CN1744884A - Solid preparation for dialysis and process for producing the same - Google Patents
Solid preparation for dialysis and process for producing the same Download PDFInfo
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- CN1744884A CN1744884A CNA2004800031381A CN200480003138A CN1744884A CN 1744884 A CN1744884 A CN 1744884A CN A2004800031381 A CNA2004800031381 A CN A2004800031381A CN 200480003138 A CN200480003138 A CN 200480003138A CN 1744884 A CN1744884 A CN 1744884A
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- Prior art keywords
- dialysis
- preparation
- glucose
- chloride
- solid formulation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 101
- 239000007787 solid Substances 0.000 title claims abstract description 86
- 238000000502 dialysis Methods 0.000 title claims abstract description 65
- 238000000034 method Methods 0.000 title description 34
- 230000008569 process Effects 0.000 title description 9
- 239000000203 mixture Substances 0.000 claims abstract description 112
- 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 abstract description 62
- 239000008103 glucose Substances 0.000 claims abstract description 61
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract description 52
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 52
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 46
- 235000002639 sodium chloride Nutrition 0.000 claims abstract description 45
- 239000001632 sodium acetate Substances 0.000 claims abstract description 37
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 35
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 35
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 35
- 239000001110 calcium chloride Substances 0.000 claims abstract description 34
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 34
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract description 26
- 239000011780 sodium chloride Substances 0.000 claims abstract description 26
- 239000001103 potassium chloride Substances 0.000 claims abstract description 23
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000003792 electrolyte Substances 0.000 claims abstract description 18
- 238000002233 thin-film X-ray diffraction Methods 0.000 claims abstract description 12
- 235000011147 magnesium chloride Nutrition 0.000 claims abstract description 7
- 235000011148 calcium chloride Nutrition 0.000 claims abstract description 5
- 239000011248 coating agent Substances 0.000 claims description 49
- 238000000576 coating method Methods 0.000 claims description 49
- 238000009472 formulation Methods 0.000 claims description 46
- 239000007864 aqueous solution Substances 0.000 claims description 35
- 239000000843 powder Substances 0.000 claims description 34
- 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 22
- 239000000463 material Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 238000010008 shearing Methods 0.000 claims description 14
- 239000002351 wastewater Substances 0.000 claims description 13
- 239000005022 packaging material Substances 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 230000035699 permeability Effects 0.000 claims description 3
- 230000004888 barrier function Effects 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 29
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 abstract description 8
- 238000003860 storage Methods 0.000 abstract description 8
- 239000000385 dialysis solution Substances 0.000 abstract description 4
- 238000000354 decomposition reaction Methods 0.000 abstract description 3
- 239000003002 pH adjusting agent Substances 0.000 abstract 2
- 238000005299 abrasion Methods 0.000 abstract 1
- 239000011247 coating layer Substances 0.000 abstract 1
- 238000004040 coloring Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 22
- 238000002156 mixing Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- 238000005469 granulation Methods 0.000 description 10
- 230000003179 granulation Effects 0.000 description 10
- 239000008187 granular material Substances 0.000 description 9
- 239000010408 film Substances 0.000 description 7
- 239000011550 stock solution Substances 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 235000001727 glucose Nutrition 0.000 description 5
- 239000005001 laminate film Substances 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
- 239000011575 calcium Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000002216 antistatic agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000015556 catabolic process Effects 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
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000000853 adhesive 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
- 239000004411 aluminium Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 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
- 239000000428 dust Substances 0.000 description 2
- 238000000635 electron micrograph Methods 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 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
- 238000012856 packing Methods 0.000 description 2
- 238000005453 pelletization Methods 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011435 rock Substances 0.000 description 2
- 235000017454 sodium diacetate Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000003068 static effect Effects 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
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002546 agglutinic effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation 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
- 238000004458 analytical method Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 150000004687 hexahydrates Chemical class 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002500 ions Chemical class 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
- 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
- WALYXZANOBBHCI-UHFFFAOYSA-K magnesium sodium trichloride hydrate Chemical compound O.[Cl-].[Na+].[Mg+2].[Cl-].[Cl-] WALYXZANOBBHCI-UHFFFAOYSA-K 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 239000002699 waste material Substances 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)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
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- Diabetes (AREA)
- External Artificial Organs (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A solid agent for dialysis comprising an electrolyte, glucose and a pH adjusting agent required for the preparation of a bicarbonate dialyzing fluid, which solid agent for dialysis ensures stable presence of glucose in the stage of not only production but also storage, being free from the danger of decomposition and coloring and excels in storage stability, content uniformity and abrasion resistance, realizing extremely high workability on medical spots. In particular, a solid agent for dialysis comprising an electrolyte composition (the electrolyte composition composed of sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate), a pH adjusting agent and glucose characterized in that base particles are covered by a coating layer comprising a salt having, in thin-film X-ray diffraction, specified peaks at 2theta = 21.3 to 21.5 DEG and 2theta = 27.6 to 27.8 DEG (CuK alpha: lambda = 1.54058, and incident angle theta = 1 DEG).
Description
Technical field
The present invention relates to a kind of solid formulation for dialysis that is used for modulating the bicarbonate dialysis liquid system that renal failure patient dialysis therapy uses; In particular to a kind of solid formulation for dialysis and preparation method thereof, the plocoid coating that is contained specific salts as the surface of the particle (coatingparticles) of parent nucleus during described solid preparation pelletize coats, and its stability, content uniformity and wearability are all good.
Background technology
Dialysis therapy has been asserted a kind of method for the treatment of the renal failure patient, and this method is implemented with the form that continues treatment regularly for getting rid of refuse in the body, regulating electrolytical purpose.In order to the dialysis solution of dialysis therapy, be to form according to the composition modulation that is similar to the normal serum electrolyte concentration, in recent years in, adopt the few hydrocarbonate dialysis agent of burden concerning organism.For bicarbonate dialysis liquid system, because sodium bicarbonate and calcium chloride or magnesium chloride produce carbonate deposition, so, generally speaking, to contain calcium chloride or magnesium chloride but do not contain the preparation (A agent) of sodium bicarbonate and contain sodium bicarbonate but two kinds of preparations of preparation (B agent) of not containing calcium chloride or magnesium chloride separately, before use respectively the dissolving, diluted mixture, be modulated into bicarbonate dialysis liquid system.
Now, the main preparation type that uses in hemodialysis has following 3 kinds: " powder-powder type " of " liquid-liquid type " of concentrated stock solution A+ concentrated stock solution B, " liquid-powder type " of concentrated stock solution A+ powder B (sodium bicarbonate) and powder A+ powder B.In " liquid-liquid type ", " liquid-powder type ", for the concentrated stock solution preparation, the concentrated stock solution about 10kg of normally in the polyethylene container made, packing into, therefore, volume is big and heavy, in transportation, carrying, memory space, using method, exist variety of problems with the aspects such as waste treatment of back container.
In order to address these problems, in recent years, to develop and a kind ofly A agent powdered is obtained " powder-powder type " solid preparation and be applied.Medical treatment is on-the-spot in hospital etc., can use special-purpose dissolver, in case this solid preparation is dissolved as stock solution with the concentrated stock solution same concentrations of " liquid-liquid type ", can continue dissolving, dilution then, is modulated to the concentration of dialysis solution.
The preparation method of such solid preparation, known in the prior art have: spray drying method, wet granulation, dry pelletizing method etc.Every kind of method has its pros and cons, do not reach satisfied degree talkative aspect preparation method or the quality.With preparation that spray drying method is obtained, volume is big, moisture and inhomogeneous, the sour composition volatilization of granularity, therefore is difficult to the pH value that reaches certain.On TOHKEMY 2002-102337 communique, the double-formulation solid shape bicarbonate dialysis that uses rotation stirring fluidized bed prilling granulator the to be obtained preparation method of preparation is disclosed, still, in the method, collide between the mobile pelletize thing, therefore the shortcoming that exists coating to be easy to come off.Simultaneously, owing to contain in the electrolyte ingredient of some sodium chloride and the water that glucose is dissolved in a great deal of, therefore must carry out spray drying, thereby energy unit consumption is significantly worsened.In wet granulation and the dry pelletizing method,, can't avoid pulverizing in order to keep uniformity, numerous and diverse step such as mixing, exist from device therefor or the outside shortcoming of sneaking into impurity and very easily polluting.
So, be conceived to these problems, need not the preparation method of numerous and diverse steps such as pulverizing, the scheme of the good compact-type solid preparation of bulk density, angle of repose and dissolution velocity has been proposed.For example, once the artificial kidney perfusion that open graininess that is made of the pelletize thing or granuliform bicarbonate are used to dialyse is with the preparation method (with reference to No. 2769592 communique of special permission) of A agent, the pelletize thing obtains through the following step: various electrolyte compounds are mixed, heat (73 ℃) in the presence of sodium acetate, water, add glucose then, mix with acetic acid, several sodium chloride particles are by this coating combination.In addition, solid-state dialysis preparation (with reference to No. 2987488 communique of special permission) was once disclosed, described solid-state dialysis preparation carries out pelletize at 60 ℃, double-layer structure with stratum nucleare and double salt layer, stratum nucleare comprise be selected from sodium chloride and potassium chloride at least a material as main component, the double salt layer contains double salt, other electrolyte compositions and the pH regulator agent that the reaction of sodium acetate and calcium chloride forms.
But, exist serious problems in these preparation methoies.In other words, in No. 2769592 communique of special permission, sodium chloride, potassium chloride, magnesium chloride, calcium chloride mix, stir, heat with pure water, add sodium acetate and continue to heat when mixing; In No. 2987488 communique of special permission, sodium chloride, potassium chloride, magnesium chloride, sodium acetate mix, stir, heat with pure water, add calcium chloride and continue to heat when mixing; In either case, content all can produce specific viscosity, causes viscosity obviously to increase, and stirs difficulty.Adopt general agitating device to be difficult to be prepared, need the extremely strong equipment of stirring capacity, because of the particularization of equipment, maximize so, the problem that exists the preparation expense obviously to increase, therefore thirst for a kind of both can be at a low price and the preparation of easy manufacture.
In addition, open in the 2002-102337 communique No. 2769592 communique of special permission, No. 2987488 communique of special permission and spy, all need be in long-time heating more than 60 ℃, in granulation process, breakdown of glucose, painted probability are very big, and there is the danger of variation in the content uniformity of the dialysis preparation that obtains by said method.And then, preparation according to this preparation method preparation, its coating reason fine particle by adhesive attachment, be laminated, so be vulnerable to the influence of external cause, so have the decomposition of glucose, the painted shortcoming that further develops of As time goes on being easy to, aspect storage stability, exist big defective.
And then because the constructional characteristic of coating, coating comes off easily when transportation, becomes the preparation of easy generation fine powder, adds the generation electrostatic interaction, causes the appearance of various problem.For example, during filling product, produced static in the time of airborne dust in process of production, the problem that sealing-strength reduces appears in the mouth-sealed portion branch absorption fine powder of packaging bag, and the worst situation is the danger that broken bag is arranged.On the other hand, in dialysis execute-in-place process, can kick up during the modulation dialysis solution and contain the dust of acetic acid, this also can produce because electrostatic effect makes solid preparation easily remain in problem in the bag when causing working environment to worsen.Also have, the outside of packaging material is because electrostatic effect also can be adsorbed foreign body, and one of reason that impurity is sneaked into when becoming dissolving is demanded urgently improving.
The purpose of this invention is to provide the fabulous solid formulation for dialysis of a kind of operation, described solid preparation comprises the necessary electrolyte of modulation bicarbonate dialysis liquid system, glucose and pH regulator agent, even wherein in fabrication stage, memory phase, glucose is stable existence also, acomia estranged separating and painted danger, have superior storage stability, content uniformity, wearability, dissolubility, powder attitude thing is also few, and has prevented electrostatic generation.
Summary of the invention
The present inventor has carried out unremitting research in order to achieve the above object, found that, in the system that glucose, calcium chloride and sodium acetate exist, in the presence of low amounts of water, if whipping temp and shearing force are set within the limits prescribed and are mixed more than the official hour, then can be under the situation of not using complicated pelletize operation and special equipment, the coating of formation plocoid is finished above-mentioned problem on coatingparticles.
In other words, the present invention (1) is a kind of solid formulation for dialysis, comprise electrolyte composition, pH regulator agent and glucose comprising sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, it is characterized in that, coatingparticles is coated by coating, and this coating contains in the thin film X-ray diffraction in 2 θ=21.3-21.5 ° and 2 θ=27.6-27.8 ° of (CuK α; λ=1.54058 , angle of incidence θ=1 °) locates to have the salt at specific peak.
And the present invention (2) is according to invention (1) described solid formulation for dialysis, is graininess and/or acinous.
And the present invention (3) is that wherein, described salt is the reaction product of glucose and calcium chloride and sodium acetate according to invention (1) or (2) described solid formulation for dialysis.
And the present invention (4) is that wherein, described coating is a plocoid according to one of invention (1)-(3) described solid formulation for dialysis.
And the present invention (5) is the hydrocarbonate dialysis solid preparation, comprises one of invention (1)-(4) described solid formulation for dialysis and the solid preparation that contains sodium bicarbonate.
And the present invention (6) is according to one of invention (1)-(5) described solid formulation for dialysis, wherein, is concealed in moisture permeability (40 ℃, 90%RH) 2.0g/m
224hr (hour) following, water vapor proof barrier packaging material with lit-par-lit structure of backplate effect.
And, the present invention (7) is a kind of preparation method for preparing solid formulation for dialysis, to comprise sodium chloride, potassium chloride, calcium chloride, the electrolyte composition of magnesium chloride and sodium acetate, pH regulator agent and glucose are raw material, it is characterized in that, comprise the following steps: in containing the powder body and/or plastochondria of material composition more than a kind of this solid preparation, to purify waste water or to contain the aqueous solution of material composition more than a kind of this solid preparation, mixed phase for the water of this powder body and/or plastochondria weight 0.1-2 weight % (percentage by weight) (at this, this mixture contains glucose at least, calcium chloride and sodium acetate), below 50 ℃, more than 1 minute, with the shearing force more than this mixture of every 1kg 0.003kW/kg to this mixture stirring-granulating.
" shearing force " refers to the value by following formula calculating in addition, in the present invention:
Shearing force [kW/kg]={ (current value [A] the during current value during load [A]-zero load)/load current value [A] } * motor load amount [kW]/content weight [kg]
Current value during load: during stirring-granulating, the stirring motor current value [A] of agitating type mixing granulation device
Current value when zero load: the stirring motor current value [A] of (with stirring-granulating time revolution identical) this device during idle running
Load current value: the stirring motor load current value [A] of this device
Motor load amount: the motor load amount [kW] of the stirring motor of this device
Content weight: this mixture weight [kg] during stirring-granulating in this device
And the present invention (8) is (7) described preparation method according to the present invention, and wherein, this viscosity in aqueous solution is 0.001-2Pas.
And the present invention (9) is (7) or (8) described preparation method according to the present invention, and wherein, this aqueous solution is the aqueous solution that contains glucose and magnesium chloride.
And the present invention (10) is one of invention (7)-(a 9) described preparation method, and wherein solid formulation for dialysis is one of invention (1)-(6) described solid formulation for dialysis.
Description of drawings
Fig. 1 is at first view can not be on the surface or the sketch map of the solid preparation profile status of the present invention of the type of inside confirmation particle.In addition, 1 is coating among the figure, and 2 is coatingparticles.
Fig. 2 is for confirming the sketch map of the solid preparation profile status of the present invention of the type that particle exists in surperficial and inside.In addition, A is a particle among the figure, and B is a fused layer.
Fig. 3 is the prior art solid preparation profile status sketch map of heaped-up for countless particles.In addition, 1 ' is accumulation horizon among the figure, and 2 ' is coatingparticles, and C is a particle.
Fig. 4 is for showing the sketch map of " plocoid " meaning among the present invention.
Fig. 5 is for showing the sketch map of " heaped-up " meaning in the prior art.In addition, D is a binding agent among the figure.
Fig. 6 is the digit microscope photo (digital photograph) of embodiment 1 gained solid formulation for dialysis.
Fig. 7 is the electron micrograph (digital photograph) of embodiment 1 gained solid formulation for dialysis.
Fig. 8 is the results of elemental analyses (formula x-ray analysis equipment (EDX) can loose) of the coatingparticles of embodiment 1 gained solid formulation for dialysis.
Fig. 9 is the results of elemental analyses (formula x-ray analysis equipment (EDX) can loose) of the coating of embodiment 1 gained solid formulation for dialysis.
Figure 10 is the thin film X-ray diffraction result of embodiment 1 gained solid formulation for dialysis.
Figure 11 is the thin film X-ray diffraction result of embodiment 2 gained solid formulation for dialysis.
Figure 12 is the electron micrograph (digital photograph) of comparative example 1 gained solid formulation for dialysis.
Figure 13 is the thin film X-ray diffraction result of comparative example 1 gained solid formulation for dialysis.
Figure 14 is the thin film X-ray diffraction result of comparative example 2 gained solid formulation for dialysis.
The specific embodiment
At first, solid formulation for dialysis of the present invention is described.Solid formulation for dialysis of the present invention, the solid preparation of its composition and prior art does not have variation in essence, comprises various electrolyte (sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate), pH regulator agent and glucose.At this, as the pH regulator agent, so long as the material of on the pharmacology, allowing, then have no particular limits, for example, can enumerate liquid acids such as acetic acid, hydrochloric acid, solid peracids such as lactic acid, citric acid, malic acid, sodium diacetate, these acid can be used separately, also can multiplely be used in combination.Wherein, preferred acetic acid and sodium diacetate.
Solid formulation for dialysis of the present invention is characterised in that the coating that coatingparticles is contained specific salts coats.
At first, earlier coating of the present invention is described.This coating contains in the thin film X-ray diffraction in 2 θ=21.3-21.5 ° and 2 θ=27.6-27.8 ° of (CuK α; λ=1.54058 , angle of incidence θ=1 °) locates to have the salt at specific peak.At this, the necessary composition of this salt is identified that the result determines that this salt is the reaction product of glucose and calcium chloride and sodium acetate by method of elimination.
Usually, can promote the decomposition of glucose when raw material calcium chloride and glucose coexistence, the storage stability of preparation is significantly descended, but, solid formulation for dialysis of the present invention, in the stirring-granulating process, most calcium chloride and glucose and sodium acetate are considered to take place specific response, form this salt, and be included in the coating, so its storage stability is fabulous.In addition, identifiablely be, if contain in the water that the solid formulation for dialysis of this salt is dissolved in ormal weight the electrolyte ion concentration and the concentration of glucose that then can obtain stipulating.
In addition, coating of the present invention also can contain other composition except that described salt, for example, and as sodium chloride, potassium chloride, magnesium chloride, sodium acetate, glucose and/or the pH regulator agent of solid preparation raw material.
In addition, coating of the present invention is a plocoid.At first, " plocoid " its outward appearance after meaning fused mass and solidifying also can claim " shape condenses ".In addition, mean that outward appearance is a plocoid, rather than the actual meaning that is heated to the above fusion of its melting point.Also have, also can be rendered as noncrystal shape (this is not meant the meaning that is made of noncrystal, and is meant that showing as outward appearance is non-crystal appearance).In addition, not that all permeate integral body is also passable, also can be on the surface or the inner state that contains particle.At this, use sketch map to describe the coating of prior art solid formulation for dialysis and the difference of " plocoid coating " of the present invention.At first, the coating of prior art is to be deposited in structure on the coatingparticles 2 ' with countless particle C as shown in Figure 3.So, as shown in Figure 5, can be understood as between particle C and the particle C by binding agent D bondingly, or to adopt only be that particle adheres to the structure that forms mutually.Otherwise, " plocoid coating " of the present invention as shown in Figure 1, particle is not to pile up, but most of particle merge, integrated, have the outward appearance of such formation.But, most of incorporate outward appearance also can, as Fig. 2 and shown in Figure 4, coating 1 the surface or inner, even exist the particle A that is not the fusion state, also belong to what is called of the present invention " plocoid coating ".
Below, coatingparticles of the present invention is described.Coatingparticles of the present invention does not have special restriction, comprises the material composition of solid preparation.For example, can enumerate the coatingparticles that comprises sodium chloride, the coatingparticles that comprises other compositions (for example, potassium chloride, sodium acetate, glucose).Also have, for example, in an embodiment, the coatingparticles of most of particle comprises sodium chloride, and the coatingparticles of all the other particles comprises other material compositions.
As mentioned above, as long as in coating, contain this salt, so, for example, even in coating, contain sodium chloride or in coatingparticles, contain glucose, and then even contain or all contain in the two the material composition or the reaction product of solid preparation in one of coatingparticles coating, all it doesn't matter.But, wherein preferably in coating, contain magnesium chloride.
Solid formulation for dialysis of the present invention typically is graininess and/or granuliform pelletize thing.Preferred its mean diameter is about 220-800 μ m, and coating thickness is 10-70 μ m.Wherein, this pelletize thing can be the single particle have coating to form on the coatingparticles surface, also can be the pelletize thing that a plurality of coatingparticles that coating arranged are combined into by coating.In the pelletize thing, the shape of single particle is to be circular a little cube.In addition, the pelletize thing that is bonded by coating is the shape that several particles that cubic of coating is arranged are bonded.
Secondly, solid formulation for dialysis preparation method of the present invention is described.The preparation method of solid formulation for dialysis of the present invention comprises, in containing the powder body and/or granule of material composition more than a kind of this solid preparation, to purify waste water or to contain the aqueous solution of this solid preparation material composition more than a kind, mixed phase for the water of this powder body and/or plastochondria weight 0.1-2 weight % (at this, this mixture contains glucose, calcium chloride and sodium acetate at least), below 50 ℃, more than 1 minute, with the shearing force more than this mixture of every 1kg 0.003kW/kg to this mixture stirring-granulating.Below describe in detail.
At first, " powder body and/or plastochondria " of the present invention described." powder body and/or plastochondria " of the present invention comprises the material composition (be selected from a kind or more the material of raw material sodium chloride, potassium chloride, sodium acetate, calcium chloride, magnesium chloride, glucose and pH regulator agent) of this solid preparation more than a kind.In addition, this powder body and/or plastochondria are drying regime basically, with the occasion situation, also can be in aqueous pH regulator agent infiltration state wherein.
At this, as " powder body and/or plastochondria ", when using sodium chloride, potassium chloride, sodium acetate, glucose, though there is not the particle diameter of each particle of particular determination, the combination that each particle diameter difference is as far as possible little is preferred from keeping the uniformity aspect to consider.In other words, preferred mean diameter is about 200-600 μ m person, preferably the mean diameter difference of each particle all particles mean diameter 30% within combination.In addition, in order to promote the reaction with glucose and sodium acetate, below the preferred 300 μ m of the particle diameter of calcium chloride.
Secondly, " aqueous solution " in " purify waste water or contain the aqueous solution of material composition more than a kind of this solid preparation " of the present invention described.Below so long as do not specify, then claim this aqueous solution to be " this aqueous solution ".Solute for this aqueous solution does not have particular determination, can be the material more than a kind that is selected from solid preparation material compositions such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, pH regulator agent and glucose.In addition, each composition need not whole dissolvings, and a part is that solid state also can.
Preferred version is the aqueous solution that contains glucose and magnesium chloride.Like this, can form firmer coating.At this, the preferred 10-70 weight of the concentration of the glucose in aqueous solution %, more preferably 20-60 weight %, the preferred 10-70 weight of the concentration % of magnesium chloride (hexahydrate), more preferably 25-60 weight %.So, state { pH value of aqueous solution is acid state (for example about 4.5) } in both coexistences, when making the glucose maintenance stable, can dissolve both to exceed a lot of high concentrations than single dissolubility, and, can suitably reduce this viscosity in aqueous solution, adjust to the viscosity that is suitable for pelletize.Therefore, compare, use the aqueous solution of minute quantity, and can evenly coat all at short notice with other comminution granulations.In addition, also can contain the composition except that these in this aqueous solution, for example, can also contain electrolyte such as calcium chloride.Also have,, just can modulate this aqueous solution simply as long as in magnesium chloride brine, dissolve glucose.
Preferred this solution viscosity is 0.001-2Pas, more preferably 0.01-1.5Pas, further preferred 0.015-1Pas.In addition, said viscosity is the value that records according to Brookfield viscometer.
Comprise that " powder body and/or plastochondria " reaches the mixture of " purify waste water or contain the aqueous solution of material composition more than a kind of this solid preparation ", wherein contains glucose, calcium chloride and sodium acetate at least.At this, these compositions be only be contained in powder body and/or the plastochondria, can or only be contained in the aqueous solution or in both, all contain.
If enumerate the preferred compositions example of " powder body and/or plastochondria " and " aqueous solution ", then " powder body and/or plastochondria " for containing sodium chloride, potassium chloride, sodium acetate, glucose, and contain " powder body and/or plastochondria " that calcium chloride is any composition; " aqueous solution " for containing glucose, magnesium chloride, and contain " aqueous solution " that calcium chloride is any composition.
In addition, need not to use whole raw materials of solid preparation in " powder body and/or plastochondria "+" aqueous solution ", wherein a part of raw material can add in the step afterwards.For example, the pH regulator agent can in " powder body and/or plastochondria ", add in advance, also can in granulation process, add, also can be before dry, in the drying, the interpolation of dry back.
Secondly, various conditions in the preparation method are described.At first, the amount of water in " purify waste water or contain the aqueous solution of material composition more than a kind of this solid preparation " of adding in system is preferably the 0.1-2.0 weight % of " powder body and/or the plastochondria " total amount that exists in the system, more preferably 0.2-1.4 weight %.At this, do not comprise the water of crystallization in the raw material in the water yield of in system, adding.
From interpolation purify waste water or this aqueous solution up to time that pelletize is over, the content uniformity of the pelletize thing that consider this reactant salt required time, is generated and dry and comfortableization are (although become the moisture content that contains the 2 weight % that have an appointment, but good fluidity, moisture resistance height, cause and adhere to or pelletize thing that agglutinative Free water does not almost have on the coating surface), preferred more than 1 minute, more preferably more than 3 minutes, further preferred more than 10 minutes.In addition, from the viewpoint that prevents to pulverize, preferred below 30 minutes.
The shearing force that applies during secondly, to stirring describes.At first, the definition to shearing force of the present invention describes.Use under the situation of agitating type mixing granulation device, when stirring-granulating of the present invention,, this mixture between stirring paddle and this device inwall is applied shearing force by the rotation of stirring paddle.The size of this shearing force is with the loading of this device stirring motor (motor current value), calculates according to aforementioned formula, and its value is for being applied to the shearing force on this mixture of every 1kg.Secondly, necessary shearing force be above, the preferred 0.01kW/kg of 0.003kW/kg, more preferably more than the 0.05kW/kg.In addition, about higher limit, rise or broken viewpoint from preventing interior temperature, below the preferred 0.1kW/kg.
In addition, implement to get final product about the temperature room temperature of stirring-granulating, can be to preventing that breakdown of glucose from extremely implementing pelletize under the efficient temperature.In other words, the temperature of the invention process pelletize, from generating the viewpoint of this salt, necessary is that interior temperature is below 50 ℃.Though it is lower limit does not have particular restriction, preferred more than 0 ℃.And, more preferably 10-50 ℃, most preferably 20-40 ℃.
Purify waste water or the method for this aqueous solution in powder body and/or plastochondria, adding, no particular restriction, disposable interpolation also can, separately interpolation also can, also can with spray pattern.In addition, purify waste water or preferred 15-50 ℃ of the temperature of this aqueous solution (before adding).
And, the agitating type mixing granulation device that in the stirring-granulating step, uses, preferred high-speed stirred type prilling granulator.Affected condition can fully achieve the goal in the generic condition scope of pelletize usually.
The step after granulation step or the device of use, operating condition do not have particular restriction, dry gained pelletize thing, and before and after dry, add the agent of mixing pH regulator as required, by granulate, obtain graininess and/or granuliform solid formulation for dialysis of the present invention.
Solid formulation for dialysis of the present invention and sodium bicarbonate are dissolved in the quantitative water, can modulate the bicarbonate dialysis liquid system of following concentration:
Na
+ 125-150mEq/l
K
+ 1.0-3.0mEq/l
Ca
2+ 1.5-3.5mEq/l
Mg
2+ 0.5-1.5mEq/l
Cl
- 90.0-135mEq/l
CH
3CO
2 - 5.0-10.0mEq/l
HCO
3 - 20.0-30.0mEq/l
Glucose 0.5-2.5g/l
The packaging material of the solid formulation for dialysis that so obtains, good and the material of preferred moisture-proof characteristic with backplate effect.Though prior art has and antistatic agent is fused into resin makes thin film, be processed into the example that packaging material with electrostatic-proof function use then, but, since from resin ooze out phenomenon so, very easily occur foreign body is sneaked into the medium improper situation of goods.In contrast to this, because antistatic agent is included in the binding agent that is used for adhering film among the present invention, thus can osmotic membrane, can not ooze out phenomenon.Antistatic agent is in the binding agent of the inboard that is arranged in the face that contacts with solid formulation for dialysis, so constitute a kind of laminate film that all has electrostatic-proof function until the back side that comprises.In other words, preferably adopt moisture permeability (40 ℃, 90%RH) at 2.0g/m
2The film that 24hr is following, silica steam plating film for example, employing is with the static electricity resistance binding agent, (ボ Application デ イ Star プ) (production of Ke Nixi (コ ニ シ) company) of for example " tying up the Depew " bonding and the packing that obtains of laminate film processing with backplate effect, solid formulation for dialysis is loaded, packs.Laminate film with lit-par-lit structure like this, its formation can be exemplified below:
PET/SiO
x/ tie up Depew/PE,
PVA/SiO
x/ tie up Depew/PE,
ONY/SiO
x/ tie up Depew/PE,
PET/SiO
x/ tie up Depew/CPP,
OPP/SiO
x/ tie up Depew/CPP,
These can be processed as packaging material uses.Laminate film can be made at an easy rate with known method.For example, as an example of manufacture method, can enumerate such method: the antistatic adhesive agent of getting necessary amount, with solvent dilution etc., mix making solution even as required, use coating machine coatings on above-mentioned film such as intaglio plate roll coater, reverse coater, use temperature air-dry dry, make it to harden fully.The gained laminate film can be processed into packaging material by heat-sealing.
Embodiment
Embodiments of the invention below are shown, carry out more specific description.
Embodiment 1
In high-speed stirred type prilling granulator (dark river Pa Wudeku (パ ウ テ Star Network) Co., Ltd. produces FS-GS-25J type super mixer), add 5000.0g sodium chloride, 121.6g potassium chloride, 178.5g calcium chloride, 667.4g sodium acetate, 760.2g glucose, mix stirring.Mix on one side with rotating speed 60rpm (shearing force 0.04kW/kg) and to stir, on one side under 25 ℃ of conditions of interior temperature, add modulate in advance, to be dissolved in that 36.4g purifies waste water, liquid temperature with 54.6g glucose and 82.8g magnesium chloride be 30 ℃ aqueous solution (viscosity: 0.035Pas).Be moistening emboliform content after the interpolation and stir, be dry and comfortable graininess through 15 minutes mixing.Take out the pelletize thing, be dried to moisture and reach below the 0.5 weight %.In gained pelletize thing, add 98.3g acetic acid, mix and stir after 5 minutes, take out the pelletize thing and carry out granulate, obtain graininess and acinous preparation.
In high-speed stirred type prilling granulator, add 5000.0g sodium chloride, 122.7g potassium chloride, 181.5g calcium chloride, 202.3g sodium acetate, 767.6g glucose, mix and stir.Mix on one side with revolution 70rpm (shearing force 0.06kW/kg) and to stir, on one side under 25 ℃ of conditions of interior temperature, add modulate in advance, to be dissolved in that 55.2g purifies waste water, liquid temperature with 55.2g glucose and 83.7g magnesium chloride be 30 ℃ aqueous solution (viscosity: 0.043Pas).Be moistening emboliform content after the interpolation and be dry and comfortable graininess through mixing stirring in 10 minutes.This pelletize thing is taken out, and being dried to moisture is below the 0.5 weight %.And then, in gained pelletize thing, add modulate in advance, 98.7g acetic acid is adsorbed in the material of 202.0g sodium acetate, after mixing, granulate, obtains graininess and acinous preparation.
Comparative example 1
Adding 1063.5g sodium chloride, 26.1g potassium chloride, 17.8g magnesium chloride, 86.1g sodium acetate, 175.0g glucose, 20.0g purify waste water in kneader (production of gloomy mountain (モ リ ヤ マ) company), heat while mix to stir.Increase since 55 ℃ of left and right sides viscosity, when 60 ℃ of interior temperature, be sticky shape.After adding 38.6g calcium chloride, former state continues 60 ℃ of stirrings, and the content volume increases and viscosity strengthens.Add 21.0g acetic acid, continue to stir, though mixture can be dry and comfortable gradually, a part forms block, and little powder is also arranged.Take out content, the granulate after drying obtains preparation.
Comparative example 2
26.1g potassium chloride, 17.8g magnesium chloride, 38.6g calcium chloride and 86.1g sodium acetate are dissolved in during 400.0g purifies waste water, make aqueous solution.Adding 1063.6g sodium chloride and 175.0g glucose in rotational flow layer prilling granulator, is under the condition of 0.7m3/ branch at 80 ℃ of the temperature of supplying gas, rotor speed 150rpm, the air quantity of supplying gas, with above-mentioned aqueous solution spraying and dry simultaneously, and acquisition pelletize thing.Behind the granulate, in gained pelletize thing, add 21.0g acetic acid, mix obtaining preparation.
Comparative example 3
1063.6g sodium chloride, 26.1g potassium chloride, 17.8g magnesium chloride, 38.6g calcium chloride and 86.1g sodium acetate, 175.0g glucose powder are broken into about 75 μ m, after the mixing, use the pelletize of compression rotary comminutor.Behind the granulate, in gained pelletize thing, add acetic acid, mix obtaining preparation.
Test case 1
Embodiment 1 gained preparation, its microphotograph (this (キ-エ Application ス) corporate system of its grace) as shown in Figure 6.Thus figure as can be known, embodiment 1 this preparation of gained has form with single particle to exist, and also has with several coatingparticles to exist by the form of coating in conjunction with the aggregation that forms.In addition, the coating of Numeral operation type ultramicroscope (Hitachi's production) same preparation of taking the photograph structure photo as shown in Figure 7.Scheme as can be known thus, the coating of same preparation has the plocoid outward appearance.In addition, the results of elemental analyses of coatingparticles and coating (EDX) is shown in Fig. 8,9.Can confirm that by Fig. 8 sodium chloride exists with the coatingparticles form.In addition, other coatingparticles have been carried out elementary analysis, confirmed that also potassium chloride, sodium acetate and glucose exist with the coatingparticles form.
Also have, as shown in Figure 9, in coating, have magnesium chloride, potassium chloride, glucose etc.
The thin film X-ray diffraction result of embodiment 1,2 each preparation of gained is shown in Figure 10,11.
For the coating structure of clearer and more definite preparation, use thin film X-ray diffraction device (CuK α; λ=1.54058 , angle of incidence θ=1 °), measure according to the thin film X-ray diffraction method.
Method of sample preparation is described.Get about 0.5g sample respectively from each preparation, use the tablet machine compression forming, make the disk shape sample that is of uniform thickness.Film-making pressure is not as the criterion so that the preparation coatingparticles is broken, and sample size is diameter 20mm, thickness 2mm.
By Figure 10,11 as can be known, near 2 θ=21.4 of the reaction product that shows glucose and calcium chloride and sodium acetate ° and 27.7 °, detect the peak.
Test case 3
Take out 1 from comparative example 1 gained preparation, its section is observed with Numeral operation type ultramicroscope, the result as shown in figure 12.Thus figure as can be known, different with embodiment 1, fine particle is heaped-up and exists in said preparation.
Also have,, use the method identical to measure with test case 2 with comparative example 1 and each preparation of comparative example 2 gained, its thin film X-ray diffraction result such as Figure 13-shown in Figure 14.Near 2 θ=21.4 of the reaction product that shows glucose and calcium chloride and sodium acetate ° and 27.7 °, do not detect the peak as can be known.
Test case 4
Randomly draw 6 samplings from embodiment 1 gained preparation, detect sample, 8.5g is water-soluble with sample, accurately reaches 200ml, dilute 50 times, with eastern rope (East ソ one for each) the ion-chromatographic analyzer measuring N a of company's production
+, K
+, Mg
2+, Ca
2+, Cl
-, CH
3COO
-Each electrolyte concentration.In addition, equally that sample 8.5g is water-soluble for glucose, accurately reaching 100ml, with eastern rope (East ソ one) chromatograph of liquid produced of company measures.Measurement result is as shown in table 1.
Table 1
| Na + | K + | Ca 2+ | Mg 2+ | Cl - | CH 3COO - | Glucose | |
| Theoretical value | 115 | 2.0 | 3.0 | 1.0 | 111 | 12 | 1.0 |
| n＝1 | 115.2 | 2.05 | 3.01 | 0.99 | 111.7 | 11.9 | 1.02 |
| n＝2 | 115.0 | 2.01 | 3.05 | 0.98 | 111.1 | 12.0 | 1.00 |
| n＝3 | 115.8 | 2.02 | 3.01 | 0.99 | 110.4 | 12.1 | 0.99 |
| n＝4 | 116.2 | 2.00 | 3.05 | 0.98 | 111.8 | 12.2 | 097 |
| n＝5 | 115.1 | 2.01 | 3.02 | 1.00 | 111.4 | 11.9 | 1.00 |
| n＝6 | 116.4 | 2.00 | 3.06 | 0.98 | 110.9 | 12.0 | 1.01 |
| Meansigma methods | 115.62 | 2.02 | 3.03 | 0.99 | 111.22 | 12.02 | 1.00 |
| Standard deviation | 0.60 | 0.02 | 0.02 | 0.008 | 0.53 | 0.12 | 0.02 |
| Coefficient of variation | 0.52 | 0.93 | 0.74 | 0.83 | 0.47 | 0.79 | 1.73 |
(notes) unit: glucose is that g/L, other compositions are mEq/L
Test case 5
About each constituent concentration of embodiment 2 gained preparations, identical with the method for measuring embodiment 1, its result is as shown in table 2.
Table 2
| Na + | K + | Ca 2+ | Mg 2+ | Cl - | CH 3COO - | Glucose | |
| Theoretical value | 110 | 2.0 | 3.0 | 1.0 | 110 | 8.0 | 1.0 |
| n＝1 | 111.3 | 2.00 | 3.01 | 0.99 | 111.5 | 8.1 | 0.99 |
| n＝2 | 110.1 | 2.01 | 3.06 | 1.00 | 110.3 | 8.1 | 1.00 |
| n＝3 | 110.8 | 2.00 | 3.00 | 0.98 | 110.6 | 8.3 | 1.02 |
| n＝4 | 110.3 | 1.99 | 3.02 | 0.99 | 111.2 | 8.0 | 1.02 |
| n＝5 | 109.9 | 2.02 | 2.99 | 1.00 | 110.1 | 7.8 | 1.03 |
| n＝6 | 111.4 | 2.01 | 3.05 | 0.99 | 110.4 | 7.9 | 1.00 |
| Meansigma methods | 110.63 | 2.01 | 3.02 | 0.99 | 110.68 | 8.03 | 1.01 |
| Standard deviation | 0.63 | 0.01 | 0.03 | 0.008 | 0.55 | 0.18 | 0.02 |
| Coefficient of variation | 0.57 | 0.52 | 0.92 | 0.76 | 0.50 | 2.18 | 1.53 |
(notes) unit: glucose is that g/L, other compositions are mEq/L
Test case 6
The preparation of embodiment 1, embodiment 2, comparative example 1, comparative example 2 is respectively charged in the aluminium packaging material, after sealing, under 40 ℃ of (RH=75%) conditions, implements stability test.Be to measure the breakdown of glucose rate, the ultraviolet-visible absorbance measuring method of the glucose injection purity test of putting down in writing according to the 14th revision Japanese Pharmacopoeia is carried out the measurement of absorbance.Its result is as shown in table 3.
Table 3
| After the preparation soon | After 2 months | After 4 months | After 6 months | |
| Embodiment 1 | 0.01 | 0.06 | 0.13 | 0.21 |
| | 0.01 | 0.04 | 0.10 | 0.14 |
| Comparative example 1 | 0.01 | 0.54 | 1.21 | 2.10 |
| Comparative example 2 | 0.01 | 0.75 | 1.61 | 2.60 |
Test case 7
Take by weighing embodiment 1, embodiment 2 and comparative example 1 preparation 230g each 2 parts, be respectively charged in 130mm * 85mm aluminium packaging material, after sealing, under 40 ℃ of (RH=75%) conditions, evenly apply 30kg in the above and bear a heavy burden, its situation that hardens is observed in passing in time.The test result that hardens is as shown in table 4.Sample is broken a seal after the heavy burden of stipulated time, sieve gently, measure and sieved residual quantity with 16 mesh sieves.Sieved residual quantity 10 weight % with interior usefulness zero, 10-50 weight % with △, the expression of usefulness * respectively more than the 50 weight %.
Table 4
| After the preparation soon | After 72 hours | After 144 hours | |
| Embodiment 1 | ○ | ○ | ○ |
| | ○ | ○ | ○ |
| Comparative example 1 | ○ | △ | × |
Test case 8
In the beaker of 1000ml, inject the water of 400ml (20 ℃),, measure its time when dissolving fully while stir each the preparation 120g that adds embodiment 2 and comparative example 1-3.Measurement result is as shown in table 5.
Table 5
| | Comparative example 1 | Comparative example 2 | Comparative example 3 | |
| Dissolution time (second) | 100 | 110 | 140 | 300 |
Test case 9
Take by weighing embodiment 1, embodiment 2, comparative example 1 and comparative example 2 each 20g of gained preparation respectively, add the 20ml chloroform, slightly rock mixing after, extract supernatant.In addition, take by weighing each preparation 20g vibration 5 minutes equally, add the 20ml chloroform, slightly rock mixing after, extract supernatant.
According to the situation that adopts the Kaolin titer among the JISK 0101 " water for industrial use method of testing ", carry out the turbidity test of each sample.Will be owing to the fine-powder amount difference that vibration produces is estimated as the difference of turbidity before and after the vibration.Its result is as shown in table 6, can reach a conclusion: gained preparation of the present invention is compared with comparative example, and the fine-powder amount is few, even be subjected to vibration to wait physical action, also is difficult to be affected.
Table 6
So this class is formed with each composition in the preparation of the coating agent coating that is in the plocoid attitude, shown in table 1,2, is the preparation of extremely forming near theoretical value, each composition of solid formulation for dialysis of the present invention has good content uniformity.In addition, as shown in table 3, the stability test result is also very outstanding, as shown in table 4, and the result of the test of hardening is also very good, but is a kind of preparation of long term storage.Also have, as shown in table 5, dissolution velocity is fast, and, as shown in table 6, because powder attitude thing is few, thereby become a kind of reagent that very easily uses.
The invention effect
Solid pharmaceutical preparation of the present invention can reach following effect: for a kind of coating by firm plocoid coats the granules that coatingparticles gets, with other method of use, such as use with the electrolyte such as sodium chloride, potassium chloride, D/W spray form by the preparations such as spraying granulation method of overlay film by overlay film or compared by overlay film as shown in Figure 3, because its surface compact, thereby be not subject to external factor impact, superior performance aspect extended storage stability, and, because also good aspect flowability or wearability, anti-compaction, be difficult for dirt and dissolution velocity is fast, thus extremely good compared with prior art at the on-the-spot dissolving operation task of medical treatment.
Also have, according to solid pharmaceutical preparation preparation method of the present invention, compared with prior art, owing to need not to carry out long-time heating, so can avoid in the granulation process that glucose decomposes, painted danger, simultaneously, the loaded down with trivial details operating process such as saved pulverizing, sieve can make the solid pharmaceutical preparation of content excellent uniformity. Particularly, the method according to this invention can be with moistening particle shape mixture, is the dry and comfortable graininess of outward appearance and/or acinous granules at about normal temperature state inner drying of lower short time, easily finishes granulation. Thereby, make the operations such as follow-up transmission, drying, mixing become very easy.
Claims (10)
1. solid formulation for dialysis, comprise electrolyte composition, pH regulator agent and glucose, electrolyte composition comprises sodium chloride, potassium chloride, calcium chloride, magnesium chloride and sodium acetate, it is characterized in that, coatingparticles is coated by coating, and coating contains in the thin film X-ray diffraction at 2 θ=21.3-21.5 ° and 2 θ=27.6-27.8 ° of (CuK α; λ=1.54058 , angle of incidence θ=1 °) locates to have the salt at specific peak.
2. according to the solid formulation for dialysis of claim 1, it is characterized in that, be graininess and/or acinous.
3. according to the solid formulation for dialysis of claim 1 or 2, it is characterized in that described salt is the reaction product of glucose and calcium chloride and sodium acetate.
4. according to the solid formulation for dialysis of one of claim 1-3, it is characterized in that described coating is a plocoid.
5. hydrocarbonate dialysis solid preparation comprises the solid formulation for dialysis of one of claim 1-4 and contains the solid preparation of sodium bicarbonate.
6. according to the solid formulation for dialysis of one of claim 1-5, it is characterized in that, be concealed in moisture permeability (40 ℃, 90%RH) and be 2.0g/m
2Below 24 hours, have a water vapor proof barrier packaging material of the lit-par-lit structure of backplate effect.
7. preparation method for preparing solid formulation for dialysis, to comprise sodium chloride, potassium chloride, calcium chloride, the electrolyte composition of magnesium chloride and sodium acetate, pH regulator agent and glucose are raw material, it is characterized in that, contain the following step: in the powder body and/or plastochondria that contain this solid preparation material composition more than a kind, to purify waste water or to contain the aqueous solution of material composition more than a kind of this solid preparation, mixed phase for the water of this powder body and/or plastochondria weight 0.1-2 weight % (at this, this mixture contains glucose at least, calcium chloride and sodium acetate), below 50 ℃, more than 1 minute, with the shearing force more than this mixture of every 1kg 0.003kW/kg to this mixture stirring-granulating.
8. according to the preparation method of claim 7, it is characterized in that this viscosity in aqueous solution is 0.001-2Pas.
9. according to the preparation method of claim 7 or 8, it is characterized in that this aqueous solution is the aqueous solution that contains glucose and magnesium chloride.
10. according to the preparation method of one of claim 7-9, it is characterized in that solid formulation for dialysis is the solid formulation for dialysis of one of claim 1-6.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP023261/2003 | 2003-01-31 | ||
| JP2003023261 | 2003-01-31 | ||
| JPPCT/JP03/07356 | 2003-06-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1744884A true CN1744884A (en) | 2006-03-08 |
| CN100387222C CN100387222C (en) | 2008-05-14 |
Family
ID=32820718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800031381A Expired - Lifetime CN100387222C (en) | 2003-01-31 | 2004-01-30 | Solid preparation for dialysis and process 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) |
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| CN103720708A (en) * | 2012-10-10 | 2014-04-16 | 富田制药株式会社 | Dialysis agent a containing acetic acid and acetate salt, and a two-part dialysis agent using thereof |
| CN104586884A (en) * | 2015-01-09 | 2015-05-06 | 李淑秀 | Novel hemodialysis concentrate |
| 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 |
| CN109350626A (en) * | 2017-11-27 | 2019-02-19 | 北京市四维医药科技研究所 | Stable composite electrolyte solid pharmaceutical preparation |
| CN109843845A (en) * | 2016-10-28 | 2019-06-04 | 富田制药株式会社 | Advanced acetate compounds and solid-like dialysis agent using it |
| 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023148315A1 (en) * | 2022-02-03 | 2023-08-10 | Basf Se | Potassium-sodium tartrate as granulating aid |
Family Cites Families (12)
| 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 |
| JP2769592B2 (en) * | 1992-12-14 | 1998-06-25 | 富田製薬株式会社 | Method for producing artificial kidney perfusion agent for bicarbonate dialysis and artificial kidney perfusion agent |
| 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 |
| JP2987488B2 (en) * | 1995-08-02 | 1999-12-06 | 富田製薬株式会社 | Solid dialysis agent and method for producing the same |
| JP3032660U (en) * | 1996-06-20 | 1996-12-24 | 株式会社ダイワパックス | Packaging bag |
| 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
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| 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 |
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| CN103720708A (en) * | 2012-10-10 | 2014-04-16 | 富田制药株式会社 | 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 |
| CN104586884A (en) * | 2015-01-09 | 2015-05-06 | 李淑秀 | Novel hemodialysis concentrate |
| CN109843845A (en) * | 2016-10-28 | 2019-06-04 | 富田制药株式会社 | Advanced acetate compounds and solid-like dialysis agent using it |
| 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 |
| 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 |
| CN109350626A (en) * | 2017-11-27 | 2019-02-19 | 北京市四维医药科技研究所 | Stable composite electrolyte solid pharmaceutical preparation |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1089089A1 (en) | 2006-11-24 |
| JP4603977B2 (en) | 2010-12-22 |
| WO2004067014A1 (en) | 2004-08-12 |
| CN100387222C (en) | 2008-05-14 |
| JPWO2004066977A1 (en) | 2006-05-18 |
| TW200413029A (en) | 2004-08-01 |
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