CN1569861A - Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use - Google Patents
Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use Download PDFInfo
- Publication number
- CN1569861A CN1569861A CN 200410034994 CN200410034994A CN1569861A CN 1569861 A CN1569861 A CN 1569861A CN 200410034994 CN200410034994 CN 200410034994 CN 200410034994 A CN200410034994 A CN 200410034994A CN 1569861 A CN1569861 A CN 1569861A
- Authority
- CN
- China
- Prior art keywords
- adefovir ester
- acid
- salt
- adefovir
- aspartic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 38
- 239000002253 acid Substances 0.000 title claims abstract description 30
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 title abstract description 7
- 229960003205 adefovir dipivoxil Drugs 0.000 title abstract description 7
- -1 aspartic acid adefovir dipivoxil ester salt Chemical class 0.000 claims abstract description 99
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 38
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 37
- XOAAWQZATWQOTB-UHFFFAOYSA-N Taurine Natural products NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960003080 taurine Drugs 0.000 claims abstract description 17
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims abstract description 15
- 235000012208 gluconic acid Nutrition 0.000 claims abstract description 11
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000174 gluconic acid Substances 0.000 claims abstract description 10
- 229960001997 adefovir Drugs 0.000 claims description 101
- 239000000654 additive Substances 0.000 claims description 29
- 230000000996 additive effect Effects 0.000 claims description 29
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 14
- 229940040102 levulinic acid Drugs 0.000 claims description 10
- 239000007924 injection Substances 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 239000003708 ampul Substances 0.000 claims description 2
- 229940046011 buccal tablet Drugs 0.000 claims description 2
- 239000006189 buccal tablet Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000006071 cream Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 210000000214 mouth Anatomy 0.000 claims description 2
- 229940023488 pill Drugs 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 abstract 1
- 229930091371 Fructose Natural products 0.000 abstract 1
- 239000005715 Fructose Substances 0.000 abstract 1
- 229960005261 aspartic acid Drugs 0.000 description 37
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 10
- 229950006191 gluconic acid Drugs 0.000 description 8
- 210000005229 liver cell Anatomy 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- NAOLWIGVYRIGTP-UHFFFAOYSA-N 1,3,5-trihydroxyanthracene-9,10-dione Chemical compound C1=CC(O)=C2C(=O)C3=CC(O)=CC(O)=C3C(=O)C2=C1 NAOLWIGVYRIGTP-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 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 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000004722 levulinic acids Chemical class 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 230000009972 noncorrosive effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses four pharmaceutical acid addition salts of adefovir dipivoxil, including aspartic acid adefovir dipivoxil ester salt, taurine adefovir dipivoxil ester salt, gluconic acid adefovir dipivoxil ester salt, fructose adefovir dipivoxil and their pharmaceutical use.
Description
Technical fieldThe invention belongs to medical technical field, relate to the additive salt of four kinds of pharmaceutically acceptable acids of antiviral adefovir ester, and these adefovir ester salt application on medicine.
Background technologyAdefovir ester (Adefovir Dipivoxil is called for short AD), its chemical name is: two (the pivalyl oxygen methoxyl group) phosphatidyl methoxies of 9-[2-[] ethyl] VITAMIN B4, its chemical structural formula is:
Molecular formula C
20H
32N
5O
8P, adefovir ester are a kind of novel antiviral, are used to suppress people or Mammals retroviral infection, the especially hepatitis b virus infected treatment of hepatitis virus.
Usually adefovir ester all obtains with the oily matter form, consider at aspects such as medication preparation, storage, uses often with its curing for the ease of it, domestic patent disclosure technology about adefovir ester curing or crystallization is more: Chinese invention patent application number 98803744.0 and 00137059.6 discloses the crystal habit of several adefovir esters, wherein also relates to some organic acids of adefovir ester and the crystal salt of mineral acid; Chinese invention patent application number 02111037.9 discloses amorphous cured article of a kind of adefovir ester and preparation method thereof; Chinese invention patent application number 02137905.X, Chinese invention patent application number 02148744.8, Chinese invention patent application number 02151028.8 and 02151032.6, Chinese invention patent application number 03100167.X etc. disclose the crystalline structure of several adefovir esters.
Summary of the inventionThe basic center that is present in VITAMIN B4 in the structure of adefovir ester, form the composite form of addition hydrochlorate than easily carrying out addition reaction with acid, the additive salt that the purpose of this invention is to provide the pharmaceutically acceptable acid of several adefovir esters, these salt can be the crystalline structure forms, also can be the structural form of amorphous solid, also comprise the application of these salt on medicine.
The structural formula of the acid salt of adefovir ester of the present invention is as follows:
C
20H
32N
5O
8The medicinal acid of P.a[]; consider the pharmacological action of hepatitis B virus resisting of adefovir ester and selected acid toxic side effect to liver; also consider the adefovir ester salt of disclosed a series of organic acids of Chinese invention patent application number 98803744.0 and mineral acid; the selected medicinal acid of the present invention comprises Aspartic Acid, taurine, gluconic acid and levulinic acid, and adefovir ester is Aspartic Acid adefovir ester salt, taurine adefovir ester salt, gluconic acid adefovir ester salt, levulinic acid adefovir ester salt with the additive salt of these four kinds of acid respectively.
Be explained respectively with these four kinds of acid and with the additive salt of adefovir ester below.
The Aspartic Acid chemical name claims alpha-amino group Succinic Acid, molecular formula C again
4H
7NO
4Contain two carboxyls and an amino in the molecular structure, belong to acidic amino acid, the Aspartic Acid that the present invention adopts has levo form L-Aspartic Acid, dextrorotatory form D-Aspartic Acid and raceme DL-Aspartic Acid. and Aspartic Acid extensively is present in all proteins, the avidity of its pair cell is very strong, and the effect of certain enhancing liver function is also arranged, and has no side effect, also the medicinal acid carrier of Chang Zuowei uses, and the molecular formula of Aspartic Acid adefovir ester additive salt is as follows
C
20H
32N
5O
8P.aC
4H
7NO
4Wherein a is the molecule number with the salifiable Aspartic Acid of adefovir ester, that is the ratio of two active centre Aspartic Acids and the mole number of adefovir ester in the Aspartic Acid adefovir ester additive salt, the span of a is 0.01～50, the value of a can be a decimal, also can be integer, preferred a=0.5 and 1.In preparation, the reacting weight that feeds intake of control Aspartic Acid and adefovir ester, the value difference of may command a makes the Aspartic Acid adefovir ester additive salt of different salify ratios.
Taurine chemistry 2-aminoethyl sulfonic acid by name, molecular formula C
2H
7NO
3S, taurine are a kind of sulfur-containing amino acid, are present in the humans and animals body, have multiple pharmacologically active, and liver is had provide protection.The molecular formula of taurine adefovir ester addition hydrochlorate is as follows
C
20H
32N
5O
8P.aC
2H
7NO
3S wherein a is a molecule number with the salifiable taurine of adefovir ester; that is the ratio of two active centre taurines and the mole number of adefovir ester in the taurine adefovir ester additive salt, the span of a is 0.01～50, the value of a can be a decimal; also can be integer, preferred a=1.In the preparation, the reacting weight that feeds intake of control taurine and adefovir ester, the value difference of may command a makes the taurine adefovir ester additive salt of different salify ratios.
Gluconic acid chemistry hexonic acid by name, molecular formula C
6H
12O
7, be a kind of nontoxic, non-corrosive organic monoacid, the oxidation that is glucose is for hitting a product, and the Chang Zuowei nutrient additive for food uses, and also the medicinal acid carrier of Chang Zuowei uses.The molecular formula of gluconic acid adefovir ester addition hydrochlorate is as follows
C
20H
32N
5O
8P.aC
6H
12O
7Wherein a is the molecule number with the salifiable gluconic acid of adefovir ester, that is the ratio of two active centre gluconic acids and the mole number of adefovir ester in the gluconic acid adefovir ester additive salt, the span of a is 0.01～50, the value of a can be a decimal, also can be integer, preferred a=1. controls the reacting weight that feeds intake of gluconic acid and adefovir ester in preparation, the value difference of may command a makes the gluconic acid adefovir ester additive salt of different salify ratios.
