CN115634206A - Minodronic acid tablet and preparation method thereof - Google Patents
Minodronic acid tablet and preparation method thereof Download PDFInfo
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- CN115634206A CN115634206A CN202110821830.0A CN202110821830A CN115634206A CN 115634206 A CN115634206 A CN 115634206A CN 202110821830 A CN202110821830 A CN 202110821830A CN 115634206 A CN115634206 A CN 115634206A
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- CN
- China
- Prior art keywords
- minodronic acid
- suspension
- tablet according
- oil
- minodronate
- Prior art date
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- VMMKGHQPQIEGSQ-UHFFFAOYSA-N minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229950011129 minodronic acid Drugs 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 239000000725 suspension Substances 0.000 claims description 46
- 238000002156 mixing Methods 0.000 claims description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 238000000227 grinding Methods 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 239000008187 granular material Substances 0.000 claims description 14
- 238000005507 spraying Methods 0.000 claims description 14
- 238000001238 wet grinding Methods 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 13
- 239000004519 grease Substances 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 13
- 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 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 239000003463 adsorbent Substances 0.000 claims description 10
- 229960000913 crospovidone Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 10
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 10
- 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 9
- 239000003921 oil Substances 0.000 claims description 9
- 235000019198 oils Nutrition 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 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 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 7
- 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 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 229920000858 Cyclodextrin Polymers 0.000 claims description 6
- 239000001116 FEMA 4028 Substances 0.000 claims description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 6
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 6
- 229960004853 betadex Drugs 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 6
- 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 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000003549 soybean oil Substances 0.000 claims description 5
- 235000012424 soybean oil Nutrition 0.000 claims description 5
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229940083542 sodium Drugs 0.000 claims description 4
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 3
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 3
- 235000019483 Peanut oil Nutrition 0.000 claims description 3
- 239000000312 peanut oil Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 229940008099 dimethicone Drugs 0.000 claims 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims 1
- 239000004205 dimethyl polysiloxane Substances 0.000 claims 1
- 229940057917 medium chain triglycerides Drugs 0.000 claims 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000004090 dissolution Methods 0.000 description 16
- 239000002245 particle Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 15
- 239000000463 material Substances 0.000 description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 7
- 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 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 239000001341 hydroxy propyl starch Substances 0.000 description 5
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229910002012 Aerosil® Inorganic materials 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 208000006386 Bone Resorption Diseases 0.000 description 2
- 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 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 230000024279 bone resorption Effects 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical group O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Chemical group 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 229940083037 simethicone Drugs 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000018083 Bone metabolism disease Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037118 bone strength Effects 0.000 description 1
- 230000008416 bone turnover Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 208000022458 calcium metabolism disease Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZZIHCLFHIXETF-UHFFFAOYSA-N dimethylsilicon Chemical compound C[Si]C JZZIHCLFHIXETF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 230000001599 osteoclastic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- -1 pyrophosphate farnesyl ester Chemical class 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a minodronic acid tablet and a preparation method thereof.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a minodronic acid tablet and a preparation method thereof.
Background
With the rapid entrance of modern society into aging society, bone and calcium metabolism diseases such as osteoporosis become one of chronic diseases which puzzle the health of middle-aged and elderly people in various countries, and fracture, bedridden and the like caused by the diseases lead to the reduction of life quality and the increase of death risk. The remarkable characteristics of the disease are bone resorption of patients, reduction of bone mass per unit volume, weakening of bone strength, increase of blood calcium content and the like caused by pathological or physiological factors exceeding bone formation. Osteoporosis is also a common frequently occurring disease in postmenopausal women and patients with malignant tumors. The preventive and therapeutic drugs thereof have become hot spots for the development of new drugs at present.
Minodronic acid is a novel heterocyclic bisphosphonic acid compound, is a third generation nitrogen-containing aromatic heterocyclic bisphosphate, inhibits osteoclastic bone resorption and reduces bone turnover by inhibiting the activity of pyrophosphate farnesyl ester synthase in osteoclasts, and has the effect of preventing and treating osteoporosis, and the minodronic acid is developed by Nissan Xiaoye drug industry Co., ltd and Japanese Astelas pharmaceutical Co., ltd, and is approved by Japan Kakko province for sale in Japan 1-21 of 2009.
