JP4603977B2 - Dialysis solid preparation and method for producing the same - Google Patents
Dialysis solid preparation and method for producing the same Download PDFInfo
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- JP4603977B2 JP4603977B2 JP2005504763A JP2005504763A JP4603977B2 JP 4603977 B2 JP4603977 B2 JP 4603977B2 JP 2005504763 A JP2005504763 A JP 2005504763A JP 2005504763 A JP2005504763 A JP 2005504763A JP 4603977 B2 JP4603977 B2 JP 4603977B2
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- Prior art keywords
- glucose
- dialysis
- chloride
- preparation
- coating layer
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- 239000007787 solid Substances 0.000 title claims description 70
- 238000002360 preparation method Methods 0.000 title claims description 60
- 238000000502 dialysis Methods 0.000 title claims description 52
- 238000004519 manufacturing process Methods 0.000 title claims description 25
- 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 52
- 239000008103 glucose Substances 0.000 claims description 51
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 46
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 42
- 235000002639 sodium chloride Nutrition 0.000 claims description 38
- 239000007864 aqueous solution Substances 0.000 claims description 34
- 239000001632 sodium acetate Substances 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 32
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 32
- 239000001110 calcium chloride Substances 0.000 claims description 32
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 32
- 235000017281 sodium acetate Nutrition 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 29
- 239000000843 powder Substances 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 25
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 24
- 239000011780 sodium chloride Substances 0.000 claims description 23
- 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 claims description 21
- 239000008187 granular material Substances 0.000 claims description 21
- 239000001103 potassium chloride Substances 0.000 claims description 21
- 235000011164 potassium chloride Nutrition 0.000 claims description 21
- 239000002994 raw material Substances 0.000 claims description 19
- 239000003792 electrolyte Substances 0.000 claims description 13
- 239000003002 pH adjusting agent Substances 0.000 claims description 11
- 238000010008 shearing Methods 0.000 claims description 10
- 235000011147 magnesium chloride Nutrition 0.000 claims description 7
- 235000011148 calcium chloride Nutrition 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000002245 particle Substances 0.000 description 59
- 239000003795 chemical substances by application Substances 0.000 description 47
- 239000011247 coating layer Substances 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000005469 granulation Methods 0.000 description 22
- 230000003179 granulation Effects 0.000 description 22
- 239000000047 product Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 15
- 238000012360 testing method Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000002233 thin-film X-ray diffraction Methods 0.000 description 10
- 239000005022 packaging material Substances 0.000 description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 8
- 239000010408 film Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 230000005611 electricity Effects 0.000 description 5
- 235000001727 glucose Nutrition 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 230000003068 static effect Effects 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000000385 dialysis solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000005001 laminate film Substances 0.000 description 4
- 238000010298 pulverizing process Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000005299 abrasion Methods 0.000 description 3
- 239000002216 antistatic agent Substances 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000428 dust Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000009775 high-speed stirring Methods 0.000 description 3
- 235000014666 liquid concentrate Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 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
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 238000007596 consolidation process Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 238000010410 dusting Methods 0.000 description 2
- 238000000635 electron micrograph Methods 0.000 description 2
- 239000004503 fine granule Substances 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001000 micrograph Methods 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- HFNQLYDPNAZRCH-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O.OC(O)=O HFNQLYDPNAZRCH-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012792 core layer Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- OPGYRRGJRBEUFK-UHFFFAOYSA-L disodium;diacetate Chemical compound [Na+].[Na+].CC([O-])=O.CC([O-])=O OPGYRRGJRBEUFK-UHFFFAOYSA-L 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940093181 glucose injection Drugs 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
- 230000005484 gravity Effects 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000008235 industrial water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017454 sodium diacetate Nutrition 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- 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
- A61M1/1654—Dialysates therefor
- A61M1/1656—Apparatus for preparing dialysates
- A61M1/1666—Apparatus for preparing dialysates by dissolving solids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Vascular Medicine (AREA)
- Emergency Medicine (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- External Artificial Organs (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本発明は、腎不全患者の透析療法に使用される重炭酸透析液調製用の透析用固形剤に関し、詳しくは、造粒の際に母核となる粒子（母粒子）の表面が、特定の塩を含む融着状の被覆層で覆われた、安定性及び含量均一性更には耐摩損性に優れた透析用固形剤及びその製造方法に関する。 The present invention relates to a solid preparation for dialysis for preparing a bicarbonate dialysis solution used for dialysis therapy of renal failure patients. More specifically, the surface of particles (mother particles) serving as a mother nucleus during granulation has a specific surface. The present invention relates to a solid preparation for dialysis excellent in stability and content uniformity and further in abrasion resistance, which is covered with a fusion-type coating layer containing salt, and a method for producing the same.
透析療法は、腎不全患者の治療方法として確立されており、老廃物の除去、電解質の調節等を目的に定期的な永続的治療として行われている。透析療法に用いられる透析液は、正常な血清電解質濃度に類似した組成を持つように作成されており、近年では生体に負担の少ない重炭酸透析剤が用いられている。重炭酸透析液は、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と反応して炭酸塩の沈殿を生じるため、一般的に塩化カルシウムや塩化マグネシウムを含み重炭酸ナトリウムを含まない製剤（Ａ剤）と重炭酸ナトリウムを含み塩化カルシウムや塩化マグネシウムを含まない製剤（Ｂ剤）の２剤に分けられており、使用直前にそれぞれが溶解、希釈混合されて重炭酸透析液が調製される。
現在、血液透析で使用されている主な製剤の形式は、Ａ濃厚原液＋Ｂ濃厚原液の「液液タイプ」、Ａ濃厚原液＋Ｂ粉末剤（重炭酸ナトリウム）の「液粉タイプ」、Ａ粉末剤＋Ｂ粉末剤の「粉粉タイプ」の３種類がある。「液液タイプ」、「液粉タイプ」のうち濃厚原液の製剤は、通常ポリエチレン製の容器に１０ｋｇ前後の濃厚液が充填されているため容器の嵩が大きく重量があり、輸送、搬入、保管スペース、取り扱い方法、使用済み容器の廃棄等について種々の課題を抱えている。
これらの問題を解決するために、近年、Ａ剤を粉末化した「粉粉タイプ」の固形剤が開発されて使用されつつある。この固形剤は、病院などの医療現場で専用の溶解装置を使用して「液液タイプ」の濃厚原液と同程度の濃度の原液に一旦溶解され、その後更に溶解、希釈され透析液濃度に調製される。
このような固形剤の製剤化方法としては、従来よりスプレードライ法、湿式造粒法、乾式造粒法などがよく知られている。いずれの方法も一長一短があり、製造方法や品質の面で満足すべきものとは言えない。スプレードライ法による製剤は、嵩高く、水分や粒度にばらつきがあり、酸成分が揮散するため一定のｐＨを与えるのが難しい。特開２００２−１０２３３７号公報では、転動撹拌流動層造粒装置を用いた２剤型固形重曹透析用製剤の製造方法が開示されており、この方法は流動している造粒物同士の衝突により被覆層がはがれやすいという欠点がある。更に、一部塩化ナトリウムを含む電解質成分やブドウ糖を相当量の水に溶解した上に、噴霧乾燥をしなければならないために、エネルギー原単位を著しく悪化させている。湿式造粒法や乾式造粒法は、均一性を保持するために、粉砕、混合等の煩雑な工程が避けられず、使用設備や外部からの異物混入により汚染されやすいという欠点がある。
そこで、このような点に着目した、粉砕等の煩雑な工程が不要な製造方法で、嵩比重、安息角及び溶解速度が良好でコンパクトな固形製剤の提案がなされている。例えば、各電解質化合物を酢酸ナトリウム、水の存在下で混合、加熱（７３℃）し、その後にブドウ糖を加え、酢酸と混合して、複数個の塩化ナトリウム粒子が該コーティング層を介して結合した造粒物からなる顆粒状乃至は細粒状の重炭酸透析用人工腎臓灌流用のＡ剤の製造方法が示されている（特許第２７６９５９２号公報参照）。また、造粒を６０℃で行い、塩化ナトリウム及び塩化カリウムからなる群から選ばれる少なくとも１種を主成分として含む核層と、酢酸ナトリウムと塩化カルシウムの反応により生成した複塩、他の電解質組成物及びｐＨ調整剤を含む複塩層との二層構造を有する固形透析用剤が示されている（特許第２９８７４８８号公報参照）。
ところが、この製造方法には大きな問題が含まれている。すなわち、特許第２７６９５９２号公報では、塩化ナトリウム、塩化カリウム、塩化マグネシウム、塩化カルシウムと純水を混合、攪拌、加熱し酢酸ナトリウムを添加し加熱混合を続けた場合、特許第２９８７４８８号公報では、塩化ナトリウム、塩化カリウム、塩化マグネシウム、酢酸ナトリウムと純水を混合、攪拌、加熱し塩化カルシウムを添加し加熱混合を続けた場合、いずれの場合においても、内容物に特異な粘りが生じ、粘度が著しく増大し攪拌が困難になる。通常の攪拌装置では製造が困難であり、攪拌能力の極めて大きな設備が必要となり、設備が特殊化、大型化するために製造費用が著しく増加するという問題があり、安価に、容易に製造できる製剤が求められている。
また、特許第２７６９５９２号公報、特許第２９８７４８８号公報及び特開２００２−１０２３３７号公報のいずれにおいても、６０℃以上で長時間加熱する必要があり、造粒中にブドウ糖が分解、着色しているおそれが強く、上記方法により得られる透析用製剤は含量均一性に劣る恐れがある。更に、このような製造方法によって製造された製剤の被覆層は、微細な粒子が結合剤を介して付着、積層されたもので、外部要因の影響を受けやすくなるためブドウ糖の分解、着色が経時的により一層進みやすいという欠点を有し、保存安定性に欠けるという大きな問題を抱えている。
更には、被覆層の構造上の特性より、輸送時に被覆層が剥離しやすく微粉が生じやすい製剤となっており、静電気の発生と相まって種々の問題が発生している。例えば、製造工程では製品充填時に発塵と同時に静電気が発生し、包装袋のシール部に微粉が付着してシール強度が低下するという不都合が見られ、最悪の場合破袋することも考えられる。一方、透析現場の取り扱い時においては、透析液調製時に酢酸を含んだ粉塵が飛散し作業環境が悪くなるとともに、静電気により固形剤が袋の中に残りやすいという問題点が生じている。更に、包材外側にも静電気の発生により異物が付着し、溶解時の異物混入の原因にもなっており、改善が強く求められている。
