CN117122570A - 一种提高稳定性的美阿沙坦钾片及其制备方法 - Google Patents
一种提高稳定性的美阿沙坦钾片及其制备方法 Download PDFInfo
- Publication number
- CN117122570A CN117122570A CN202210544979.3A CN202210544979A CN117122570A CN 117122570 A CN117122570 A CN 117122570A CN 202210544979 A CN202210544979 A CN 202210544979A CN 117122570 A CN117122570 A CN 117122570A
- Authority
- CN
- China
- Prior art keywords
- potassium
- tablet
- parts
- metartan
- 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.)
- Granted
Links
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 239000011591 potassium Substances 0.000 title claims abstract description 60
- 229910052700 potassium Inorganic materials 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title abstract description 36
- 239000008187 granular material Substances 0.000 claims abstract description 45
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims abstract description 26
- 229960003194 meglumine Drugs 0.000 claims abstract description 26
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000011975 tartaric acid Substances 0.000 claims abstract description 24
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 23
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 16
- 238000002156 mixing Methods 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000003381 stabilizer Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000002083 C09CA01 - Losartan Substances 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 9
- 229960000519 losartan potassium Drugs 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 9
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims abstract description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 8
- 239000000853 adhesive Substances 0.000 claims abstract description 6
- 230000001070 adhesive effect Effects 0.000 claims abstract description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000001530 fumaric acid Substances 0.000 claims abstract description 4
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims abstract description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000011230 binding agent Substances 0.000 claims abstract description 3
- 235000015165 citric acid Nutrition 0.000 claims abstract description 3
- 235000011087 fumaric acid Nutrition 0.000 claims abstract description 3
- 239000004310 lactic acid Substances 0.000 claims abstract description 3
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 3
- 239000001630 malic acid Substances 0.000 claims abstract description 3
- 235000011090 malic acid Nutrition 0.000 claims abstract description 3
- 229960000502 poloxamer Drugs 0.000 claims abstract description 3
- 229920001983 poloxamer Polymers 0.000 claims abstract description 3