The minodronate is white crystal in raw material property, light in weight, small in bulk density, easy to complex with metal, high in adsorbability, easy to adsorb on the metal inner wall of pharmaceutical machinery, and easy to cause sticking in the production process. Minodronic acid has poor water solubility, the absolute bioavailability is only 1.21 percent (0.71 to 2.07 percent), and the conventional process is difficult to improve the bioavailability.
Patent W09400462A1 discloses a formulation of minodronic acid, which is formulated into tablets by adding lactose, corn starch, 10% hydroxypropylcellulose aqueous solution, and magnesium stearate, but the in vitro dissolution effect is not satisfactory.
Patent CN102114025A discloses a technique of micronizing minodronic acid raw material to improve the dissolution rate of minodronic acid (up to 99.7% in 60 minutes), but the raw material is more likely to aggregate after micronization, which increases the difficulty of mixing and is likely to cause uneven content.
Patent CN102078323A discloses a technique, which adds sodium carbonate and other additives into minodronic acid preparation to improve the dissolution rate of the medicine, but sodium carbonate has strong alkalinity, has destructive effect on gastric acid, and has poor patient compliance.
Therefore, a minodronate tablet and a preparation method thereof are needed, which can overcome the defects, on one hand, reduce the irritation of the medicine, improve the medicine taking compliance of patients, improve the absorption rate, and enable the medicine to better serve the majority of patients; on the other hand, the production fault tolerance of the prescription and the process is high, and the quality of the product can be guaranteed by using common machine equipment. The minodronic acid tablet can meet the requirements of safety, effectiveness and controllable quality, and has simple and efficient preparation process and high product yield.
Disclosure of Invention
The invention provides a minodronic acid tablet, which solves the technical problem of sticking and washing of minodronic acid tablets, and can be quickly dissolved out and has high bioavailability.
Aiming at the defects of the prior art, the inventor realizes that the dissolution rate can be improved by micronization of raw materials, but the sticking phenomenon is more and more obvious along with the reduction of the particle size due to the nature of minodronic acid.
The inventors consider that sticking can be solved by using a large amount of lubricant, but the amount of lubricant used is increased at the expense of a decrease in dissolution and deterioration in compressibility.
The inventor adds grease into the prescription, and surprisingly finds that the prescription added with the grease greatly reduces the sticking problem of minodronate tablets and improves the dissolution of the tablets.
Aiming at the problems, the invention provides a minodronic acid tablet, which is realized by the following technologies:
a minodronic acid tablet comprises minodronic acid, oil adsorbent, filler, binder, disintegrant, and lubricant.
Preferably, the oil is selected from one or more of simethicone, soybean oil, glycerol monolinoleate, medium chain triglyceride, peanut oil and glycerol monooleate, and is further preferably simethicone.
Preferably, the weight ratio of the minodronic acid to the grease is 1.
Preferably, the grease adsorbent is selected from one or more of silica gel micropowder, talcum powder, beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.
Preferably, the weight ratio of the grease to the grease adsorbent is 1.
More preferably, the weight ratio of the oil and fat to the oil and fat adsorbent is 1.
Preferably, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin; the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, polyethylene glycol and silicon dioxide; the binder is selected from hydroxypropyl cellulose or polyvinylpyrrolidone.
Preferably, the weight ratio of the minodronic acid to the filler is 1:10 to 20, more preferably 1.
Preferably, the weight ratio of the minodronic acid to the binder is 1:0.4 to 1.4, and more preferably 1.6 to 1.0.
Preferably, the weight ratio of the minodronic acid to the disintegrant is 1:1 to 3, more preferably 1.
Preferably, the weight ratio of the minodronic acid to the lubricant is 1:0.2 to 0.6, more preferably 1.
