CN111603450B - Isosorbide mononitrate tablet and preparation process thereof - Google Patents
Isosorbide mononitrate tablet and preparation process thereof Download PDFInfo
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- CN111603450B CN111603450B CN201910133734.XA CN201910133734A CN111603450B CN 111603450 B CN111603450 B CN 111603450B CN 201910133734 A CN201910133734 A CN 201910133734A CN 111603450 B CN111603450 B CN 111603450B
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- isosorbide mononitrate
- tablet
- proline
- isosorbide
- sheet
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- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 title claims abstract description 197
- 229960003827 isosorbide mononitrate Drugs 0.000 title claims abstract description 196
- 238000002360 preparation method Methods 0.000 title abstract description 34
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 44
- 229960002429 proline Drugs 0.000 claims abstract description 44
- 229930182821 L-proline Natural products 0.000 claims abstract description 43
- 239000005995 Aluminium silicate Substances 0.000 claims abstract description 30
- 235000012211 aluminium silicate Nutrition 0.000 claims abstract description 30
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000463 material Substances 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- 239000000853 adhesive Substances 0.000 claims abstract description 4
- 230000001070 adhesive effect Effects 0.000 claims abstract description 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- 229960000829 kaolin Drugs 0.000 claims abstract description 3
- 238000002156 mixing Methods 0.000 claims description 49
- 239000011259 mixed solution Substances 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 41
- 238000005303 weighing Methods 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 23
- 239000008187 granular material Substances 0.000 claims description 22
- 239000002245 particle Substances 0.000 claims description 22
- 239000008213 purified water Substances 0.000 claims description 22
- 238000005507 spraying Methods 0.000 claims description 22
- 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 18
- 239000008101 lactose Substances 0.000 claims description 18
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 13
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 13
- 229960000913 crospovidone Drugs 0.000 claims description 11
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 11
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229920003109 sodium starch glycolate Polymers 0.000 claims 1
- 229940079832 sodium starch glycolate Drugs 0.000 claims 1
- 239000008109 sodium starch glycolate Substances 0.000 claims 1
- 229940032147 starch Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 230000008569 process Effects 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 91
- 230000000052 comparative effect Effects 0.000 description 26
- 238000004080 punching Methods 0.000 description 20
- 239000013078 crystal Substances 0.000 description 15
- 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 description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 229920003082 Povidone K 90 Polymers 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- 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 description 3
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 3
- 239000003405 delayed action preparation Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- FGRBYDKOBBBPOI-UHFFFAOYSA-N 10,10-dioxo-2-[4-(N-phenylanilino)phenyl]thioxanthen-9-one Chemical compound O=C1c2ccccc2S(=O)(=O)c2ccc(cc12)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 FGRBYDKOBBBPOI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 235000019766 L-Lysine Nutrition 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- JYWNYMJKURVPFH-UHFFFAOYSA-N N-gamma-Acetyl-N-2-Formyl-5-Methoxykynurenamine Chemical compound COC1=CC=C(NC=O)C(C(=O)CCNC(C)=O)=C1 JYWNYMJKURVPFH-UHFFFAOYSA-N 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229960000201 isosorbide dinitrate Drugs 0.000 description 2
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
- A61K9/2009—Inorganic compounds
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isosorbide mononitrate tablet and a preparation process thereof. The isosorbide mononitrate tablet provided by the invention comprises active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials, wherein the weight ratio of isosorbide mononitrate to L-proline to kaolin is 1:0.1-0.4:0.5-1.5, and the other pharmaceutically acceptable auxiliary materials comprise a filler, an adhesive, a disintegrating agent and a lubricant. The isosorbide mononitrate tablet prepared by the invention has good stability, is not easy to crystallize in the storage process, is quickly dissolved out and is beneficial to improving the bioavailability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isosorbide mononitrate tablet and a preparation process thereof.