- 229950008882 polysorbate Drugs 0.000 claims abstract description 3
- 229920000136 polysorbate Polymers 0.000 claims abstract description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 229960003975 potassium Drugs 0.000 claims description 20
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 17
- 229930195725 Mannitol Natural products 0.000 claims description 17
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 235000010355 mannitol Nutrition 0.000 claims description 17
- 239000000594 mannitol Substances 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 15
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 15
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 15
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 15
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 15
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 13
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 229960001855 mannitol Drugs 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 235000007686 potassium Nutrition 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims 1
- 229940083542 sodium Drugs 0.000 claims 1
- 229960001367 tartaric acid Drugs 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 5
- 238000005507 spraying Methods 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003125 aqueous solvent Substances 0.000 abstract 1
- 239000007884 disintegrant Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000005485 Azilsartan Substances 0.000 description 5
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 5
- 229960002731 azilsartan Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 102000005862 Angiotensin II Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- IHWFKDWIUSZLCJ-UHFFFAOYSA-M azilsartan kamedoxomil Chemical compound [K+].C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3[N-]C(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C IHWFKDWIUSZLCJ-UHFFFAOYSA-M 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000011361 granulated particle Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- -1 ester salt Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种美阿沙坦钾片及其制备方法。该美阿沙坦钾片由下述原料制成:美阿沙坦钾、稳定剂、增溶剂、填充剂、崩解剂、粘合剂和润滑剂;稳定剂选自酒石酸、富马酸、枸橼酸、乳酸和苹果酸中至少一种;增溶剂选自葡甲胺、泊洛沙姆、聚山梨酯和十二烷基硫酸钠中至少一种。制备方法如下:将美阿沙坦钾、填充剂、崩解剂于湿法制粒机中混匀,喷雾粘合剂、稳定剂、增溶剂的水溶剂将混合物进行制粒,流化床干燥;所得颗粒使用1.5mm筛网整粒;加入润滑剂并混匀;将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。该处方既能解决当前美阿沙坦钾片贮藏困难或工业化生产条件要求苛刻的问题,也能解决其溶解度差的问题。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种提高稳定性的美阿沙坦钾片及其制备方法。
背景技术
美阿沙坦钾片是由武田制药开发的一款用于治疗原发性高血压的口服药物制剂,是一款血管紧张素Ⅱ受体阻滞剂,血管紧张素Ⅱ由血管紧张素Ⅰ在血管紧张素酶催化作用下转换而来。血管紧张素Ⅱ是肾素-血管紧张素系统的主要升压剂,具有促进血管收缩、刺激醛固酮的合成和释放、激动心脏和促进肾脏对钠重吸收等多种生理作用。
美阿沙坦钾是一种口服前药,在吸收过程中可被体内酯酶迅速代谢为活性成分阿齐沙坦。美阿沙坦钾为酯盐,其在水分或高湿条件下容易水解为阿齐沙坦,因此,在药学上开发出一个相对稳定的美阿沙坦钾片处方,对于美阿沙坦钾片的长期保存来说至关重要。目前,市场上现有产品的内包装系统(铝塑泡罩或瓶装)均需要加入干燥剂,CN101677961B公开的原研制剂的制备工艺也需要长达16小时的减压干燥,以保障产品的水分处于绝对低的水平,生产条件较为苛刻。
另外,美阿沙坦钾和阿齐沙坦均属于难溶性药物,其溶解度均较低,在处方中加入增溶剂或通过超微粉碎、固体分散体等其它工艺技术,也可以有效改善本品的溶解度。
美阿沙坦钾,英文名称为Azilsartan Medoxomil Potassium,化学名称为2-乙氧基 -1-{[2′-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)联苯-4-基]甲基}-1H-苯并咪唑-7-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯钾盐,CAS号为863031-24-7,其结构式如下所示:
发明内容
本发明的目的是提供一种提高美阿沙坦钾片稳定性的处方,该处方既能解决当前美阿沙坦钾片贮藏困难或工业化生产条件要求苛刻的问题,也能解决其溶解度差的问题。
本发明所提供的美阿沙坦钾片,由下述原料制成:活性成分、稳定剂、增溶剂、填充剂、崩解剂、粘合剂和润滑剂;
所述活性成分为美阿沙坦钾;
所述稳定剂选自酒石酸、富马酸、枸橼酸、乳酸和苹果酸中至少一种,优选为酒石酸。
所述增溶剂选自葡甲胺、泊洛沙姆、聚山梨酯和十二烷基硫酸钠中至少一种,优选为葡甲胺。
所述填充剂选自甘露醇、乳糖、微晶纤维素、粉状纤维素、硅化微晶纤维素和淀粉中至少一种;优选为甘露醇和微晶纤维素组成,两者的质量比可为6:1。
所述崩解剂选自交联羧甲基纤维素钠、羟丙纤维素、交联聚维酮、羧甲淀粉钠和淀粉中至少一种;优选为交联羧甲基纤维素钠。
所述粘合剂选自羟丙基纤维素、聚维酮、羟丙甲纤维素、羟乙纤维素和聚乙烯醇中至少一种;优选为羟丙甲纤维素。
所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂富马酸钠和二氧化硅中至少一种。
进一步的,所述美阿沙坦钾片由下述质量份的原料制成:美阿沙坦钾85.36份;稳定剂4份;增溶剂5.6份;填充剂223.04份;崩解剂27.6份;粘合剂10.8份;润滑剂3.6份。
根据本发明的一个实施例,所述美阿沙坦钾片由下述质量份的原料制成:美阿沙坦钾85.36份、酒石酸4.0份、葡甲胺5.6份、甘露醇191.26份、微晶纤维素31.78份、交联羧甲基纤维素钠27.6份、羟丙基纤维素10.8份、硬脂酸镁3.6份。
本发明还提供了上述美阿沙坦钾片的制备方法。
本发明所提供的美阿沙坦钾片的制备方法,包括下述步骤:将美阿沙坦钾、填充剂、崩解剂于湿法制粒机中均匀混合,喷雾处方量粘合剂、稳定剂、增溶剂的水溶剂将混合物进行制粒,并使用流化床进行干燥;所得颗粒使用1.5mm筛网整粒;在整粒后的颗粒中加入处方量的润滑剂,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
与现有技术相比,本发明具有如下有益效果:
本发明的处方工艺可解决当前美阿沙坦钾片贮藏困难或工业化生产条件要求苛刻的问题,另外葡甲胺的引入,既作为碱性剂同酸性剂酒石酸共同提高了产品稳定性,又作为增溶剂增加了难溶性药物美阿沙坦钾的溶解度。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明并不限于以下实施例。所述方法如无特别说明均为常规方法。所述原材料如无特别说明均能从公开商业途径获得。
实施例1、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(40℃减压干燥16小时)的处方及制备方法。
表1实施例1处方
上述处方中,葡甲胺既可以作为碱性剂(稳定剂),又可以作为增溶剂。作为碱性剂,它同酒石酸共同组成缓冲pH,维持产品稳定性;作为增溶剂,它可以增加美阿沙坦钾溶解度。制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。将压制完成的素片于减压干燥箱中40℃干燥16小时。
实施例2、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(不进行减压干燥处理)的处方及制备方法。
表2实施例2处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
实施例3、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(增溶剂不同用量8mg/片)的处方及制备方法。
表3实施例3处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
实施例4、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(增溶剂不同用量9.3mg/片)的处方及制备方法。
表4实施例4处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
对比例1、美阿沙坦钾片的制备
参考CN101677961B中实施例1制备美阿沙坦钾片,如下:
表5对比例1处方
制备工艺:
将处方量的美阿沙坦钾、甘露醇于流化床中均匀混合,喷雾处方量羟丙基纤维素、富马酸和氢氧化钠水溶液将混合物进行制粒,并在流化床中干燥。所得颗粒使用1.5mm 筛网整粒。在整粒后的颗粒中加入处方量的交联羧甲基纤维素钠、微晶纤维素和硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。将压制完成的素片于减压干燥箱中40℃干燥16小时。
对比例2、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(枸橼酸和葡甲胺)的处方及制备方法,如下:
表6对比例2处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、枸橼酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
对比例3、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(酒石酸和碳酸钠)的处方及制备方法,如下:
表7对比例3处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和碳酸钠水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
对比例4、美阿沙坦钾片的制备
提供了制备美阿沙坦钾片(酒石酸:葡甲胺为1:2)的处方及制备方法,如下:
表8对比例4处方
制备工艺:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀。将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
将原研制剂、实施例1片剂、实施例2片剂、实施例3片剂、实施例4片剂和对比例1片剂、对比例2片剂、对比例3片剂、对比例4片剂,使用HPLC法对有关物质进行检查,结果如下:
表9有关物质检查结果汇总
将原研制剂、实施例1片剂、实施例2片剂、实施例3片剂、实施例4片剂和对比例1片剂,于0.5%十二烷基硫酸钠的pH6.8磷酸盐缓冲液中进行溶出曲线考察(37℃,转速50rpm,介质900ml),使用UV法对溶出样品进行检查,结果如下:
表10溶出曲线检查结果汇总
由表6可知,原研制剂、实施例1片剂、实施例2片剂和对比例1片剂,有关物质检查结果均未见显著性差异;实施例2片剂与实施例3片剂、实施例4片剂对比有关物质检查结果,随着葡甲胺用量增加,高温60℃/10天的主要降解产物阿齐沙坦增加明显。处方中葡甲胺用量在5.6mg/片,可制备出同原研制剂相当的产品;实施例2片剂与对比例2片剂对比高温60℃/10天的主要降解产物阿齐沙坦,葡甲胺与酒石酸配伍制备的片剂质量明显优于葡甲胺与枸橼酸配伍制备的片剂;实施例2片剂与对比例3片剂对比0天及高温60℃/10天的有关物质,酒石酸与葡甲胺配伍制备的片剂质量明显优于酒石酸与碳酸钠配伍制备的片剂;实施例2片剂与对比例4片剂对比0天及高温60℃/10天的有关物质,酒石酸与葡甲胺按5:7配伍制备的片剂质量明显优于酒石酸与葡甲胺1:2配伍制备的片剂。
由表7可知,原研制剂、实施例1片剂、实施例2片剂、实施例3片剂、实施例4片剂和对比例1片剂、对比例2片剂、对比例4片剂,溶出曲线检查结果均未见显著性差异,表明处方中加入葡甲胺和酒石酸,片剂不进行减压干燥处理也一样可以制备出质量同原研制剂相当的产品。对比例4片剂与其他批次对比溶出曲线,5分钟溶出量差异较大,表明酒石酸与碳酸钠不宜配伍。
Claims (9)
1.一种美阿沙坦钾片,由下述原料制成:活性成分、稳定剂、增溶剂、填充剂、崩解剂、粘合剂和润滑剂;
所述活性成分为美阿沙坦钾;
所述稳定剂选自酒石酸、富马酸、枸橼酸、乳酸和苹果酸中至少一种;
所述增溶剂选自葡甲胺、泊洛沙姆、聚山梨酯和十二烷基硫酸钠中至少一种。
2.根据权利要求1所述的美阿沙坦钾片,其特征在于:所述稳定剂为酒石酸;所述增溶剂为葡甲胺。
3.根据权利要求1或2所述的美阿沙坦钾片,其特征在于:所述填充剂选自甘露醇、乳糖、微晶纤维素、粉状纤维素、硅化微晶纤维素和淀粉中至少一种;优选为甘露醇和微晶纤维素组成,两者的质量比为6:1。
4.根据权利要求1-3中任一项所述的美阿沙坦钾片,其特征在于:
所述崩解剂选自交联羧甲基纤维素钠、羟丙纤维素、交联聚维酮、羧甲淀粉钠和淀粉中至少一种;优选为交联羧甲基纤维素钠。
5.根据权利要求1-4中任一项所述的美阿沙坦钾片,其特征在于:
所述粘合剂选自羟丙基纤维素、聚维酮、羟丙甲纤维素、羟乙纤维素和聚乙烯醇中至少一种;优选为羟丙甲纤维素。
6.根据权利要求1-5中任一项所述的美阿沙坦钾片,其特征在于:
所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂富马酸钠和二氧化硅中至少一种。
7.根据权利要求1-6中任一项所述的美阿沙坦钾片,其特征在于:所述美阿沙坦钾片由下述质量份的原料制成:美阿沙坦钾85.36份;稳定剂4份;增溶剂5.6份;填充剂223.04份;崩解剂27.6份;粘合剂10.8份;润滑剂3.6份。
8.根据权利要求1-6中任一项所述的美阿沙坦钾片,其特征在于:所述美阿沙坦钾片由下述质量份的原料制成:美阿沙坦钾85.36份、酒石酸4.0份、葡甲胺1.38份、甘露醇191.26份、微晶纤维素36份、交联羧甲基纤维素钠27.6份、羟丙基纤维素10.8份、硬脂酸镁3.6份。
9.权利要求8所述的美阿沙坦钾片的制备方法,包括下述步骤:
将处方量的美阿沙坦钾、微晶纤维素、甘露醇、交联羧甲基纤维素钠于湿法制粒机中均匀混合,喷雾处方量羟丙基纤维素、酒石酸和葡甲胺水溶液将混合物进行制粒,并使用流化床进行干燥。所得颗粒使用1.5mm筛网整粒。在整粒后的颗粒中加入处方量的硬脂酸镁,并于混合机中混合均匀;将混合均匀的总混颗粒,使用旋转压片机,以理论片重360mg进行压片。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210544979.3A CN117122570B (zh) | 2022-05-19 | 2022-05-19 | 一种提高稳定性的美阿沙坦钾片及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210544979.3A CN117122570B (zh) | 2022-05-19 | 2022-05-19 | 一种提高稳定性的美阿沙坦钾片及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117122570A true CN117122570A (zh) | 2023-11-28 |
CN117122570B CN117122570B (zh) | 2024-04-09 |
Family
ID=88855066
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210544979.3A Active CN117122570B (zh) | 2022-05-19 | 2022-05-19 | 一种提高稳定性的美阿沙坦钾片及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117122570B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115969985A (zh) * | 2022-12-05 | 2023-04-18 | 北京百奥药业有限责任公司 | 美阿沙坦钾片及其制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101677961A (zh) * | 2007-03-28 | 2010-03-24 | 武田药品工业株式会社 | 包含苯并咪唑-7-羧酸酯衍生物和ph控制剂的固体药物组合物 |