The invention also provides a preparation method of the minodronic acid tablet, which comprises the following steps: adding minodronic acid into grease, stirring to form a suspension, adding the suspension into a wet grinding machine, grinding, spraying the ground suspension onto a filler, an adhesive and a grease adsorbent, preparing into granules, adding a disintegrating agent, mixing uniformly, adding a lubricating agent, mixing uniformly, and tabletting.
Preferably, the wet mill has a speed of 6-10rpm, preferably 8rpm.
Preferably, the particle size of the suspension after grinding is 1-5 μm.
Compared with the prior art, the invention has the following beneficial effects:
the invention can effectively inhibit the sticking problem of minodronate tablets by adding grease into the prescription, and obviously improves the dissolution rate and the bioavailability of minodronate.
Detailed Description
The advantageous effects of the present invention will now be further described by the following examples, which are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art according to the present invention are also included in the scope of the present invention.
Example 1
1) Prescription
2) Preparation process
Adding minodronic acid into dimethyl silicon oil, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding at the rotating speed of 8rpm until the particle size is 1-5 mu m, adding mannitol, hydroxypropyl cellulose, aerosil and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding the cross-linked sodium carboxymethyl cellulose with the formula amount, mixing uniformly, adding magnesium stearate, mixing uniformly, and tabletting.
Example 2
1) Prescription
2) Preparation process
Adding minodronic acid into soybean oil, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding until the particle size is 1-5 mu m, adding beta-cyclodextrin, lactose, hydroxypropyl cellulose and starch into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone with the amount of the prescription, mixing uniformly, adding sodium stearate fumarate, mixing uniformly, and tabletting.
Example 3
1) Prescription
2) Preparation process
Adding minodronic acid into glycerol monolinoleate, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding until the particle size is 1-5 mu m, adding starch, polyvinylpyrrolidone, aerosil and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding the carboxymethyl starch sodium in the formula amount, mixing uniformly, adding the magnesium stearate in the formula amount, mixing uniformly, and tabletting.
Example 4
1) Prescription
2) The preparation process comprises the steps of adding minodronic acid into medium-chain triglyceride, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding the suspension until the particle size is 10-15 mu m, adding hydroxypropyl beta-cyclodextrin, lactose, hydroxypropyl cellulose and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone according to the formula amount, mixing uniformly, adding sodium fumarate stearate and magnesium stearate, mixing uniformly, and tabletting.
Example 5
1) Prescription
2) Adding minodronic acid into peanut oil, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding at the rotating speed of 8rpm until the particle size is 1-5 mu m, adding mannitol, aerosil, polyvinylpyrrolidone and lactose into a fluidized bed for premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding the cross-linked sodium carboxymethyl cellulose in the formula amount, mixing uniformly, adding the magnesium stearate in the formula amount, mixing uniformly, and tabletting.
Example 6
1) Prescription
2) Preparation process
Adding minodronic acid into glycerol monooleate, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding at a rotating speed of 10rpm until the particle size is 10-15 mu m, adding hydroxypropyl beta-cyclodextrin, mannitol, hydroxypropyl methylcellulose and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone with the amount of the prescription, mixing uniformly, adding magnesium stearate with the amount of the prescription, mixing uniformly, and tabletting.
Example 7
1) Prescription
2) Preparation process
Adding minodronic acid into soybean oil, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding until the particle size is 1-5 mu m, adding beta-cyclodextrin, lactose, hydroxypropyl methylcellulose and starch into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone with the amount of the prescription, mixing uniformly, adding sodium stearate fumarate with the amount of the prescription, mixing uniformly, and tabletting.
Example 8
1) Prescription
2) The preparation process comprises the steps of adding minodronic acid into medium-chain triglyceride, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding at the rotating speed of 10rpm until the particle size is 1-5 mu m, adding hydroxypropyl beta-cyclodextrin, hydroxypropyl methyl cellulose, lactose and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding the formula amount of crospovidone, mixing uniformly, adding the formula amount of sodium fumarate stearate and magnesium stearate, mixing uniformly, and tabletting.
