CN115813867B - Lanthanum carbonate freeze-dried tablet and preparation method thereof - Google Patents
Lanthanum carbonate freeze-dried tablet and preparation method thereof Download PDFInfo
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- 229910017569 La2(CO3)3 Inorganic materials 0.000 title claims abstract description 56
- NZPIUJUFIFZSPW-UHFFFAOYSA-H lanthanum carbonate Chemical compound [La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O NZPIUJUFIFZSPW-UHFFFAOYSA-H 0.000 title claims abstract description 56
- 229960001633 lanthanum carbonate Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000008213 purified water Substances 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 9
- 238000009777 vacuum freeze-drying Methods 0.000 claims abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 8
- 239000000853 adhesive Substances 0.000 claims abstract description 7
- 230000001070 adhesive effect Effects 0.000 claims abstract description 7
- 239000000796 flavoring agent Substances 0.000 claims abstract description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 239000006188 syrup Substances 0.000 claims description 8
- 235000020357 syrup Nutrition 0.000 claims description 8
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 7
- 235000010413 sodium alginate Nutrition 0.000 claims description 7
- 239000000661 sodium alginate Substances 0.000 claims description 7
- 229940005550 sodium alginate Drugs 0.000 claims description 7
- 239000004376 Sucralose Substances 0.000 claims description 6
- 235000019408 sucralose Nutrition 0.000 claims description 6
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 6
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 5
- 108010011485 Aspartame Proteins 0.000 claims description 5
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 5
- 229960004998 acesulfame potassium Drugs 0.000 claims description 5
- 239000000619 acesulfame-K Substances 0.000 claims description 5
- 239000000605 aspartame Substances 0.000 claims description 5
- 235000010357 aspartame Nutrition 0.000 claims description 5
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 5
- 229960003438 aspartame Drugs 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 229940085605 saccharin sodium Drugs 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims description 2
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 239000002131 composite material Substances 0.000 claims 1
- 230000012447 hatching Effects 0.000 claims 1
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 abstract description 11
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 abstract description 11
- 238000007710 freezing Methods 0.000 abstract description 10
- 230000008014 freezing Effects 0.000 abstract description 10
- 238000011534 incubation Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
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- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 230000007794 irritation Effects 0.000 abstract description 3
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- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 35
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 238000011049 filling Methods 0.000 description 6
- 201000005991 hyperphosphatemia Diseases 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 208000020832 chronic kidney disease Diseases 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 208000028208 end stage renal disease Diseases 0.000 description 4
- 201000000523 end stage renal failure Diseases 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- 238000000159 protein binding assay Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- GZHCNRONBGZNAH-UHFFFAOYSA-N phosphanylidynelanthanum Chemical compound [La]#P GZHCNRONBGZNAH-UHFFFAOYSA-N 0.000 description 3
- 238000010146 3D printing Methods 0.000 description 2
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 229910052746 lanthanum Inorganic materials 0.000 description 2
- 229940016193 lanthanum carbonate chewable tablet Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 241000220479 Acacia Species 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- ZQBZAOZWBKABNC-UHFFFAOYSA-N [P].[Ca] Chemical compound [P].[Ca] ZQBZAOZWBKABNC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940099065 fosrenol Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002694 phosphate binding agent Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- 229940116362 tragacanth Drugs 0.000 description 1
- 229910009111 xH2 O Inorganic materials 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lanthanum carbonate freeze-dried tablet and a preparation method thereof. The lanthanum carbonate freeze-dried tablet consists of lanthanum carbonate, a framework material, an adhesive, a flavoring agent and purified water, wherein the framework material is dissolved in the water, and then the lanthanum carbonate, the adhesive and the flavoring agent are added and mixed to form a uniform solution; and (3) after the solution is degassed, pre-freezing, ice crystal incubation and vacuum freeze drying are sequentially carried out, so that the lanthanum carbonate freeze-dried tablet is obtained. The lanthanum carbonate freeze-dried tablet disclosed by the invention has the advantages of good taste, uniform drug content, rapid dissolution under the action of saliva after being taken, great improvement of phosphate binding capacity and administration compliance, convenience in administration, small irritation to mucous membrane of digestive tract and the like, and the compliance of patients is improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a lanthanum carbonate freeze-dried tablet and a preparation method thereof.
Background
Hyperphosphatemia is one of the important complications of end-stage renal failure, and 80% of renal dialysis patients suffer from this disease. Studies have shown that in patients with end-stage renal failure, sustained calcium-phosphorus product elevation and hyperphosphatemia are directly related to mortality in the patient. Therefore, the control of the hyperphosphatemia has important significance for improving the life quality of patients with end-stage renal failure and reducing the death rate.
