WO2014071819A1 - 醋酸镧或其水合物治疗血磷酸盐过多症的用途 - Google Patents
醋酸镧或其水合物治疗血磷酸盐过多症的用途 Download PDFInfo
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- WO2014071819A1 WO2014071819A1 PCT/CN2013/086396 CN2013086396W WO2014071819A1 WO 2014071819 A1 WO2014071819 A1 WO 2014071819A1 CN 2013086396 W CN2013086396 W CN 2013086396W WO 2014071819 A1 WO2014071819 A1 WO 2014071819A1
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- Prior art keywords
- acetate
- hydrate
- cerium
- lanthanum acetate
- carbonate
- Prior art date
Links
- 201000005991 hyperphosphatemia Diseases 0.000 title claims abstract description 11
- JLRJWBUSTKIQQH-UHFFFAOYSA-K lanthanum(3+);triacetate Chemical compound [La+3].CC([O-])=O.CC([O-])=O.CC([O-])=O JLRJWBUSTKIQQH-UHFFFAOYSA-K 0.000 title claims abstract description 9
- 150000004677 hydrates Chemical class 0.000 title abstract 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 239000008297 liquid dosage form Substances 0.000 claims description 4
- 239000008184 oral solid dosage form Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000011574 phosphorus Substances 0.000 abstract description 12
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 12
- 238000012360 testing method Methods 0.000 abstract description 9
- -1 phosphorus ions Chemical class 0.000 abstract description 4
- 229910017569 La2(CO3)3 Inorganic materials 0.000 abstract description 3
- 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 abstract description 3
- 229960001633 lanthanum carbonate Drugs 0.000 abstract description 3
- VGBWDOLBWVJTRZ-UHFFFAOYSA-K cerium(3+);triacetate Chemical compound [Ce+3].CC([O-])=O.CC([O-])=O.CC([O-])=O VGBWDOLBWVJTRZ-UHFFFAOYSA-K 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- 239000011230 binding agent Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 229910019142 PO4 Inorganic materials 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 8
- 239000010452 phosphate Substances 0.000 description 8
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- BDAGIHXWWSANSR-NJFSPNSNSA-N hydroxyformaldehyde Chemical compound O[14CH]=O BDAGIHXWWSANSR-NJFSPNSNSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910000018 strontium carbonate Inorganic materials 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- AERUOEZHIAYQQL-UHFFFAOYSA-K cerium(3+);triacetate;hydrate Chemical compound O.[Ce+3].CC([O-])=O.CC([O-])=O.CC([O-])=O AERUOEZHIAYQQL-UHFFFAOYSA-K 0.000 description 5
- RXSHXLOMRZJCLB-UHFFFAOYSA-L strontium;diacetate Chemical compound [Sr+2].CC([O-])=O.CC([O-])=O RXSHXLOMRZJCLB-UHFFFAOYSA-L 0.000 description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 229910000420 cerium oxide Inorganic materials 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- ITHZDDVSAWDQPZ-UHFFFAOYSA-L barium acetate Chemical compound [Ba+2].CC([O-])=O.CC([O-])=O ITHZDDVSAWDQPZ-UHFFFAOYSA-L 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- GHLITDDQOMIBFS-UHFFFAOYSA-H cerium(3+);tricarbonate Chemical compound [Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GHLITDDQOMIBFS-UHFFFAOYSA-H 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 description 2
- 206010036790 Productive cough Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- YXVOGOMWPQXYGF-UHFFFAOYSA-N acetic acid;hydrazine;hydrate Chemical compound O.NN.CC(O)=O YXVOGOMWPQXYGF-UHFFFAOYSA-N 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- DXVWRJRZCMCNEU-UHFFFAOYSA-N dimercaptoamine Chemical compound SNS DXVWRJRZCMCNEU-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 229910052712 strontium Inorganic materials 0.000 description 2
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QYIGOGBGVKONDY-UHFFFAOYSA-N 1-(2-bromo-5-chlorophenyl)-3-methylpyrazole Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1Br QYIGOGBGVKONDY-UHFFFAOYSA-N 0.000 description 1
- 241001674044 Blattodea Species 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- 206010020669 Hypermagnesaemia Diseases 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- YFHNDHXQDJQEEE-UHFFFAOYSA-N acetic acid;hydrazine Chemical compound NN.CC(O)=O YFHNDHXQDJQEEE-UHFFFAOYSA-N 0.000 description 1
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- JMJZZPYODPTULV-UHFFFAOYSA-L dicesium;carbonate;hydrate Chemical compound O.[Cs+].[Cs+].[O-]C([O-])=O JMJZZPYODPTULV-UHFFFAOYSA-L 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 206010016766 flatulence Diseases 0.000 description 1
- 229940099065 fosrenol Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- DXTIKTAIYCJTII-UHFFFAOYSA-N guanidine acetate Chemical compound CC([O-])=O.NC([NH3+])=N DXTIKTAIYCJTII-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002694 phosphate binding agent Substances 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- 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
Definitions
- the present invention relates to the field of medical technology, and more particularly to the use of strontium acetate or a hydrate thereof for the treatment of hyperphosphatemia. Background technique
- Hyperphosphatemia a hyperphosphatemia
- the disease also causes damage to the cardiovascular system. It is reported that about 50% of patients will die as a result (Shen Lei, Jin Zhan. Antihyperphosphoric acid new drug strontium carbonate) Progress in Pharmaceutical Sciences, 2005, 29(6): 286-287 ⁇ ).
