CN102432055A - Lanthanum carbonate nano-particles for treating hyperphosphatemia, preparation method and application thereof - Google Patents
Lanthanum carbonate nano-particles for treating hyperphosphatemia, preparation method and application thereof Download PDFInfo
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- CN102432055A CN102432055A CN2011102870072A CN201110287007A CN102432055A CN 102432055 A CN102432055 A CN 102432055A CN 2011102870072 A CN2011102870072 A CN 2011102870072A CN 201110287007 A CN201110287007 A CN 201110287007A CN 102432055 A CN102432055 A CN 102432055A
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- 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 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 201000005991 hyperphosphatemia Diseases 0.000 title claims abstract description 21
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 21
- 229910017569 La2(CO3)3 Inorganic materials 0.000 title abstract 6
- 229960001633 lanthanum carbonate Drugs 0.000 title abstract 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000002245 particle Substances 0.000 claims abstract description 27
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 24
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 24
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 claims abstract description 22
- 238000000498 ball milling Methods 0.000 claims abstract description 15
- GAYSPCNXZCAPHX-UHFFFAOYSA-H lanthanum(3+);tricarbonate;octahydrate Chemical compound O.O.O.O.O.O.O.O.[La+3].[La+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GAYSPCNXZCAPHX-UHFFFAOYSA-H 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 6
- 230000018044 dehydration Effects 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 239000012153 distilled water Substances 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000009423 ventilation Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003643 water by type Substances 0.000 abstract 1
- 150000003016 phosphoric acids Chemical class 0.000 description 18
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 239000011574 phosphorus Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- 238000000151 deposition Methods 0.000 description 7
- 229910019142 PO4 Inorganic materials 0.000 description 6
- 239000010452 phosphate Substances 0.000 description 6
- 238000004448 titration Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
- 229910052782 aluminium Inorganic materials 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- WYWFMUBFNXLFJK-UHFFFAOYSA-N [Mo].[Sb] Chemical compound [Mo].[Sb] WYWFMUBFNXLFJK-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000004411 aluminium Substances 0.000 description 4
- 238000001965 diffuse reflectance infrared spectroscopy Methods 0.000 description 4
- 229910052750 molybdenum Inorganic materials 0.000 description 4
- 239000011733 molybdenum Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000000630 rising effect Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- JKSVDWSKYFEURH-UHFFFAOYSA-N carbonic acid;lanthanum Chemical compound [La].OC(O)=O JKSVDWSKYFEURH-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
- PPQREHKVAOVYBT-UHFFFAOYSA-H dialuminum;tricarbonate Chemical compound [Al+3].[Al+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O PPQREHKVAOVYBT-UHFFFAOYSA-H 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052746 lanthanum Inorganic materials 0.000 description 2
- FZLIPJUXYLNCLC-UHFFFAOYSA-N lanthanum atom Chemical compound [La] FZLIPJUXYLNCLC-UHFFFAOYSA-N 0.000 description 2
- CZMAIROVPAYCMU-UHFFFAOYSA-N lanthanum(3+) Chemical compound [La+3] CZMAIROVPAYCMU-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011787 zinc oxide Substances 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 208000030136 Marchiafava-Bignami Disease Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 150000001669 calcium Chemical class 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- -1 calcium class phosphate Chemical class 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 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
- 238000000502 dialysis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002389 environmental scanning electron microscopy Methods 0.000 description 1
- 238000000407 epitaxy Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 150000002603 lanthanum Chemical class 0.000 description 1
- LQFNMFDUAPEJRY-UHFFFAOYSA-K lanthanum(3+);phosphate Chemical compound [La+3].[O-]P([O-])([O-])=O LQFNMFDUAPEJRY-UHFFFAOYSA-K 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- IAQLJCYTGRMXMA-UHFFFAOYSA-M lithium;acetate;dihydrate Chemical compound [Li+].O.O.CC([O-])=O IAQLJCYTGRMXMA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 238000002798 spectrophotometry method Methods 0.000 description 1
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- ORZHVTYKPFFVMG-UHFFFAOYSA-N xylenol orange Chemical compound OC(=O)CN(CC(O)=O)CC1=C(O)C(C)=CC(C2(C3=CC=CC=C3S(=O)(=O)O2)C=2C=C(CN(CC(O)=O)CC(O)=O)C(O)=C(C)C=2)=C1 ORZHVTYKPFFVMG-UHFFFAOYSA-N 0.000 description 1
Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种用于治疗高磷血症的碳酸镧纳米颗粒的制备方法，包括以下步骤：1)把碳酸氢钠溶液加入氯化镧溶液中，制备八水合碳酸镧，2)然后在常压，40～120℃条件下脱水制备出稳定的含有1～4个水的碳酸镧，3)最后通过球磨的方法，把制备的样品从微米颗粒球磨成纳米颗粒。本发明还涉及由此制备方法获得的八水合碳酸镧La2(CO3)3·8H2O、含有1～4个水的碳酸镧La2(CO3)3·xH2O(其中x在1-4之间)以及碳酸镧纳米颗粒，及该碳酸镧纳米颗粒在制备用于治疗高磷血症的药物中的应用。The present invention relates to a kind of preparation method of the lanthanum carbonate nano particle that is used for treating hyperphosphatemia, comprises the following steps: 1) sodium bicarbonate solution is added in the lanthanum chloride solution, prepares octahydrate lanthanum carbonate, 2) then in normal pressure, and dehydration at 40-120°C to prepare stable lanthanum carbonate containing 1-4 water. 3) Finally, the prepared sample is ball-milled from micron particles to nano-particles by ball milling. The present invention also relates to lanthanum carbonate octahydrate La 2 (CO 3 ) 3 ·8H 2 O obtained by this preparation method, lanthanum carbonate La 2 (CO 3 ) 3 ·xH 2 O containing 1 to 4 waters (wherein x is 1-4) and lanthanum carbonate nanoparticles, and the application of the lanthanum carbonate nanoparticles in the preparation of medicines for treating hyperphosphatemia.