Levulinic acid has another name called left-handed saccharic acid, levulinic acid, chemistry Laevulinic Acid by name, molecular formula C
5H
8O
3, be a kind of nontoxic organic acid, the Chang Zuowei nutrient additive for food uses, and also the medicinal acid carrier of Chang Zuowei uses.The molecular formula of levulinic acid adefovir ester addition hydrochlorate is as follows
C
20H
32N
5O
8P.aC
5H
8O
3Wherein a is the molecule number with the salifiable levulinic acid of adefovir ester, that is the ratio of two active centre levulinic acids and the mole number of adefovir ester in the levulinic acid adefovir ester additive salt, the span of a is 0.01～50, the value of a can be a decimal, also can be integer, preferred a=1. controls the reacting weight that feeds intake of levulinic acid and adefovir ester in preparation, the value difference of may command a makes the levulinic acid adefovir ester additive salt of different salify ratios.
Those of skill in the art of the present invention are appreciated that, the adefovir ester additive salt of above-mentioned four kinds of acid for keeping distinctive crystalline structure, can contain crystal water in crystallisation process, therefore, the adefovir ester additive salt of the above-mentioned four kinds of acid of the present invention also comprises its crystalline hydrate.
The preparation method of the adefovir ester additive salt of four kinds of acid of the present invention is dissolved in suitable solvent with the oily matter of adefovir ester or unformed cured article or xln, contact with medicinal acid thorough mixing in solution that the present invention selects for use again, adefovir ester is contacted and salify in liquid environment with medicinal acid, again solvent is removed by methods such as filtration or evaporation or lyophilizes, promptly obtained the adefovir ester additive salt of solid form.
The application of adefovir ester additive salt on medicine of four kinds of acid of the present invention, be used to prepare the medicine of antiviral especially anti-hepatitis B virus, adopt different pharmaceutical excipient and preparation method, can be made into acceptable pharmaceutical dosage form on any medicine, comprise the tablet, capsule, granule, pill, the oral fluid agent that orally use, injection liquid, powder ampoule agent for injection that injection is used, the emulsion of external application, cream creme are through the oral cavity or the buccal tablet of sublingual administration etc.
The positively effect of the medicinal acid addition salt form of adefovir ester of the present invention is, for the application of adefovir ester on medicine provides new compound form, opened up the range of application of adefovir ester, and through experimental verification, the stable in properties of these four kinds of acid salt, and because organic acid of the present invention is the pharmaceutically acceptable acid that dependent interaction is arranged, it has certain drug effect promoter action to the agent structure adefovir ester of additive salt to a certain extent.The inventor has compared the affine experiment of external animal liver cell of adefovir ester and Aspartic Acid adefovir ester salt of the present invention, found that Aspartic Acid adefovir ester salt has better cellular affinity than adefovir ester, verify the curative effect advantage of the present invention's Aspartic Acid adefovir ester salt medicine wherein with experimentation on animals, experimentation is as follows:
The liver cell of utilization healthy rat is cultivated the variation of back strength of solution and verifies the affinity of liver cell to different pharmaceutical in different pharmaceutical solution.Experimental technique:
1. it is an amount of to get Aspartic Acid adefovir ester salt and adefovir ester, adopt identical solubilizing agent with physiological saline respectively with its dissolving, make the normal saline solution of Aspartic Acid adefovir ester salt and adefovir ester respectively, the about 20 μ mol/L of strength of solution, respectively get the solution of equal volume, stand-by.
2. get five of healthy rats, the sacrificed by exsanguination rat is taken out its liver immediately, and liver is mixed and made into ice physiological saline tissue homogenate, and is centrifugal, removes supernatant liquor, gets the liver cell of equal volume, stand-by.
3. the healthy rat liver cell with equal volume in 2 is added to the Aspartic Acid adefovir ester salt of equal volume in 1 and the normal saline solution of adefovir ester respectively, educate in the case in 35 ℃ and to cultivate 0.5 hour, precipitation, HPLC method are measured in two kinds of culture tubes the concentration of Aspartic Acid adefovir ester salt and adefovir ester in the supernatant liquor.Experimental data:
| Group | Aspartic Acid adefovir ester salt group | The adefovir ester group |
| Concentration before cultivating in physiological saline | ??21.4μmol/L | ?22.7μmol/L |
| Concentration behind the cultivation 0.5h in the supernatant liquor | ??17.7μmol/L | ?19.8μmol/L |
| Both differences before and after cultivating | ??3.8μmol/L | ?2.9μmol/L |
By last table data as can be seen, the change in concentration of Aspartic Acid adefovir ester salt group is greater than the adefovir ester group before and after cultivating, exceed 31% approximately, as seen Aspartic Acid adefovir ester salt group has more adefovir ester to combine or enter in the liver cell with the rat liver cell, analyzing its reason may be that Aspartic Acid has promoted adefovir ester to hepatocellular avidity as a kind of mediation group, illustrated that Aspartic Acid adefovir ester salt is stronger to hepatocellular avidity than adefovir ester, more help suppressing the virus in the liver cell, demonstrated the curative effect advantage of Aspartic Acid adefovir ester salt medicine.
EmbodimentWith following several embodiment, preparation and pharmaceutical preparation thereof by adefovir ester salt of the present invention further specify the present invention, but do not represent the embodiment limitation of the present invention.
The preparation of embodiment 1. Aspartic Acid adefovir ester salt
502g adefovir ester oily matter or amorphous cured article or crystal are dissolved in the 1.8L ethanol, under appropriateness stirs, slowly drip Aspartic Acid (the preferred L-Aspartic Acid) aqueous solution that contains 133g to solution, 40 ℃ of insulated and stirred, with about 20 minutes the Aspartic Acid aqueous solution is dropwised, insulation continues to stir after 5 minutes reduces to room temperature gradually, continue to remove behind the slow stir about 5hr liquid composition (adopting vacuum-drying or lyophilize to handle) in the mixture, the solids that obtains off-white color promptly is an Aspartic Acid adefovir ester salt (1: 1).
Present embodiment Aspartic Acid adefovir ester is Aspartic Acid and the adefovir ester additive salt with 1: 1 ratio be combined into of mol ratio, and its molecular formula is C
20H
32N
5O
8P.C
4H
7NO
4
Embodiment 2. changes the charging capacity 133g of Aspartic Acid among the embodiment 1 into 66.5g, can make Aspartic Acid and the adefovir ester additive salt with 1: 2 ratio be combined into, and its molecular formula is C
20H
32N
5O
8P.1/2C
4H
7NO
4
The preparation of embodiment 3. taurine adefovir ester salt
502g adefovir ester oily matter or amorphous cured article or crystal are dissolved in the 2L Virahol; under appropriateness stirs; slowly drip the taurine aqueous isopropanol that contains 125g to solution; 45 ℃ of insulated and stirred; with about 20 minutes the taurine aqueous isopropanol is dropwised; insulation continue to be stirred and to be reduced to room temperature gradually, continues to remove behind the slow stir about 5hr liquid composition (adopting vacuum-drying or lyophilize to handle) in the mixture, and the solids that obtains promptly is a taurine adefovir ester salt (1: 1).
Present embodiment taurine adefovir ester salt is taurine and the adefovir ester additive salt with 1: 1 ratio be combined into of mol ratio, and its molecular formula is C
20H
32N
5O
8P.C
2H
7NO
3S.
The preparation of embodiment 4. Aspartic Acid adefovir ester sheets
Get the Aspartic Acid adefovir ester additive salt 12.65g of embodiment 1 preparation; even with 170g lactose, 40g Microcrystalline Cellulose, 18g sodium starch glycolate thorough mixing in nodulizer; with the wetting softwood of making of ethanol; the drying of granulating back adds the 2.8g Magnesium Stearate; mixing; be pressed into 1000, promptly get Aspartic Acid adefovir ester sheet, every contains 12.65mg Aspartic Acid adefovir ester (the wherein about 10mg/ sheet of active substance adefovir ester).
Claims (9)
1. the Aspartic Acid additive salt of adefovir ester, its structural formula is C
20H
32N
5O
8P.aC
4H
7NO
4
2. the taurine additive salt of adefovir ester, its structural formula is C
20H
32N
5O
8P.aC
2H
7NO
3S.
3. the gluconic acid additive salt of adefovir ester, its structural formula is C
20H
32N
5O
8P.aC
6H
12O
7
4. the levulinic acid additive salt of adefovir ester, its structural formula is C
20H
32N
5O
8P.aC
5H
8O
3
5. according to any one is described in the claim 1 to 4, it is characterized in that a is and the mole number of the salifiable medicinal acid of adefovir ester, the span of a is 0.01～50.
6. according to claim 5, preferred a=0.5 and 1, preferred especially a=1.
7. according to the medicinal acid addition salt of any one described adefovir ester in the claim 1 to 4, its preparation method comprises makes adefovir ester contact in liquid environment with medicinal acid.
8. pharmaceutical composition, it comprises as the medicinal acid addition salt of any one described adefovir ester in the claim 1 to 4 and pharmaceutically acceptable vehicle.
9. described according to Claim 8, it is characterized in that pharmaceutical dosage form comprises tablet, capsule, granule, pill, the oral fluid agent that orally uses, injection liquid, powder ampoule agent for injection that injection is used, the emulsion of external application, cream creme are through the oral cavity or the buccal tablet of sublingual administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410034994 CN1569861A (en) | 2004-05-06 | 2004-05-06 | Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410034994 CN1569861A (en) | 2004-05-06 | 2004-05-06 | Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1569861A true CN1569861A (en) | 2005-01-26 |
Family
ID=34481562
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410034994 Pending CN1569861A (en) | 2004-05-06 | 2004-05-06 | Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1569861A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7935817B2 (en) * | 2008-03-31 | 2011-05-03 | Apotex Pharmachem Inc. | Salt form and cocrystals of adefovir dipivoxil and processes for preparation thereof |
-
2004
- 2004-05-06 CN CN 200410034994 patent/CN1569861A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7935817B2 (en) * | 2008-03-31 | 2011-05-03 | Apotex Pharmachem Inc. | Salt form and cocrystals of adefovir dipivoxil and processes for preparation thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2913194C (en) | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor | |
| CN1263464A (en) | Pharmaceutical preparations containing hydrosoluble ketoprofen salts and their application | |
| AU2014336747B2 (en) | Crystal form of (r)-praziquantel and preparation method and application thereof | |
| CN109678715B (en) | Salt, the preparation method and the usage that 2- (1- acyl-oxygen n-pentyl) benzoic acid and basic amino acid or aminoguanidine are formed | |
| WO2015007181A1 (en) | 5-BROMINE-2-(α-HYDROXYPENTYL)BENZOIC ACID SODIUM SALTS IN DIFFERENT CRYSTAL FORMS, AND PREPARATION METHOD THEREOF | |
| KR101700734B1 (en) | Complexes of germanium with amino acids and carboxylic acids and method for preparing the same | |
| CN112552196B (en) | Method for preparing lysine-piprolin | |
| CN1081631C (en) | N-methyl-N- [ (1S) -1-phenyl-2- ((3S) -3-hydroxypyrrolidin-1-yl ] ethyl ] -2, 2-diphenylacetamide | |
| CN105061636A (en) | Preparation method of chitosan, citric acid and rare earth coordination compound | |
| CN1103339C (en) | Prepn. method of medicinal-grade peat sodium fulvic acid | |
| WO2010074591A1 (en) | Creatine amides, a method for the production thereof and an agent exhibiting a neuroprotective action | |
| CN1569861A (en) | Pharmaceutical acid addition salt of adefovir dipivoxil and its pharmaceutical use | |
| CN107001276B (en) | Sodium salt of uric acid transport protein inhibitor and crystal form thereof | |
| JPS58131952A (en) | Manufacture of novel amino acid derivative | |
| US4973553A (en) | Salt or organogermanium compound and medicine containing the same | |
| JPH0587064B2 (en) | ||
| CN102180785A (en) | Synthesis and application of ibuprofen lysine | |
| CN116139164B (en) | Supramolecular hydrogel derived from Maxingshi Gantn decoction and having antipyretic and anti-inflammatory effects | |
| CN1216037C (en) | Process for preparing 3-hydroxy-3-methylbutyrate (HMB) amino acid salt | |
| US7704976B2 (en) | Use of N-acetyl-D-glucosamine for preparing medicines for urogenital tract infection's treatment and prevention | |
| JP2885261B2 (en) | Infusion preparation comprising 3-hydroxybutyric acid oligomer and salt thereof | |
| CN115073368B (en) | Milrinone-5-sulfosalicylic acid crystal form | |
| CN114835767B (en) | Arbutin conjugate and application thereof | |
| CN115160204B (en) | Fibroblast activation protein inhibitor and preparation method and application thereof | |
| CN1226302C (en) | Ibuprofen ribavirin ester and preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20060908 Address after: 32F, global Plaza, No. 54, 158, Fuzhou Applicant after: Guangshengtang pharmaceutical Industry Co., Ltd. Fujian Address before: Room 1, unit 10, building 36, No. two, 404 Road, Qingdao, Shandong, Anshan Applicant before: Yang Xihong |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |