CN116196330A - Preparation process of medicine for treating hyperphosphatemia - Google Patents
Preparation process of medicine for treating hyperphosphatemia Download PDFInfo
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- CN116196330A CN116196330A CN202310256281.6A CN202310256281A CN116196330A CN 116196330 A CN116196330 A CN 116196330A CN 202310256281 A CN202310256281 A CN 202310256281A CN 116196330 A CN116196330 A CN 116196330A
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- medicine
- treating hyperphosphatemia
- drying
- sodium carbonate
- preparing
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- 239000003814 drug Substances 0.000 title claims abstract description 61
- 201000005991 hyperphosphatemia Diseases 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 96
- 229910052742 iron Inorganic materials 0.000 claims abstract description 48
- 239000000463 material Substances 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000002775 capsule Substances 0.000 claims abstract description 30
- 238000002156 mixing Methods 0.000 claims abstract description 27
- 238000001035 drying Methods 0.000 claims abstract description 24
- 238000011049 filling Methods 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 35
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 claims description 29
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 21
- 229930006000 Sucrose Natural products 0.000 claims description 21
- 239000005720 sucrose Substances 0.000 claims description 21
- 238000007873 sieving Methods 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 19
- 238000005303 weighing Methods 0.000 claims description 17
- 239000011812 mixed powder Substances 0.000 claims description 16
- 239000000725 suspension Substances 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 229920000881 Modified starch Polymers 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 229920001592 potato starch Polymers 0.000 claims description 9
- 239000008119 colloidal silica Substances 0.000 claims description 7
- 238000003825 pressing Methods 0.000 claims description 6
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 210000004051 gastric juice Anatomy 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 230000002572 peristaltic effect Effects 0.000 claims description 5
- 238000007789 sealing Methods 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 16
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 abstract description 10
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 abstract description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 8
- 238000000227 grinding Methods 0.000 abstract description 7
- 230000001965 increasing effect Effects 0.000 abstract description 5
- 210000005239 tubule Anatomy 0.000 abstract description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000002552 dosage form Substances 0.000 abstract description 2
- 238000010981 drying operation Methods 0.000 abstract description 2
- 206010067484 Adverse reaction Diseases 0.000 abstract 1
- 230000006838 adverse reaction Effects 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 19
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 17
- 239000011574 phosphorus Substances 0.000 description 17
- 229910052698 phosphorus Inorganic materials 0.000 description 17
- 229910019142 PO4 Inorganic materials 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 239000010452 phosphate Substances 0.000 description 9
- 239000002245 particle Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 239000007910 chewable tablet Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 3
- 229960004887 ferric hydroxide Drugs 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 3
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 208000020084 Bone disease Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229940068682 chewable tablet Drugs 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- 206010053260 Secondary hyperthyroidism Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000002694 phosphate binding agent Substances 0.000 description 1
- -1 polysaccharide iron compound Chemical class 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000002037 soft tissue calcification Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation process of a medicine for treating hyperphosphatemia, which belongs to the technical field of medicine preparation and comprises the steps of S1 synthesis, S2 drying, mixing of S3 raw material medicines and auxiliary materials, and S4 capsule filling. According to the invention, by improving the preparation process of the original grinding medicine, a similar micro-reaction channel process is arranged in the synthesis step, and the consistency of the reaction microenvironment of the raw materials is ensured by utilizing the Y tubule so as to keep the consistency of the products, thereby improving the activity of the products; then different conventional fluidized bed drying operations are arranged, so that the surface area of the combined phosphoric acid is increased, and the activity of the combined phosphoric acid is further improved; meanwhile, the dosage form is changed into a quick-release capsule, so that the problem of medication compliance and adverse reaction are reduced, the iron release is reduced, the phosphate binding efficiency is improved, the drug activity is improved, and the curative effect of the drug is greatly improved.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation process of a medicine for treating hyperphosphatemia.