Comparative example 1
1) Prescription
2) Preparation process
Adding minodronic acid into water, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding to the particle size of 1-5 mu m, adding beta-cyclodextrin, lactose, hydroxypropyl methyl cellulose and starch into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone according to the prescription amount, mixing uniformly, adding sodium stearate fumarate, mixing uniformly, and tabletting.
Comparative example 2
1) Prescription
2) Preparation process
Adding minodronic acid into soybean oil, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding to the particle size of 1-5 mu m, adding lactose, hydroxypropyl methyl cellulose and starch into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding formula amount of crospovidone, mixing uniformly, adding sodium stearate fumarate, mixing uniformly, and tabletting.
Comparative example 3
1) Prescription
2) Preparation process
Adding minodronic acid into water, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding the suspension until the particle size is 1-5 mu m, adding starch, polyvinylpyrrolidone and microcrystalline cellulose into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding the carboxymethyl starch sodium in a prescribed amount, mixing uniformly, adding the magnesium stearate, mixing uniformly, and tabletting.
Comparative example 4
1) Prescription
2) Preparation process
Pulverizing minodronic acid with air flow to obtain powder with particle diameter D90 of 5 μm, weighing dimethyl silicone oil, silica gel micropowder, mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, and croscarmellose sodium, mixing, granulating, sieving with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.
Comparative example 5
1) Prescription
2) Preparation process
The average particle size D50 of minodronic acid is 15 mu m, the minodronic acid, mannitol and part of croscarmellose sodium in the amount of the prescription are weighed and uniformly mixed, then 7% of hydroxypropyl cellulose water solution is added for fluidized bed granulation, after drying, microcrystalline cellulose, the rest of croscarmellose sodium and magnesium stearate are added for uniform mixing, and tabletting is carried out.
Comparative example 6
1) Prescription
2) Preparation process
Adding minodronic acid into water, stirring uniformly to prepare a suspension, adding the suspension into a wet grinding machine, grinding until the particle size is 1-5 mu m, adding beta-cyclodextrin, lactose, hydroxypropyl methylcellulose and starch into a fluidized bed, premixing, spraying the minodronic acid suspension onto premixed auxiliary materials in the fluidized bed to prepare granules, adding crospovidone with the amount of the prescription, mixing uniformly, adding magnesium stearate, mixing uniformly, and tabletting.
Verification of the embodiments
1. Appearance: visual inspection of
TABLE 1 measurement results
| Examples | Appearance of the product |
| Example 1 | White, smooth and tidy |
| Example 2 | White, smooth and tidy |
| Example 3 | White, smooth and tidy |
| Example 4 | White, smooth and tidy |
| Example 5 | White, smooth and tidy |
| Example 6 | White, smooth and tidy |
| Example 7 | White, smooth and tidy |
| Example 8 | White, smooth and tidy |
| Comparative example 1 | White, non-smooth surface |
| Comparative example 2 | White and non-smooth surface |
| Comparative example 3 | White, non-smooth surface |
| Comparative example 4 | White, non-smooth surface |
| Comparative example 5 | White, smooth and tidy |
| Comparative example 6 | White and smooth surface |
2. Dissolution determination
Determining dissolution rate of the minodronate tablet by high performance liquid chromatography, and bonding a silica gel chromatographic column with octadecylsilane chemically bonded; a 0.1% phosphoric acid solution-methanol (80); the flow rate was 1.0ml per minute; the detection wavelength was 223nm. Taking another appropriate amount of minodronic acid reference substance, precisely weighing, adding methanol to dissolve and dilute to obtain a solution containing about 56 μ g of minodronic acid per 1ml, and using the solution as a reference substance solution. And precisely measuring 10 mu l of each of the two solutions, respectively injecting the two solutions into a liquid chromatograph, recording a chromatogram, and calculating the dissolution rate of the minodronic acid in the test solution by peak area according to an external standard method. The dissolution rate of the product in 15min should be not less than 90% (Q) of the marked amount.