Lanthanum carbonate (Fosrenol) is a novel phosphate binder developed by the first company of the company xiale (Shire) in the united kingdom, and has the molecular formula La 2(CO3)3·xH2 O (x=4-5) and molecular weight 529.90 (tetrahydrate), and is used for treating hyperphosphatemia in chronic renal failure patients who undergo hemodialysis or continuous ambulatory peritoneal dialysis. Lanthanum carbonate has the advantages of high phosphate binding speed, large amount, almost no absorption in gastrointestinal tract, low accumulation in vivo tissues, good tolerance and the like, and is a novel drug with the best selectivity for treating hyperphosphatemia in kidney diseases at present.
The intake of water should be controlled by patients with renal end-stage renal failure, and at present, lanthanum carbonate oral dosage forms mainly comprise chewable tablets on the market, have large tablet weight and are inconvenient to take, and especially for middle-aged and elderly patients and children patients with difficulty in chewing and swallowing.
Patent CN107213126B discloses a method for preparing an oral rapid disintegrating tablet for treating hyperphosphatemia by a 3D printing technology, the 3D printing technology has high cost, an organic solvent is used in the preparation process, the operation is complex, the preparation process is complex, and the industrial production is difficult.
Disclosure of Invention
The invention aims to solve the technical problems that: the lanthanum carbonate freeze-dried tablet has good taste and uniform drug content, is quickly dissolved under the action of saliva after being taken, greatly improves the phosphate binding capacity and the drug delivery compliance, has the advantages of convenient administration, small irritation to mucous membrane of digestive tract and the like, and improves the compliance of patients; the invention also provides a preparation method, which has simple process and is easy for industrial production.
The lanthanum carbonate freeze-dried tablet disclosed by the invention is prepared from the following components in percentage by weight:
preferably, the lanthanum carbonate freeze-dried tablet is prepared from the following components in percentage by weight:
In the invention, the framework material is one or more of glycine, sodium alginate, mannitol, lactose, dextrin, dextran, ethylene cellulose, polyoxyethylene, glycerol, agar, starch, acacia, tragacanth and methylcellulose.
In the invention, the adhesive is one or more of hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, starch, dextrin, polyacrylate, ethylene-vinyl acetate copolymer, vinyl acetate resin and acrylic resin.
In the invention, the flavoring agent is one or more of stevioside, sucralose, aspartame, acesulfame potassium, saccharin sodium, orange peel syrup and citric syrup.
The preparation method of the lanthanum carbonate freeze-dried tablet comprises the following steps:
Dissolving a framework material in purified water, then adding lanthanum carbonate, an adhesive and a flavoring agent, and mixing to obtain a uniform solution; and (3) after degassing the solution, pre-freezing for 0-1 h at the temperature of minus 20 to minus 110 ℃ under normal pressure, and then vacuum freeze-drying for 1-20 h at the temperature of minus 30 to minus 0 ℃ under the pressure of 0.01-10 mbar to obtain the lanthanum carbonate freeze-dried tablet.
Preferably, after pre-freezing, ice crystal incubation is carried out for 1-20 hours under the conditions of normal pressure, -10 to-70 ℃ and then vacuum freeze drying is carried out. When pre-freezing, the liquid medicine forms ice crystals initially, and then ice crystal incubation is carried out, so that the pores in the ice crystals can be increased, and the sublimation efficiency is improved.
Preferably, vacuum deaeration or standing deaeration is adopted in the deaeration treatment of the solution.
The lanthanum carbonate freeze-dried tablet prepared by the invention can be completely dissolved in water at 37 ℃ for 5 min.
Compared with the prior art, the invention has the following beneficial effects:
(1) The lanthanum carbonate freeze-dried tablet disclosed by the invention has good taste and uniform drug content, is quickly dissolved under the action of saliva after being taken, greatly improves the drug administration compliance, is suitable for patients with dysphagia such as the elderly and children, has the advantages of convenience in administration, small irritation to mucous membrane of digestive tract and the like, and improves the compliance of the patients;
(2) The preparation method disclosed by the invention is simple in process and easy for industrial production.
Drawings
FIG. 1 is a graph showing the results of the test for binding between fosinox and phosphate in the lanthanum carbonate lyophilized tablet of example 1 and comparative example 1;
FIG. 2 is a graph showing the results of the test for binding between lanthanum carbonate freeze-dried tablets and phosphate in examples 1-2.