本発明の目的は、重炭酸透析液を調製するために必要な電解質、ブドウ糖及びｐＨ調整剤からなる透析用固形剤において、製造段階においても、保存時においてもブドウ糖が安定に存在し、分解や着色の恐れがなく、保存安定性、含量均一性、耐摩損性、溶解性に優れ、粉立ちも極めて少なく、静電気の発生を防止した作業性の極めて良好な透析用固形剤を提供する事にある。
発明の要旨
本発明者らは、上記の目的を達成するため鋭意研究を重ねた結果、ブドウ糖と塩化カルシウムと酢酸ナトリウムとが存在する系において、少量の水の存在下で、攪拌温度と剪断力を所定範囲に設定し所定時間以上攪拌混合すると、複雑な造粒操作や特殊な設備を用いることなく、母粒子に融着状の被覆層が形成され、上記の課題が達成される事を見出した。
即ち、本発明（１）は、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム及び酢酸ナトリウムからなる電解質組成物、ｐＨ調整剤並びにブドウ糖からなる透析用固形剤において、薄膜Ｘ線回折で２θ＝２１．３〜２１．５°及び２θ＝２７．６〜２７．８°（ＣｕＫα；λ＝１．５４０５８Å、入射角θ＝１°）に特定のピークを有する塩を含む被覆層で母粒子が覆われていることを特徴とする透析用固形剤である。
また、本発明（２）は、顆粒状及び／又は細粒状である、前記発明（１）の透析用固形剤である。
更に、本発明（３）は、該塩がブドウ糖と塩化カルシウムと酢酸ナトリウムとの反応生成物である、前記発明（１）又は（２）の透析用固形剤である。
また、本発明（４）は、該被覆層が融着状である、前記発明（１）〜（３）のいずれか一つの透析用固形剤である。
更に、本発明（５）は、前記発明（１）〜（４）のいずれか一つの透析用固形剤と重炭酸ナトリウムを含む固形剤とからなる重炭酸透析用固形剤である。
また、本発明（６）は、透湿度（４０℃、９０％ＲＨ）２．０ｇ／ｍ２・２４ｈｒ以下であり、背面電極効果を有する積層構造の防湿包材に収納されている、前記発明（１）〜（５）のいずれか一つの透析用固形剤である。
更に、本発明（７）は、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム及び酢酸ナトリウムからなる電解質組成物、ｐＨ調整剤並びにブドウ糖を原料として製造される透析用固形剤の製造方法において、該固形剤の１種以上の原料成分を含む粉体及び／又は粒体に、該粉体及び／又は粒体の重量に対して０．１〜２重量％の水を、精製水又は該固形剤の原料成分を１種以上含有する水溶液の形態で混合し（ここで、該混合物は、少なくともブドウ糖、塩化カルシウム及び酢酸ナトリウムを含む）、５０℃以下で１分以上、該混合物１ｋｇあたり０．００３ｋＷ／ｋｇ以上の剪断力下で該混合物を攪拌造粒する工程を含むことを特徴とする製造方法である。
尚、本明細書における「剪断力」は、以下式で算出された値をいう：
剪断力［ｋＷ／ｋｇ］＝｛（負荷時の電流値［Ａ］−無負荷時の電流値［Ａ］）／定格電流値［Ａ］｝×モーター容量［ｋＷ］／内容物重量［ｋｇ］
負荷時の電流値：撹拌造粒時における撹拌型混合造粒装置の撹拌モーターの電流値［Ａ］
無負荷時の電流値：空運転時（撹拌造粒時と同回転数）における該装置の撹拌モーターの電流値［Ａ］
定格電流値：該装置の撹拌モーターの定格電流値［Ａ］
モーター容量：該装置の撹拌モーターのモーター容量［ｋＷ］
内容物重量：撹拌造粒時における該装置内の該混合物重量［ｋｇ］
また、本発明（８）は、該水溶液の粘度が０．００１〜２Ｐａ・ｓである、前記発明（７）の製造方法である。
更に、本発明（９）は、該水溶液がブドウ糖と塩化マグネシウムを含む水溶液である、前記発明（７）又は（８）の製造方法である。
また、本発明（１０）は、透析用固形剤が、前記発明（１）〜（６）のいずれか一つの透析用固形剤である、前記発明（７）〜（９）のいずれか一つの製造方法である。Dialysis therapy has been established as a treatment method for patients with renal failure, and is performed as a regular permanent treatment for the purpose of removing wastes, adjusting electrolytes, and the like. The dialysate used for dialysis therapy is prepared so as to have a composition similar to a normal serum electrolyte concentration, and in recent years, a bicarbonate dialysis agent having a small burden on a living body is used. Since bicarbonate bicarbonate reacts with calcium chloride and magnesium chloride to cause precipitation of carbonate, bicarbonate dialysate generally contains a preparation (agent A) that contains calcium chloride or magnesium chloride and does not contain sodium bicarbonate. It is divided into two preparations containing sodium carbonate and not calcium chloride or magnesium chloride (agent B), and each is dissolved, diluted and mixed immediately before use to prepare a bicarbonate dialysate.
Currently, the main formulation types used in hemodialysis are A liquid concentrate + B liquid concentrate “liquid type”, A liquid concentrate + B powder (sodium bicarbonate) “liquid powder type”, A powder There are three types of "powder type" of + B powder. Concentrated concentrates of “Liquid / Liquid Type” and “Liquid Powder Type” are usually filled with about 10kg of concentrated liquid in a polyethylene container, so the container is bulky and heavy, and it is transported, loaded and stored. It has various issues regarding space, handling methods, disposal of used containers, etc.
In order to solve these problems, in recent years, a “powder type” solid preparation obtained by pulverizing the agent A has been developed and used. This solid preparation is once dissolved in a stock solution of the same concentration as the "liquid-liquid type" concentrated stock solution using a dedicated dissolution apparatus in medical sites such as hospitals, and then further dissolved and diluted to prepare a dialysate concentration. Is done.
Conventionally known methods for formulating such solid agents include spray drying, wet granulation, and dry granulation. Both methods have advantages and disadvantages, and are not satisfactory in terms of manufacturing method and quality. The preparation by the spray drying method is bulky, varies in moisture and particle size, and the acid component is volatilized, so that it is difficult to give a constant pH. Japanese Patent Application Laid-Open No. 2002-102337 discloses a method for producing a two-part solid sodium bicarbonate dialysis preparation using a tumbling stirred fluidized bed granulator, and this method involves collision of fluidized granules. Therefore, there is a drawback that the coating layer is easily peeled off. Furthermore, since the electrolyte component and glucose partly containing sodium chloride must be dissolved in a considerable amount of water and then spray-dried, the energy intensity is remarkably deteriorated. In order to maintain uniformity, the wet granulation method and the dry granulation method cannot avoid complicated processes such as pulverization and mixing, and have a drawback that they are easily contaminated by foreign substances mixed in from the equipment used or from the outside.
Thus, a compact solid preparation with good bulk specific gravity, angle of repose, and dissolution rate has been proposed by a production method that pays attention to such points and does not require complicated steps such as pulverization. For example, each electrolyte compound is mixed and heated (73 ° C.) in the presence of sodium acetate and water, then glucose is added and mixed with acetic acid, and a plurality of sodium chloride particles are bonded through the coating layer. A method for producing a granulated or fine granule A preparation for artificial kidney perfusion for bicarbonate dialysis is disclosed (see Japanese Patent No. 2769592). Further, granulation is performed at 60 ° C., a core layer containing at least one selected from the group consisting of sodium chloride and potassium chloride as a main component, a double salt formed by the reaction of sodium acetate and calcium chloride, and other electrolyte compositions An agent for solid dialysis having a two-layer structure with a double salt layer containing a product and a pH adjusting agent is shown (see Japanese Patent No. 2987488).
However, this manufacturing method includes a big problem. That is, in Japanese Patent No. 2769592, when sodium chloride, potassium chloride, magnesium chloride, calcium chloride and pure water are mixed, stirred and heated, sodium acetate is added and heating and mixing is continued, Japanese Patent No. 2987488 discloses chloride. Mixing, stirring and heating sodium, potassium chloride, magnesium chloride, sodium acetate and pure water, adding calcium chloride, and continuing to heat and mix, in any case, a unique viscosity occurs in the contents and the viscosity is remarkably high. Increases and makes stirring difficult. Preparations that are difficult to manufacture with ordinary agitators, require equipment with extremely high agitation capacity, and have the problem of significant increase in manufacturing costs due to the specialization and enlargement of equipment. Is required.
Moreover, in any of patent 2769592, patent 2987488, and Unexamined-Japanese-Patent No. 2002-102337, it is necessary to heat at 60 degreeC or more for a long time, and glucose is decomposed | disassembled and colored during granulation. There is a strong possibility that the preparation for dialysis obtained by the above method may be inferior in content uniformity. Furthermore, the coating layer of the preparation produced by such a production method is a layer in which fine particles are attached and laminated via a binder, and is easily affected by external factors. It has the disadvantage that it is easier to proceed, and lacks storage stability.
Furthermore, due to the structural characteristics of the coating layer, the coating layer is easily peeled off during transportation and a fine powder is easily generated, and various problems occur in combination with the generation of static electricity. For example, in the manufacturing process, static electricity is generated at the same time as dust generation at the time of product filling, and there is an inconvenience that fine powder adheres to the sealing portion of the packaging bag and the sealing strength is lowered. In the worst case, the bag may be broken. On the other hand, at the time of handling at the dialysis site, dust containing acetic acid is scattered during preparation of the dialysis solution and the working environment is deteriorated, and the solid agent tends to remain in the bag due to static electricity. Furthermore, foreign matter adheres to the outside of the packaging material due to the generation of static electricity, which causes foreign matter to be mixed during melting, and there is a strong demand for improvement.