CN109157527A (zh) * | 2018-07-25 | 2019-01-08 | 珠海润都制药股份有限公司 | 一种厄贝沙坦胶囊及其制备方法 |
-
2022
- 2022-05-19 CN CN202210544979.3A patent/CN117122570B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101677961A (zh) * | 2007-03-28 | 2010-03-24 | 武田药品工业株式会社 | 包含苯并咪唑-7-羧酸酯衍生物和ph控制剂的固体药物组合物 |
CN109157527A (zh) * | 2018-07-25 | 2019-01-08 | 珠海润都制药股份有限公司 | 一种厄贝沙坦胶囊及其制备方法 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115969985A (zh) * | 2022-12-05 | 2023-04-18 | 北京百奥药业有限责任公司 | 美阿沙坦钾片及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN117122570B (zh) | 2024-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7943172B2 (en) | Film-coated tablet or granules containing as active ingredient a pyridylpyrimidine compound or a pharmaceutically acceptable salt of this compound | |
EP1843754B1 (en) | New pharmaceutical composition containing candesartan cilexetil as lipophilic crystalline substance | |
EP2939662A1 (en) | Pharmaceutical composition with improved stability, containing temozolomide, and preparation method therefor | |
CN101951889A (zh) | 伊马替尼组合物 | |
EP3606511B1 (en) | Pharmaceutical composition comprising lenvatinib mesylate | |
JP6399115B2 (ja) | アンギオテンシンii拮抗作用を有する化合物を含有する固形医薬組成物 | |
EP2242483B1 (en) | Raloxifene composition | |
EA023529B1 (ru) | Способ получения твердых лекарственных форм солифенацина и его фармацевтически приемлемых солей для перорального введения | |
CN117122570B (zh) | 一种提高稳定性的美阿沙坦钾片及其制备方法 | |
CN109875972B (zh) | 一种奥美沙坦酯氨氯地平药物组合物 | |
CN106913529B (zh) | 一种来那替尼或其可药用盐药物组合物的制备方法 | |
KR101485421B1 (ko) | 이토프라이드 염산염을 함유하는 제어 방출성 경구 제제의 조성물 및 그의 제조방법 | |
EP3632436B1 (en) | Pharmaceutical composition comprising lenvatinib salts | |
JP4774739B2 (ja) | 漢方エキス含有錠剤組成物およびその製造方法 | |
EP1864677B1 (en) | Stable formulation comprising a moisture sensitive drug and manufacturing procedure thereof | |
JPS6412248B2 (zh) | ||
CN110693884A (zh) | 一种复方制剂缬沙坦氨氯地平片及其制备方法 | |
KR101809886B1 (ko) | 소형화된 클래리트로마이신 경구투여 제제 | |
WO2007142628A1 (en) | Stable formulation comprising moisture sensitive drug/s and manufacturing procedure thereof | |
EP4302832A1 (en) | Palbociclib formulation containing glucono delta lactone | |
CN117017993B (zh) | 一种儿童复方氨酚肾素药物组合物、制剂及其制备工艺 | |
CN1214792C (zh) | 吸收性很好的固体制剂 | |
EP4302755A1 (en) | Palbociclib formulation containing an amino acid | |
RU2449792C1 (ru) | Лекарственное средство в виде таблеток, обладающее противовирусным и интерфероногенным действием, и способ его получения | |
WO2023036980A1 (en) | Pharmaceutical composition of bempedoic acid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |