid component is suppressed. In addition, if C, which is a ratio of “water removal amount of calcium chloride” and “water content of the entire dialysis agent”, is equal to or less than a predetermined value, the presence of water with a high degree of freedom in the airtight container is reduced, and It has been found that the generation of hydrogen is suppressed and the production of 5-HMF is suppressed. That is, the calcium chloride, which is generally a small component of the raw materials contained in the dialysis agent, is dried to remove not only the adhering water but also the crystal water, and the dry calcium chloride functions as a “desiccant”. It is something that has In the present invention, in a dialysis agent in which each component is filled in a container as a single solid component, a parameter called a ratio C between “water removal amount of calcium chloride” and “water content of the entire dialysis agent” It is of great significance to have found a relationship with the suppression of flocculation and aggregation.
「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率Ｃは、１６３％未満であるが、１１３％以下が好ましい。また、「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率Ｃは、８２％未満であることがより好ましく、７７％以下であることがさらに好ましい。「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率Ｃが８２％未満であると、透析用剤が糖質成分として無水結晶ブドウ糖を含む場合でも無水結晶ブドウ糖の分解が抑制される。「塩化カルシウムの除水量」と「透析用剤全体の含水量」との比率Ｃは、気密容器外から入ってくる水分等を考慮すると、５５％以下であることがさらにより好ましく、長期保管等の観点から、４０％以下であることが特に好ましい。比率Ｃは低ければ低い方が好ましいが、比率Ｃが低すぎると、比率Ｃを小さくするには塩化カルシウムの過剰な乾燥処理が必要となる場合があるので、適度な乾燥処理で十分であるように比率Ｃは２％以上であればよく、４％以上であることが好ましく、７％以上であることがより好ましい。 The ratio C between the “water removal amount of calcium chloride” and the “water content of the entire dialysis agent” is less than 163%, but is preferably 113% or less. Further, the ratio C between the “water removal amount of calcium chloride” and the “water content of the entire dialysis agent” is more preferably less than 82%, and further preferably 77% or less. When the ratio C between the “water removal amount of calcium chloride” and the “water content of the entire dialysis agent” is less than 82%, the anhydrous crystal glucose is decomposed even when the dialysis agent contains anhydrous crystal glucose as a carbohydrate component. It is suppressed. The ratio C between the “water removal amount of calcium chloride” and the “moisture content of the dialysis agent as a whole” is even more preferably 55% or less in consideration of moisture entering from the outside of the airtight container, such as long-term storage. In view of the above, it is particularly preferably 40% or less. If the ratio C is low, it is preferable. However, if the ratio C is too low, an excessive drying treatment of calcium chloride may be required to reduce the ratio C. Therefore, an appropriate drying treatment seems to be sufficient. The ratio C may be 2% or more, preferably 4% or more, and more preferably 7% or more.
比率Ｃが１６３％未満であれば、透析用剤の固結、凝集の原因となる自由度の高い水分を乾燥塩化カルシウムが吸水するため、透析用剤の固結、凝集が抑制されると考えられる。比率Ｃが８２％未満であれば、無水結晶ブドウ糖の分解の原因となる自由度の高い水分を乾燥塩化カルシウムが十分に吸水するため、透析用剤が糖質成分として無水結晶ブドウ糖を含む場合でも無水結晶ブドウ糖の分解が抑制されると考えられる。透析用剤の固結、凝集および無水結晶ブドウ糖の分解を抑制するのに必要な塩化カルシウムの除水量を処方内容（例えばＡ剤の成分量）ごとに必要最小限にすることができるので、乾燥工程の効率化を図ることができる。また、顆粒剤に成形する透析用剤の製造方法と比較して、単位操作が短縮、簡略化され生産性が向上し、異物の混入の可能性が減少する。また、品種切換（各成分の濃度変更）による製造条件の確立が容易になる。さらに、品種切換（各成分の濃度変更）時に生産設備に残る原料を除去しなくてもよく、生産性が向上する。したがって、低コストかつ質の高い透析用剤が実現される。 If the ratio C is less than 163%, dry calcium chloride absorbs water with a high degree of freedom causing caking and aggregation of the dialysis agent, so that caking and aggregation of the dialysis agent are suppressed. It is done. If the ratio C is less than 82%, dry calcium chloride sufficiently absorbs water with a high degree of freedom that causes decomposition of anhydrous crystalline glucose, so even if the dialysis agent contains anhydrous crystalline glucose as a carbohydrate component. It is thought that the decomposition of anhydrous crystalline glucose is suppressed. Drying is possible because the amount of calcium chloride dewatering required to suppress dialysis solidification, aggregation and decomposition of anhydrous crystalline glucose can be minimized for each formulation (for example, component A). Process efficiency can be improved. Moreover, compared with the manufacturing method of the dialysis agent shape | molded to a granule, unit operation is shortened and simplified, productivity improves, and the possibility of mixing in a foreign material decreases. In addition, it becomes easy to establish manufacturing conditions by changing the product type (changing the concentration of each component). Furthermore, it is not necessary to remove the raw material remaining in the production facility at the time of product type change (concentration change of each component), and productivity is improved. Therefore, a low-cost and high-quality dialysis agent is realized.
また、気密容器内の自由度の高い水分を吸湿する乾燥塩化カルシウムを気密容器内に内包することにより、気密容器内の自由度の高い水分が各成分の結晶に液架橋を形成することによる凝集、凝集物の乾燥を繰り返して粒子間に再結晶を起こして生じる固結の発生を抑制することができると考えられる。 In addition, by containing dry calcium chloride that absorbs moisture with high degree of freedom in the airtight container in the airtight container, the water with high degree of freedom in the airtight container is aggregated by forming a liquid bridge on the crystals of each component. It is thought that the occurrence of solidification caused by recrystallization between particles by repeated drying of the aggregate can be suppressed.
また、気密容器内の自由度の高い水分、および気密容器外から入ってくる水分を吸湿するのに十分な乾燥塩化カルシウムを気密容器内に内包することにより、無水結晶ブドウ糖の分解の原因となる自由度の高い水分を乾燥塩化カルシウムが吸水するので、無水結晶ブドウ糖の分解を抑制することができると考えられる。 In addition, the inclusion of dry calcium chloride sufficient to absorb moisture in the airtight container and moisture entering from outside the airtight container in the airtight container causes decomposition of anhydrous crystalline glucose. Since dry calcium chloride absorbs moisture with a high degree of freedom, it is considered that decomposition of anhydrous crystalline glucose can be suppressed.
本実施形態に係る透析用剤において、塩化カルシウムの水分含有率は１％〜２２％の範囲であり、１４％〜２２％の範囲であることが好ましく、１４％〜１６％の範囲であることがより好ましい。「水分含有率」は、物質に含まれる水分の割合（質量％）を示す。塩化カルシウムの水分含有率が１％〜２２％の範囲であることにより、製造工程が簡略化でき、生産性が向上し、異物混入の問題が少なくなる。水分含有率が１４％〜２２％の範囲の塩化カルシウムは、水分含有率が１％未満の塩化カルシウムと比べて製造（乾燥）に用いるエネルギーをかけずに透析剤の製造をすることができるという利点がある。比率Ｃを上記範囲の値とすれば、水分含有率が１４％〜２２％の範囲の塩化カルシウムであっても薬剤の安定性を図ることができる。また、例えば、１００℃の雰囲気で塩化カルシウム二水和物を乾燥した場合、塩化カルシウムの水分含有率が１４％〜１６％の範囲で脱水速度が緩やかになり、１４％程度で脱水がほとんど進まなくなる（図３参照）。したがって、水分含有率が１４％〜１６％の範囲の塩化カルシウムは、水分含有率を管理しやすいという利点がある。また、水分含有率が１４％〜１６％の範囲の塩化カルシウムを用いることにより、水分含有率が安定した塩化カルシウムを使用し透析用剤を製造することができるので、透析用剤のカルシウム含有量の精度が安定化するという利点もある。塩化カルシウム二水和物を乾燥して水分含有率を１４％〜１６％の範囲としたものを用いることにより、吸湿速度が速い水分含有率が１％未満の塩化カルシウムを用いるよりも、取り扱いが容易であり、さらにコストを低減することができる。 In the dialysis agent according to this embodiment, the water content of calcium chloride is in the range of 1% to 22%, preferably in the range of 14% to 22%, and in the range of 14% to 16%. Is more preferable. “Moisture content” indicates the proportion (mass%) of water contained in the substance. When the moisture content of calcium chloride is in the range of 1% to 22%, the manufacturing process can be simplified, the productivity is improved, and the problem of contamination is reduced. Calcium chloride having a moisture content in the range of 14% to 22% can produce a dialysate without applying energy used for production (drying) compared to calcium chloride having a moisture content of less than 1%. There are advantages. If the ratio C is set to a value within the above range, the stability of the drug can be achieved even with calcium chloride having a moisture content in the range of 14% to 22%. Also, for example, when calcium chloride dihydrate is dried in an atmosphere of 100 ° C., the dehydration rate becomes slow when the water content of calcium chloride is in the range of 14% to 16%, and dehydration almost proceeds at about 14%. Disappear (see FIG. 3). Therefore, calcium chloride having a moisture content in the range of 14% to 16% has an advantage that the moisture content can be easily managed. In addition, by using calcium chloride having a moisture content in the range of 14% to 16%, it is possible to produce a dialysis agent using calcium chloride having a stable moisture content. Therefore, the calcium content of the dialysis agent There is also an advantage that the accuracy of the is stabilized. By using calcium chloride dihydrate dried to have a moisture content in the range of 14% to 16%, handling is faster than using calcium chloride with a moisture absorption rate of less than 1%. It is easy and the cost can be further reduced.
このように、本実施形態に係る透析用剤の製造方法により、顆粒剤に成形することにより品種切換（各成分の濃度変更）による複雑な製造条件の確率が必要になるという問題が解決される。また、顆粒剤に成形することにより単位操作が複雑になり、生産性が低下し、単位操作が増えることにより異物の混入の可能性が増大するという問題が解決される。さらに、顆粒剤に成形することにより品種切換（各成分の濃度変更）による製造条件の確立が困難となるという問題が解決される。また、品種切換（各成分の濃度変更）時に生産設備に残る原料を除去しなければならず、製品ロスおよび時間ロス等が生じて生産性が低下するという問題が解決される。したがって、低コストかつ品質の高い透析用剤が実現される。 As described above, the method for producing a dialysis agent according to the present embodiment solves the problem of requiring probabilities of complicated production conditions by changing the type (changing the concentration of each component) by forming into granules. . Moreover, the problem that the unit operation becomes complicated by molding into a granule, the productivity is lowered, and the possibility that foreign matter is mixed in by increasing the unit operation is solved. Furthermore, the problem that it becomes difficult to establish production conditions by changing the product type (changing the concentration of each component) by forming into granules is solved. In addition, it is necessary to remove the raw material remaining in the production facility at the time of product type change (concentration change of each component), which solves the problem that product loss, time loss, etc. occur and productivity is lowered. Therefore, a low-cost and high-quality dialysis agent is realized.
本実施形態に係る透析用剤において、塩化カルシウムが乾燥処理されていることが好ましく、塩化カルシウムが７５℃以上の雰囲気で乾燥処理されていることがより好ましい。塩化カルシウムの加熱乾燥処理において雰囲気が７５℃以上の温度であると、塩化カルシウムの水分が除去されやすく、塩化カルシウムの除水量と透析用剤全体の含水量との比率１６３％未満２％以上、および塩化カルシウムの水分含有率が１％〜２２％の範囲が達成されやすい。 In the dialysis agent according to this embodiment, it is preferable that the calcium chloride is dried, and it is more preferable that the calcium chloride is dried in an atmosphere of 75 ° C. or higher. When the atmosphere is 75 ° C. or higher in the heat drying treatment of calcium chloride, the water content of calcium chloride is easily removed, and the ratio of the water content of calcium chloride to the total water content of the dialysis agent is less than 163% and 2% or more. And the moisture content of calcium chloride tends to be achieved in the range of 1% to 22%.
本実施形態に係る透析用剤には、糖質成分を含むことが好ましい。糖質成分としては、例えば、無水結晶ブドウ糖等が挙げられる。 The dialysis agent according to this embodiment preferably contains a carbohydrate component. Examples of the carbohydrate component include anhydrous crystalline glucose.
電解質成分としては、塩化カルシウムの他に、例えば、塩化ナトリウム、塩化カリウム、塩化マグネシウム等が挙げられる。好ましい電解質成分としては、塩化カルシウムの他に、塩化ナトリウム、塩化カリウム、塩化マグネシウムである。 Examples of the electrolyte component include sodium chloride, potassium chloride, magnesium chloride and the like in addition to calcium chloride. Preferred electrolyte components are sodium chloride, potassium chloride, and magnesium chloride in addition to calcium chloride.
本実施形態に係る透析用剤は、アルカリ化成分を含むことが好ましい。アルカリ化成分としては、例えば、炭酸水素ナトリウム（重炭酸ナトリウム）等が挙げられる。 The dialysis agent according to this embodiment preferably contains an alkalinizing component. Examples of the alkalinizing component include sodium bicarbonate (sodium bicarbonate).
本実施形態に係る透析用剤は、ｐＨ調整成分として例えば酢酸ナトリウムおよび氷酢酸の混合物である酢酸混合物を含む。酢酸ナトリウムとしては、酢酸ナトリウム無水物、酢酸ナトリウム三水和物等が挙げられる。酢酸ナトリウムおよび氷酢酸の混合物は、酢酸ナトリウムと氷酢酸とを混合して粉末化したものである。この酢酸混合物において、酢酸ナトリウムの少なくとも一部と氷酢酸とは錯体を形成していると考えられる。この酢酸混合物において、錯体を形成してない未反応の酢酸ナトリウムを含んでいてもよい。なお、酢酸ナトリウムと氷酢酸とが錯体を形成していることは、Ｘ線回折法により確認することができる。 The dialysis agent according to the present embodiment includes, for example, an acetic acid mixture that is a mixture of sodium acetate and glacial acetic acid as a pH adjusting component. Examples of sodium acetate include sodium acetate anhydrous and sodium acetate trihydrate. The mixture of sodium acetate and glacial acetic acid is a powdered mixture of sodium acetate and glacial acetic acid. In this acetic acid mixture, it is considered that at least a part of sodium acetate and glacial acetic acid form a complex. This acetic acid mixture may contain unreacted sodium acetate which has not formed a complex. The formation of a complex between sodium acetate and glacial acetic acid can be confirmed by an X-ray diffraction method.
透析用剤に使用するｐＨ調整剤を酢酸ナトリウムと氷酢酸とを混合して粉末化した酢酸混合物とせずに、酢酸ナトリウムと氷酢酸をｐＨ調整剤として透析用剤を気密容器内に充填した場合、氷酢酸が無水結晶ブドウ糖を脱水し、５−ヒドロキシメチルフルフラール（５−ＨＭＦ）を産生し、また液体である氷酢酸が薬剤を固結・凝集する。 When the dialysis agent is filled in an airtight container using sodium acetate and glacial acetic acid as a pH adjuster instead of a mixture of powdered sodium acetate and glacial acetic acid. Glacial acetic acid dehydrates anhydrous crystalline glucose to produce 5-hydroxymethylfurfural (5-HMF), and liquid glacial acetic acid solidifies and aggregates the drug.
酢酸混合物における酢酸ナトリウムと氷酢酸とのモル比は、１：１〜５：１の範囲であることが好ましく、３：１〜４：１の範囲であることがより好ましい。酢酸ナトリウムに対する氷酢酸のモル比が１以上であると、氷酢酸が酢酸ナトリウムと結合しきれずに粉末化できず薬剤の安定性を害する場合がある。氷酢酸に対する酢酸ナトリウムのモル比が５以上のＡ剤では、炭酸水素ナトリウムを含んでなるＢ剤と組み合わせて調製された際の透析液のｐＨおよびアルカリ化剤濃度が透析治療に適さない。この酢酸混合物としては、酢酸ナトリウムと氷酢酸との１：１混合物（二酢酸ナトリウム（粉末酢酸））、酢酸ナトリウムと氷酢酸との３：１混合物、酢酸ナトリウムと氷酢酸との８：２．２混合物、酢酸ナトリウムと氷酢酸との１０：２混合物等が挙げられる。これらのうち、酢酸ナトリウムと氷酢酸との１：１〜５：１混合物を用いると、透析用剤で用いられる酢酸ナトリウムおよび氷酢酸の全量を粉末化した混合物として添加することができ、必要な酢酸ナトリウムを別途添加しなくてもよく、製造工程の短縮化につながるという利点がある。また、酢酸ナトリウム無水物と氷酢酸との３：１〜４：１混合物は、酢酸ナトリウム無水物に氷酢酸を添加しても粒度の安定した酢酸混合物を製造することができる。 The molar ratio of sodium acetate to glacial acetic acid in the acetic acid mixture is preferably in the range of 1: 1 to 5: 1, more preferably in the range of 3: 1 to 4: 1. If the molar ratio of glacial acetic acid to sodium acetate is 1 or more, glacial acetic acid cannot be combined with sodium acetate and cannot be powdered, which may impair the stability of the drug. In the case of agent A having a molar ratio of sodium acetate to glacial acetic acid of 5 or more, the pH and alkalizing agent concentration of the dialysate when prepared in combination with agent B containing sodium bicarbonate are not suitable for dialysis treatment. The acetic acid mixture includes a 1: 1 mixture of sodium acetate and glacial acetic acid (sodium diacetate (powdered acetic acid)), a 3: 1 mixture of sodium acetate and glacial acetic acid, and 8: 2. 2 mixture, a 10: 2 mixture of sodium acetate and glacial acetic acid, and the like. Of these, using a 1: 1 to 5: 1 mixture of sodium acetate and glacial acetic acid allows the total amount of sodium acetate and glacial acetic acid used in the dialysis agent to be added as a powdered mixture, which is necessary. There is an advantage that sodium acetate does not have to be added separately, leading to shortening of the manufacturing process. Further, a 3: 1 to 4: 1 mixture of sodium acetate anhydride and glacial acetic acid can produce an acetic acid mixture having a stable particle size even when glacial acetic acid is added to sodium acetate anhydride.
ｐＨ調整成分としては、その他に、クエン酸、リンゴ酸、乳酸、フマル酸、コハク酸、マロン酸等の有機固体酸や、クエン酸ナトリウム等のクエン酸塩、乳酸ナトリウム等の乳酸塩、リンゴ酸ナトリウム等のリンゴ酸塩、フマル酸ナトリウム等のフマル酸塩、コハク酸ナトリウム等のコハク酸塩、マロン酸ナトリウム等のマロン酸塩等の有機酸塩等を含んでもよい。 Other pH adjusting components include organic solid acids such as citric acid, malic acid, lactic acid, fumaric acid, succinic acid and malonic acid, citrates such as sodium citrate, lactates such as sodium lactate, malic acid Malate such as sodium, fumarate such as sodium fumarate, succinate such as sodium succinate, and organic acid salts such as malonate such as sodium malonate may be included.
本実施形態に係る透析用剤における各成分の配合量は、適切な濃度に希釈、混合した場合に、透析液として、例えば、下記の濃度であることが好ましい。本実施形態に係る透析用剤では、下記のように、透析用剤における塩化カルシウムの配合量が少量であっても精度よく容器に充填される。
Ｎａ＋ １４０．６〜１３５．２ｍＥｑ／Ｌ
Ｋ＋ ２．０ｍＥｑ／Ｌ
Ｃａ２＋ ３．５〜２．５ｍＥｑ／Ｌ
Ｍｇ２＋ １．５〜１ｍＥｑ／Ｌ
Ｃｌ− １１３〜１１０．５ｍＥｑ／Ｌ
ＨＣＯ３ − ３５〜２５ｍＥｑ／Ｌ
無水結晶ブドウ糖 １５０〜１００ｍｇ／ｄｌ
クエン酸イオン ２．４〜０ｍＥｑ／Ｌ
または、酢酸イオン １２〜０ｍＥｑ／Ｌ
The blending amount of each component in the dialysis agent according to the present embodiment is preferably the following concentration, for example, as a dialysis solution when diluted and mixed to an appropriate concentration. In the dialysis agent according to this embodiment, as described below, the container is accurately filled even if the amount of calcium chloride in the dialysis agent is small.
Na + 140.6-135.2 mEq / L
K + 2.0 mEq / L
Ca 2+ 3.5-2.5 mEq / L
Mg 2+ 1.5-1mEq / L
Cl − 113 to 110.5 mEq / L
HCO 3 - 35~25mEq / L
Anhydrous crystalline glucose 150-100mg / dl
Citrate ion 2.4-0 mEq / L
Or acetate ion 12-0mEq / L
本実施形態に係る透析用剤において、容器への充填方法としては、「単一の固体成分」として充填されていればよく、特に制限はない。通常は、塩化カルシウムを含む電解質成分、無水結晶ブドウ糖等の糖質成分およびｐＨ調整成分を含む「Ａ剤」と、炭酸水素ナトリウム等のアルカリ化成分を含む「Ｂ剤」との２剤構成となっている。顆粒剤に成形しない「単一の固体成分」としてＡ剤が容器に充填されていればよい。また、各成分の容器への充填順序についても特に制限はない。さらに、「Ａ剤」の主要な電解質成分である「塩化ナトリウム」を別の包装にし、３剤構成とすることも可能である。本実施形態における「Ａ剤」とは、少なくとも塩化マグネシウムを含む電解質成分と、無水結晶ブドウ糖およびｐＨ調整剤とを含む製剤を意味する。 In the dialysis agent according to this embodiment, the filling method into the container is not particularly limited as long as it is filled as a “single solid component”. Usually, a two-component configuration of an “A agent” containing an electrolyte component containing calcium chloride, a saccharide component such as anhydrous crystalline glucose and a pH adjusting component, and a “B agent” containing an alkalinizing component such as sodium bicarbonate, It has become. It is only necessary that the A agent is filled in the container as a “single solid component” that is not formed into granules. Moreover, there is no restriction | limiting in particular also about the filling order to the container of each component. Furthermore, “sodium chloride”, which is the main electrolyte component of “agent A”, can be packaged separately to form a three-component composition. The “agent A” in the present embodiment means a preparation containing an electrolyte component containing at least magnesium chloride, anhydrous crystalline glucose and a pH adjusting agent.
＜透析用剤の製造方法＞
本発明の実施形態に係る、少なくとも塩化カルシウムを含む電解質成分と、ｐＨ調整剤とを含有する透析用剤の製造方法において、塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上となり、塩化カルシウムの水分含有率が１％〜２２％の範囲となるように塩化カルシウムを乾燥する乾燥処理工程と、各含有成分を単一の固体成分として容器に充填する充填工程と、を含む。乾燥処理工程において、塩化カルシウムの除水量と透析用剤全体の含水量との比率が８２％未満２％以上となるように塩化カルシウムを乾燥することが好ましい。本実施形態に係る透析用剤の製造方法において、酢酸ナトリウムと氷酢酸とを混合して酢酸混合物を得る混合工程を含んでもよい。
<Method for producing dialysis agent>
In the method for producing a dialysis agent comprising an electrolyte component containing at least calcium chloride and a pH adjuster according to an embodiment of the present invention, the ratio between the water removal amount of calcium chloride and the total water content of the dialysis agent is 163. %, 2% or more, and a drying process for drying calcium chloride so that the moisture content of calcium chloride is in the range of 1% to 22%, and filling each container as a single solid component into a container And a process. In the drying treatment step, it is preferable to dry the calcium chloride so that the ratio of the water removal amount of the calcium chloride and the water content of the entire dialysis agent is less than 82% and 2% or more. The method for producing a dialysis agent according to this embodiment may include a mixing step of mixing sodium acetate and glacial acetic acid to obtain an acetic acid mixture.
本実施形態において、塩化カルシウムの乾燥処理の方法としては、例えば、加熱する加熱乾燥法、減圧状態にする減圧乾燥法、乾燥剤等を使用した乾燥法等のうちの１つまたはそれらの組み合わせが挙げられる。特に、加熱する加熱乾燥法、または加熱する加熱乾燥法と減圧状態にする減圧乾燥法の組み合わせが塩化カルシウムの乾燥効率の観点から好ましい。また、乾燥処理の効率化等の点から、塩化カルシウムは他の成分とは別に、個別に乾燥されることが好ましい。 In the present embodiment, as a method of drying calcium chloride, for example, one of a heat drying method for heating, a vacuum drying method for reducing the pressure, a drying method using a desiccant, or the like, or a combination thereof is used. Can be mentioned. In particular, a heat drying method for heating or a combination of a heat drying method for heating and a reduced pressure drying method for reducing the pressure is preferable from the viewpoint of drying efficiency of calcium chloride. Moreover, it is preferable that calcium chloride is individually dried separately from other components from the viewpoint of efficiency of the drying process.
加熱乾燥法の場合、塩化カルシウムの乾燥処理温度は、例えば、７５℃〜１１０℃であり、乾燥時間は、例えば、１５分〜５時間である。塩化カルシウムの除水量と透析用剤全体の含水量との比率を１６３％未満２％以上とし、塩化カルシウムの水分含有率を１％〜２２％の範囲とするためには、乾燥処理温度は、７５℃以上であり、乾燥時間は、１５分以上であることが好ましく、乾燥処理温度が、１００℃以上であり、乾燥時間は、３０分以上であることがより好ましい。 In the case of the heat drying method, the drying treatment temperature of calcium chloride is, for example, 75 ° C. to 110 ° C., and the drying time is, for example, 15 minutes to 5 hours. In order to set the ratio of the water content of calcium chloride to the water content of the entire dialysis agent to be less than 163% and 2% or more, and the water content of calcium chloride in the range of 1% to 22%, the drying treatment temperature is: It is 75 ° C. or higher, the drying time is preferably 15 minutes or longer, the drying treatment temperature is 100 ° C. or higher, and the drying time is more preferably 30 minutes or longer.
このようにして製造された本実施形態に係る透析用剤から透析液を調製するには、本実施形態に係る透析用剤を「Ａ剤」として、所定量の精製水に溶解してＡ原液を作製し、「Ｂ剤」を所定量の精製水に溶解してＢ原液を作製し、これらのＡ原液とＢ原液とを所定の比率で混合希釈する。例えば、実施例１のサンプル７−１の透析用剤Ａ剤を９Ｌになるように精製水で溶解してＡ原液を作製し、炭酸水素ナトリウム６６１．６ｇのＢ剤を１１．３４Ｌになるように精製水で溶解してＢ原液を作製する。そして、Ａ原液：Ｂ原液：精製水＝１：１．２６：３２．７４の割合で混合すれば、３１５Ｌの透析液を調製することができる。 In order to prepare a dialysis solution from the dialysis agent according to this embodiment manufactured as described above, the dialysis agent according to this embodiment is referred to as “agent A” and dissolved in a predetermined amount of purified water to prepare a stock A solution. The “B agent” is dissolved in a predetermined amount of purified water to prepare a B stock solution, and these A stock solution and B stock solution are mixed and diluted at a predetermined ratio. For example, the dialysis agent A of the sample 7-1 of Example 1 is dissolved in purified water so as to be 9 L to prepare an A stock solution, and 661.6 g of sodium bicarbonate B is adjusted to 11.34 L. A B stock solution is prepared by dissolving in purified water. And if it mixes in the ratio of A undiluted solution: B undiluted solution: purified water = 1: 1.26: 32.74, 315L dialysate can be prepared.
以下、実施例および比較例を挙げ、本発明をより具体的に詳細に説明するが、本発明は、以下の実施例に限定されるものではない。 Hereinafter, although an example and a comparative example are given and the present invention is explained more concretely in detail, the present invention is not limited to the following examples.
＜各種測定方法＞
実施例における各種測定は以下の通りに行った。
［水分含有率（％）］
物質に含まれる水分の割合（質量％）を水分含有率と定義する。詳細な測定方法は以下の通りである。
<Various measurement methods>
Various measurements in the examples were performed as follows.
[Moisture content (%)]
The proportion (% by mass) of moisture contained in the substance is defined as the moisture content. The detailed measurement method is as follows.
塩化ナトリウム、無水結晶ブドウ糖、塩化カリウム、クエン酸、クエン酸ナトリウム、酢酸ナトリウムの水分含有率測定は、第１６改正日本薬局方に記載されている水分含有率測定方法に準じて行った。 The water content of sodium chloride, anhydrous crystalline glucose, potassium chloride, citric acid, sodium citrate, and sodium acetate was measured according to the water content measurement method described in the 16th revised Japanese Pharmacopoeia.
塩化カルシウム、塩化マグネシウム、粉末酢酸の水分含有率測定は、室温２５℃±２．５℃、相対湿度４０％±２．５％の雰囲気において、ＪＩＳ Ｋ００６８のカールフィッシャ滴定法、容量滴定法、直接滴定に準じて行った。カールフィッシャ測定器（京都電子工業株式会社製；型番ＭＫＡ−５１０）を用いて、溶媒としてメタノール（関東化学株式会社製）３０ｍｌを使用して行った。水分測定用試薬は、カールフィッシャ試薬（シグマ・アルドリッチ・ジャパン社製；製品名ハイドラナール−コンポジット５）を使用した（参照：ＪＩＳ Ｋ００６８）。 The moisture content of calcium chloride, magnesium chloride, and powdered acetic acid was measured in a JIS K0068 Karl Fischer titration method, volumetric titration method, direct measurement in an atmosphere of room temperature 25 ° C. ± 2.5 ° C. and relative humidity 40% ± 2.5%. Performed according to titration. A Karl Fischer measuring instrument (manufactured by Kyoto Electronics Co., Ltd .; model number MKA-510) was used, and 30 ml of methanol (manufactured by Kanto Chemical Co., Inc.) was used as a solvent. A Karl Fischer reagent (manufactured by Sigma-Aldrich Japan; product name Hydranal-Composite 5) was used as the reagent for moisture measurement (see JIS K0068).
［固結率］
固結率とは、透析用剤の全成分合計重量に対する固結重量の割合と定義する。固結重量とは、試験用ふるい（目開き５．６ｍｍ）を通過しない試料の重量と定義する。詳細な測定方法は以下の通りである。
[Consolidation rate]
The consolidation rate is defined as the ratio of the consolidated weight to the total weight of all components of the dialysis agent. The consolidated weight is defined as the weight of the sample that does not pass through the test sieve (mesh opening 5.6 mm). The detailed measurement method is as follows.
所定の水分含有量の塩化カルシウムを使用した透析用剤を密閉容器に入れ、次に、恒温恒湿器（タバイエスペック（株）社製；型式 ＰＲ−３ＫＰ）において４０℃、相対湿度７５％の条件下で１４日安定性試験を実施した。１４日保存された透析用剤を開封し、試験用ふるい（目開き５．６ｍｍ）の上にあけ、固結の量（ｇ）を確認した。 A dialysis agent using calcium chloride having a predetermined water content is put in a sealed container, and then at 40 ° C. and a relative humidity of 75% in a thermo-hygrostat (manufactured by Tabai Espec Co., Ltd .; model PR-3KP). A 14 day stability test was performed under the conditions. The dialysis agent stored for 14 days was opened and opened on a test sieve (mesh opening 5.6 mm), and the amount of consolidation (g) was confirmed.
［５−ＨＭＦ試験］
所定の水分含有量の塩化カルシウムを使用した透析用剤を密閉容器に入れ、次に、恒温恒湿器（タバイエスペック（株）社製；型式 ＰＲ−３ＫＰ）において４０℃、相対湿度７５％の条件下で１４日安定性試験を実施した。１４日保存された透析用剤を開封し、当該透析用剤をＲＯ水で溶解した。溶解された透析用剤Ａ原液の無水結晶ブドウ糖の分解率を測定するため、第１６改正日本薬局方に記載されているブドウ糖注射液の純度試験の紫外可視吸光度測定法に基づき波長２８４ｎｍにおける吸光度の測定を行った。
[5-HMF test]
A dialysis agent using calcium chloride having a predetermined water content is put in a sealed container, and then at 40 ° C. and a relative humidity of 75% in a thermo-hygrostat (manufactured by Tabai Espec Co., Ltd .; model PR-3KP). A 14 day stability test was performed under the conditions. The dialysis agent stored for 14 days was opened, and the dialysis agent was dissolved in RO water. In order to measure the degradation rate of anhydrous crystalline glucose in the dissolved dialysis agent A stock solution, the absorbance at a wavelength of 284 nm was determined based on the UV-visible absorbance measurement method of the glucose injection purity test described in the 16th revision Japanese Pharmacopoeia. Measurements were made.
＜塩化カルシウムの乾燥＞
以下のようにして、塩化カルシウムの乾燥処理を行った。
［加熱乾燥］
塩化カルシウム・二水和物（ＣａＣｌ２・２Ｈ２Ｏ）５０ｇをステンレス角型バット（外寸法（ｍｍ）２１０×１７０×３１：底寸法（ｍｍ）１７０×１３０：ＳＵＳ３０４）に取り、平らに均し、所定の温度、時間で加熱乾燥した。乾燥後の塩化カルシウムを２０００μｍと２１２μｍメッシュの篩を通過させて、２１２μｍの篩上に残った試料だけを使用した。乾燥温度は、１００℃または１８０℃とした。乾燥時間は、１００℃で３０分、１時間、３．５時間、１８０℃で２時間とした。乾燥機は、ヤマト科学社製、型式ＤＫ６００Ｔを使用した。
<Drying of calcium chloride>
The calcium chloride was dried as follows.
[Heat drying]
Take 50 g of calcium chloride dihydrate (CaCl 2 .2H 2 O) into a stainless steel square bat (outside dimension (mm) 210 × 170 × 31: bottom dimension (mm) 170 × 130: SUS304) and flatten it evenly. And dried by heating at a predetermined temperature and time. The dried calcium chloride was passed through 2000 μm and 212 μm mesh sieves, and only the sample remaining on the 212 μm sieve was used. The drying temperature was 100 ° C. or 180 ° C. The drying time was 30 minutes at 100 ° C., 1 hour, 3.5 hours, and 2 hours at 180 ° C. As the dryer, model DK600T manufactured by Yamato Scientific Co., Ltd. was used.
得られた乾燥試料（ＣａＣｌ２）および乾燥処理を行っていない塩化カルシウム・二水和物について、水分含有率を測定した。結果を表１に示す。 The moisture content of the obtained dry sample (CaCl 2 ) and calcium chloride dihydrate not subjected to the drying treatment was measured. The results are shown in Table 1.
＜実施例１＞
乾燥工程を経ることによって、乾燥剤としての機能を向上させた塩化カルシウム（ＣａＣｌ２）（水分含有率１％、１５％、１９％、２２％）を使用して、表２の割合で塩化ナトリウム、塩化カリウム、塩化マグネシウム六水和物、無水クエン酸、無水クエン酸ナトリウム、無水結晶ブドウ糖、塩化カルシウムを容器に充填した後、容器を密閉して透析用剤を作製した（サンプル１−１〜１−４）。
<Example 1>
By using calcium chloride (CaCl 2 ) (moisture content 1%, 15%, 19%, 22%) whose function as a desiccant has been improved by passing through a drying step, sodium chloride at a ratio shown in Table 2 , Potassium chloride, magnesium chloride hexahydrate, anhydrous citric acid, anhydrous sodium citrate, anhydrous crystalline glucose, and calcium chloride were filled in a container, and then the container was sealed to prepare a dialysis agent (Sample 1-1 to 1-1) 1-4).
塩化ナトリウム、塩化カリウム、塩化マグネシウム六水和物、無水クエン酸、無水クエン酸ナトリウム、無水結晶ブドウ糖の各成分の付着水水分量を上記水分含有率の測定方法により測定し、付着水量を求めた。結果を表３に示す。 The amount of adhering water of each component of sodium chloride, potassium chloride, magnesium chloride hexahydrate, anhydrous citric acid, anhydrous sodium citrate, and anhydrous crystalline glucose was measured by the method for measuring the moisture content, and the amount of adhering water was determined. . The results are shown in Table 3.
上記透析用剤について安定性試験（４０℃、７５％ＲＨ、１４日間）を実施して、固結の有無を調べ、上記の方法で評価した。また、上記安定性試験を受けた透析用剤をＲＯ水で溶解して透析用剤Ａ原液を作製した。透析用剤Ａ原液の無水結晶ブドウ糖の分解率を測定するため、上記の方法で５−ＨＭＦの吸光度の測定を行った。結果を表４に示す。また、塩化カルシウムの除水量および透析用剤全体の含水量を算出し、比率Ｃを算出した結果を表４に示す。 The dialysis agent was subjected to a stability test (40 ° C., 75% RH, 14 days), examined for the presence of caking, and evaluated by the above method. Moreover, the dialysis agent which received the said stability test was melt | dissolved with RO water, and the dialysis agent A stock solution was produced. In order to measure the degradation rate of anhydrous crystalline glucose in the dialysis agent A stock solution, the absorbance of 5-HMF was measured by the above method. The results are shown in Table 4. Table 4 shows the results of calculating the ratio C by calculating the water removal amount of calcium chloride and the water content of the entire dialysis agent.
＜実施例２＞
ｐＨ調整成分として無水クエン酸と無水クエン酸ナトリウムとの組み合わせの代わりに、表５に示す通り、無水クエン酸とクエン酸ナトリウム二水和物との組み合わせを用いた以外は、実施例１と同様にして評価を行った。結果を表６，７に示す。
<Example 2>
Instead of the combination of anhydrous citric acid and anhydrous sodium citrate as the pH adjusting component, the same as in Example 1 except that a combination of anhydrous citric acid and sodium citrate dihydrate was used as shown in Table 5. And evaluated. The results are shown in Tables 6 and 7.
＜実施例３＞
ｐＨ調整成分として無水クエン酸と無水クエン酸ナトリウムとの組み合わせの代わりに、表８に示す通り、クエン酸一水和物と無水クエン酸ナトリウムとの組み合わせを用いた以外は、実施例１と同様にして評価を行った。結果を表９，１０に示す。
<Example 3>
Instead of the combination of anhydrous citric acid and anhydrous sodium citrate as a pH adjusting component, the same as in Example 1 except that a combination of citric acid monohydrate and anhydrous sodium citrate was used as shown in Table 8. And evaluated. The results are shown in Tables 9 and 10.
＜実施例４＞
ｐＨ調整成分として無水クエン酸と無水クエン酸ナトリウムとの組み合わせの代わりに、表１１に示す通り、クエン酸一水和物とクエン酸ナトリウム二水和物との組み合わせを用いた以外は、実施例１と同様にして評価を行った。結果を表１２，１３に示す。
<Example 4>
Examples except that a combination of citric acid monohydrate and sodium citrate dihydrate was used as a pH adjusting component instead of the combination of anhydrous citric acid and anhydrous sodium citrate as shown in Table 11. Evaluation was performed in the same manner as in Example 1. The results are shown in Tables 12 and 13.
＜実施例５＞
塩化カルシウムの配合量を表１４の通りとした以外は、実施例４と同様にして評価を行った。結果を表１５，１６に示す。
<Example 5>
Evaluation was performed in the same manner as in Example 4 except that the amount of calcium chloride was changed as shown in Table 14. The results are shown in Tables 15 and 16.
＜実施例６＞
塩化カルシウムの配合量を表１７の通りとした以外は、実施例４と同様にして評価を行った。結果を表１８，１９に示す。
<Example 6>
Evaluation was performed in the same manner as in Example 4 except that the amount of calcium chloride was changed as shown in Table 17. The results are shown in Tables 18 and 19.
＜実施例７＞
ｐＨ調整成分として無水クエン酸と無水クエン酸ナトリウムとの組み合わせの代わりに、表２０に示す通り、粉末酢酸と酢酸ナトリウム無水物との組み合わせを用いた以外は、実施例１と同様にして評価を行った。結果を表２１，２２に示す。粉末酢酸は、酢酸ナトリウム無水物と氷酢酸とをモル比１：１で混合して得た。
<Example 7>
Evaluation was performed in the same manner as in Example 1 except that a combination of powdered acetic acid and sodium acetate anhydride was used as a pH adjusting component instead of a combination of anhydrous citric acid and anhydrous sodium citrate as shown in Table 20. went. The results are shown in Tables 21 and 22. Powdered acetic acid was obtained by mixing sodium acetate anhydride and glacial acetic acid in a molar ratio of 1: 1.
＜実施例８＞
ｐＨ調整成分として無水クエン酸と無水クエン酸ナトリウムとの組み合わせの代わりに、表２３に示す通り、粉末酢酸と酢酸ナトリウム三水和物との組み合わせを用いた以外は、実施例１と同様にして評価を行った。結果を表２４，２５に示す。
<Example 8>
Instead of the combination of anhydrous citric acid and anhydrous sodium citrate as a pH adjusting component, as shown in Table 23, the same procedure as in Example 1 was used except that a combination of powdered acetic acid and sodium acetate trihydrate was used. Evaluation was performed. The results are shown in Tables 24 and 25.
各サンプルをＲＯ水で溶解して３１５Ｌとした時の各成分の濃度を表２６に示す。 Table 26 shows the concentration of each component when each sample was dissolved in RO water to give 315 L.
以上の結果をまとめて、比率Ｃと固結率との関係を図１に示し、比率Ｃと５−ＨＭＦの吸光度との関係を図２に示す。 The above results are summarized, the relationship between the ratio C and the consolidation rate is shown in FIG. 1, and the relationship between the ratio C and the absorbance of 5-HMF is shown in FIG.
このように、塩化カルシウムの除水量と透析用剤全体の含水量との比率Ｃを１６３％未満２％以上とすることにより、安定性試験において薬剤の固結、凝集が抑制された。また、塩化カルシウムの除水量と透析用剤全体の含水量との比率を８２％未満２％以上とすることにより、安定性試験において５−ＨＭＦの産生が抑制された。 Thus, by setting the ratio C between the water removal amount of calcium chloride and the water content of the entire dialysis agent to be less than 163% and 2% or more, the caking and aggregation of the drug were suppressed in the stability test. Moreover, the production | generation of 5-HMF was suppressed in the stability test by making the ratio of the water removal amount of calcium chloride and the water content of the whole dialysis agent into less than 82% and 2% or more.
＜実施例９＞
［酢酸混合物の調製］
酢酸ナトリウム無水物（３８．８ｇ）を容器に投入し、氷酢酸（２８．４ｇ）を投入量６ｍＬ／分で投入しながら混合し、酢酸ナトリウム無水物と氷酢酸との混合物である酢酸混合物（１．５：１．５）（酢酸ナトリウム無水物：氷酢酸（モル比）＝１．５：１．５）を得た。
<Example 9>
[Preparation of acetic acid mixture]
Sodium acetate anhydride (38.8 g) was charged into a container, and glacial acetic acid (28.4 g) was mixed while being charged at a rate of 6 mL / min, and an acetic acid mixture (a mixture of sodium acetate anhydride and glacial acetic acid ( 1.5: 1.5) (anhydrous sodium acetate: glacial acetic acid (molar ratio) = 1.5: 1.5).
酢酸ナトリウム無水物（７７．５ｇ）を容器に投入し、氷酢酸（５６．７ｇ）を投入量６ｍＬ／分で投入しながら混合し、酢酸ナトリウム無水物と氷酢酸との混合物である酢酸混合物（３：３）（酢酸ナトリウム無水物：氷酢酸（モル比）＝３：３）を得た。 Sodium acetate anhydrous (77.5 g) was charged into a container, glacial acetic acid (56.7 g) was mixed while being charged at a charging rate of 6 mL / min, and an acetic acid mixture (a mixture of sodium acetate anhydrous and glacial acetic acid ( 3: 3) (anhydrous sodium acetate: glacial acetic acid (molar ratio) = 3: 3) was obtained.
酢酸ナトリウム無水物（１５４．８ｇ）を容器に投入し、氷酢酸（３７．８ｇ）を投入量６ｍＬ／分で投入しながら混合し、酢酸ナトリウム無水物と氷酢酸との混合物である酢酸混合物（６：２）（酢酸ナトリウム無水物：氷酢酸（モル比）＝６：２）を得た。 Sodium acetate anhydrous (154.8 g) was charged into a container, and glacial acetic acid (37.8 g) was mixed while charging at 6 mL / min, and an acetic acid mixture (a mixture of sodium acetate anhydrous and glacial acetic acid ( 6: 2) (anhydrous sodium acetate: glacial acetic acid (molar ratio) = 6: 2).
酢酸ナトリウム無水物（２０６．７ｇ）を容器に投入し、氷酢酸（４２．０ｇ）を投入量６ｍＬ／分で投入しながら混合し、酢酸ナトリウム無水物と氷酢酸との混合物である酢酸混合物（８：２．２）（酢酸ナトリウム無水物：氷酢酸（モル比）＝８：２．２）を得た。 Sodium acetate anhydrous (206.7 g) was charged into a container, and glacial acetic acid (42.0 g) was mixed while being charged at a charging rate of 6 mL / min, and an acetic acid mixture (a mixture of sodium acetate anhydrous and glacial acetic acid ( 8: 2.2) (anhydrous sodium acetate: glacial acetic acid (molar ratio) = 8: 2.2).
酢酸ナトリウム無水物（２５８．４ｇ）を容器に投入し、氷酢酸（３７．８ｇ）を投入量６ｍＬ／分で投入しながら混合し、酢酸ナトリウム無水物と氷酢酸との混合物である酢酸混合物（１０：２）（酢酸ナトリウム無水物：氷酢酸（モル比）＝１０：２）を得た。 Sodium acetate anhydrous (258.4 g) was charged into a container, and glacial acetic acid (37.8 g) was mixed while being charged at a charging rate of 6 mL / min, and an acetic acid mixture (a mixture of sodium acetate anhydrous and glacial acetic acid ( 10: 2) (anhydrous sodium acetate: glacial acetic acid (molar ratio) = 10: 2).