- the current treatment of the disease is mainly diet control and the use of phosphate binders. Phosphate binders can sequester phosphorus in food and prevent the absorption of phosphorus in the gastrointestinal tract.
- Commonly used phosphate binders include aluminum-containing phosphorus binders such as aluminum hydroxide; calcium-containing phosphorus binders such as calcium carbonate and calcium acetate; and magnesium-containing phosphorus binders such as magnesium carbonate.
- aluminum hydroxide is the phosphorus-reducing drug with the strongest phosphorus binding ability, but long-term clinical observations that aluminum preparations are prone to aluminum poisoning, and have been used less frequently.
- calcium salts long-term use can easily cause flatulence, belching and constipation, leading to cardiovascular diseases such as cardiovascular calcification.
- a magnesium-containing phosphorus binder it is prone to cause hypermagnesemia in patients with renal failure.
- the present invention provides a pharmaceutical composition comprising lanthanum acetate in the form of La(CH 2 COO ) 3 ⁇ 2 0 and a pharmaceutically acceptable carrier (or adjuvant), herein, X
- X The value is 0-9, preferably 0, 0.5, 1, 1.5, 2, 3, 4, 5, or 6, more preferably 0.5-1.5.
- the pharmaceutical composition of cerium acetate provided by the present invention wherein the content of cerium acetate in the pharmaceutical composition is from 1 to 99%, preferably from 10 to 80%, wherein the weight percentage is anhydrous Calcium acetate.
- the bismuth acetate pharmaceutical composition provided by the invention can be formulated into a dosage form suitable for oral administration, including an oral solid dosage form, such as a tablet (including a chewable tablet), a capsule, a powder, a granule or a coated pellet; or an oral liquid dosage form. , such as suspension or sugar paddles.
- the guanidine acetate pharmaceutical composition provided by the present invention is formulated into an oral solid dosage form or an oral liquid dosage form, and the carrier (or adjuvant) described herein may be selected from those known in the art, and, those skilled in the art may There is a need to select a conventional carrier (or adjuvant) suitable for the preparation of an oral solid dosage form or an oral liquid dosage form.
- a conventional carrier or adjuvant suitable for the preparation of an oral solid dosage form or an oral liquid dosage form.
- the present invention provides a method of preparing a pharmaceutical composition comprising cerium acetate, comprising the steps of:
- the invention provides a method for preparing a pharmaceutical composition containing barium acetate, wherein the anhydrous barium acetate can be prepared by the following method:
- Method A The obtained hydrazine acetate hydrate was heated to a constant weight at 150 ° C under vacuum to obtain hydrazine acetate without water.
- Method B 10 g of the obtained cerium acetate hydrate is placed in a reaction flask, 150 mL of anhydrous N,N-dimercaptoamide is added, and the cerium acetate is dissolved in DMF as much as possible, followed by the addition of anhydrous benzene. 200 mL, the toluene water azeotrope was distilled off, and the resulting La(CH 3 COO) 3 'DMF was precipitated. Filtration, washing with diethyl ether, collecting the crystals and storing them in a vacuum desiccator containing anhydrous calcium chloride and phosphorus pentoxide.
- the crystal was placed in a vacuum drying oven and heated at about 180 ° C to remove DMF to obtain anhydrous cesium acetate.
- the lanthanum acetate in the form of La(CH 2 COO ) 3 ⁇ 2 0 used in the present invention was tested by elemental analysis (La, C and H) and TGA analysis to determine its molecular formula.
- the present invention provides the use of a pharmaceutical composition comprising strontium acetate for the treatment of hyperphosphatemia.
- a usual pharmacological method can be used to determine a suitable dose.
- the daily dose of strontium acetate required is 0.1-20 g (based on anhydrous cesium acetate), preferably about 0.5-15 g; it can be administered orally, and it can be used once or more times a day.
- the present invention provides the possibility of combining the acid salt without the need to introduce any sputum into the bloodstream so that it does not cause toxic effects.
- the cerium acetate pharmaceutical composition provided by the invention has the advantages of better safety and lowering the speed of riding the acid salt.
- the TGA test apparatus and test conditions involved in the present invention are: Perkin Elmer Thermal Analysis Pyris 1 TGA; heated at 10 ° C / min, from 25 ° C to 500 ° C.
- FIG. 1 shows a TGA pattern of the preparation of cerium acetate hydrate in Example 2.
- BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be further described by way of specific examples. For the person skilled in the art, the following examples may be modified according to the prior art, but still fall within the scope of the claimed invention.
- Example 1 10 g of cerium oxide was added to a reaction flask containing 500 mL of acetic anhydride, heated under stirring, and refluxed for 6-10 hours until the end of the reaction.
- the resulting product is deposited on the bottom of the vessel, filtered, and the product is dried in a vacuum desiccator containing solid potassium hydroxide and anhydrous calcium chloride for more than 24 hours, and the product is placed in a vacuum oven at 100 ° C. - Dry at 0.095MPa.
- the obtained anhydrous cerium acetate powder is mixed with Abbas sin to obtain a powder.
- Example 2 10 g of cerium oxide was dissolved in 500 mL of a 50% acetic acid solution, and stirred and dissolved by heating in a steam bath. If a small amount of insoluble matter remains on the bottom of the container, it is removed by filtration. The resulting filtrate was concentrated under reduced pressure to remove most of solvent. After standing to cool, crystals were precipitated.
- Method B Take 10 g of hydrazine acetate hydrate, place it in a reaction flask, add 150 mL of anhydrous N,N-dimercaptoamide, stir to dissolve cesium acetate in DMF as much as possible, and then add 200 mL of anhydrous benzene.
- the toluene water azeotrope was distilled off, and the resulting La(CH 3 COO) 3 'DMF was precipitated. Filtration, washing with diethyl ether, collecting the crystals and storing them in a vacuum desiccator containing anhydrous calcium chloride and phosphorus pentoxide.
- the crystal was placed in a vacuum drying oven and heated at about 180 ° C to remove DMF to obtain anhydrous cesium acetate.
- the anhydrous cerium acetate obtained above is prepared into a tablet or a capsule by a conventional method in a conventional manner.
- Example 1 The anhydrous cesium acetate and cesium carbonate obtained in Example 1 or 1 were respectively subjected to the following tests:
- a base solution was prepared by dissolving 31.76 g of anhydrous Na 2 HP0 4 and 19.63 g of NaCl in 2.5 liters of deionized water.
- the rats of Example 1 or 2 of the present invention were used to obtain anhydrous cesium acetate at a dose of 20 mg/kg, and three rats were cultured in a feeding cage to collect metabolic feces and urine.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了醋酸镧或其水合物治疗血磷酸盐过多症的用途，本发明的醋酸镧或其水合物在许多试验中比碳酸镧表现出更好的与磷离子结合的能力，且有优于碳酸镧的性能。
Description
醋酸镧或其水合物治疗血磷酸盐过多症的用途 技术领域 本发明涉及医药技术领域， 更具体地说， 涉及醋酸镧或其水合物治疗血 磷酸盐过多症的用途。 背景技术
血磷酸盐过多症即高磷血症， 是慢性肾衰的并发症之一， 80%的肾透析 病人患有此症。 该病症除引起骨折等骨骼方面的疾病外， 还会造成心血管系 统的损害，据报导患者中约有 50% 的患者会因此而死亡（沈磊、 晋展.抗高 磷酸血症新药碳酸镧. 药学进展， 2005,29(6): 286-287· )。 目前该病的治疗主要为饮食控制和使用磷酸盐结合剂。磷酸盐结合剂可 以螯合食物中的磷及阻止胃肠道中磷的吸收。常用的磷酸盐结合剂包括含铝 的磷结合剂， 如氢氧化铝； 含钙的磷结合剂， 如碳酸钙、 醋酸钙； 以及含镁 的磷结合剂， 如碳酸镁等。 其中， 氢氧化铝是磷结合力最强的降磷药物， 但 长期临床发现服用铝制剂易有铝中毒现象， 目前已较少使用。在使用钙盐时， 长期服用易引起胀气、 嗳气及便秘， 导致心血管钙化等心血管疾病。 在使用 含镁的磷结合剂时， 对于肾衰者容易引起高血镁症。 此外， 先令公司（Shire)研发上市了碳酸镧， 商品名为 Fosrenol。作为一 种非钙、 非铝的磷酸结合剂，碳酸镧具有与传统结合剂同样降低病人血清中 的磷酸盐水平的作用。 水合碳酸镧已用于治疗高磷血症（参见例如美国专利 5,968,976 )和肾衰 竭者的高磷血症（参见例如 JP 1876384 ) 。 经选择的碳酸镧水合物可以经胃 肠道施用用于治疗肾衰竭病人的血磷酸盐过多症（ CN 96193918.4,
1996.3.19 ) 。
然而临床结果表明， 碳酸镧应避免长期服用， 虽然一般认为稀土元素是 低毒元素， 但金属镧在体内蓄积的安全后果还缺少临床数据。 服用碳酸镧最 常见的副作用是胃肠道反应， 其发生率比传统的磷酸结合剂高约 6%, 这种 差距可以解释为长期给药之故。 碳酸镧与传统药物相比， 严重副作用的发生
率和致死率分别为 65.4%和 51.0%及 6.0% 和 2.6% (沈磊、 晋展.抗高磷酸 血症新药碳酸镧. 药学进展， 2005,29(6): 286-287· )。 因此， 本领域仍然存在这样的需求： 希望得到一种临床使用更安全有效 的、 与磷离子结合能力更好的、 性能优越的磷结合剂。 发明内容
本发明人对醋酸镧进行了大量的研究，令人惊奇地发现了醋酸镧在许多 试验中比标准的商品碳酸镧表现出更好的与磷离子结合的能力，且有优于碳 酸镧的性能。 本发明的目的是提供醋酸镧或其水合物治疗血磷酸盐过多症的用途。 具体地说，一方面，本发明提供了一种药物组合物，其包含 La( CH2COO ) 3·ΧΗ20形式的醋酸镧和药学上可接受的载体（或辅料） ， 这里， X的值为 0-9, 优选 0、 0.5、 1、 1.5、 2、 3、 4、 5、 或 6, 更优选 0.5-1.5。 本发明提供的醋酸镧药物组合物， 其中， 醋酸镧在所述药物组合物中的 重量百分比含量为 1至 99%, 优选地， 10至 80%, 这里， 所述重量百分比 是以无水的醋酸镧计。 本发明提供的醋酸镧药物组合物可制成适于口服的剂型， 包括口服固体 剂型， 如片剂 （包括咀嚼片） 、 胶嚢、 散剂、 颗粒剂或包衣丸； 也可以是口 服液体剂型， 如悬浮液或糖桨。 本发明提供的醋酸镧药物组合物制成适于口服固体剂型或口服液体剂 型， 这里所述的载体（或辅料）可选自现有技术中已知的， 而且， 本领域的 技术人员可根据需要选择适于制备口服固体剂型或口服液体剂型的常规载 体（或辅料） 。 例如参考一一奚念朱主编， 《药剂学》 （第三版）， 人民卫生 出版社， 1994年。 另一个方面， 本发明提供了含醋酸镧药物组合物的制备方法， 包括如下 步骤：
( 1 )制备 La ( CH2COO ) 3·ΧΗ20形式的醋酸镧；
( 2 )将步骤（1 )得到的 La ( CH2COO ) 3·ΧΗ20形式的醋酸镧与药学 上可接受的载体混合。 本发明提供的含醋酸镧药物组合物的制备方法， 其中， 无水的醋酸镧可 以采用下列方法制备：
( i )取 10g氧化镧加至盛有 500mL醋酸酐的反应瓶中， 搅拌下加热， 回流反应 6 ~ 10h至反应结束； 生成的产物沉积于容器底部， 过滤， 产物置 于装有固体氢氧化钾和无水氯化钙的真空干燥器中干燥 24小时以上， 再将 产物置于真空干燥箱中， 于 100°C , - 0.095MPa下干燥。 或者 （ ii )取 10g氧化镧溶于 500mL 50%醋酸溶液中， 用蒸气浴加热下 搅拌溶解； 若有少量不溶物残留在容器底部， 过滤将之除去； 将所得滤液置 减压浓缩除去大部分溶剂； 放置冷却后析出晶体； 过滤收集晶体， 将其置于 装有粒状氢氧化钠及高氯酸镁的真空干燥器中， 抽真空进行干燥， 得到水合 醋酸镧； 可用下述 A法或 B法除去结晶水。
A法： 将得到的水合醋酸镧在 150°C于抽真空条件下加热至恒重，得到无 水醋酸镧。
B法： 取 10g得到的醋酸镧水合物， 置于反应瓶中， 加入无水的 N, N - 二曱基曱酰胺 150mL, 搅拌使醋酸镧尽可能溶解于 DMF中， 然后加入无水 曱苯 200mL, 蒸馏除去曱苯水共沸物， 生成的 La(CH3COO)3'DMF析出。 过 滤， 用乙醚洗涤， 收集晶体放至置无水氯化钙和五氧化二磷的真空保干器中 保存。 最后将晶体置于真空干燥箱置中在 180°C左右加热， 以除去 DMF, 得 到无水醋酸镧。 本发明中所使用的 La( CH2COO )3·ΧΗ20形式的醋酸镧用元素分析（ La、 C和 H ) 、 TGA分析测试， 从而确定其分子式。 第三方面，本发明提供了含有醋酸镧药物组合物治疗血磷酸盐过多症的 药物方面的应用。 对于本发明的含有醋酸镧药物组合物，可以用通常的药理学方法来确定 适用的剂量。 每日需要的醋酸镧剂量为 0.1-20g (以无水醋酸镧计），优选约 0.5-15g; 可采用口服的方式， 并且可以采用每日一次或多次的方式。
本发明提供了不用将任何的镧进入血流就能结合騎酸盐的可能性， 这样 就不会引起毒性作用的问题。 与现有技术相比， 本发明提供的醋酸镧药物组合物具有安全性更好、 降 低騎酸盐更迅速的优点。 本发明所涉及的 TGA测试仪器及测试条件为： 美国 Perkin Elmer Thermal Analysis Pyris 1 TGA； 以 10 °C /min速度加热， 从 25 °C至 500 °C。 附图说明 图 1表示的是实施例 2制备水合醋酸镧的 TGA图谱。 具体实施方式 下面通过具体的实例来进一步叙述本发明的实施方案。对于本领域普通 技术人员而言， 在本发明的教导下， 根据现有技术可对下列实例进行修改， 但仍然属于本发明请求保护的范围。 实施例 1 取 10g氧化镧加至盛有 500mL醋酸酐的反应瓶中， 搅拌下加热， 回流 反应 6 ~ 10h至反应结束。 生成的产物沉积于容器底部， 过滤， 产物置于装 有固体氢氧化钾和无水氯化钙的真空干燥器中干燥 24小时以上， 再将产物 置于真空干燥箱中， 于 100°C , - 0.095MPa下干燥。 将得到的无水醋酸镧粉 状物与阿巴斯甜混合即得散剂。 实施例 2 取 10g氧化镧溶于 500mL 50%醋酸溶液中， 用蒸气浴加热下搅拌溶解。 若有少量不溶物残留在容器底部， 过滤将之除去。 将所得滤液置减压浓缩除 去大部分溶剂。 放置冷却后析出晶体。 过滤收集晶体， 将其置于装有粒状氢 氧化钠及高氯酸镁的真空干燥器中，抽真空进行干燥，得到水合醋酸镧（0.5、 1、 1.5、 2、 3、 4、 5、 或 6摩尔水）。 其中 1.5摩尔水的水合醋酸镧 TGA如 图 1。
A法： 将上述的水合醋酸镧在 150°C于抽真空条件下加热至恒重， 得到 无水醋酸镧。
B法： 取 10g醋酸镧水合物， 置于反应瓶中， 加入无水的 N, N -二曱 基曱酰胺 150mL, 搅拌使醋酸镧尽可能溶解于 DMF中， 然后加入无水曱苯 200mL, 蒸馏除去曱苯水共沸物， 生成的 La(CH3COO)3'DMF析出。 过滤， 用乙醚洗涤， 收集晶体放至置无水氯化钙和五氧化二磷的真空保干器中保 存。 最后将晶体置于真空干燥箱置中在 180°C左右加热， 以除去 DMF, 得到 无水醋酸镧。 将上述得到的无水醋酸镧以常规剂量、 常规的方法制备成片剂或胶嚢 剂。
试验例 1
以实施例 1或 1得到的无水醋酸镧与碳酸镧分别开展如下的试验：
( 1 )将 31.76克无水 Na2HP04、 19.63克 NaCl溶解在 2.5升去离子水中 制备成基础溶液。
( 2 )加入浓盐酸， 取 100ml基础溶液调节至 pH3.0。
( 3 )取 5ml试液通过 0.02μηι滤膜的过滤器，得到标记为时间 0的试样。 用 "σ诊断比色磷测试盒"对其进行分析。
( 4 )加入 5ml新鲜的基础溶液使得重新达到 100ml并重新将溶液的 pH 值调到 3.0。
( 5 )在室温下搅拌加入一定量的粉状醋酸镧 (实例 1或 2 )、 或者碳酸 镧， 加入量是以使溶液中的镧离子比磷酸盐过剩两倍的摩尔数进行计算。
( 6 ) 以 0.5至 10分钟的时间间隔进行取样， 测定騎酸盐的百分比。 结 果如表 1 所示。 表 1
除去的磷酸盐％
时间 （min ) 试样
碳酸镧 醋酸镧
0
0.5 23.4 36.1
1 42.3 57.9
1.5 55.9 75.1
2 68.9 87.8
2.5 79.1 95.2
3 91.9 99.1
4 94.0 100
5 100 100
10 100 100
从表 1中很容易看出，醋酸镧在除去磷酸盐的效果上要比碳酸镧起效快, 更能达到临床效果。
试验例 2
以 20mg/ kg的剂量用本发明实施例 1或 2得到无水醋酸镧对三只大鼠 养在饲养笼中给药， 收集代谢粪便和尿。
结果列于下面表 2 中。
上述结果表明： 72小时以后， 所有的镧都排泄出去了。 在尿样中， 镧的 量低于检出限。 在试验以后取试验用大鼠， 分析肾、 肝和股骨中的镧含量。 结果镧的含 量都小于 0.1ppm。
Claims
1、 醋酸镧或其水合物在制备治疗血磷酸盐过多症的药物中的应用， 这 里， 所述的水合物为大于 0、 且小于或等于 9个摩尔的水。
2、 根据权利要求 1 所述的应用， 其中， 所述的水合物为 0.5、 1、 1.5、 2、 3、 4、 5、 或 6个摩尔的水。
3、 根据权利要求 2所述的应用， 其中， 所述的水合物为 0.5-1.5个摩尔 的水。
4、 根据权利要求 1 至 3 中任一权利要求所述的应用， 其中， 所述的药 物为口服给药。
5、 根据权利要求 4 所述的应用， 其中， 所述的口服给药为口服固体剂 型或口服液体剂型。
6、 根据权利要求 4所述的应用， 其中， 所述的口服给药， 每日醋酸镧剂 量为 0.1-20g, 并且可采用每日一次或多次的方式。
7、 根据权利要求 6 所述的应用， 其中， 所述的口服给药， 每日醋酸镧 剂量为约 0.5-15g。
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