Detailed Description
The invention is further illustrated below with reference to examples. The raw materials used in the examples, unless otherwise specified, were all commercially available conventional raw materials; the process used in the examples, unless otherwise specified, is conventional in the art.
Example 1
Prescription: each lanthanum carbonate lyophilized tablet contains 60% lanthanum carbonate (954 mg), 16.8% sodium alginate (266.8 mg), 3% polyvinylpyrrolidone (47 mg), 0.2% aspartame (3.2 mg), 20% purified water (319 mg).
The preparation method comprises the following steps:
26.68kg of sodium alginate is dissolved in 31.9kg of purified water according to the dosage of 10 ten thousand tablets, and then 95.4kg of lanthanum carbonate, 4.7kg of polyvinylpyrrolidone and 0.32kg of aspartame are added and mixed into a uniform solution; and (3) standing and defoaming the solution, filling the solution into a mould, pre-freezing the mould for 0.5h at normal pressure and minus 60 ℃, incubating ice crystals for 2h at normal pressure and minus 50 ℃, transferring the mould into a freeze dryer, and performing vacuum freeze drying for 10h at the temperature of 1mbar and minus 30-30 ℃ to obtain the lanthanum carbonate freeze-dried tablet.
Example 2
The recipe is as in example 1, and the preparation method is as follows:
26.68kg of sodium alginate is dissolved in 31.9kg of purified water according to the dosage of 10 ten thousand tablets, and then 95.4kg of lanthanum carbonate, 4.7kg of polyvinylpyrrolidone and 0.32kg of aspartame are added and mixed into a uniform solution; and (3) standing and defoaming the solution, filling the solution into a mould, pre-freezing the solution for 0.5h at normal pressure and minus 60 ℃, transferring the solution into a freeze dryer, and performing vacuum freeze drying for 10h at the temperature of minus 30-30 ℃ to obtain the lanthanum carbonate freeze-dried tablet.
Example 3
Prescription: each lanthanum carbonate lyophilized tablet contains 60% lanthanum carbonate (954 mg), 10% sodium alginate (159 mg), 5% glycine (79 mg), 2% polyvinylpyrrolidone (31 mg), 1% hypromellose (16 mg), 1% orange peel syrup (16 mg), 1% sucralose (16 mg), 20% purified water (319 mg).
The preparation method comprises the following steps:
15.9kg of sodium alginate and 7.9kg of glycine are dissolved in 31.9kg of purified water according to the dosage of 10 ten thousand tablets, and then 95.4kg of lanthanum carbonate, 3.1kg of polyvinylpyrrolidone, 1.6kg of hypromellose, 1.6kg of orange peel syrup and 1.6kg of sucralose are added and mixed into a uniform solution; and (3) after the solution is defoamed in vacuum, filling the solution into a mould, pre-freezing the mould for 0.5h at normal pressure and minus 70 ℃, incubating the pre-frozen mould filled with the solution for 20h at normal pressure and minus 30 ℃, transferring the mould into a freeze dryer, and performing vacuum freeze drying for 10h at the temperature of 1mbar and minus 25-30 ℃ to obtain the lanthanum carbonate freeze-dried tablet.
Example 4
Prescription: each lanthanum carbonate lyophilized tablet contained 60% lanthanum carbonate (954 mg), 15% lactose (238 mg), 2% polyvinylpyrrolidone (31 mg), 1% hypromellose (16 mg), 1% orange peel syrup (16 mg), 1% sucralose (16 mg), 20% purified water (319 mg).
The preparation method comprises the following steps:
23.8kg of lactose is dissolved in 31.9kg of purified water according to the dosage of 10 ten thousand tablets, and then 95.4kg of lanthanum carbonate, 3.1kg of polyvinylpyrrolidone, 1.6kg of hydroxypropyl methylcellulose, 1.6kg of orange peel syrup and 1.6kg of sucralose are added and mixed into a uniform solution; and (3) after the solution is defoamed in vacuum, filling the solution into a mould, pre-freezing the mould for 0.5h at normal pressure and minus 70 ℃, incubating the pre-frozen mould filled with the solution for 13h at normal pressure and minus 40 ℃, transferring the mould into a freeze dryer, and performing vacuum freeze drying for 10h at the temperature of 1mbar and minus 25-30 ℃ to obtain the lanthanum carbonate freeze-dried tablet.
Example 5
Prescription: each lanthanum carbonate lyophilized tablet contained 80% lanthanum carbonate (960 mg), 5% hypromellose (60 mg), 2% acesulfame potassium (24 mg), 13% purified water (156 mg).
The preparation method comprises the following steps:
96.0kg of lanthanum carbonate, 6.0kg of hypromellose and 2.4kg of acesulfame potassium are dissolved in 15.6kg of purified water according to the dosage of 10 ten thousand tablets and are mixed into a uniform solution; and (3) standing and defoaming the solution, filling the solution into a mould, pre-freezing the solution for 0.5h at normal pressure and minus 70 ℃, transferring the solution into a freeze dryer, and performing vacuum freeze drying for 10h at the temperature of 1mbar and minus 25-30 ℃ to obtain the lanthanum carbonate freeze-dried tablet.
The preparation method comprises the following steps:
Adding lanthanum carbonate and acesulfame potassium into hypromellose solution, and mixing to obtain a uniform solution; and (3) degassing the solution, filling the solution into a mould, pre-freezing for 0.5h at the temperature of minus 60 ℃, transferring the solution into a freeze dryer, and freeze-drying for 10h at the temperature of minus 30-30 ℃ under vacuum pressure of about 1mbar to obtain the lanthanum carbonate freeze-dried tablet.
Comparative example 1
Commercial forskolin (lanthanum carbonate chewable tablet), and xiali.
Phosphate binding test assay was performed on the lanthanum carbonate lyophilized tablet products prepared in each example and the commercially available fosinox (lanthanum carbonate chewable tablet) of comparative example 1, as follows:
Incubation was performed in phosphate solution of a certain concentration using one formulation unit, all incubations should be continued with gentle shaking at 37 ℃. In addition, the study should be performed at pH1.2, pH3.0, and pH5.0, respectively, with a solution volume of 250mL. Lanthanum-phosphorus binding should be monitored periodically, at least 8 time points are selected to detect lanthanum-phosphorus binding until the lanthanum-phosphorus binding is equilibrated. The ion chromatography measurement method is shown in Table 1, and the detection results are shown in tables 2-4.
Table 1 phosphate binding assay ion chromatography assay
Table 2 phosphate binding assay results (ph=1.2)
Table 3 phosphate binding assay results (ph=3.0)
Table 4 phosphate binding assay results (ph=5.0)
As can be seen from tables 2-4 and fig. 1-2, the lanthanum carbonate freeze-dried tablet prepared by the invention has more pores than the common tablet, absorbs water faster, facilitates the dissolution of lanthanum ions, enhances the binding efficiency of lanthanum ions and phosphate, has stronger phosphate binding capacity, and is more beneficial to reducing the phosphate level of patients (as shown in fig. 1); compared with example 2, the example 1 is added with an ice crystal incubation process to prepare a lanthanum carbonate freeze-dried tablet, which has more pores, faster dissolution and stronger phosphate binding capacity (as shown in figure 2); example 5 lacks the framework material and has slightly reduced phosphate binding capacity, because the framework material can maintain the lanthanum carbonate freeze-dried tablet type, keep the stability of the lanthanum carbonate freeze-dried tablet, and is beneficial to the formation of pores of the lanthanum carbonate freeze-dried tablet.
Claims (4)
1. The lanthanum carbonate freeze-dried tablet is characterized in that: the composite material is prepared from the following components in percentage by weight:
50 to 84.8 percent of lanthanum carbonate,
5-20% Of framework material,
0.1 To 5 percent of adhesive,
0.1 To 5 percent of flavoring agent,
Purified water 10-30%;
the framework material is one of sodium alginate and lactose;
the preparation method of the lanthanum carbonate freeze-dried tablet comprises the following steps:
Dissolving a framework material in purified water, then adding lanthanum carbonate, an adhesive and a flavoring agent, and mixing to obtain a uniform solution; the solution is degassed and pre-frozen for 0.5 to 1 hour under the condition of normal pressure, -20 to-110 ℃, then ice crystal hatching is carried out for 1 to 20 hours under the condition of normal pressure, -10 to-70 ℃, and then vacuum freeze drying is carried out for 1 to 20 hours under the condition of 0.01 to 10mbar, -30 to 0 ℃ to obtain the lanthanum carbonate freeze-dried tablet which can be completely dissolved in water at 37 ℃ for 5 minutes.
2. The lanthanum carbonate freeze-dried tablet of claim 1, wherein: the adhesive is one or more of hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyoxyethylene, starch and dextrin.
3. The lanthanum carbonate freeze-dried tablet of claim 1, wherein: the flavoring agent is one or more of stevioside, sucralose, aspartame, acesulfame potassium, saccharin sodium, orange peel syrup and citric acid syrup.
4. The lanthanum carbonate freeze-dried tablet of claim 1, wherein: the solution is deaerated by vacuum deaeration or standing deaeration.
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