Dissolution medium: water, volume of medium: 900ml, stirring paddle speed 50rpm. Dissolution test method referring to the second method of dissolution and release test method of 0931 in the four parts of the year-old edition of the Chinese pharmacopoeia 2020, the results are shown in Table 2.
TABLE 2 dissolution rate measurement results
As can be seen from the table, the minodronate tablets obtained by the embodiments 1-8 of the invention by adopting the formula and the preparation method have good appearance and rapid dissolution characteristics; comparative example 4 adopts a conventional method for preparing a tablet, and although the amount of the lubricant used was increased to reduce the sticking phenomenon, sticking still occurred and the dissolution of the tablet was reduced. Comparative example 2, although the process of grinding suspension is adopted, no fat adsorbent is added, the minodronic acid is only granulated together with auxiliary materials, and the dissolution rate of the minodronic acid can be improved, so that the sticking phenomenon cannot be solved.
3. Pharmacokinetic testing
The formulations prepared in inventive example 1, example 2, example 5, example 8 and comparative example 5, and a commercially available minodronic acid tablet (trade name:
) A fasting pharmacokinetic test is carried out, 6 healthy Beagle dogs in each group weigh 12.5-15Kg, 50mg of minodronic acid is orally taken once every 12h before taking the medicine, 25ml of warm water is simultaneously taken, about 3ml of blood is collected by measuring subcutaneous veins in forelimbs after 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 8h, 12h, 24h, 48h and 72h after taking the medicine, the blood is placed in a heparinized test tube, the blood concentration is measured, the Cmax and the AUC are calculated, and the weight of the test is similar to that of a commercially available minodronic acid tablet (trade name:
) Comparison, further calculation for
The ratio of Cmax to AUC results are shown in Table 3.
TABLE 3 pharmacokinetic testing results
Claims (10)
1. A minodronic acid tablet is characterized by comprising minodronic acid, grease, a grease adsorbent, a filler, a binder, a disintegrant and a lubricant.
2. The minodronate tablet according to claim 1, wherein said oil is selected from the group consisting of dimethicone, soybean oil, glycerol monolinoleate, medium chain triglycerides, peanut oil, glycerol monooleate.
3. The minodronic acid tablet according to claim 1, wherein the weight ratio of minodronic acid to the fat/oil is 1.
4. The minodronate tablet according to claim 1, wherein the fat adsorbent is selected from the group consisting of silica gel micropowder, talc, β -cyclodextrin, and hydroxypropyl- β -cyclodextrin.
5. The minodronate tablet according to claim 1, wherein the weight ratio of the oil to the oil adsorbent is 1.
6. The minodronate tablet according to claim 1, wherein said filler is selected from the group consisting of one or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin; the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, polyethylene glycol and silicon dioxide, and the binder is selected from hydroxypropyl cellulose or polyvinylpyrrolidone.
7. The minodronic acid tablet according to claim 1, wherein the weight ratio of said minodronic acid to said filler is 1:10 to 20.
8. The minodronic acid tablet according to claim 1, wherein the weight ratio of said minodronic acid to said disintegrant is 1:1 to 3, preferably 1.
9. The minodronic acid tablet according to claim 1, wherein the weight ratio of said minodronic acid to said lubricant is 1:0.2 to 0.6.
10. A method of preparing the minodronate tablet of claim 1, comprising the steps of: adding minodronic acid into grease, stirring to form a suspension, adding the suspension into a wet grinding machine for grinding, spraying the ground suspension onto a filler, an adhesive and a grease adsorbent to prepare granules, adding a disintegrating agent, uniformly mixing, adding a lubricating agent, uniformly mixing and tabletting.
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| CN202110821830.0A CN115634206A (en) | 2021-07-19 | 2021-07-19 | Minodronic acid tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110821830.0A CN115634206A (en) | 2021-07-19 | 2021-07-19 | Minodronic acid tablet and preparation method thereof |
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