The object of the present invention is to provide a solid solution for dialysis composed of an electrolyte, glucose and a pH adjuster necessary for preparing a bicarbonate dialysis solution. To provide a solid dialysis preparation with excellent workability that prevents coloring and has excellent storage stability, content uniformity, abrasion resistance, solubility, extremely little dusting, and prevents generation of static electricity. is there.
SUMMARY OF THE INVENTION As a result of intensive studies to achieve the above object, the present inventors have found that in a system in which glucose, calcium chloride, and sodium acetate are present, stirring temperature and shearing force are present in the presence of a small amount of water. Is set to a predetermined range, and when stirring and mixing for a predetermined time or more, the above-mentioned problem is achieved by forming a fused coating layer on the mother particles without using a complicated granulation operation or special equipment. It was.
That is, the present invention (1) is an electrolyte composition comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, a pH adjuster and a dialysis solid comprising glucose, and 2θ = 21 by thin film X-ray diffraction. 3 to 21.5 ° and 2θ = 27.6 to 27.8 ° (CuKα; λ = 1.54058 mm, incident angle θ = 1 °), and the base particle is covered with a coating layer containing a salt having a specific peak. It is a solid agent for dialysis characterized by the above.
Moreover, this invention (2) is a solid preparation for dialysis of the said invention (1) which is a granular form and / or a fine granule.
Furthermore, the present invention (3) is the solid preparation for dialysis according to the above invention (1) or (2), wherein the salt is a reaction product of glucose, calcium chloride and sodium acetate.
The present invention (4) is the solid agent for dialysis according to any one of the inventions (1) to (3), wherein the coating layer is fused.
Further, the present invention (5) is a bicarbonate dialysis solid agent comprising the dialysis solid agent according to any one of the inventions (1) to (4) and a solid agent containing sodium bicarbonate.
Further, the present invention (6) has a water vapor transmission rate (40 ° C., 90% RH) of 2.0 g / m 2 · 24 hr or less, and is housed in a moisture-proof packaging material having a laminated structure having a back electrode effect. It is a solid agent for dialysis according to any one of (1) to (5).
Furthermore, the present invention (7) provides an electrolyte composition comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, a pH adjuster, and a method for producing a dialysis solid preparation produced from glucose as a raw material. To powder and / or granules containing one or more raw material components of solid agent, 0.1 to 2% by weight of water with respect to the weight of the powder and / or granules, purified water or the solid agent In the form of an aqueous solution containing at least one raw material component (wherein the mixture contains at least glucose, calcium chloride, and sodium acetate) at 50 ° C. or lower for 1 minute or longer and 0.003 kW per kg of the mixture. It is a manufacturing method characterized by including the process of stirring and granulating this mixture under the shear force of / kg or more.
In addition, the “shearing force” in the present specification refers to a value calculated by the following formula:
Shear force [kW / kg] = {(Current value [A] at load-Current value [A] at no load) / Rated current value [A]} × Motor capacity [kW] / Content weight [kg]
Current value during loading: Current value of the stirring motor of the stirring type mixing granulator during stirring granulation [A]
Current value at no load: Current value [A] of the stirring motor of the apparatus during idling (same rotation speed as stirring granulation)
Rated current value: Rated current value [A] of the stirring motor of the device
Motor capacity: Motor capacity [kW] of the stirring motor of the device
Content weight: Weight of the mixture in the apparatus during stirring granulation [kg]
Moreover, this invention (8) is a manufacturing method of the said invention (7) whose viscosity of this aqueous solution is 0.001-2 Pa.s.
Furthermore, the present invention (9) is the production method of the invention (7) or (8), wherein the aqueous solution is an aqueous solution containing glucose and magnesium chloride.
Further, the present invention (10) is the dialysis solid agent according to any one of the inventions (7) to (9), wherein the dialysis solid agent is any one of the dialysis solid agents according to the invention (1) to (6). It is a manufacturing method.
図１は、一見して表面や内部に粒子が確認できないタイプの、本発明に係る固形剤の断面の状態を示したイメージ図である。尚、図中、１は被覆層、２は母粒子を示す。
図２は、表面及び内部に粒子が存在することが確認できるタイプの、本発明に係る固形剤の断面の状態を示したイメージ図である。尚、図中、Ａは粒子、Ｂは融着層を示す。
図３は、無数の粒子が堆積したように見える、従来の固形剤の断面の状態を示したイメージ図である。尚、図中、１′は堆積層、２′は母粒子、Ｃは粒子を示す。
図４は、本発明における「融着状」の意義を示したイメージ図である。
図５は、従来技術における「堆積状」の意義を示したイメージ図である。尚、図中、Ｄは結合剤を示す。
図６は、実施例１で得られた透析用固形剤のデジタル顕微鏡写真である（デジタル写真）。
図７は、実施例１で得られた透析用固形剤の電子顕微鏡写真である（デジタル写真）。
図８は、実施例１で得られた透析用固形剤の母粒子の元素分析結果（エネルギー分散型Ｘ線分析装置（ＥＤＸ））を示す。
図９は、実施例１で得られた透析用固形剤の被覆層の元素分析結果（エネルギー分散型Ｘ線分析装置（ＥＤＸ））を示す。
図１０は、実施例１で得られた透析用固形剤の薄膜Ｘ線回折の結果を示す。
図１１は、実施例２で得られた透析用固形剤の薄膜Ｘ線回折の結果を示す。
図１２は、比較例１で得られた透析用固形剤の電子顕微鏡写真である（デジタル写真）。
図１３は、比較例１で得られた透析用固形剤の薄膜Ｘ線回折の結果を示す。
図１４は、比較例２で得られた透析用固形剤の薄膜Ｘ線回折の結果を示す。FIG. 1 is an image diagram showing a cross-sectional state of a solid agent according to the present invention, in which particles cannot be confirmed on the surface or inside at first glance. In the figure, 1 represents a coating layer and 2 represents a mother particle.
FIG. 2 is an image view showing a cross-sectional state of the solid agent of the present invention, which can be confirmed to have particles on the surface and inside. In the figure, A indicates particles and B indicates a fusion layer.
FIG. 3 is an image diagram showing a cross-sectional state of a conventional solid agent that appears to have accumulated countless particles. In the figure, 1 'represents a deposited layer, 2' represents a mother particle, and C represents a particle.
FIG. 4 is an image diagram showing the meaning of “fused” in the present invention.
FIG. 5 is an image showing the significance of “deposition” in the prior art. In the figure, D represents a binder.
FIG. 6 is a digital micrograph of the dialysis solid agent obtained in Example 1 (digital photograph).
FIG. 7 is an electron micrograph of the dialysis solid agent obtained in Example 1 (digital photograph).
FIG. 8 shows the elemental analysis results (energy dispersive X-ray analyzer (EDX)) of the base particles of the dialysis solid agent obtained in Example 1.
FIG. 9 shows an elemental analysis result (energy dispersive X-ray analyzer (EDX)) of the coating layer of the dialysis solid agent obtained in Example 1.
FIG. 10 shows the results of thin film X-ray diffraction of the dialysis solid agent obtained in Example 1.
FIG. 11 shows the results of thin-film X-ray diffraction of the dialysis solid agent obtained in Example 2.
FIG. 12 is an electron micrograph of the dialysis solid agent obtained in Comparative Example 1 (digital photograph).
FIG. 13 shows the results of thin film X-ray diffraction of the dialysis solid agent obtained in Comparative Example 1.
14 shows the results of thin film X-ray diffraction of the dialysis solid agent obtained in Comparative Example 2. FIG.
まず、本発明に係る透析用固形剤について説明する。本発明に係る透析用固形剤は、組成的には、従来のそれと本質的には変わりなく、各種電解質（塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム及び酢酸ナトリウム）、ｐＨ調整剤及びブドウ糖からなるものである。ここで、ｐＨ調整剤としては、薬理学的に許容されるものであれば特に制限されるものではなく、例えば、酢酸、塩酸等の液体状の酸、乳酸、クエン酸、りんご酸、二酢酸ナトリウム等の固体状の酸を挙げることができ、これらを単独で乃至は複数組み合わせて用いてもよい。好適には、酢酸及び二酢酸ナトリウムである。
本発明に係る透析用固形剤の特徴は、特定の塩を含む被覆層で母粒子が覆われている点にある。
まず、はじめに本発明に係る被覆層につき説明する。該被覆層は、薄膜Ｘ線回折において、２θ＝２１．３〜２１．５°及び２θ＝２７．６〜２７．８°（ＣｕＫα；λ＝１．５４０５８Å、入射角θ＝１°）に特定のピークを有する塩を含む。ここで、該塩の必須成分の特定を消去法により行った結果、該塩がブドウ糖と塩化カルシウムと酢酸ナトリウムとの反応生成物であることが判明した。
通常、原料である塩化カルシウムは、ブドウ糖と共存するとブドウ糖の分解を促進させ、著しく剤の保存安定性を劣化させるが、本発明に係る透析用固形剤は、攪拌造粒工程において大半の塩化カルシウムがブドウ糖及び酢酸ナトリウムと特異的に反応して該塩として被覆層に含まれると推定されることから、保存安定性が極めて良好である。また、該塩を含む透析用固形剤は、所定の水に溶解すれば所定の電解質イオン濃度及びブドウ糖濃度になることが確認されている。
尚、本発明に係る被覆層は、該塩以外の成分を含んでいてもよく、例えば、固形剤の原料である、塩化ナトリウム、塩化カリウム、塩化マグネシウム、酢酸ナトリウム、ブドウ糖及び／又はｐＨ調整剤を含んでいてもよい。
また更に、本発明に係る被覆層は融着状である。まず、「融着状」とは、溶融物を固化させたときのような外観であることを意味し、「凝集状」ともいい得る。尚、外観が融着状であるという意であり、実際に融点以上に加熱して溶融させることを意味するものではない。また、非晶質状（これは、非晶質より構成されるという意ではなく、外観が非晶質であるように見えるさまを意味する）という表現も可能である。尚、すべてが一体的に融着していなくともよく、表面や内部に粒子を含んでいる状態であってもよい。ここで、従来の透析用固形剤の被覆層と本発明に係る「融着状被覆層」との違いをイメージ図をもって説明する。まず、従来の被覆層は、図３に示すように、無数の粒子Ｃが母粒子２′上に堆積したような構造となっている。そして、図５に示すように、粒子Ｃと粒子Ｃは、結合剤Ｄを介して結合しているか、単に粒子上に乗った構造を採っていると理解される。他方、本発明に係る「融着状被覆層」は、図１に示すように、粒子が堆積したというよりも、大部分の粒子が融着して一体化してしまったかのような外観を有する。但し、大部分が一体化しているような外観であればよく、図２や図４に示すように被覆層１の表面や内部に、融着状態にない粒子Ａが存在していても、本発明にいう「融着状被覆層」に該当する。
次に、本発明に係る母粒子につき説明する。本発明に係る母粒子は、特に限定されず、固形剤の原料成分からなる。例えば、塩化ナトリウムからなる母粒子、他の成分（例えば、塩化カリウム、酢酸ナトリウム、ブドウ糖）からなる母粒子を挙げることができる。尚、例えば、実施例においては、大半の粒子の母粒子は塩化ナトリウムからなり、残りの粒子の母粒子は他の原料成分からなる。
以上述べたように、被覆層中に該塩が含まれている限り、例えば、塩化ナトリウムが被覆層に含まれていても、ブドウ糖が母粒子に含まれていても、更には、固形剤の原料成分や反応生成物が、母粒子・被覆層のいずれに含まれていても、或いは両方に含まれていても構わない。ただし、塩化マグネシウムは被覆層に含まれるのが好ましい。
本発明に係る透析用固形剤は、典型的には、顆粒状及び／又は細粒状の造粒物である。そして、その平均粒径は、約２２０〜８００μｍであり、被覆層の厚さは１０〜７０μｍであることが好適である。ここで、該造粒物は、母粒子の表面に被覆層が形成された単独の粒子であってもよいし、複数の被覆された母粒子が被覆層を介して結合したものであってもよい。造粒物のうち単独の粒子の形状は、やや丸みを帯びた立方体のものが中心である。他方、被覆層を介して結合したものは、数個の被覆された立方体状の粒子が結合した形状である。
次に、本発明に係る透析用固形剤の製造方法につき説明する。本発明に係る透析用固形剤の製造方法は、該固形剤の１種以上の原料成分を含む粉体及び／又は粒体に、該粉体及び／又は粒体の重量に対して０．１〜２重量％の水を、精製水又は該固形剤の原料成分を１種以上含有する水溶液の形態で混合し（ここで、該混合物は、少なくともブドウ糖、塩化カルシウム及び酢酸ナトリウムを含む）、５０℃以下で１分以上、該混合物１ｋｇあたり０．００３ｋＷ／ｋｇ以上の剪断力下で該混合物を攪拌造粒する工程を含む。以下に詳述する。
まず、本発明に係る「粉体及び／又は粒体」について説明する。本発明に係る「粉体及び／又は粒体」は、該固形剤の１種以上の原料成分（塩化ナトリウム、塩化カリウム、酢酸ナトリウム、塩化カルシウム、塩化マグネシウム、ブドウ糖及びｐＨ調整剤からなる原料群から選択される１種以上）からなる。加えて、該粉体及び／又は粒体は、基本的には乾燥形態にあり、場合により、液状のｐＨ調整剤が含浸した状態にある。
ここで、「粉体及び／又は粒体」として、塩化ナトリウム、塩化カリウム、酢酸ナトリウム、ブドウ糖を用いる場合、各粒子の粒子径は特に限定されるものではないが、各粒子径の差ができるだけ小さくなるような組み合わせが、均一性の保持という面からは好ましい。即ち、平均粒径は２００〜６００μｍ程度のものが好ましく、それぞれの粒子の平均粒径の差が、全粒子の平均粒径の３０％以内になるような組み合わせが好ましい。また、塩化カルシウムの粒径は、ブドウ糖と酢酸ナトリウムとの反応を促進させるため、３００μｍ以下が望ましい。
次に、本発明に係る「精製水又は該固形剤の原料成分を１種以上含有する水溶液」の内、「水溶液」に関して説明する。以下、特記しない限り、この水溶液を「該水溶液」という。該水溶液の溶質は、特に限定されず、固形剤の原料成分である、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、酢酸ナトリウム、ｐＨ調整剤及びブドウ糖からなる群より選択される１種以上である。尚、各成分は、全量が溶解している必要は無く、一部が固体状態であってもよい。
好ましい態様は、ブドウ糖及び塩化マグネシウムを含む水溶液である。この場合には、より強固な被覆層を形成することができる。ここで、この水溶液におけるブドウ糖濃度は、好適には１０〜７０重量％、より好適には２０〜６０重量％であり、塩化マグネシウム（六水和物）の濃度は、好適には１０〜７０重量％、より好適には２５〜６０重量％である。このように、両者が共存した状態｛水溶液のｐＨが酸性状態になる（例えば約４．５）｝では、ブドウ糖が安定保持されると共に、単独の溶解度より遥かに高濃度に両者を溶解させることができ、しかもこの水溶液の粘度を適度に低下させ、造粒に好適な粘度に調整することができる。このため、他の造粒法に比べて極めて少量の水溶液で、しかも短時間で全体を均一に被覆することができる。尚、この水溶液は、これら以外の成分を含んでいてもよく、例えば、塩化カルシウム等の電解質を更に含んでいる態様を挙げることができる。尚、この水溶液は、塩化マグネシウムの水溶液にブドウ糖を溶解するだけで簡単に調製できる。
該水溶液は、粘度が０．００１〜２Ｐａ・ｓであることが好適であり、より好適には０．０１〜１．５Ｐａ・ｓ、更に好適には０．０１５〜１Ｐａ・ｓである。尚、ここでの粘度は、Ｂ型粘度計により測定された値を指す。
「粉体及び／又は粒体」及び「精製水又は該固形剤の原料成分を１種以上含有する水溶液」とからなる混合物は、少なくともブドウ糖、塩化カルシウム及び酢酸ナトリウムを含有する。ここで、これら成分は、粉体及び／又は粒体にのみ含まれていても、水溶液にのみ含まれていても、両者に含まれていてもよい。
「粉体及び／又は粒体」と「水溶液」の組み合わせの好適例を挙げると、「粉体及び／又は粒体」が、塩化ナトリウム、塩化カリウム、酢酸ナトリウム、ブドウ糖を含み、任意成分として、塩化カルシウムを含むものであり、「水溶液」が、ブドウ糖、塩化マグネシウムを含み、任意成分として塩化カルシウムを含むものである。
尚、固形剤の全原料を「粉体及び／又は粒体」＋「水溶液」に使用する必要はなく、原料の一部を以後の工程で添加してもよい。例えば、ｐＨ調整剤に関しては、「粉体及び／又は粒体」中にあらかじめ添加しても、造粒中に添加しても、乾燥前に添加しても、乾燥中に添加しても、乾燥後に添加してもよい。
次に、製造方法における各種条件につき説明する。まず、系に添加する「精製水又は該固形剤の原料成分を１種以上含有する水溶液」における水の量は、系内に存在する「粉体及び／又は粒体」の総量の０．１〜２．０重量％が好ましく、より好適には０．２〜１．４重量％である。ここで、系に添加する水の量には、原料中の結晶水は含まれない。
精製水又は該水溶液添加から造粒完了までの時間は、該塩の反応に要する時間、生成した造粒物の含量均一性及びさらさら化（水分を約２重量％含有するにもかかわらず、流動性が良く、防湿性が高く、付着や凝集の要因となる自由水が、被覆層の表面にほとんどない造粒物になること）を考慮すると、１分以上が好適であり、より好適には３分以上であり、更に好適には１０分以上である。また、破砕防止の観点から３０分以下が好適である。
次に、撹拌時に加える剪断力について説明する。まず、本発明に係る剪断力の定義につき説明する。撹拌型混合造粒装置を使用した場合、本発明に係る撹拌造粒時において、撹拌翼の回転によって撹拌翼と該装置内壁との間で該混合物に剪断力が加わる。この剪断力の大きさを、該装置の撹拌モーターの負荷量（モーターの電流値）を用いて前記式にて算出し、その値を該混合物１ｋｇあたりに加えた剪断力とした。次に、必要な該剪断力は、０．００３ｋＷ／ｋｇ以上であり、好適には０．０１ｋＷ／ｋｇであり、更に好適には０．０５ｋＷ／ｋｇ以上である。また、上限に関しては、内温上昇や破砕防止の観点から、０．１ｋＷ／ｋｇ以下であることが好適である。
また、攪拌造粒を実施する温度は、常温付近の温度で充分であり、ブドウ糖の分解防止に極めて有効な温度で造粒を実施できる。すなわち、本発明の造粒を実施する温度は、該塩生成の観点から、内温５０℃以下であることが必須である。下限値は、特に限定されないが、好適には０℃以上である。尚、より好適には１０〜５０℃であり、最も好ましくは２０〜４０℃である。
該粉体及び／又は粒体中に精製水や該水溶液を添加する方法であるが、特に制限はなく、一括添加もしくは分割添加でもよく、噴霧する方式であってもよい。また、精製水又は該水溶液の温度（添加前）は、好適には、１５〜５０℃である。
尚、攪拌造粒工程で使用する攪拌型混合造粒装置としては、高速攪拌型造粒装置が好適である。操作条件は、通常造粒する一般的条件の範囲内で目的は充分達成される。
造粒工程以降の工程や使用する装置、操作条件は特に限定されないが、得られた造粒物を乾燥し、必要に応じて、乾燥前又は後にｐＨ調整剤を添加混合し、整粒して顆粒状及び／又は細粒状の本透析用固形剤を得る。
本発明に係る透析用固形剤と重炭酸ナトリウムを所定の水に溶解すれば重炭酸透析液を、例えば下記の濃度に調整することができる：
Ｎａ＋ １２５〜１５０ｍＥｑ／ｌ
Ｋ＋ １．０〜３．０ｍＥｑ／ｌ
Ｃａ２＋ １．５〜３．５ｍＥｑ／ｌ
Ｍｇ２＋ ０．５〜１．５ｍＥｑ／ｌ
Ｃｌ− ９０．０〜１３５ｍＥｑ／ｌ
ＣＨ３ＣＯ２ − ５．０〜１０．０ｍＥｑ／ｌ
ＨＣＯ３ − ２０．０〜３０．０ｍＥｑ／ｌ
ブドウ糖 ０．５〜２．５ｇ／ｌ
この様にして得られる透析用固形剤の包装材料としては防湿性能が良く、しかも背面電極効果を有するものが好ましい。従来より帯電防止剤を樹脂に練りこんでフィルムを作成し、帯電防止機能を有する包装材料に加工して使用された例はあったが、樹脂からのブリード現象により製品に異物が混入するなどの不都合が見られた。これに比べ、本発明において帯電防止剤はフィルムの接着に使用する接着剤中に含まれているためフィルムを浸透することはなく、ブリード現象は起こりえない。帯電防止剤は透析用固形剤と接するフィルム面の裏側にある接着剤中にあり、背面まで帯電防止機能を有するラミネートフィルムである。すなわち、透湿度（４０℃、９０％ＲＨ）２．０ｇ／ｍ２・２４ｈｒ以下のフィルム、例えばシリカ蒸着フィルムを用い、静電防止性接着剤、例えばボンディップ（コニシ社製）を用いて接着したラミネートフィルムを用いて加工した背面電極効果を有する包装材料に透析用固形剤を充填、包装するのが好ましい。その様な積層構造を有するラミネートフィルムの構成例としては、
ＰＥＴ／ＳｉＯｘ／ボンディップ／ＰＥ、
ＰＶＡ／ＳｉＯｘ／ボンディップ／ＰＥ、
ＯＮＹ／ＳｉＯｘ／ボンディップ／ＰＥ、
ＰＥＴ／ＳｉＯｘ／ボンディップ／ＣＰＰ、
ＯＰＰ／ＳｉＯｘ／ボンディップ／ＣＰＰ、
を挙げることができ、これを包装材料に加工して用いることができる。ラミネートフィルムは公知の方法により容易に製造できる。製造方法の一例としては、静電防止性接着剤の必要量を計り取り、必要により溶剤で希釈するなどして液が均一になるように混合し、グラビアコーター、リバースコーター等のコーターを用いて上記のフィルムに塗布し、温風乾燥して完全に硬化させる方法を挙げることができる。得られたラミネートフィルムはヒートシールすることによって包装材料に加工することができる。First, the dialysis solid preparation according to the present invention will be described. The solid preparation for dialysis according to the present invention is essentially the same as the conventional composition, and includes various electrolytes (sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate), pH adjusters and glucose. It will be. Here, the pH adjuster is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include liquid acids such as acetic acid and hydrochloric acid, lactic acid, citric acid, malic acid, and diacetic acid. Examples thereof include solid acids such as sodium, and these may be used alone or in combination. Preference is given to acetic acid and sodium diacetate.
The feature of the solid agent for dialysis according to the present invention is that the base particles are covered with a coating layer containing a specific salt.
First, the coating layer according to the present invention will be described. The coating layer is specified as 2θ = 21.3-21.5 ° and 2θ = 27.6-27.8 ° (CuKα; λ = 1.54058 mm, incident angle θ = 1 °) in thin film X-ray diffraction. Salt having a peak of Here, as a result of performing identification of the essential components of the salt by the elimination method, it was found that the salt was a reaction product of glucose, calcium chloride and sodium acetate.
Usually, calcium chloride as a raw material, when coexisting with glucose, accelerates the degradation of glucose and significantly deteriorates the storage stability of the agent. However, the solid preparation for dialysis according to the present invention is most of calcium chloride in the stirring granulation step. Is presumably contained in the coating layer as the salt by reacting specifically with glucose and sodium acetate, so that the storage stability is very good. In addition, it has been confirmed that the dialysis solid preparation containing the salt has a predetermined electrolyte ion concentration and glucose concentration when dissolved in predetermined water.
In addition, the coating layer according to the present invention may contain components other than the salt. For example, sodium chloride, potassium chloride, magnesium chloride, sodium acetate, glucose and / or a pH adjuster which are raw materials for solid agents May be included.
Furthermore, the coating layer according to the present invention is fused. First, “fused” means an appearance as when the melt is solidified, and can also be referred to as “aggregated”. In addition, it means that the appearance is fused, and does not mean that it is actually heated to the melting point or higher to be melted. It can also be expressed as amorphous (this does not mean that it is composed of amorphous material, but means that the appearance appears to be amorphous). In addition, not all need to be integrally fused, and may be in a state of containing particles on the surface or inside. Here, the difference between the coating layer of the conventional dialysis solid agent and the “fused coating layer” according to the present invention will be described with reference to an image diagram. First, as shown in FIG. 3, the conventional coating layer has a structure in which an infinite number of particles C are deposited on the base particle 2 '. And as shown in FIG. 5, it is understood that the particle | grains C and the particle | grains C are couple | bonded through the binder D, or have taken the structure on which it just got on the particle | grains. On the other hand, as shown in FIG. 1, the “fused coating layer” according to the present invention has an appearance as if most of the particles are fused and integrated, rather than the particles being deposited. However, it is sufficient that the appearance is mostly integrated. Even if particles A that are not fused are present on the surface or inside of the
Next, the mother particles according to the present invention will be described. The mother particle according to the present invention is not particularly limited, and is composed of a raw material component of a solid agent. For example, mother particles made of sodium chloride and mother particles made of other components (for example, potassium chloride, sodium acetate, glucose) can be mentioned. For example, in the embodiment, the mother particles of most particles are made of sodium chloride, and the mother particles of the remaining particles are made of other raw material components.
As described above, as long as the salt is contained in the coating layer, for example, even if sodium chloride is contained in the coating layer, glucose is contained in the mother particles, The raw material component and the reaction product may be contained in either the mother particle or the coating layer, or in both. However, magnesium chloride is preferably included in the coating layer.
The dialysis solid preparation according to the present invention is typically a granulated and / or fine granulated product. And the average particle diameter is about 220-800 micrometers, and it is suitable that the thickness of a coating layer is 10-70 micrometers. Here, the granulated product may be a single particle in which a coating layer is formed on the surface of the mother particle, or a plurality of coated mother particles may be bonded via the coating layer. Good. Of the granulated material, the shape of a single particle is centered on a slightly rounded cube. On the other hand, what is bonded via the coating layer is a shape in which several coated cubic particles are bonded.
Next, the manufacturing method of the solid preparation for dialysis which concerns on this invention is demonstrated. In the method for producing a solid preparation for dialysis according to the present invention, the powder and / or granule containing one or more raw material components of the solid preparation is 0.1% based on the weight of the powder and / or granule. ˜2% by weight of water is mixed in the form of purified water or an aqueous solution containing one or more raw ingredients of the solid agent (wherein the mixture comprises at least glucose, calcium chloride and sodium acetate), 50 A step of stirring and granulating the mixture under a shearing force of 0.003 kW / kg or more per kg of the mixture at 1 ° C. or lower for 1 minute or more. This will be described in detail below.
First, “powder and / or granules” according to the present invention will be described. The “powder and / or granule” according to the present invention is a raw material group comprising one or more raw material components (sodium chloride, potassium chloride, sodium acetate, calcium chloride, magnesium chloride, glucose, and a pH adjuster) of the solid agent. 1 type or more selected from. In addition, the powders and / or granules are basically in a dry form, and in some cases are impregnated with a liquid pH adjuster.
Here, when sodium chloride, potassium chloride, sodium acetate, or glucose is used as the “powder and / or granule”, the particle diameter of each particle is not particularly limited. A combination that reduces the size is preferable in terms of maintaining uniformity. That is, the average particle size is preferably about 200 to 600 μm, and a combination in which the difference in average particle size of each particle is within 30% of the average particle size of all particles is preferable. The particle size of calcium chloride is preferably 300 μm or less in order to promote the reaction between glucose and sodium acetate.
Next, the “aqueous solution” in the “aqueous solution containing at least one raw material of purified water or the solid agent” according to the present invention will be described. Hereinafter, this aqueous solution is referred to as “the aqueous solution” unless otherwise specified. The solute of the aqueous solution is not particularly limited, and may be one or more selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, a pH adjuster, and glucose, which are raw material components of the solid agent. is there. In addition, each component does not need to be dissolved in its entirety, and a part thereof may be in a solid state.
A preferred embodiment is an aqueous solution containing glucose and magnesium chloride. In this case, a stronger coating layer can be formed. Here, the glucose concentration in this aqueous solution is preferably 10 to 70% by weight, more preferably 20 to 60% by weight, and the concentration of magnesium chloride (hexahydrate) is preferably 10 to 70% by weight. %, More preferably 25 to 60% by weight. Thus, in the state where both coexist {the pH of the aqueous solution is in an acidic state (for example, about 4.5)}, glucose is stably maintained and both are dissolved at a concentration much higher than the single solubility. In addition, the viscosity of the aqueous solution can be lowered to a suitable level for granulation. For this reason, compared with other granulation methods, the whole can be uniformly coated with a very small amount of aqueous solution in a short time. In addition, this aqueous solution may contain components other than these, For example, the aspect which further contains electrolytes, such as a calcium chloride, can be mentioned. This aqueous solution can be prepared simply by dissolving glucose in an aqueous solution of magnesium chloride.
The aqueous solution preferably has a viscosity of 0.001 to 2 Pa · s, more preferably 0.01 to 1.5 Pa · s, and still more preferably 0.015 to 1 Pa · s. In addition, the viscosity here points out the value measured with the B-type viscometer.
The mixture consisting of “powder and / or granules” and “an aqueous solution containing one or more raw components of purified water or the solid agent” contains at least glucose, calcium chloride and sodium acetate. Here, these components may be contained only in the powder and / or the granule, may be contained only in the aqueous solution, or may be contained in both.
As a suitable example of the combination of “powder and / or granules” and “aqueous solution”, “powder and / or granules” contains sodium chloride, potassium chloride, sodium acetate, glucose, It contains calcium chloride, and the “aqueous solution” contains glucose and magnesium chloride, and contains calcium chloride as an optional component.
Note that it is not necessary to use all the raw materials for the solid agent in “powder and / or granules” + “aqueous solution”, and a part of the raw materials may be added in the subsequent steps. For example, regarding the pH adjuster, it may be added in advance in “powder and / or granules”, added during granulation, added before drying, or added during drying, It may be added after drying.
Next, various conditions in the manufacturing method will be described. First, the amount of water in “purified water or an aqueous solution containing at least one raw material component of the solid agent” added to the system is 0.1% of the total amount of “powder and / or granules” present in the system. The content is preferably -2.0% by weight, more preferably 0.2-1.4% by weight. Here, the amount of water added to the system does not include crystallization water in the raw material.
The time from the addition of purified water or the aqueous solution to the completion of granulation is the time required for the reaction of the salt, the uniform content of the granulated product and freezing (in spite of containing about 2% by weight of water, 1 minute or more is preferable, more preferably, considering that the free water that causes good adhesion, high moisture resistance, and the cause of adhesion and aggregation is almost free from the surface of the coating layer) It is 3 minutes or more, more preferably 10 minutes or more. Moreover, 30 minutes or less is suitable from a viewpoint of prevention of crushing.
Next, the shearing force applied at the time of stirring is demonstrated. First, the definition of the shearing force according to the present invention will be described. When a stirring type mixing granulator is used, during the stirring granulation according to the present invention, a shearing force is applied to the mixture between the stirring blade and the inner wall of the device by the rotation of the stirring blade. The magnitude of this shear force was calculated by the above formula using the load of the stirring motor (current value of the motor) of the apparatus, and the value was defined as the shear force applied per 1 kg of the mixture. Next, the necessary shearing force is 0.003 kW / kg or more, preferably 0.01 kW / kg, and more preferably 0.05 kW / kg or more. Further, the upper limit is preferably 0.1 kW / kg or less from the viewpoint of increasing the internal temperature and preventing crushing.
In addition, the temperature for carrying out the stirring granulation is sufficient at a temperature around room temperature, and granulation can be carried out at a temperature extremely effective for preventing the decomposition of glucose. That is, it is essential that the temperature at which the granulation of the present invention is carried out is an internal temperature of 50 ° C. or less from the viewpoint of the salt formation. Although a lower limit is not specifically limited, It is 0 degreeC or more suitably. In addition, it is 10-50 degreeC more suitably, Most preferably, it is 20-40 degreeC.
Although it is a method of adding purified water or the aqueous solution to the powder and / or granules, there is no particular limitation, and batch addition or divided addition may be used, or a spraying method may be used. Moreover, the temperature (before addition) of purified water or this aqueous solution is 15-50 degreeC suitably.
In addition, as a stirring type mixing granulator used in a stirring granulation process, a high-speed stirring type granulating apparatus is suitable. The purpose of the operation is sufficiently achieved within the range of general conditions for normal granulation.
The process after the granulation process, the apparatus to be used, and the operating conditions are not particularly limited, but the obtained granulated product is dried, and if necessary, added and mixed before or after drying, and sized. A granular and / or finely divided solid preparation for dialysis is obtained.
The bicarbonate dialysis solution can be adjusted to the following concentration, for example, by dissolving the dialysis solid agent and sodium bicarbonate according to the present invention in a predetermined water:
Na + 125 to 150 mEq / l
K + 1.0 to 3.0 mEq / l
Ca 2+ 1.5-3.5 mEq / l
Mg 2+ 0.5-1.5 mEq / l
Cl - 90.0-135 mEq / l
CH 3 CO 2 - 5.0~10.0mEq / l
HCO 3 - 20.0~30.0mEq / l
Glucose 0.5-2.5 g / l
As a packaging material for the solid preparation for dialysis thus obtained, a material having good moisture-proof performance and having a back electrode effect is preferable. There has been an example where a film was made by kneading an antistatic agent into a resin and then processed into a packaging material having an antistatic function, but foreign substances are mixed into the product due to the bleeding phenomenon from the resin. Inconvenience was seen. In contrast, in the present invention, since the antistatic agent is contained in the adhesive used for bonding the film, it does not penetrate the film, and the bleeding phenomenon cannot occur. The antistatic agent is a laminate film that is in the adhesive on the back side of the film surface in contact with the dialysis solid agent and has an antistatic function up to the back surface. That is, a film having a moisture permeability (40 ° C., 90% RH) of 2.0 g / m 2 · 24 hr or less, such as a silica vapor deposited film, is bonded using an antistatic adhesive such as Bondip (manufactured by Konishi). It is preferable to fill and package a dialysis solid agent in a packaging material having a back electrode effect processed using the laminated film. As a configuration example of a laminate film having such a laminated structure,
PET / SiO x / Bondip / PE,
PVA / SiO x / Bondip / PE,
ONY / SiO x / Bondip / PE,
PET / SiO x / Bondip / CPP,
OPP / SiO x / Bondip / CPP,
Which can be processed into a packaging material and used. The laminate film can be easily produced by a known method. As an example of the manufacturing method, measure the necessary amount of antistatic adhesive, mix with a solution such as diluting with a solvent if necessary, and use a coater such as a gravure coater or reverse coater. The method of apply | coating to said film, drying by warm air, and making it harden | cure can be mentioned. The obtained laminate film can be processed into a packaging material by heat sealing.
以下に本発明の実施例を示して、更に具体的に説明する。 Hereinafter, the present invention will be described more specifically with reference to examples.
塩化ナトリウム５０００．０ｇ、塩化カリウム１２１．６ｇ、塩化カルシウム１７８．５ｇ、酢酸ナトリウム６６７．４ｇ、ブドウ糖７６０．２ｇを高速攪拌型造粒装置（深江パウテック株式会社製 ハイスピードミキサー ＦＳ−ＧＳ−２５Ｊ）に添加し混合攪拌した。回転数６０ｒｐｍ（剪断力０．０４ｋＷ／ｋｇ）で混合攪拌しながら、内温が２５℃で、あらかじめ調製しておいたブドウ糖５４．６ｇと塩化マグネシウム８２．８ｇを精製水３６．４ｇに溶解した液温が３０℃の水溶液（粘度：０．０３５Ｐａ・ｓ）を添加した。添加直後に湿潤な粒子状であった内容物が、１５分間混合攪拌するとさらさらとした顆粒状となった。一旦造粒物を取り出して水分が０．５重量％以下になるまで乾燥した。得られた造粒物に酢酸９８．３ｇを添加し５分混合攪拌した後、造粒物を取り出し整粒して顆粒状及び細粒状の製剤を得た。 5000.0 g of sodium chloride, 121.6 g of potassium chloride, 178.5 g of calcium chloride, 667.4 g of sodium acetate, and 760.2 g of glucose are mixed with a high-speed stirring granulator (High Speed Mixer FS-GS-25J, manufactured by Fukae Pautech Co., Ltd.) And mixed and stirred. While mixing and stirring at a rotational speed of 60 rpm (shearing force 0.04 kW / kg), 54.6 g of glucose prepared in advance and 82.8 g of magnesium chloride were dissolved in 36.4 g of purified water at an internal temperature of 25 ° C. An aqueous solution (viscosity: 0.035 Pa · s) having a liquid temperature of 30 ° C. was added. The contents which were in the form of wet particles immediately after the addition were mixed and stirred for 15 minutes to form smooth granules. The granulated product was once taken out and dried until the water content was 0.5% by weight or less. 98.3 g of acetic acid was added to the obtained granulated product and mixed and stirred for 5 minutes, and then the granulated product was taken out and sized to obtain granular and fine granular preparations.
塩化ナトリウム５０００．０ｇ、塩化カリウム１２２．７ｇ、塩化カルシウム１８１．５ｇ、酢酸ナトリウム２０２．３ｇ、ブドウ糖７６７．６ｇを高速攪拌型造粒装置に添加し混合撹拌した。回転数７０ｒｐｍ（剪断力０．０６ｋＷ／ｋｇ）で混合撹拌しながら、内温が２５℃で、あらかじめ調製しておいたブドウ糖５５．２ｇと塩化マグネシウム８３．７ｇを精製水５５．２ｇに溶解した液温が３０℃の水溶液（粘度：０．０４３Ｐａ・ｓ）を添加した。添加直後に湿潤な粒子状であった内容物が、１０分間混合撹拌するとさらさらとした顆粒状となった。この造粒物を取り出し、水分が０．５重量％以下になるまで乾燥した。更に造粒物にあらかじめ調製しておいた酢酸９８．７ｇを酢酸ナトリウム２０２．０ｇに吸着させたものを添加し、撹拌混合した後、整粒して顆粒状及び細粒状の製剤を得た。
［比較例１］
塩化ナトリウム１０６３．５ｇ、塩化カリウム２６．１ｇ、塩化マグネシウム１７．８ｇ、酢酸ナトリウム８６．１ｇ、ブドウ糖１７５．０ｇ、精製水２０．０ｇをニーダー（モリヤマ社製）に加え混合攪拌しながら加熱した。５５℃付近より粘度が上がり始め、内温６０℃でペースト状になった。塩化カルシウム３８．６ｇを加えてそのまま６０℃で攪拌を続けると、内容物が嵩高くなり更に粘度が上昇した。酢酸２１．０ｇを添加して攪拌を継続し、内容物がさらさらしてくるが、一部は塊状になり、微粉状のものもあった。内容物を取り出し、整粒後乾燥して製剤を得た。
［比較例２］
塩化カリウム２６．１ｇ、塩化マグネシウム１７．８ｇ、塩化カルシウム３８．６ｇ及び酢酸ナトリウム８６．１ｇを精製水４００．０ｇに溶解して水溶液を調製した。転動流動層造粒装置に塩化ナトリウム１０６３．６ｇとブドウ糖１７５．０ｇを投入し、給気温度８０℃、ローター回転数１５０ｒｐｍ、給気風量０．７ｍ３／分の条件下で、前記水溶液を噴霧すると同時に乾燥させ、造粒物を得た。整粒後、得られた造粒物に酢酸２１．０ｇを添加混合して製剤を得た。
［比較例３］
塩化ナトリウム１０６３．６ｇ、塩化カリウム２６．１ｇ、塩化マグネシウム１７．８ｇ、塩化カルシウム３８．６ｇ及び酢酸ナトリウム８６．１ｇ、ブドウ糖１７５．０ｇを７５μｍ程度に粉砕し、混合した後、圧縮回転式造粒機にて造粒した。整粒後、得られた造粒物に酢酸を添加混合して製剤を得た。
［試験例１］
実施例１で得られた製剤の顕微鏡写真（キーエンス社製）を図６に示す。この図より、実施例１で得た本製剤が、単独の粒子として存在したり、各母粒子の複数個が被覆層を介して結合した集合体として存在していることが分かる。また、同製剤のデジタル操作型電子顕微鏡（日立製作所製）による被覆層の構造を図７に示す。この図より、同製剤の被覆層が融着したような外観を有していることが確認できる。更に、母粒子及び被覆層の元素分析結果（ＥＤＸ）を図８及び図９に夫々示す。図８より、母粒子として塩化ナトリウムが存在することが確認された。尚、他の母粒子につき元素分析を行ってみたところ、塩化カリウム、酢酸ナトリウム及びブドウ糖が母粒子として存在することも確認された。
また、図９より被覆層中には塩化マグネシウム、塩化カリウム、ブドウ糖などが存在することが確認された。
［試験例２］
実施例１、実施例２で得られた各製剤の薄膜Ｘ線回折の結果を図１０、図１１に示す。
測定は、製剤の被覆層構造をより明確にするために薄膜Ｘ線回折法を用い、薄膜Ｘ線回折装置（ＣｕＫα：λ＝１．５４０５８Å、入射角θ＝１°）にて行った。
試料作製方法について説明する。試料は各製剤から約０．５ｇを取り、打錠機を用いて厚みが一様な円盤状に圧縮成型した。打錠圧力は製剤の母粒子が破砕しない程度とし、試料の大きさは直径約２０ｍｍ、厚さは約２ｍｍとした。
図１０、図１１より、ブドウ糖と塩化カルシウムと酢酸ナトリウムの反応生成物を示す２θ＝２１．４°及び２７．７°付近にピークが検出されているのがわかる。
［試験例３］
比較例１で得られた製剤のうち、１粒子を取り出してその断面をデジタル操作型電子顕微鏡で観察したものが図１２である。この図より、実施例１のそれとは異なり、該製剤においては、微細な粒子が堆積した状態にあることが分かる。
また、比較例１及び比較例２で得られた各製剤を、試験例２と同様の方法で測定した薄膜Ｘ線回折結果を図１３〜図１４に示す。ブドウ糖と塩化カルシウムと酢酸ナトリウムの反応生成物を示す２θ＝２１．４°及び２７．７°付近にピークが検出されていないのがわかる。
［試験例４］
実施例１で得られた製剤からランダムに６箇所サンプリングを行い、それぞれの検体についてサンプル８．５０ｇを水に溶かして正確に２００ｍｌとし、これを５０倍希釈してＮａ＋、Ｋ＋、Ｍｇ２＋、Ｃａ２＋、Ｃｌ−、ＣＨ３ＣＯＯ−の各電解質濃度を東ソー社製イオンクロマトグラフにより測定した。また、ブドウ糖については、同様にサンプル８．５０ｇを水に溶かして正確に１００ｍｌとし、東ソー社製液体クロマトグラフにより測定した。測定結果を表１に示す。
実施例２で得られた製剤の各成分濃度についても、実施例１と同様に行い、その結果を表２に示す。
実施例１、実施例２、比較例１、比較例２の製剤をそれぞれアルミニウム製包材に充填し、ヒートシールした後、４０℃（ＲＨ＝７５％）の条件下で安定性試験を実施した。ブドウ糖の分解率を測定するため第１４改正日本薬局方に記載の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吸光度の測定を行った。その結果を表３に示す。
実施例１、実施例２及び比較例１の製剤２３０ｇを２検体ずつ量り取り、それぞれ１３０ｍｍ×８５ｍｍのアルミニウム製包材に充填し、ヒートシールした後、４０℃（ＲＨ＝７５％）の条件下で３０ｋｇの荷重を均等にかけ、経時的に固結状態を観察した。固結試験の結果を表４に示した。サンプルは、所定の時間荷重をかけた後開封し、１６メッシュのふるいで軽く篩過して篩い残の量を測定した。篩い残が１０重量％以内の場合は○、１０〜５０重量％の場合は△、それ以上は×で表した。
１０００ｍｌのビーカーに水４００ｍｌ（２０℃）を入れ、撹拌しながら実施例２及び比較例１〜３の各製剤を１２０ｇ投入し、完全に溶解するまでの時間を測定した。測定結果を表５に示す。
実施例１、実施例２、比較例１及び比較例２で得られた各製剤から２０ｇを採取し、クロロホルム２０ｍｌを添加して軽く振り混ぜた後、上澄みを採取した。また、同様に各製剤から２０ｇを採取して５分間振とうし、クロロホルム２０ｍｌを添加して軽く振り混ぜた後、上澄みを採取した。それぞれの試料の濁度試験をＪＩＳ Ｋ ０１０１「工業用水試験方法」のカオリン標準液を用いる場合に準じて行った。振とうにより生じた微粉末の量の差を、振とう前後の濁度の差として評価した。その結果は表６に示す通りで、本発明によって得られる製剤は比較例と比較して微粉末の量が少なく、振とうのような物理的な力によってもその影響を受けにくいという結果が得られた。
[Comparative Example 1]
1063.5 g of sodium chloride, 26.1 g of potassium chloride, 17.8 g of magnesium chloride, 86.1 g of sodium acetate, 175.0 g of glucose, and 20.0 g of purified water were added to a kneader (manufactured by Moriyama Co., Ltd.) and heated with mixing and stirring. The viscosity started to increase from around 55 ° C and became a paste at an internal temperature of 60 ° C. When 38.6 g of calcium chloride was added and stirring was continued as it was at 60 ° C., the contents became bulky and the viscosity further increased. Although 21.0 g of acetic acid was added and stirring was continued, the contents were free flowing, but some of them became agglomerated and some were finely powdered. The contents were taken out, sized and dried to obtain a preparation.
[Comparative Example 2]
An aqueous solution was prepared by dissolving 26.1 g of potassium chloride, 17.8 g of magnesium chloride, 38.6 g of calcium chloride and 86.1 g of sodium acetate in 400.0 g of purified water. 1063.6 g of sodium chloride and 175.0 g of glucose are put into a rolling fluidized bed granulator, and the aqueous solution is added under the conditions of a supply air temperature of 80 ° C., a rotor rotation speed of 150 rpm, and a supply air flow rate of 0.7 m 3 / min. At the same time as spraying, it was dried to obtain a granulated product. After the sizing, 21.0 g of acetic acid was added to and mixed with the obtained granulated product to obtain a preparation.
[Comparative Example 3]
1063.6 g of sodium chloride, 26.1 g of potassium chloride, 17.8 g of magnesium chloride, 38.6 g of calcium chloride, 86.1 g of sodium acetate, and 175.0 g of glucose are ground to about 75 μm, mixed, and then compressed and rotated granulated. Granulated with a machine. After sizing, acetic acid was added to and mixed with the obtained granulated product to obtain a preparation.
[Test Example 1]
A micrograph (manufactured by Keyence Corporation) of the preparation obtained in Example 1 is shown in FIG. From this figure, it can be seen that the present preparation obtained in Example 1 exists as a single particle or as an aggregate in which a plurality of each mother particle is bonded via a coating layer. Moreover, the structure of the coating layer by the digital operation type electron microscope (made by Hitachi Ltd.) of the formulation is shown in FIG. From this figure, it can be confirmed that the coating layer of the preparation has an appearance as fused. Further, elemental analysis results (EDX) of the mother particles and the coating layer are shown in FIGS. 8 and 9, respectively. From FIG. 8, it was confirmed that sodium chloride was present as mother particles. When elemental analysis was performed on other mother particles, it was confirmed that potassium chloride, sodium acetate and glucose were present as mother particles.
Further, from FIG. 9, it was confirmed that magnesium chloride, potassium chloride, glucose and the like exist in the coating layer.
[Test Example 2]
The results of thin film X-ray diffraction of each preparation obtained in Example 1 and Example 2 are shown in FIGS.
The measurement was performed using a thin film X-ray diffraction method (CuKα: λ = 1.54058 mm, incident angle θ = 1 °) using a thin film X-ray diffraction method in order to clarify the coating layer structure of the preparation.
A sample preparation method will be described. About 0.5 g of the sample was taken from each preparation, and compression-molded into a disk having a uniform thickness using a tableting machine. The tableting pressure was such that the mother particles of the preparation were not crushed, the sample size was about 20 mm in diameter, and the thickness was about 2 mm.
10 and 11, it can be seen that peaks are detected in the vicinity of 2θ = 21.4 ° and 27.7 ° indicating the reaction product of glucose, calcium chloride, and sodium acetate.
[Test Example 3]
FIG. 12 shows one of the preparations obtained in Comparative Example 1 taken out and its cross section observed with a digital operation electron microscope. From this figure, it can be seen that, unlike that of Example 1, in the preparation, fine particles are deposited.
Moreover, the thin film X-ray-diffraction result which measured each formulation obtained by the comparative example 1 and the comparative example 2 by the method similar to the test example 2 is shown in FIGS. It can be seen that no peaks are detected in the vicinity of 2θ = 21.4 ° and 27.7 ° indicating the reaction product of glucose, calcium chloride and sodium acetate.
[Test Example 4]
Six samples were randomly sampled from the preparation obtained in Example 1, and 8.50 g of each sample was dissolved in water to make exactly 200 ml, and this was diluted 50 times to obtain Na + , K + , Mg 2+. , Ca 2+ , Cl − , and CH 3 COO − were measured by an ion chromatograph manufactured by Tosoh Corporation. As for glucose, 8.50 g of a sample was dissolved in water to make exactly 100 ml, and measured with a liquid chromatograph manufactured by Tosoh Corporation. The measurement results are shown in Table 1.
The concentration of each component of the preparation obtained in Example 2 was also the same as in Example 1, and the results are shown in Table 2.
Each of the preparations of Example 1, Example 2, Comparative Example 1, and Comparative Example 2 was filled in an aluminum packaging material, heat sealed, and then subjected to a stability test at 40 ° C. (RH = 75%). . In order to measure the decomposition rate of glucose, the absorbance was measured based on the ultraviolet-visible absorbance measurement method of the glucose injection purity test described in the 14th revised Japanese Pharmacopoeia. The results are shown in Table 3.
230 g of each of the preparations of Example 1, Example 2 and Comparative Example 1 were weighed, filled into 130 mm × 85 mm aluminum packaging materials, heat sealed, and then subjected to conditions of 40 ° C. (RH = 75%). A load of 30 kg was applied uniformly and the consolidated state was observed over time. The results of the consolidation test are shown in Table 4. The sample was opened after applying a load for a predetermined time, and lightly sieved with a 16-mesh sieve to measure the amount of sieve residue. When the sieving residue was within 10% by weight, it was indicated by ◯, when it was 10-50% by weight, Δ, and more than that by ×.
400 ml of water (20 ° C.) was put into a 1000 ml beaker, 120 g of each preparation of Example 2 and Comparative Examples 1 to 3 was added while stirring, and the time until complete dissolution was measured. Table 5 shows the measurement results.
20 g was collected from each preparation obtained in Example 1, Example 2, Comparative Example 1 and Comparative Example 2, 20 ml of chloroform was added, and the mixture was lightly shaken, and then the supernatant was collected. Similarly, 20 g was collected from each preparation and shaken for 5 minutes. After adding 20 ml of chloroform and lightly mixed, the supernatant was collected. The turbidity test of each sample was performed according to the case of using the kaolin standard solution of JIS K 0101 “Industrial water test method”. The difference in the amount of fine powder produced by shaking was evaluated as the difference in turbidity before and after shaking. The results are shown in Table 6. The preparation obtained by the present invention has a smaller amount of fine powder than the comparative example, and the result is that it is not easily affected by physical force such as shaking. It was.
本発明に係る固形剤は、強固に融着した状態の被覆層が母粒子を被覆した造粒物であり、他の例えば、塩化ナトリウム、塩化カリウム等の電解質、ブドウ糖の水溶液を噴霧して被膜形成を行う噴霧造粒方法などで製造された被膜或いは図３に示したような被膜に比べ、表面が緻密であるため、外部要因の影響を受けにくく、長期保存・安定性に優れており、更には、流動性や耐摩損性、耐固結性も良好で発塵しにくく溶解速度も速いため、医療現場での溶解操作の作業性が従来と比較して極めて良好であるという効果を奏する。
更には、本発明に係る固形剤の製造方法によれば、従来と比べて長時間加熱する必要が無いので、造粒中にブドウ糖が分解、着色している危険性を回避できると共に、粉砕、篩などの煩雑な操作を必要とすることなく、含量均一性に優れた固形剤を得ることができる。具体的には、本発明の製法によると、湿潤な粒子状であった混合物が、常温付近で短時間に、さらさらとした見かけ上乾燥した顆粒状及び／又は細粒状の造粒物となり、容易に造粒が完了する。したがって、次工程である移送、乾燥、混合等のハンドリングが極めて容易となる。The solid agent according to the present invention is a granulated product in which a coating layer in a strongly fused state is coated with mother particles, and is coated with an electrolyte such as sodium chloride or potassium chloride or an aqueous solution of glucose. Compared to the coating produced by spray granulation method or the like as shown in FIG. 3 or the coating as shown in FIG. 3, the surface is dense, so it is not easily affected by external factors, and has excellent long-term storage and stability. In addition, fluidity, abrasion resistance, and caking resistance are good, dust generation is difficult, and dissolution speed is fast, so that the workability of the melting operation in the medical field is extremely good compared to the conventional one. .
Furthermore, according to the method for producing a solid preparation according to the present invention, since it is not necessary to heat for a long time compared to the conventional case, the risk that glucose is decomposed and colored during granulation can be avoided, and pulverization. A solid agent excellent in content uniformity can be obtained without requiring a complicated operation such as sieving. Specifically, according to the production method of the present invention, the mixture that was in the form of wet particles becomes a granular and / or fine granulated product that appears to be dry and apparently dry in a short time near room temperature, and is easy. Granulation is completed. Therefore, handling such as transfer, drying, and mixing, which are the next steps, becomes extremely easy.
Claims (3)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003023261 | 2003-01-31 | ||
| JP2003023261 | 2003-01-31 | ||
| JPPCT/JP03/07356 | 2003-06-10 | ||
| PCT/JP2003/007356 WO2004067014A1 (en) | 2003-01-31 | 2003-06-10 | Solid preparation for dialysis and process for producing the same |
| PCT/JP2004/000892 WO2004066977A1 (en) | 2003-01-31 | 2004-01-30 | Solid agent for dialysis and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPWO2004066977A1 JPWO2004066977A1 (en) | 2006-05-18 |
| JP4603977B2 true JP4603977B2 (en) | 2010-12-22 |
Family
ID=32820718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005504763A Expired - Lifetime JP4603977B2 (en) | 2003-01-31 | 2004-01-30 | Dialysis solid preparation and method for producing the same |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP4603977B2 (en) |
| CN (1) | CN100387222C (en) |
| HK (1) | HK1089089A1 (en) |
| TW (1) | TW200413029A (en) |
| WO (1) | WO2004067014A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US10525078B2 (en) | 2013-10-02 | 2020-01-07 | Tomita Pharmaceutical Co., Ltd. | Solid dialysis A agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104586884A (en) * | 2015-01-09 | 2015-05-06 | 李淑秀 | Novel hemodialysis concentrate |
| CN109843845B (en) * | 2016-10-28 | 2022-02-18 | 富田制药株式会社 | Higher acetate compound and solid dialysis agent using same |
| CN107753506A (en) * | 2017-11-27 | 2018-03-06 | 北京市四维医药科技研究所 | Stable composite electrolyte solid pharmaceutical preparation |
| CN107753450A (en) * | 2017-11-27 | 2018-03-06 | 北京市四维医药科技研究所 | A kind of composite electrolyte three-layer tablet |
| CN107811988A (en) * | 2017-11-27 | 2018-03-20 | 北京市四维医药科技研究所 | A kind of composite electrolyte cored shape piece |
| CN107823165A (en) * | 2017-11-27 | 2018-03-23 | 北京市四维医药科技研究所 | A kind of flat cylindricality piece of composite electrolyte |
| CN109223822A (en) * | 2018-11-16 | 2019-01-18 | 秦皇岛迈淩医疗设备有限公司 | A kind of haemodialysis solid pharmaceutical preparation and preparation method thereof |
| WO2023148316A1 (en) * | 2022-02-03 | 2023-08-10 | Basf Se | Magnesium diacetate x 4h 2o and/or magnesium dichloride x 6h 2o and/or magnesium sulfate x 7h 2o and/or disodium sulfate x 10 h 2o and/or sodium thiosulfate x 5h 2o and/or na 3po 4 x 12 h 2o and/or na 2hpo 4 x 12h 2o/7h 2o and/or sodium acetate x 3h 2o as granulating aid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06178802A (en) * | 1992-12-14 | 1994-06-28 | Tomita Seiyaku Kk | Production of agent for artificial kidney perfusion for bicarbonate dialysis and the agent |
| JP3032660U (en) * | 1996-06-20 | 1996-12-24 | 株式会社ダイワパックス | Packaging bag |
| JPH0940562A (en) * | 1995-08-02 | 1997-02-10 | Tomita Seiyaku Kk | Solid agent for dialysis and its production |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2749375B2 (en) * | 1989-05-26 | 1998-05-13 | テルモ 株式会社 | Preparation for hemodialysis and method for producing the same |
| JP3384841B2 (en) * | 1993-04-02 | 2003-03-10 | 味の素ファルマ株式会社 | Baking soda dialysis agent |
| JP3530235B2 (en) * | 1994-09-27 | 2004-05-24 | 味の素ファルマ株式会社 | Hemodialysis agent |
| JP3415291B2 (en) * | 1994-09-27 | 2003-06-09 | 味の素ファルマ株式会社 | Bicarbonate dialysis agent |
| JPH11343230A (en) * | 1998-05-27 | 1999-12-14 | Nissho Corp | Agent for solid sodium bicarbonate dialysis |
| JP4062719B2 (en) * | 1999-11-25 | 2008-03-19 | ニプロ株式会社 | Solid baking soda dialysis agent and method for producing the same |
| JP3899506B2 (en) * | 2000-09-27 | 2007-03-28 | ニプロ株式会社 | Preparation for solid dialysis and method for producing the same |
| JP2002102336A (en) * | 2000-09-27 | 2002-04-09 | Nipro Corp | Solid dialyzing pharmaceutical preparation and method of preparing for the same |
| JP4370729B2 (en) * | 2001-03-30 | 2009-11-25 | 味の素株式会社 | Solid dialysis agent and method for producing the same |
-
2003
- 2003-06-10 WO PCT/JP2003/007356 patent/WO2004067014A1/en not_active Application Discontinuation
- 2003-06-11 TW TW092115792A patent/TW200413029A/en unknown
-
2004
- 2004-01-30 CN CNB2004800031381A patent/CN100387222C/en not_active Expired - Lifetime
- 2004-01-30 JP JP2005504763A patent/JP4603977B2/en not_active Expired - Lifetime
-
2006
- 2006-08-28 HK HK06109554A patent/HK1089089A1/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06178802A (en) * | 1992-12-14 | 1994-06-28 | Tomita Seiyaku Kk | Production of agent for artificial kidney perfusion for bicarbonate dialysis and the agent |
| JPH0940562A (en) * | 1995-08-02 | 1997-02-10 | Tomita Seiyaku Kk | Solid agent for dialysis and its production |
| JP3032660U (en) * | 1996-06-20 | 1996-12-24 | 株式会社ダイワパックス | Packaging bag |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US10251988B2 (en) | 2012-10-10 | 2019-04-09 | Tomita Pharmaceutical Co., Ltd. | Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof |
| US10525078B2 (en) | 2013-10-02 | 2020-01-07 | Tomita Pharmaceutical Co., Ltd. | Solid dialysis A agent containing alkali metal diacetate, and two-part type low-acetate dialysis agent using same |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004067014A1 (en) | 2004-08-12 |
| HK1089089A1 (en) | 2006-11-24 |
| JPWO2004066977A1 (en) | 2006-05-18 |
| CN1744884A (en) | 2006-03-08 |
| CN100387222C (en) | 2008-05-14 |
| TW200413029A (en) | 2004-08-01 |
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