Background
Isosorbide Mononitrate (Isosorbide Mononitrate) is known as 1, 4, 3, 6-dianhydro-D-sorbitol-5-nitrate, has a molecular formula of C6H9NO6 and a molecular weight of 191.14, is a white needle-shaped crystal or crystalline powder, is easily soluble in methanol or acetone, is soluble in chloroform or water, is almost insoluble in hexane, has a solubility of more than 250mg/mL in each medium of ph1.0 to ph6.8, belongs to a high-solubility drug, and has a structural formula as follows:
isosorbide mononitrate is the main bioactive metabolite of isosorbide mononitrate, is a new generation of nitrate antianginal drug, is suitable for long-term treatment of coronary heart disease, prevention of angina pectoris and treatment of persistent angina after myocardial infarction, and can be used in combination with digitalis and/or diuretics to treat chronic congestive heart failure. Clinical research results show that the medicine has the characteristics of rapid absorption, no first-pass effect, high bioavailability, wide effective concentration range, long duration of action of the medicine, high clinical curative effect and the like, has the outstanding advantages of small individual difference, low toxicity and the like, and is one of the best medicines for preventing and treating angina at present. At present, isosorbide mononitrate dosage forms on the market comprise tablets, dispersible tablets, sustained-release capsules, sustained-release tablets and the like.
Isosorbide mononitrate has a low melting point, and raw materials are easy to separate out and crystallize in the preparation and storage processes. In order to solve the problem, in patent CN103610650B, lactose is used as a stabilizer, povidone represented by PVP K90, copovidone, and the like are used as a binder and a crystal inhibitor, so that the remarkable change of the in vitro release degree of the drug caused by crystallization of isosorbide mononitrate is avoided. PVP K90 has higher viscosity, the effect of inhibiting crystallization is poorer when the dosage is less, the dissolution is slower when the dosage is larger, and PVP K90 adopted in the sustained-release preparation is not thickly enough, but if the sustained-release preparation is applied to a common tablet, the dissolution is slower inevitably, so that the sustained-release preparation has problems in the aspects of in-vitro similarity and in-vivo bioequivalence with the original preparation.
Patent application CN104055744A provides an isosorbide mononitrate tablet and a preparation method thereof, the tablet contains crospovidone and other pharmaceutically usable auxiliary materials, and good stability can be realized without adding a large amount of adhesive to inhibit crystal precipitation. According to the invention, the weight ratio of isosorbide mononitrate to crospovidone is 1:1-3, the minimum specification of the existing isosorbide mononitrate tablet is 20mg, and the dosage of each crospovidone is calculated to be 20-60mg, so that the cross-linked povidone is extremely easy to absorb moisture, and pocks are easy to appear on the surface of the tablet when too much dosage is used.
The prior art does not mention the technical scheme which can avoid the crystallization of the medicine, has better tablet surface, lower impurity content and higher dissolution rate.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide an isosorbide mononitrate tablet and a preparation process thereof. The isosorbide mononitrate tablet provided by the invention is not easy to crystallize, and has high stability and rapid drug dissolution.
Aiming at the problem that isosorbide mononitrate tablets are prone to crystallization, the inventor firstly adds high-molecular polymers or porous substances such as crospovidone, silicon dioxide and the like, and through a large number of experiments, the crystallization inhibiting effect is not obvious. In the process of screening the auxiliary materials, the inventor unexpectedly finds that the kaolin has a certain crystal inhibition effect, but the acceleration stability is still poor. Then, the inventor tries to add amino acid substances and kaolin to achieve the purpose of stabilizing the isosorbide mononitrate, so that the preparation added with the L-proline is not easy to crystallize, but does not have the effect when other amino acids are used, and the structure of the preparation is related to the existence of the pyrrolidinyl.
Specifically, the purpose of the invention is realized by the following technical scheme:
an isosorbide mononitrate tablet comprises active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials.
The weight ratio of the isosorbide mononitrate to the L-proline to the kaolin is 1 (0.1-0.3) to 0.5-1.5.
Preferably, the weight ratio of isosorbide mononitrate to L-proline to kaolin is 1:0.2: 1.
The pharmaceutically acceptable other auxiliary materials comprise a filler, a binder, a disintegrant and a lubricant.
Preferably, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, lactose and starch.
Preferably, the binder is selected from one or more of hydroxypropyl cellulose, hypromellose and povidone.
Preferably, the disintegrating agent is selected from one or more of sodium carboxymethyl starch, crospovidone, sodium croscarmellose and low-substituted hydroxypropyl cellulose.
Preferably, the lubricant is selected from one or more of magnesium stearate, magnesium aluminum silicate and sodium stearate fumarate.
The isosorbide mononitrate tablet comprises the following components in parts by weight:
meanwhile, the invention provides a preparation process of the isosorbide mononitrate tablet, which comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution for later use;
(2) weighing a filler, an adhesive and a disintegrating agent, adding into a fluidized bed, uniformly mixing, spraying the mixed solution obtained in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate granules for later use;
(3) and (3) uniformly mixing the isosorbide mononitrate particles obtained in the step (2) with a lubricant, and tabletting to obtain the isosorbide mononitrate tablet.
Compared with the prior art, the isosorbide mononitrate tablet is not easy to crystallize in the storage process, has high stability and quick drug dissolution, and is beneficial to improving the bioavailability. In addition, isosorbide mononitrate belongs to nitrate drugs, and is easy to explode in the crushing and sieving processes.
Detailed Description
The invention will be further described by the following description of specific embodiments, it being properly understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.
All raw materials and reagents in the invention are commercially available.
EXAMPLE 1 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl starch according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 2 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 3 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the formula amounts of pregelatinized starch, microcrystalline cellulose, povidone K30 and crospovidone XL-10, adding into a fluidized bed, mixing uniformly, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
Example 4 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, povidone K30 and sodium carboxymethyl starch according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
EXAMPLE 5 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 6 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, pregelatinized starch, hydroxypropyl cellulose and sodium carboxymethyl cellulose in the formula amount, adding into a fluidized bed, mixing uniformly, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Example 7 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and crospovidone XL-10 according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 8 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing microcrystalline cellulose, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with magnesium aluminum silicate, punching a sheet with a diameter of 8mm in a shallow arc, and obtaining the isosorbide mononitrate sheet with the hardness of 50-80N.
Example 9 isosorbide mononitrate tablets
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the pregelatinized starch, the hydroxypropyl methylcellulose and the croscarmellose sodium in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Example 10 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing mannitol, hydroxypropyl methylcellulose and croscarmellose sodium in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with talcum powder, punching the tablets with a shallow arc of phi 8mm and hardness of 50-80N to obtain the isosorbide mononitrate tablets.
EXAMPLE 11 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the dextrin, the lactose, the starch slurry and the crosslinked sodium carboxymethyl cellulose according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with zinc stearate, punching the tablets by a shallow arc with the diameter of 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 12 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the pregelatinized starch, the povidone K30 and the crospovidone XL-10 according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and granulating to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
Example 13 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 1 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate into purified water, stirring until the isosorbide mononitrate is completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 2 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate into purified water, stirring until the isosorbide mononitrate is completely dissolved to obtain an isosorbide mononitrate water solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the aqueous solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 3 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and histidine into purified water, stirring until the isosorbide mononitrate and the histidine are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 4 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-lysine into purified water, stirring until the isosorbide mononitrate and the L-lysine are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 5 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, and stirring until the isosorbide mononitrate and the L-proline are completely dissolved to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching into a shallow arc tablet with the diameter of 8mm, and obtaining the isosorbide mononitrate tablet with the hardness of 50-80N.
Comparative example 6 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding talcum powder, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 7 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
weighing the main drug with the prescription amount, fully mixing the main drug with the auxiliary materials of lactose, sodium chloride, povidone K30 and silicon dioxide by an equivalent gradual addition method, sieving and uniformly mixing, then adding a proper amount of 90% ethanol solution to prepare a proper soft material, granulating by a 20-mesh sieve, drying, adding the magnesium stearate with the prescription amount, granulating, fully and uniformly mixing, and tabletting to obtain the isosorbide mononitrate tablet.
Comparative example 8 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
and (3) screening isosorbide mononitrate and crospovidone by a sieve of 80 meshes, weighing according to the prescription, adding microcrystalline cellulose according to the prescription, mixing uniformly, adding magnesium stearate according to the prescription, mixing uniformly, and tabletting to obtain the isosorbide mononitrate tablet.
Comparative example 9 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and povidone K90 into purified water, and stirring until the isosorbide mononitrate and the povidone K90 are completely dissolved to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching into a shallow arc tablet with the diameter of 8mm, and obtaining the isosorbide mononitrate tablet with the hardness of 50-80N.
Verification examples
1. Test materials: isosorbide mononitrate tablets and original formulations prepared in examples 1-13 and comparative examples 1-9.
2. Test method
(1) Stability test
Placing the sample in a room temperature environment, and inspecting the appearance of each isosorbide mononitrate tablet sample at month 6; referring to the requirements of 'Chinese pharmacopoeia' (2015 edition) appendix <9001 raw material medicament and preparation stability test guiding principle >, a sample is placed in a constant temperature incubator with the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-10%, appearance characters of each isosorbide mononitrate tablet sample at 0 th month and 6 th month of various products are inspected, and the content (%) of related substances is tested.
The related substance content test method comprises the following steps: grinding the sample to prepare solution containing lmg in lmL as test solution; and taking a proper amount of an isosorbide dinitrate reference substance and an isosorbide 2-mononitrate reference substance, precisely weighing, adding a mobile phase for dissolving and quantitatively diluting to prepare a mixed solution containing about 0.25mg of each lmL, precisely weighing 2mL, placing in a 200mL measuring flask, precisely adding a test solution lmL, diluting to a scale with the mobile phase, and shaking uniformly to obtain the reference solution. And (3) injecting 20 mu L of the control solution into a liquid chromatograph, adjusting the detection sensitivity to enable the peak height of the isosorbide mononitrate peak to be about 25% of the full range, precisely measuring 20 mu L of each of the test solution and the control solution, injecting the test solution and the control solution into the liquid chromatograph, and recording the chromatogram until the retention time of the isosorbide mononitrate peak is 1.1 times. If chromatographic peaks consistent with retention time of isosorbide dinitrate and isosorbide 2-mononitrate exist in a chromatogram of the test solution, the chromatographic peaks are not more than 0.25 percent calculated by the peak area according to an external standard method; the peak area of other single impurities is not more than 0.5 times (0.25%) of the peak area of isosorbide mononitrate in the control solution, and the total amount of the impurities is not more than 0.5%.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water (25: 75) as mobile phase; the detection wavelength is 210 nm. Taking a proper amount of isosorbide mononitrate and 2-isosorbide mononitrate as reference substances, adding mobile phase for dissolving and diluting to prepare solutions containing about 5 mu g of each lmL, taking 20 mu L of human-injection liquid chromatograph, wherein the theoretical plate number is not less than 3000 according to the peak of isosorbide mononitrate, and the separation degree of the peak of isosorbide mononitrate and the peak of 2-isosorbide mononitrate is more than 2.0.
(2) Dissolution test
The samples were placed in a constant temperature incubator at 40. + -. 2 ℃ and a relative humidity of 75. + -. 10% to test the dissolution rate at month 0 and month 6. A sample was taken, and the solution was filtered at 5 and 10 minutes according to the dissolution method (0931, the general rule of the four departments of the 2015 edition, China pharmacopoeia) using 900mL of water as dissolution medium and 50 rpm, and 20. mu.L of filtrate was accurately obtained and injected into a liquid chromatograph, and the chromatogram was recorded. And precisely weighing isosorbide mononitrate as a reference substance, adding a dissolving-out medium to dissolve the isosorbide mononitrate, quantitatively diluting the isosorbide mononitrate with the dissolved medium to prepare solution containing about 22 mu g of the isosorbide mononitrate in lmL, and measuring by the same method. The elution amount of each tablet was calculated by peak area according to the external standard method.
Chromatographic conditions and stability test.
3. And (3) test results: the test results are shown in tables 1, 2 and 3.
TABLE 1 isosorbide mononitrate tablets appearance characteristics
| Sample (I) | 0 month | Room temperature for 6 months | Accelerated for 6 months |
| Example 1 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 2 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 3 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 4 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 5 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 6 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean |
| Example 7 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 8 | The surface of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 9 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 10 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 11 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 12 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 13 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Comparative example 1 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 2 | The surface of the sheet is smooth and clean | A large amount of crystals are separated out | A large amount of crystals are separated out |
| Comparative example 3 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 4 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 5 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 6 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 7 | The surface of the sheet is smooth and clean | The surface of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 8 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | Pocked on the surface of the sheet |
| Comparative example 9 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
Through tests, the isosorbide mononitrate tablets prepared in the examples 1 to 13 of the invention have high stability, have smooth surfaces and no crystallization phenomenon after 6-month accelerated tests, and the comparative examples 1 to 6 have crystallization at different degrees, which shows that the L-proline and kaolin are used together to have better crystal inhibition effect; comparative examples 7 and 8 respectively use silicon dioxide and crospovidone as crystal inhibitors, and the stability is lower than that of the embodiment of the invention.
Table 2 isosorbide mononitrate tablet related substance content (%)
Through tests, after the isosorbide mononitrate tablets of the embodiments 1 to 13 of the invention are accelerated for 6 months, the increase of related substances is not obvious (see table 2), and the isosorbide mononitrate tablets are superior to the original developers; the contents of related substances in the comparative examples 1 to 6 are increased to a certain extent, which shows that the combination action of the L proline and the kaolin can improve the stability of the isosorbide mononitrate tablet and prevent the substances from going bad; the increase ratio of the total impurity content in comparative examples 7 and 8 was higher than that in the examples of the present invention; the prescription of comparative example 9 contains povidone K90, and the content increase ratio of related substances is large.
TABLE 3 dissolution of isosorbide mononitrate tablets
Through tests, the isosorbide mononitrate tablets prepared in examples 1-13 of the invention still dissolve rapidly after 6 months of accelerated tests (see table 3), the dissolution rate of comparative example 8 in 5min is obviously weaker than that of the invention, and the dissolution rate of comparative example 9 is slower by taking povidone K90 as a crystal inhibitor.
Claims (8)
1. The isosorbide mononitrate tablet is characterized by comprising active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials, wherein the weight ratio of the isosorbide mononitrate to the L-proline to the kaolin is 1:0.1-0.3: 0.5-1.5.
2. The isosorbide mononitrate tablet of claim 1, wherein the weight ratio of isosorbide mononitrate to L-proline and kaolin is 1:0.2: 1.
3. The isosorbide mononitrate tablet of claim 1, wherein the pharmaceutically acceptable other excipients include a filler, a binder, a disintegrant, and a lubricant.
4. The isosorbide mononitrate tablet of claim 3, wherein the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch.
5. The isosorbide mononitrate tablet of claim 3, wherein the binder is selected from one or more of hydroxypropyl cellulose, hypromellose, povidone.
6. The isosorbide mononitrate tablet of claim 3, wherein the disintegrant is selected from the group consisting of one or more of sodium starch glycolate, crospovidone, sodium croscarmellose and low substituted hydroxypropylcellulose.
7. The isosorbide mononitrate tablet of claim 3, wherein the lubricant is selected from one or more of magnesium stearate, magnesium aluminum silicate, sodium fumarate stearate.
8. The process for preparing an isosorbide mononitrate tablet of any one of claims 1-7, comprising the steps of:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring and dissolving, then adding kaolin, and uniformly stirring to obtain a mixed solution for later use;
(2) weighing a filler, an adhesive and a disintegrating agent, adding into a fluidized bed, uniformly mixing, spraying the mixed solution obtained in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate granules for later use;
(3) and (3) uniformly mixing the isosorbide mononitrate particles obtained in the step (2) with a lubricant, and tabletting to obtain the isosorbide mononitrate tablet.
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| CN201910133734.XA Active CN111603450B (en) | 2019-02-22 | 2019-02-22 | Isosorbide mononitrate tablet and preparation process thereof |
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| CN113509446A (en) * | 2021-05-31 | 2021-10-19 | 辰欣药业股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101095661A (en) * | 2007-07-23 | 2008-01-02 | 南昌弘益科技有限公司 | Isosorbide mononitrate orally disintegrating tablets |
| CN104055744A (en) * | 2014-07-18 | 2014-09-24 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
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| CA2348452A1 (en) * | 1998-10-27 | 2000-05-04 | Biovail Technologies Ltd. | Microparticles containing peg and/or peg glyceryl esters |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101095661A (en) * | 2007-07-23 | 2008-01-02 | 南昌弘益科技有限公司 | Isosorbide mononitrate orally disintegrating tablets |
| CN104055744A (en) * | 2014-07-18 | 2014-09-24 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
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