Background
Phosphorus is a basic substance of human body, participates in constituting fat, protein and cell membrane, is a basic component constituting energy phosphate complex, and accounts for about 1% of the weight of human body, and is contained in about 600-900 g in adult human body, wherein 85.7% is concentrated in bones and teeth. Hyperphosphatemia refers to serum phosphorus levels in excess of 4.5mg/dl, with increased blood phosphorus being intimately involved in the progression of renal disease, secondary hyperthyroidism, renal bone disease, and soft tissue calcification. Hyperphosphatemia is a common complication of chronic renal failure, and has been improved in the treatment of hyperphosphatemia in uremic hemodialysis patients in recent decades, but control of blood phosphorus is still an important problem to be solved by dialysis patients, because hemodialysis has extremely limited phosphorus clearance, eating limitation can cause malnutrition and inconvenient life, while long-term hyperphosphatemia can cause secondary hyperparathyroidism, renal bone diseases, vitamin D metabolic disorders, cardiovascular and cerebrovascular diseases and the like, seriously reduce the life quality of patients, and is a main cause of increased mortality. Therefore, the control of blood phosphorus is a key to reducing cardiovascular complications, improving the quality of life of renal dialysis patients, and reducing disability rate and mortality.
In order to control the blood phosphorus level in patients with renal failure, in 2013, the us FDA approved a sucrose ferric hydroxide chewable tablet developed by Vifor Fresenius Medical Care Renal Pharma France company, which is chewed and taken while eating, and by adsorbing phosphate bound to dietary sources in the gastrointestinal tract, thereby preventing the gastrointestinal tract from absorbing phosphate, and the phosphate bound to ferric hydroxide is removed along with defecation, thereby achieving the effect of controlling blood phosphorus; adding ferric trichloride solution into sodium carbonate solution, washing the reacted hydrogel with deionized water to remove salt, then adding sucrose, potato starch and pregelatinized starch into the hydrogel, uniformly stirring to obtain suspension, then spray-drying to obtain raw material medicine powder, mixing sweetener lubricant and the like with the raw material medicine powder, and directly tabletting the mixed powder to obtain the final product. Chinese patent document CN109223824A discloses a preparation method of a medicament for treating hyperphosphatemia of a dialysis patient with chronic kidney disease, which comprises the steps of reacting ferric oxide with hydrochloric acid to generate ferric trichloride solution, reacting with sodium carbonate solution, adding sucrose and starch, stirring to prepare sucrose oxyhydroxide molten iron solution, taking the solution for freeze drying to obtain loose sucrose oxyhydroxide powder, then mixing with other components, and pressing into chewable tablets by adopting a powder direct tabletting method; chinese patent document CN109331036A discloses the application of polysaccharide iron in preparing medicine for treating hyperphosphatemia, which is to add sodium carbonate solution after ferric chloride and syrup are mixed for reaction, add volume precipitant, centrifuge, wash and dry to obtain polysaccharide iron compound; chinese patent document CN105764492a discloses a pharmaceutical composition comprising phosphate binder particles, and iron sucrose oxyhydroxide is prepared by fluidized bed drying, spray drying, wet granulation, dry granulation, etc., but the reaction with phosphate in food does not reach the optimal state, and the phosphate binding ability is not strong. In sum, the prior art often has the problems of low phosphate binding rate, low activity, troublesome administration, poor taste, poor patient compliance, large side effect, complex preparation process, poor production operability and the like.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation process of a medicament for treating hyperphosphatemia, which can reduce iron release, improve the activity of the medicament and the phosphate binding efficiency by improving the synthesis and the preparation process of the original grinding medicament, thereby greatly enhancing the curative effect of the medicament, improving the administration applicability of patients and reducing the side effect of iron release.
In order to achieve the above purpose, the invention provides a preparation process of a medicament for treating hyperphosphatemia, which comprises the following steps:
s1, synthesizing: respectively weighing ferric trichloride hexahydrate and anhydrous sodium carbonate, adding water, stirring until the ferric trichloride hexahydrate and the anhydrous sodium carbonate are completely dissolved, mixing, adding the mixture into a reaction kettle, continuously stirring, controlling the pH value, centrifuging the materials after the reaction is completed, discarding a water layer, adding water into a solid layer for washing, transferring the solid layer into a cup, adding water, rapidly stirring uniformly, sieving, measuring the iron content, adding sucrose under stirring, and rapidly stirring uniformly to obtain a suspension;
s2, drying: weighing pregelatinized starch and potato starch, adding into a fluidized bed as a base material, taking the suspension obtained in the step S1 as a feed, drying the materials, taking out the materials after the drying is finished, sieving to obtain a raw material medicine, weighing, and measuring the iron content;
s3, mixing the bulk drugs with auxiliary materials: adding auxiliary materials of colloidal silicon dioxide and magnesium stearate into the crude drug obtained in the step S2, uniformly mixing, and sieving to obtain mixed powder;
s4, filling capsules: and (3) selecting a gastric juice instant hollow capsule with proper specification, filling the hollow capsule with the mixed powder obtained in the step (S3), and filling, pressing and sealing to obtain the medicament for treating the hyperphosphatemia.
Further, the mass ratio of the ferric trichloride hexahydrate to the anhydrous sodium carbonate in the step S1 is (470-480): 500.
further, in the step S1, a peristaltic pump is used for pumping the ferric trichloride hexahydrate solution and the anhydrous sodium carbonate solution into a Y-shaped pipe, and the two solutions are mixed and reacted in a pipeline after passing through the Y-shaped pipe.
Further, the pH is controlled in the step S1 by controlling the pH between 7 and 10 through the concentration ratio of ferric trichloride hexahydrate solution and anhydrous sodium carbonate solution.
Further, the solid layer washing mode in the step S1 is to add water to wash the solid layer, stir the solid layer in water, centrifuge the solid layer again, and repeat the process 3 times.
Further, the mass ratio of the iron content to sucrose in the step S1 is 500:750.
further, in the step S2, the air inlet temperature is set to be 80-100 ℃, the air inlet is started, the air inlet quantity is regulated to enable the bottom materials to be just blown up, the small-speed feeding is started after the bottom materials reach more than 60 ℃, and the drying parameters are regulated to enable the system to dry stably.
Further, the mass ratio of the colloidal silica, magnesium stearate added in the step S3 to the iron content measured in the step S2 is 12.5:25:500.
further, the order of adding the auxiliary materials in the step S3 is that the colloidal silica auxiliary materials are firstly added, mixed for 10-20 minutes in a three-dimensional mixer at 40 revolutions per minute, sieved for several times, crushed into particles, and then added with magnesium stearate to be mixed for 5-15 minutes.
Further, the filling amount of the filled capsules in the step S4 is controlled to contain 500mg of iron per capsule according to the iron content of the mixed powder.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the invention, a similar micro-reaction channel process is arranged in the combining process, the ferric trichloride hexahydrate solution and the anhydrous sodium carbonate solution with the same volume are prepared, and the two liquids are combined through the Y tubule and then enter the reaction kettle, so that the consistency of the reaction microenvironment of the raw materials can be ensured by combining the two liquids through the Y tubule and then entering the reaction kettle, and the consistency of the products can be further maintained, thereby improving the activity of the products and the phosphate bonding capability.
2. According to the invention, different conventional fluidized bed drying operations are arranged, the bed charge starch is firstly placed in the fluidized bed, then the sucrose and iron suspension is sprayed, the obtained particles are in the form of sucrose iron coated starch, the particle size is large, and the starch disintegrates in the center of the particles, so that the surface area of the bonded phosphoric acid is improved, the pharmaceutical activity is improved, and the phosphate bonding capability is enhanced.
3. Compared with tablets, the quick-release capsule is filled with raw material medicine powder, and compared with the original chewable tablets, the characteristics of the capsule improve the medication compliance of patients with poor teeth.
Detailed Description
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1 preparation Process of the medicament for treating hyperphosphatemia of the invention
S1, synthesizing: weighing 470g of ferric trichloride hexahydrate into a plastic cup, adding 2 liters of water, and stirring until the ferric trichloride hexahydrate is completely dissolved to obtain a ferric trichloride hexahydrate solution; adding 500g of anhydrous sodium carbonate into the other cup, adding 2 liters of water, and stirring until the anhydrous sodium carbonate is completely dissolved to obtain an anhydrous sodium carbonate solution; pumping the two solutions into a Y-shaped pipe by a peristaltic pump, mixing the two solutions in a pipeline for reaction after passing through the Y-shaped pipe, allowing the reaction solution to enter a glass reaction kettle after passing through a section of pipeline, continuously stirring, and regulating and controlling the pH value to 7 by the concentration ratio of ferric trichloride hexahydrate solution and anhydrous sodium carbonate solution; stirring for 30 min to finish the reaction, transferring the materials to a centrifuge, centrifuging at 1200rpm for 20 min, discarding a water layer, washing a solid layer with water, stirring in water, centrifuging again, and repeating for 3 times; transferring the solid layer after washing into a cup, adding 2L of water to quickly and uniformly stirring, sieving, and sampling to measure the iron content; then the mass ratio of the iron content to the sucrose is 500:750, sequentially adding sucrose under stirring, and rapidly stirring to obtain uniform suspension;
s2, drying: the mass ratio of the iron content to the potato starch and the pregelatinized starch measured in the step S1 is 500:375:375, weighing pregelatinized starch and potato starch, and adding into a fluidized bed as a base material; uniformly stirring the suspension obtained in the step S1, feeding, setting the air inlet temperature to be 80-100 ℃, starting the air inlet, adjusting the air inlet quantity to enable the bottom material to be just blown up, starting the small-speed feeding after the bottom material temperature reaches above 60 ℃, adjusting the drying parameters to enable the system to be stably dried, taking out the materials after the drying is finished, sieving the materials with a 20-mesh sieve to obtain a raw material medicine, weighing, and measuring the iron content;
s3, mixing the bulk drugs with auxiliary materials: the mass ratio of the iron content to the colloidal silica and magnesium stearate measured in the step S2 is 500:12.5:25, adding colloidal silicon dioxide and magnesium stearate 2 auxiliary materials, mixing for 20 minutes in a three-dimensional mixer at 40 revolutions per minute, sieving, grinding particles, adding magnesium stearate, mixing for 15 minutes, uniformly mixing, and sieving to obtain mixed powder which can be used for filling capsules;
s4, filling capsules: selecting gastric juice instant hollow capsules with proper specification, adding the mixed powder obtained in the step S3 to fill the hollow capsules, controlling the filling amount to contain 500mg of iron in each capsule according to the iron content of the mixed powder, and filling, pressing and sealing to obtain the medicine for treating hyperphosphatemia.
Example 2 preparation Process of the medicament for treating hyperphosphatemia of the invention
S1, synthesizing: weighing 470g of ferric trichloride hexahydrate into a plastic cup, adding 2 liters of water, and stirring until the ferric trichloride hexahydrate is completely dissolved to obtain a ferric trichloride hexahydrate solution; adding 500g of anhydrous sodium carbonate into the other cup, adding 2 liters of water, and stirring until the anhydrous sodium carbonate is completely dissolved to obtain an anhydrous sodium carbonate solution; pumping the two solutions into a Y-shaped pipe by a peristaltic pump, mixing the two solutions in a pipeline for reaction after passing through the Y-shaped pipe, allowing the reaction solution to enter a glass reaction kettle after passing through a section of pipeline, continuously stirring, and regulating and controlling the pH to 7.5 by the concentration ratio of ferric trichloride hexahydrate solution and anhydrous sodium carbonate solution; stirring for 30 min to finish the reaction, transferring the materials to a centrifuge, centrifuging at 1200rpm for 20 min, discarding a water layer, washing a solid layer with water, stirring in water, centrifuging again, and repeating for 3 times; transferring the solid layer after washing into a cup, adding 2L of water to quickly and uniformly stirring, sieving, and sampling to measure the iron content; then the mass ratio of the iron content to the sucrose is 500:750, sequentially adding sucrose under stirring, and rapidly stirring to obtain uniform suspension;
s2, drying: the mass ratio of the iron content to the potato starch and the pregelatinized starch measured in the step S1 is 500:375:375, weighing pregelatinized starch and potato starch, and adding into a fluidized bed as a base material; uniformly stirring the suspension obtained in the step S1, feeding, setting the air inlet temperature to be 80-100 ℃, starting the air inlet, adjusting the air inlet quantity to enable the bottom material to be just blown up, starting the small-speed feeding after the bottom material temperature reaches above 60 ℃, adjusting the drying parameters to enable the system to be stably dried, taking out the materials after the drying is finished, sieving the materials with a 20-mesh sieve to obtain a raw material medicine, weighing, and measuring the iron content;
s3, mixing the bulk drugs with auxiliary materials: the mass ratio of the iron content to the colloidal silica and magnesium stearate measured in the step S2 is 500:12.5:25, firstly adding colloidal silicon dioxide, mixing for 10 minutes at 40 revolutions per minute in a three-dimensional mixer, sieving, grinding particles, adding magnesium stearate, mixing for 15 minutes, uniformly mixing, and sieving to obtain mixed powder which can be used for filling capsules;
s4, filling capsules: selecting gastric juice instant hollow capsules with proper specification, adding the mixed powder obtained in the step S3 to fill the hollow capsules, controlling the filling amount to contain 500mg of iron in each capsule according to the iron content of the mixed powder, and filling, pressing and sealing to obtain the medicine for treating hyperphosphatemia.
Example 3 preparation Process of the medicament for treating hyperphosphatemia of the invention
S1, synthesizing: weighing 470g of ferric trichloride hexahydrate into a plastic cup, adding 2 liters of water, and stirring until the ferric trichloride hexahydrate is completely dissolved to obtain a ferric trichloride hexahydrate solution; adding 500g of anhydrous sodium carbonate into the other cup, adding 2 liters of water, and stirring until the anhydrous sodium carbonate is completely dissolved to obtain an anhydrous sodium carbonate solution; pumping the two solutions into a Y-shaped pipe by a peristaltic pump, mixing the two solutions in a pipeline for reaction after passing through the Y-shaped pipe, allowing the reaction solution to enter a glass reaction kettle after passing through a section of pipeline, continuously stirring, and regulating and controlling the pH value to be 8 by the concentration ratio of ferric trichloride hexahydrate solution and anhydrous sodium carbonate solution; stirring for 30 min to finish the reaction, transferring the materials to a centrifuge, centrifuging at 1200rpm for 20 min, discarding a water layer, washing a solid layer with water, stirring in water, centrifuging again, and repeating for 3 times; transferring the solid layer after washing into a cup, adding 2L of water to quickly and uniformly stirring, sieving, and sampling to measure the iron content; then the mass ratio of the iron content to the sucrose is 500:750, sequentially adding sucrose under stirring, and rapidly stirring to obtain uniform suspension;
s2, drying: the mass ratio of the iron content to the potato starch and the pregelatinized starch measured in the step S1 is 500:375:375, weighing pregelatinized starch and potato starch, and adding into a fluidized bed as a base material; uniformly stirring the suspension obtained in the step S1, feeding, setting the air inlet temperature to be 80-100 ℃, starting the air inlet, adjusting the air inlet quantity to enable the bottom material to be just blown up, starting the small-speed feeding after the bottom material temperature reaches above 60 ℃, adjusting the drying parameters to enable the system to be stably dried, taking out the materials after the drying is finished, sieving the materials with a 20-mesh sieve to obtain a raw material medicine, weighing, and measuring the iron content;
s3, mixing the bulk drugs with auxiliary materials: the mass ratio of the iron content to the colloidal silica and magnesium stearate measured in the step S2 is 500:12.5:25, firstly adding colloidal silicon dioxide, mixing for 10 minutes at 40 revolutions per minute in a three-dimensional mixer, sieving, grinding particles, adding magnesium stearate, mixing for 15 minutes, uniformly mixing, and sieving to obtain mixed powder which can be used for filling capsules;
s4, filling capsules: selecting gastric juice instant hollow capsules with proper specification, adding the mixed powder obtained in the step S3 to fill the hollow capsules, controlling the filling amount to contain 500mg of iron in each capsule according to the iron content of the mixed powder, and filling, pressing and sealing to obtain the medicine for treating hyperphosphatemia.
Comparative example 1
Sucrose ferric hydroxide chewable tablet manufactured by Vifor Fresenius Medical Care Renal Pharma France company.
Comparative example 2
This comparative example differs from example 1 in that step S1 is different, and the remaining steps and parameters and the like are the same as example 1. Step S1 of this comparative example is: weighing 470g of ferric trichloride hexahydrate into a plastic cup, adding 2 liters of water, and stirring until the ferric trichloride hexahydrate is completely dissolved to obtain a ferric trichloride hexahydrate solution; adding 500g of anhydrous sodium carbonate into the other cup, adding 2 liters of water, and stirring until the anhydrous sodium carbonate is completely dissolved to obtain an anhydrous sodium carbonate solution; the ferric trichloride hexahydrate solution is directly dripped into the anhydrous sodium carbonate solution for reaction, the reaction solution enters a glass reaction kettle after passing through a section of pipeline, stirring is continued, and the pH value is regulated and controlled to be 7 by the concentration ratio of the ferric trichloride hexahydrate solution and the anhydrous sodium carbonate solution; stirring for 30 min to finish the reaction, transferring the materials to a centrifuge, centrifuging at 1200rpm for 20 min, discarding a water layer, washing a solid layer with water, stirring in water, centrifuging again, and repeating for 3 times; transferring the solid layer after washing into a cup, adding 2L of water to quickly and uniformly stirring, sieving, and sampling to measure the iron content; then the mass ratio of the iron content to the sucrose is 500:750, adding sucrose in sequence under stirring, and rapidly stirring to form uniform suspension.
Comparative example 3
This comparative example differs from example 1 in that step S2 is different, and the remaining steps and parameters and the like are the same as example 1. Step S2 of this comparative example is: atomizing the suspension obtained in the step S1 in a spray drying mode at a frequency of 25Hz, drying at a hot air temperature of 150 ℃ and an exhaust air temperature of 100 ℃ under a cyclone pressure difference of 0.7kPa, wherein the feeding speed ensures that the material does not occupy the inner wall much (glass sight hole has no liquid drops); and collecting the powder of the crude drug after the drying is finished, weighing, and measuring the iron content.
Comparative example 4
This comparative example differs from example 1 in that step S4 is different, and the remaining steps and parameters and the like are the same as example 1. Step S4 of this comparative example is: after the tablet press is installed, the filling depth is firstly adjusted to ensure that each tablet weight contains 500mg of iron, then the main compression (without pre-compression) of the tablet is adjusted to ensure that the hardness of the tablet is about 50-120N, the tablet is continuously compressed after the parameters of the tablet are stable, and the powder mixing is completed, thus obtaining the medicine for treating hyperphosphatemia.
Test examples, activity detection of drugs, and iron Release detection test
1. Test sample: the medicines prepared in examples 1-3 and comparative examples 1-4 were used as test pieces,
2. the test method comprises the following steps: adding 500mg of a test sample with iron content into a phosphorus binding medium simulating acidic pH1.2 and alkaline pH7.5 of a gastrointestinal tract, fully reacting for 4 hours by a paddle method, and measuring the residual phosphorus content in a reaction liquid before and after the reaction by a molybdenum blue method, wherein the phosphorus binding rate = 100% of phosphate concentration after the reaction/phosphate concentration before the reaction;
3. test results: see table 1 below;
TABLE 1 phosphorus binding Rate
| Phosphorus binding Rate | pH1.2 | pH7.5 |
| Example 1 | 75.7％ | 27.9％ |
| Example 2 | 74.1％ | 26.9％ |
| Example 3 | 74.8％ | 27.2％ |
| Comparative example 1 | 58.3％ | 22.2％ |
| Comparative example 2 | 62.9％ | 23.2％ |
| Comparative example 3 | 63.2％ | 23.6％ |
| Comparative example 4 | 69.6％ | 24.8％ |
As can be seen from Table 1, the phosphorus binding rate of the medicines prepared in examples 1-3 of the invention is greater than 73% at pH1.2 and is greater than 26% at pH7.5, which is obviously higher than that of the original grinding medicine of comparative example 1, showing that the medicine of the invention has obviously improved phosphate binding capacity and blood phosphorus control capacity compared with the original grinding medicine; the phosphorus binding rate of example 1 is the best, and is the best example of the invention;
in comparative example 2, the mixing mode of ferric trichloride hexahydrate solution and anhydrous sodium carbonate solution is changed, and two liquids are not combined through a plurality of Y-shaped tubules and then enter a reaction kettle, so that the phosphate binding capacity is reduced, and the activity of a product is greatly influenced by pH, and the Y-shaped tubules can ensure that the reaction microenvironment of the raw materials is consistent, so that the product is consistent, the activity of the product is ensured, and the phosphate binding capacity is improved;
comparative example 3 the phosphate binding capacity was reduced by changing the drying procedure and using spray drying, since different conventional fluidized bed drying was used, the first starch of the base material was set and then sucrose and iron suspension were sprayed in, so that the disintegration of the starch in the center of the granule helped to increase the surface area of the bound phosphoric acid, and the activity of the product was increased, thus increasing the phosphate binding capacity;
comparative example 4 since the dosage form of the drug was changed and the tablet was used, there was no feature that the immediate release capsule was able to reduce iron release and improve binding efficiency, so that the phosphorus binding rate was slightly decreased compared with example 1 and the phosphate binding ability was decreased.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The preparation process of the medicine for treating hyperphosphatemia is characterized by comprising the following steps:
s1, synthesizing: respectively weighing ferric trichloride hexahydrate and anhydrous sodium carbonate, adding water, stirring until the ferric trichloride hexahydrate and the anhydrous sodium carbonate are completely dissolved, mixing, adding the mixture into a reaction kettle, continuously stirring, controlling the pH value, centrifuging the materials after the reaction is completed, discarding a water layer, adding water into a solid layer for washing, transferring the solid layer into a cup, adding water, rapidly stirring uniformly, sieving, measuring the iron content, adding sucrose under stirring, and rapidly stirring uniformly to obtain a suspension;
s2, drying: weighing pregelatinized starch and potato starch, adding into a fluidized bed as a base material, taking the suspension obtained in the step S1 as a feed, drying the materials, taking out the materials after the drying is finished, sieving to obtain a raw material medicine, weighing, and measuring the iron content;
s3, mixing the bulk drugs with auxiliary materials: adding auxiliary materials of colloidal silicon dioxide and magnesium stearate into the crude drug obtained in the step S2, uniformly mixing, and sieving to obtain mixed powder;
s4, filling capsules: and (3) selecting a gastric juice instant hollow capsule with proper specification, filling the hollow capsule with the mixed powder obtained in the step (S3), and filling, pressing and sealing to obtain the medicament for treating the hyperphosphatemia.
2. The preparation process of the medicine for treating hyperphosphatemia according to claim 1, wherein the mass ratio of ferric trichloride hexahydrate to anhydrous sodium carbonate in the step S1 is (470-480): 500.
3. the process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the mixing in the step S1 is to pump a ferric trichloride hexahydrate solution and an anhydrous sodium carbonate solution into a Y-shaped tube by a peristaltic pump, and then to mix the two solutions in a pipeline for reaction after passing through the Y-shaped tube.
4. The process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the pH is controlled to be 7-10 by controlling the pH by the ratio of the concentration of ferric trichloride hexahydrate solution and that of anhydrous sodium carbonate solution in step S1.
5. The process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the solid layer washing step S1 is performed by adding water to the solid layer, stirring the solid layer in water, centrifuging the mixture, and repeating the process 3 times.
6. The process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the mass ratio of iron content to sucrose in the step S1 is 500:750.
7. the process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the drying in the step S2 is to set the air inlet temperature to 80-100 ℃, start the air inlet, adjust the air inlet volume to make the bed charge just blow up, start the small-speed feeding after the bed charge temperature reaches above 60 ℃, and adjust the drying parameters to make the system dry stably.
8. The process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the mass ratio of the colloidal silica added in the step S3 to the magnesium stearate to the iron content measured in the step S2 is 12.5:25:500.
9. the process for preparing the medicine for treating hyperphosphatemia according to claim 1, wherein the order of adding the auxiliary materials in the step S3 is to add colloidal silica auxiliary materials first, mix for 10-20 minutes at 40 rpm in a three-dimensional mixer, screen and crush the granules, and add magnesium stearate and mix for 5-15 minutes.
10. The process for preparing a medicament for treating hyperphosphatemia according to claim 1, wherein the filling amount of the filled capsules in step S4 is controlled to contain 500mg of iron per capsule according to the iron content of the mixed powder.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4970079A (en) * | 1989-06-05 | 1990-11-13 | Purdue Research Foundation | Method and composition of oxy-iron compounds for treatment of hyperphosphatemia |
| CN101563295A (en) * | 2006-12-14 | 2009-10-21 | 诺瓦提斯公司 | Iron (III)-carbohydrate based phosphate adsorbent |
| CN101861146A (en) * | 2007-11-16 | 2010-10-13 | 维福（国际）股份公司 | Pharmaceutical compositions |
| CN115317494A (en) * | 2022-07-22 | 2022-11-11 | 康瑞鑫(天津)药物研究院有限公司 | Sucrose ferric oxide hydroxide with high phosphate bonding force and preparation method thereof |
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- 2023-03-16 CN CN202310256281.6A patent/CN116196330A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4970079A (en) * | 1989-06-05 | 1990-11-13 | Purdue Research Foundation | Method and composition of oxy-iron compounds for treatment of hyperphosphatemia |
| CN101563295A (en) * | 2006-12-14 | 2009-10-21 | 诺瓦提斯公司 | Iron (III)-carbohydrate based phosphate adsorbent |
| CN101861146A (en) * | 2007-11-16 | 2010-10-13 | 维福（国际）股份公司 | Pharmaceutical compositions |
| CN115317494A (en) * | 2022-07-22 | 2022-11-11 | 康瑞鑫(天津)药物研究院有限公司 | Sucrose ferric oxide hydroxide with high phosphate bonding force and preparation method thereof |
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