Ｘ線回折法により、酢酸ナトリウム無水物と氷酢酸の全部または一部とが錯体を形成していることを確認した。 It was confirmed by X-ray diffraction method that sodium acetate anhydride and all or part of glacial acetic acid formed a complex.
乾燥工程を経ることによって、乾燥剤としての機能を向上させた塩化カルシウム（ＣａＣｌ２）（水分含有率１５％）を使用して、表２７の割合で塩化ナトリウム、塩化カリウム、塩化マグネシウム六水和物、無水結晶ブドウ糖、塩化カルシウム、ｐＨ調整剤（酢酸混合物（１．５：１．５）、酢酸混合物（３：３）、酢酸混合物（６：２）、酢酸混合物（８：２．２）、酢酸混合物（１０：２）、酢酸ナトリウム無水物と氷酢酸との組合せのいずれか）を容器に充填した後、容器を密閉し、容器内容物を分散して透析用剤を作製した（サンプル９−１〜９−６）。 By using calcium chloride (CaCl 2 ) (water content 15%) whose function as a desiccant has been improved by passing through the drying step, sodium chloride, potassium chloride, magnesium chloride hexahydrate in the ratio of Table 27 , Anhydrous crystalline glucose, calcium chloride, pH adjuster (acetic acid mixture (1.5: 1.5), acetic acid mixture (3: 3), acetic acid mixture (6: 2), acetic acid mixture (8: 2.2) , An acetic acid mixture (10: 2), or a combination of sodium acetate anhydride and glacial acetic acid) was filled into a container, and the container was sealed, and the contents of the container were dispersed to prepare a dialysis agent (sample) 9-1 to 9-6).
塩化ナトリウム、塩化カリウム、塩化マグネシウム六水和物、無水結晶ブドウ糖、ｐＨ調整剤の各成分の付着水水分量を上記水分含有率の測定方法により測定し、付着水量を求めた。結果を表２８に示す。 The amount of adhering water in each component of sodium chloride, potassium chloride, magnesium chloride hexahydrate, anhydrous crystalline glucose, and pH adjuster was measured by the method for measuring the water content to determine the amount of adhering water. The results are shown in Table 28.
上記透析用剤について安定性試験（４０℃、７５％ＲＨ、１４日間）を実施して、固結の有無を調べ、上記の方法で評価した。また、上記安定性試験を受けた透析用剤をＲＯ水で溶解して透析用剤Ａ原液を作製した。透析用剤Ａ原液の無水結晶ブドウ糖の分解率を測定するため、上記の方法で５−ＨＭＦの吸光度の測定を行った。結果を表２９に示す。また、塩化カルシウムの除水量および透析用剤全体の含水量を算出し、比率Ｃを算出した結果を表２９に示す。 The dialysis agent was subjected to a stability test (40 ° C., 75% RH, 14 days), examined for the presence of caking, and evaluated by the above method. Moreover, the dialysis agent which received the said stability test was melt | dissolved with RO water, and the dialysis agent A stock solution was produced. In order to measure the degradation rate of anhydrous crystalline glucose in the dialysis agent A stock solution, the absorbance of 5-HMF was measured by the above method. The results are shown in Table 29. Table 29 shows the results of calculating the ratio C by calculating the water content of calcium chloride and the water content of the entire dialysis agent.
このように、ｐＨ調整剤を酢酸ナトリウム無水物と氷酢酸との組合せではなく、酢酸ナトリウム無水物および氷酢酸の混合物である酢酸混合物を使用することにより、安定性試験において薬剤の固結、凝集が抑制された。また、安定性試験において５−ＨＭＦの産生が抑制された。酢酸ナトリウム無水物と氷酢酸とをｐＨ調整剤として透析剤を製造したサンプル９−６では、酢酸混合物を使用した場合に比べて、薬剤の固化および無水結晶ブドウ糖の分解が発生した。 Thus, by using an acetic acid mixture that is a mixture of sodium acetate anhydride and glacial acetic acid instead of a combination of sodium acetate anhydride and glacial acetic acid as a pH adjuster, the caking and aggregation of the drug in the stability test are performed. Was suppressed. In addition, the production of 5-HMF was suppressed in the stability test. In sample 9-6 in which a dialysate was produced using sodium acetate anhydride and glacial acetic acid as a pH adjuster, solidification of the drug and decomposition of anhydrous crystalline glucose occurred as compared to the case where an acetic acid mixture was used.
サンプル９−１〜９−６をＲＯ水で溶解して３１５Ｌとした時の各成分の濃度を表３０に示す。 Table 30 shows the concentration of each component when Samples 9-1 to 9-6 were dissolved in RO water to give 315 L.
Claims (4)
前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が１６３％未満２％以上となり、前記塩化カルシウムの水分含有率が１％〜２２％の範囲となるように塩化カルシウムを他の成分とは別に乾燥する乾燥処理工程と、
各含有成分を単一の固体成分として容器に充填する充填工程と、
を含むことを特徴とする透析用剤の製造方法。 A method for producing a dialysis agent comprising an electrolyte component containing at least calcium chloride and a pH adjuster,
Calcium chloride is used in such a way that the ratio of the water content of the calcium chloride to the water content of the entire dialysis agent is less than 163% and 2% or more, and the water content of the calcium chloride is in the range of 1% to 22%. A drying process for drying separately from the ingredients;
A filling step of filling each containing component into a container as a single solid component;
The manufacturing method of the agent for dialysis characterized by including.
前記乾燥処理工程において、前記塩化カルシウムの除水量と透析用剤全体の含水量との比率が８２％未満２％以上となるように塩化カルシウムを乾燥することを特徴とする透析用剤の製造方法。 It is a manufacturing method of the dialysis agent of Claim 1 ,
In the drying treatment step, the calcium chloride is dried so that the ratio of the water removal amount of the calcium chloride and the water content of the entire dialysis agent is less than 82% and 2% or more. .
前記乾燥処理工程において、前記塩化カルシウムの水分含有率が１４％〜２２％の範囲となるように塩化カルシウムを乾燥することを特徴とする透析用剤の製造方法。 It is a manufacturing method of the dialysis agent of Claim 2 ,
In the drying treatment step, the calcium chloride is dried so that the moisture content of the calcium chloride is in the range of 14% to 22%.
前記乾燥処理工程において、前記塩化カルシウムの水分含有率が１４％〜１６％の範囲となるように塩化カルシウムを乾燥することを特徴とする透析用剤の製造方法。 It is a manufacturing method of the dialysis agent of Claim 3 ,
In the drying treatment step, the calcium chloride is dried so that the moisture content of the calcium chloride is in the range of 14% to 16%.
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