Description
Technical field
The present invention relates to a kind of preparation method who is used to treat the Phosbloc nano particle of hyperphosphatemia, and the eight artificial lanthanite La that obtain of preparation method thus
2(CO
3)
38H
2O, contain the Phosbloc La of 1～4 water
2(CO
3)
3XH
2O (wherein x is between 1-4) and Phosbloc nano particle, and this Phosbloc nano particle is used to treat the application of hyperphosphatemia in preparation.
Background technology
Chronic nephropathy is the general public health problem in the whole world, and its a kind of major complications is because kidney can not be drained intravital phosphoric acid salt, causes phosphoric acid salt level in the blood to raise and the hyperphosphatemia that causes.
The symptom of hyperphosphatemia mainly is that phosphate content surpasses normal level in the blood, and may be hyperfunction with the secondary parathyroid gland, metabolic bone disease, and soft tissue calcification, cardiovascular calcifications is relevant.
The treatment of hyperphosphatemia at present mainly contains absorption, the dialysis method dephosphorization of control phosphorus on the diet, the application and the parathyroid in case of necessity excision of phosphorus wedding agent.But there is 90%～95% ESRD patient to be to use to take the phosphorus wedding agent to reduce enteron aisle to the absorption of phosphorus and treat hyperphosphatemia.
The phosphorus wedding agent mainly is divided into traditional phosphorus wedding agent two macrospecies that contain aluminium or calcareous phosphorus wedding agent and non-aluminium, non-calcium.Aluminiferous phosphorus wedding agent such as white lake, aluminium carbonate etc. can cause poisoning by aluminum if take for a long time, cause small cell anemia, osteomalacia, Ah thatch's Alzheimer disease etc.And calcareous phosphorus wedding agent such as lime carbonate, calcium acetate etc. if life-time service can increase the absorption of calcium in the enteron aisle and cause hypercalcemia, cause heart and angiosteosis.Therefore the wedding agent of ideal treatment hyperphosphatemia should be non-aluminium, non-calcium class.Phosbloc is exactly wherein a kind of.
Lanthanum is a kind of the oxygen donor atom to be had the REE of strong avidity, and lanthanum salt can combine with phosphoric acid salt in the food, forms the lanthanum orthophosphate mixture, through hindering phosphatic absorption, thereby reduces phosphatic content in the blood.Phosbloc (LC) is one of comparatively sophisticated at present non-aluminium, non-calcium class phosphate binders; It absorbs in several nothings of gi tract, gathers also seldom in the tissue in vivo, can not cause angiosteosis and other spinoff; Tolerance is also better, and it will become the novel drugs of treatment hyperphosphatemia.U.S. FDA is ratified Phosbloc in October, 2004 and is used for clinical.Up to the present, existing multinomial report with Phosbloc treatment hyperphosphatemia.
But lanthanum ion is hard Lewis acid, and very strong and hydroxide radical bonded ability are arranged, and when the preparation Phosbloc, as not noting condition, is easy to generate the basic carbonate lanthanum.Up to the present, subcarbonate can be used to treat hyperphosphatemia by drugs approved by FDA, and the security of using it for human body is not proved yet.For hyperphosphatemia patient's health, safety need be developed the reliable method of in the process of preparation Phosbloc, avoiding generating carbon basic carbonate lanthanum.
Preparing method about Phosbloc in the prior art prepares as raw material with yellow soda ash.For example there is the people in patent, to report and uses Na
2CO
3With LaCl
3Reaction prepares the method for Phosbloc, finds but repeat this method, is mingled with a certain amount of La (OH) CO in the Phosbloc deposition of generation
3In addition, the Phosbloc sample particle that existing method is produced is bigger, and major part is 3～4 μ m, and particle causes surface-area less relatively than conference, then absorbs and adsorbs phosphatic poor effect.
Summary of the invention
One of the object of the invention is exactly in order to seek a kind of method for preparing Phosbloc that can avoid the basic carbonate lanthanum to generate, can be used to treat hyperphosphatemia better after said Phosbloc is further handled.
We notice, Na
2CO
3The aqueous solution is alkalescence, and the pH value of solution in reaction process is easy to raise if do not control, and is mingled with La (OH) CO in the deposition that causes generating
3The inventor finds after deliberation, if use NaHCO
3With LaCl
3Prepare Phosbloc as raw material, in the preparation process, following two parallel reactors can take place:
(1) NaHCO
3With LaCl
3Reaction discharges H
+,
(2) H
+Meeting and HCO
3 -Reaction generates water and CO
2
These two are reflected in the preparation Phosbloc process and are running balance, can make to be reflected under the lower pH and carry out, thereby in the preparation Phosbloc, can avoid the generation of basic carbonate lanthanum again.
Inventor's research is also found; For the bigger Phosbloc sample of particle of direct method preparation,, just can make sample particle littler if adopt the method for ball milling that sample is ground; Even reach Nano grade; Therefore its surface-area enlarges markedly, thereby can absorb and adsorb phosphoric acid salt better, shows good therapeutic action at the medicine that is used for treating hyperphosphatemia.
Therefore, the present invention provides a kind of preparation method who is used to treat the Phosbloc nano particle of hyperphosphatemia, may further comprise the steps:
Step 1) adds sodium hydrogen carbonate solution in the lanthanum chloride solution, prepares eight artificial lanthanites, La
2(CO
3)
38H
2O, its diffuse reflectance infrared spectroscopy peak is mainly at 850.3cm
-1, 746.6cm
-1And 678.6cm
-1, in addition at 1477.9cm
-1And 1377.7cm
-1Also there is characteristic peak at the place; The La of said lanthanum chloride solution
3+Concentration is 0.5-5mol/L;
Step 2), then at normal pressure, 40～120 ℃, preferred 50～100 ℃, more preferably the stable Phosbloc that contains 1～4 water, La are prepared in dehydration under the condition of 60～80 ℃ of temperature
2(CO
3)
3XH
2O, wherein x is between 1-4, and its diffuse reflectance infrared spectroscopy peak is mainly at 849.6cm
-1, 747.4cm
-1And 681.0cm
-1In addition at 1483.4cm
-1And 1394.9cm
-1Also there is characteristic peak at the place.
Step 3) through the method for ball milling, becomes nano particle to the Phosbloc that contains 1～4 water from the micron particle ball milling at last, and its particle diameter is 100～400nm.
Below describe the present invention in detail.
In step 1), the equation that generates eight artificial lanthanites is following:
H
++HCO
-＝H
2O+CO
2↑
2La
3++3HCO
3 -＝La
2(CO
3)
3↓+3H
+
2La
3++6HCO
3 -＝La
2(CO
3)
3↓+3H
2O+3CO
2↑
Can find out that from equation have two reactions in the solution, one is La
3+With HCO
3 -Reaction generates La
2(CO
3)
3Deposition, another is HCO
3 -With the H in the solution
+The reaction of generation acid-base neutralisation.Above-mentioned two parallel reactor acid-base neutralisations reaction, speed of response is very fast; Another precipitates formation reaction, does not exist in reaction system under the condition of Phosbloc nucleus, and reaction is carried out hardly.When dropping sodium hydrogencarbonate speed is slow; Owing to there is not the Phosbloc nucleus to generate; Precipitin reaction is not carried out, and the sodium hydrogencarbonate that is therefore added is only participated in the acid-base neutralisation reaction, makes the pH of solution about the starting stage of reaction can be raised to 5.5 and do not see the sedimentary generation (see figure 1) of Phosbloc.Because the pH value of system is higher, the risk that is mingled with the basic carbonate lanthanum in the Phosbloc product of preparation is bigger in this case.Therefore for fear of above-mentioned risk, we take following measure:
According to the present invention, in the step 1), in reactor drum, add earlier lanthanum chloride solution, its La
3+Concentration is 0.5-5mol/L, preferred 1-3mol/L, and more preferably 2mol/L, pH is 0-3.
Wherein, in the step 1), the adding of sodium bicarbonate aqueous solution divides two stages:
In the initial stage, once in lanthanum chloride solution, add a small amount of sodium bicarbonate aqueous solution fast earlier, its concentration is 0.2-4mol/L; Preferred 0.3-3mol/L; More preferably 1mol/L, sodium bicarbonate aqueous solution accounts for the 0.05-0.4 of lanthanum chloride solution volume, preferred 0.1-0.3; More preferably 0.15-0.25, most preferably 0.2.
In the case, after once adding a small amount of sodium hydrogen carbonate solution fast, the pH value of solution has prominent getting over that is raised to about 3, occurs cotton-shaped La simultaneously
2(CO
3)
3Deposition.This is because a part of NaHCO
3The H of the system that neutralized
+, the pH value of solution is raise, on the other hand the NaHCO of pulsed
3Add affiliation and cause local NaHCO in the reaction system
3Concentration is higher, promotes HCO
3 -With La
3+Reaction generates the Phosbloc nucleus.
Then, again with 0.01mL/s-10mL/s, preferred 0.05mL/s-5mL/s, more preferably 0.08mL/s-2mL/s, most preferably the speed of 0.1mL/s-1mL/s adds sodium hydrogen carbonate solution in lanthanum chloride solution, when flex point appears in the pH value, reacts to stop.
In this process, further add HCO
3 -The pH value of afterreaction system reduces, and this mainly is because HCO
3 -With La
3+Reaction generates La
2(CO
3)
3, discharge a large amount of H
+Due to.Along with the further adding of sodium hydrogencarbonate, the La that is produced in the solution reaction system
2(CO
3)
3Quantity constantly increases, but the pH value of system remains unchanged basically, and this is because the acid-base neutralisation reaction reaches due to the running balance with precipitin reaction, so whole La
2(CO
3)
3Formation reaction is that carry out (about as 4) under a lower pH condition.La in system
3+Be reformed completely into La
2(CO
3)
3Post precipitation is along with NaHCO
3Further add, the pH of system becomes the rising of hop property, so we can judge the terminal point of reaction through last this hop.
Based on the present invention, in the step 1), after reaction stops, the suction filtration of will filtrating, and with distilled water washing three times, eight artificial lanthanite filter cakes are placed on the ventilation dry naturally.Identify that through ir spectra the diffuse reflectance infrared spectroscopy peak of this eight artificial lanthanite is mainly at 850.3cm
-1, 746.6cm
-1And 678.6cm
-1, in addition at 1477.9cm
-1And 1377.7cm
-1Also there is characteristic peak at the place.
In step 2) in, for the eight artificial lanthanites dehydration that step 1) is formed, according to the present invention; Eight artificial lanthanites are placed in the baking oven, under normal pressure, are 40～120 ℃ in temperature; Preferred 50～100 ℃; More preferably 60～80 ℃ keep 18～24h down, can obtain the Phosbloc of 1～4 more stable water, La
2(CO
3)
3XH
2O, wherein x is between 1-4, and preferred x is 1.5-3.5, and more preferably x is 2.5-3.4, and most preferably x is 3.3.
Identify that through ir spectra the diffuse reflectance infrared spectroscopy peak of the Phosbloc of this 1～4 water is mainly at 849.6cm
-1, 747.4cm
-1And 681.0cm
-1In addition at 1483.4cm
-1And 1394.9cm
-1Also there is characteristic peak at the place.
In step 3), in order to prepare nano level carbonic acid lanthanum, according to the present invention; With step 2) Phosbloc that contains 1～4 water that obtains is placed in the ball mill ball milling 1-5 hour, and preferred 1.5-3 hour, most preferably 2 hours; Obtaining particle diameter is 100～400nm, the Phosbloc particle of preferred 200～300nm.
According to above-mentioned preparation method of the present invention, in step 3), make the Phosbloc nano particle, its particle diameter is 100～400nm, is preferably 200～300nm.
The Phosbloc nano particle that makes according to the present invention can prepare the medicine that is used to treat hyperphosphatemia.
Innovation part of the present invention is mainly reflected in the following aspects:
1, form the basic carbonate lanthanum for avoiding, we use NaHCO
3Rather than Na
2CO
3And LaCl in when beginning reaction at low pH
3Once add earlier a certain amount of NaHCO in the solution down fast
3The aqueous solution makes the solution local pH too high and generate the sedimentary nucleus of Phosbloc, and then one after another drop of toward LaCl
3Solution drips NaHCO
3The aqueous solution makes newly-generated Phosbloc be deposited in epitaxy on the initial nucleus.Only in this way, two parallel reactors are carried out synchronously in the system, thereby make the pH value of reaction system realize running balance, thereby under lower pH environment, prepare Phosbloc.
2, the pH value of our complete monitoring solution is drawn the pH-reaction times curve of entire reaction course, and when the lanthanum ion in the system was converted into Phosbloc fully, hop can take place the pH of system.Can be with this hop as criterion, stopped reaction.Utilize the pH-reaction times curve of reaction process, can realize the production automation of Phosbloc.
3, the Phosbloc sample particle of direct method preparation is bigger; Major part is 3～4 μ m, in order to make the littler surface-area of sample particle increase, better absorb and to adsorb phosphoric acid salt, adopts the method for ball milling that sample is ground; Thereby obtained particle diameter is 100～400nm, the particle of preferred 200～300nm.
Description of drawings
Fig. 1: slowly drip NaHCO
3Add volume-pH change curve in the process;
Fig. 2: direct method prepare eight artificial lanthanites time-the pH change curve;
Fig. 3: synthetic eight artificial lanthanites of direct method and standard card (25-1400) are relatively;
Fig. 4: the ir spectra of eight artificial lanthanites;
Fig. 5: the Phosbloc ir spectra that contains 1～4 water; Phosbloc among this figure contains 3.3 water, and its characteristic wave number is in low band;
Fig. 6: the SEM figure of aqueous carbonic acid lanthanum;
Fig. 7: the SEM figure of the nano particle Phosbloc that obtains behind the ball milling;
Fig. 8: the thermogravimetric curve of eight artificial lanthanites;
Fig. 9: the thermogravimetric curve that contains the Phosbloc of 1～4 water;
Figure 10: phosphatic typical curve;
Figure 11: the phosphoric acid salt adsorption curve under the pH3.0 situation;
Figure 12: the phosphoric acid salt adsorption curve under the pH3.0 situation;
Figure 13: the phosphoric acid salt adsorption curve under the pH5.4 situation;
Figure 14: the XRD figure of nano particle.
Embodiment
Below further describe the present invention through embodiment, but the present invention is not limited to these embodiments.
One, the sign of Phosbloc experiment
1、XRD
X ray polycrystalline diffractometer (XRD; Rigaku Dmax-2000): CuK
monochromatic radiation; Acceleration voltage 40KV; Electric current 150mV is used for crystal formation and variation thereof, percent crystallinity, the crystallization degree of perfection of working sample.Sweep limit: 5～60 °, adopt the continuous sweep mode.And and La
2(CO
3)
38H
2O standard card 25-1400 compares.
2, titration, ultimate analysis
2.1 experiment adopts EDTA titration sample to obtain the content of lanthanum element
Preparation 250mL 0.02mol/L zinc standardized solution:
Standard substance zinc oxide is dry 5h in 1000 ℃ of retort furnaces, is cooled to 120 ℃ and is placed in the moisture eliminator, is cooled to room temperature.Take by weighing 0.8118g zinc oxide, add dissolving with hydrochloric acid, be settled to 250mL, compound concentration is 1.995 * 10
-2The zinc solution of M
Preparation EDTA solution:
Take by weighing EDTA 7.4464g, be dissolved in the 1000mL water.
EDTA demarcates:
With pipette, extract 20.00mL Zn
2+Standardized solution adds 2 xylenol orange indicator in Erlenmeyer flask, drip 200g/L vulkacit H to solution and present stable red-purple, adds the 5mL vulkacit H again.Use the EDTA titration, be terminal point when solution just changes yellow into by red-purple.Parallel survey three times.
La
3+Determination on content:
Take by weighing quantity of sample, add hydrochloric acid and dissolve fully, be settled to 100.00mL, use pipette, extract 15.00mL, titration method is demarcated with EDTA.Parallel survey three times.
2.2 ultimate analysis
Use vario EL elemental analyser (Elementar Analysensysteme GmbH) that the ultimate analysis of sample C and H is obtained the carbon content and the hydrogen content of sample, the while can come calculation sample to also have what water through H content.
3. ir spectra
Use the Thermo Scientific NICOLET iN10 MX of company micro ft-ir spectroscopy appearance; Detector: MCT/A; Beam splitter: KBr/Ge; Scanning times: 64; Resolving power: 4cm
-1
4.SEM (ESEM) observed particle size
The JSM-6700F type field emission scanning electron microscope that uses JEOL company to produce carries out, and acceleration voltage is 5kV.
5. thermogravimetric characterizes
Use the synchronous determinator of Q600SDT TGA-DTA-DSC of U.S. Thermal Analysis company, sweep limit is 10 ℃--1000 ℃, heat-up rate is 10 ℃/min.
Two, preparation embodiment
Embodiment 1:
In flask, add 50mL lanthanum chloride solution, its La earlier
3+Concentration is 2mol/L, and pH is 0～2.During beginning, once in lanthanum chloride solution, add the 10mL sodium bicarbonate aqueous solution fast earlier, its concentration is 1mol/L, and this moment, the pH value of solution had prominent getting over that is raised to about 3, occurred cotton-shaped La simultaneously
2(CO
3)
3Deposition.And then in lanthanum chloride solution, add sodium hydrogen carbonate solution with the speed of 0.08mL/s, and flex point appears until the pH value, and reaction stops when being the rising of hop property, adds sodium hydrogen carbonate solution 320mL altogether.Fig. 2 provides direct method and prepares eight artificial lanthanites time-pH change curve.
The filtrating suction filtration, and with distilled water wash three times, filter cake is placed on the ventilation dries naturally.
Fig. 3 has provided eight artificial lanthanites (being labeled as 03-25) that obtained and has compared with standard card (25-1400).The matching degree that can find out peak position basically identical and standard card is about 920 (numerical value is 1000 during 100% coupling).
Eight artificial lanthanites that obtain are placed in the baking oven, under normal pressure, keep 18h at a certain temperature; Obtain containing the Phosbloc of 1～4 water, particularly, when this temperature is 55 ℃; Obtain containing the Phosbloc of 3.3 water, when this temperature is 75 ℃, obtain containing the Phosbloc of 2.5 water; When this temperature is 120 ℃, obtain containing the Phosbloc of 1 water.
The Phosbloc that contains 1～4 water that makes is placed in the ball mill, and ball milling 2 hours obtains the Phosbloc particle of 200～300nm.
Table 1 expression EDTA titration La
2(CO
3)
38H
2La content results among the O.
Table 1
Table 3 is the results of elemental analyses before and after the eight artificial lanthanite drying and dehydratings.
Table 3
Table 4 is C and the La content before and after the sample drying.
Table 4
Thus it is clear that, do not have the existence of basic carbonate lanthanum basically.
Fig. 4 is the ir spectra of eight artificial lanthanites,
Fig. 5 is the ir spectra that contains the Phosbloc of 1～4 water.
It is thus clear that than lower wave number the time, the characteristic peak of eight artificial lanthanites is respectively 850,746,678cm
-1, and the characteristic peak of basic carbonate lanthanum is 858,724,696cm
-1Therefore ir spectra shows, the product that this embodiment obtains is Phosbloc but not basic carbonate lanthanum.
Fig. 6 is the SEM figure of aqueous carbonic acid lanthanum;
Fig. 7 is the SEM of the nano particle Phosbloc that obtains behind the ball milling.
Find out that from Fig. 6 sample is a sheet structure, particle size is 3～4 μ m;
As can be seen from Figure 7, carry out obtaining nano level particle behind the ball milling, sample particle becomes 200～300nm.
Fig. 8 is the thermogravimetric curve of eight artificial lanthanites;
Fig. 9 is the thermogravimetric curve that contains the Phosbloc of 1～4 water.
Embodiment 2:
In flask, add 50mL lanthanum chloride solution, its La earlier
3+Concentration is 2.5mol/L, and pH is 1.5.During beginning, once in lanthanum chloride solution, add the 15mL sodium bicarbonate aqueous solution fast earlier, its concentration is 0.81mol/L, and this moment, the pH value of solution had prominent getting over that is raised to about 3, occurred cotton-shaped La simultaneously
2(CO
3)
3Deposition.And then in lanthanum chloride solution, add sodium hydrogen carbonate solution with the speed of 2mL/s, and flex point appears until the pH value, and reaction stops when being the rising of hop property, adds sodium hydrogen carbonate solution 380mL altogether.The filtrating suction filtration, and with distilled water wash three times, filter cake is placed on the ventilation dries naturally.
Fig. 3 has provided eight artificial lanthanites (being labeled as 02-23) that obtained and has compared with standard card (25-1400).The matching degree that can find out peak position basically identical and standard card is about 920.
Eight artificial lanthanites that obtain are placed in the baking oven, under normal pressure, keep 24h at a certain temperature; Obtain the Phosbloc of 1～4 water, particularly, when this temperature is 60 ℃; Obtain containing the Phosbloc of 3.0 water, when this temperature is 75 ℃, obtain containing the Phosbloc of 2.4 water; When this temperature is 110 ℃, obtain containing the Phosbloc of 1.5 water.
The Phosbloc of 1～4 water that makes is placed in the ball mill, and ball milling 3 hours obtains the Phosbloc particle of 200～300nm.
Table 2EDTA titration La
2(CO
3)
38H
2La content results among the O
Table 2
Embodiment 3:
In flask, add 50mL lanthanum chloride solution, its La earlier
3+Concentration is 1.5mol/L, and pH is 1.0.During beginning, once in lanthanum chloride solution, add the 8mL sodium bicarbonate aqueous solution fast earlier, its concentration is 1.51mol/L, and this moment, the pH value of solution had prominent getting over that is raised to about 3, occurred cotton-shaped La simultaneously
2(CO
3)
3Deposition.And then in lanthanum chloride solution, add sodium hydrogen carbonate solution with the speed of 1.5mL/s, and flex point appears until the pH value, and reaction stops when being the rising of hop property, adds sodium hydrogen carbonate solution 260mL altogether.The filtrating suction filtration, and with distilled water wash three times, filter cake is placed on the ventilation dries naturally.
Eight artificial lanthanites that obtain are placed in the baking oven, under normal pressure, keep 20h at a certain temperature; Obtain the Phosbloc of 3～4 water, particularly, when this temperature is 50 ℃; Obtain containing the Phosbloc of 3.5 water, when this temperature is 80 ℃, obtain containing the Phosbloc of 2.0 water; When this temperature is 120 ℃, obtain containing the Phosbloc of 1 water.
The Phosbloc of 1～4 water that makes is placed in the ball mill, and ball milling 1.5 hours obtains the Phosbloc particle of 200～300nm.
Three, application implementation example
Phosphoric acid salt combines experiment: the anti-molybdenum blue spectrophotometry of molybdenum antimony is measured phosphate content
The drafting of phosphoric acid salt typical curve
Get 7 50mL tube comparison tubess, difference phosphoric acid standard operation solution 0mL, 0.50mL, 1.00mL, 3.00mL, 5.00mL, 10.00mL, 15.00mL adds 1mL ascorbic acid solution, mixing.Add the 2mL molybdate solution behind the 30s, fully mixing.Placing 15min, in the 700nm wavelength, is reference with the blank reagent solution, measures absorbancy, the drawing standard curve.
Figure 10 is the phosphoric acid salt typical curve.
Phosphoric acid salt binding curve under the pH2.0 situation
Preparation Padil-hydrochloric acid is 2.0 damping fluids, uses the phosphate content in the anti-molybdenum blue ultraviolet of the molybdenum antimony spectrphotometric method for measuring solution, confirms the Phosbloc combination rate.
Figure 11 is a pH2.0 phosphoric acid salt binding curve.
Flex point appears when as can beappreciated from fig. 11 being reflected at 10min, 80% PO
4 3-Be converted into LaPO
4, not having more then, polyphosphate is combined.
Phosphoric acid salt binding curve under the pH3.0 situation
Preparation acetic acid-Lithium Hydroxide MonoHydrate is 3.0 damping fluids, uses the phosphate content in the anti-molybdenum blue ultraviolet of the molybdenum antimony spectrphotometric method for measuring solution, confirms the Phosbloc combination rate.
Figure 12 is a pH3.0 phosphoric acid salt binding curve.
Flex point appears when as can beappreciated from fig. 12 being reflected at 10min, 55% PO
4 3-Be converted into LaPO
4, speed of response slows down then, through PO in the 4h solution
4 3-Almost 100% be converted into LaPO
4
Phosphoric acid salt binding curve under the pH5.4 situation
Preparation vulkacit H-HCl is the pH5.4 damping fluid, uses the phosphate content in the anti-molybdenum blue ultraviolet of the molybdenum antimony spectrphotometric method for measuring solution, confirms the Phosbloc combination rate.
Figure 13 is a pH5.4 phosphoric acid salt binding curve.
Find out that from Figure 13 under the condition of pH5.4, tangible flex point does not appear in binding curve, through 4h, the phosphoric acid salt in the solution is basically combined fully.
Claims (9)
1. preparation method who is used to treat the Phosbloc nano particle of hyperphosphatemia may further comprise the steps:
Step 1) adds sodium hydrogen carbonate solution in the lanthanum chloride solution, prepares eight artificial lanthanites, La
2(CO
3)
38H
2O, the La of said lanthanum chloride solution
3+Concentration is 0.5-5mol/L;
Step 2), then at normal pressure, 40～120 ℃, preferred 50～100 ℃, more preferably the stable Phosbloc that contains 1～4 water, La are prepared in dehydration under the condition of 60～80 ℃ of temperature
2(CO
3)
3XH
2O, wherein x is between 1-4;
Step 3) through the method for ball milling, becomes nano particle to the Phosbloc that contains 3～4 water from the micron particle ball milling at last, and its particle diameter is 100～400nm.
2. according to the preparation method of claim 1, it is characterized in that,
In the step 1), in reactor drum, add earlier lanthanum chloride solution, its La
3+Concentration is preferably 1-3mol/L, more preferably 2mol/L, and pH is 0-3;
The adding of sodium bicarbonate aqueous solution divides two stages:
In the initial stage, once in lanthanum chloride solution, add a small amount of sodium bicarbonate aqueous solution fast earlier, its concentration is 0.2-4mol/L; Preferred 0.3-3mol/L; More preferably 1mol/L, sodium bicarbonate aqueous solution accounts for the 0.05-0.4 of lanthanum chloride solution volume, preferred 0.1-0.3; More preferably 0.15-0.25, most preferably 0.2;
Then, again with 0.01mL/s-10mL/s, preferred 0.05mL/s-5mL/s, more preferably 0.08mL/s-2mL/s, most preferably the speed of 0.1mL/s-1mL/s adds sodium hydrogen carbonate solution in lanthanum chloride solution, when flex point appears in the pH value, reacts to stop.
3. according to the preparation method of claim 1 or 2, it is characterized in that,
In the step 1), after reaction stops, the filtrating suction filtration, and with distilled water wash three times, eight artificial lanthanite filter cakes are placed on the ventilation dry naturally.
4. according to the preparation method of one of claim 1 to 3, it is characterized in that,
Step 2) in, eight artificial lanthanites being placed in the baking oven, under normal pressure, is 40～120 ℃ in temperature, and preferred 50～100 ℃, more preferably 60～80 ℃ keep 18～24h down, can obtain the Phosbloc of 1～4 more stable water, La
2(CO
3)
3XH
2O, wherein x is between 1-4.
5. according to the preparation method of claim 4, it is characterized in that wherein x is 1.5-3.5, preferred x is 2.5-3.4, and more preferably x is 3.3.
6. according to the preparation method of one of claim 1 to 5, it is characterized in that,
In the step 3), the Phosbloc that will contain 3～4 water is placed in the ball mill ball milling 1-5 hour, preferred 1.5-3 hour, most preferably 2 hours, obtains the Phosbloc particle that particle diameter is preferably 200～300nm.
7. the Phosbloc nano particle that makes according to the method for one of claim 1 to 6, its particle diameter is 100～400nm.
8. according to the Phosbloc nano particle of claim 7, its particle diameter is 200～300nm.
9. that make according to the method for one of claim 1 to 6 or according to the purposes of the Phosbloc nano particle of claim 7 or 8, be used to prepare the medicine that is used to treat hyperphosphatemia.
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| CN104473963A (en) * | 2014-12-24 | 2015-04-01 | 厦门科明达科技有限公司 | Preparation method of rare earth chemical drug lanthanum carbonatechewable tablets |
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| CN107876000A (en) * | 2017-10-30 | 2018-04-06 | 浙江大学 | A kind of nanometer dephosphorization agent, preparation method and application |
| WO2020085020A1 (en) * | 2018-10-26 | 2020-04-30 | 住友化学株式会社 | Method for producing lanthanum carbonate hydrate |
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| CN107876000A (en) * | 2017-10-30 | 2018-04-06 | 浙江大学 | A kind of nanometer dephosphorization agent, preparation method and application |
| CN114524452A (en) * | 2017-10-30 | 2022-05-24 | 浙江大学 | Nano lanthanum carbonate hydrate and preparation method and application thereof |
| WO2020085020A1 (en) * | 2018-10-26 | 2020-04-30 | 住友化学株式会社 | Method for producing lanthanum carbonate hydrate |
| CN112867695A (en) * | 2018-10-26 | 2021-05-28 | 住友化学株式会社 | Method for producing hydrous lanthanum carbonate |
| JPWO2020085020A1 (en) * | 2018-10-26 | 2021-09-09 | 住友化学株式会社 | Method for producing lanthanum carbonate hydrate |
| JP7300461B2 (en) | 2018-10-26 | 2023-06-29 | 住友化学株式会社 | Method for producing lanthanum carbonate hydrate |
| WO2020162851A1 (en) * | 2019-02-07 | 2020-08-13 | Hacettepe Üni̇versi̇tesi̇ | Formulations increasing bioactivity of lantanum carbonate and methods of their preparation |
| CN113029978A (en) * | 2019-12-25 | 2021-06-25 | 远大生命科学(辽宁)有限公司 | Method for detecting phosphorus binding capacity of lanthanum-containing reagent |
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