CN113662922A - Mirabegron sustained-release composition and preparation method and application thereof - Google Patents
Mirabegron sustained-release composition and preparation method and application thereof Download PDFInfo
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- CN113662922A CN113662922A CN202011182927.3A CN202011182927A CN113662922A CN 113662922 A CN113662922 A CN 113662922A CN 202011182927 A CN202011182927 A CN 202011182927A CN 113662922 A CN113662922 A CN 113662922A
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- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 title claims abstract description 78
- 229960001551 mirabegron Drugs 0.000 title claims abstract description 76
- 239000000203 mixture Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000013268 sustained release Methods 0.000 title claims abstract description 10
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 10
- 239000007939 sustained release tablet Substances 0.000 claims abstract description 39
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 19
- 235000006708 antioxidants Nutrition 0.000 claims abstract description 19
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims abstract description 19
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 239000003349 gelling agent Substances 0.000 claims abstract description 14
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 239000002245 particle Substances 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000012744 reinforcing agent Substances 0.000 claims abstract description 4
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims abstract description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 3
- 229940046009 vitamin E Drugs 0.000 claims abstract description 3
- 239000011709 vitamin E Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 43
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 42
- 239000011248 coating agent Substances 0.000 claims description 38
- 238000000576 coating method Methods 0.000 claims description 32
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 26
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- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 26
- -1 polyoxyethylene Polymers 0.000 claims description 25
- 238000002156 mixing Methods 0.000 claims description 22
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
- 235000019359 magnesium stearate Nutrition 0.000 claims description 21
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 17
- 238000010298 pulverizing process Methods 0.000 claims description 17
- 238000007873 sieving Methods 0.000 claims description 17
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- 239000000499 gel Substances 0.000 claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000003623 enhancer Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 10
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 10
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 10
- 230000005496 eutectics Effects 0.000 claims description 10
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 10
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 9
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 9
- 239000006185 dispersion Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 208000020629 overactive bladder Diseases 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 239000011261 inert gas Substances 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
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- 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
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 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 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 2
- 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 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims description 2
- 229910052623 talc Inorganic materials 0.000 claims description 2
- 238000013265 extended release Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 10
- 239000000374 eutectic mixture Substances 0.000 abstract description 4
- 239000007888 film coating Substances 0.000 description 10
- 238000009501 film coating Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 6
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 2
- 230000001022 anti-muscarinic effect Effects 0.000 description 2
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
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- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000015005 beta-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006818 beta-adrenergic receptor activity proteins Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 238000004811 liquid chromatography Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229960003855 solifenacin Drugs 0.000 description 1
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
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Images
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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
Abstract
The invention discloses a mirabegron slow-release composition and a preparation method and application thereof. The composition comprises: active ingredients of mirabegron and pharmaceutic adjuvant; the pharmaceutic adjuvant at least contains an antioxidant, and the antioxidant is selected from at least one of dibutyl hydroxy toluene, butyl hydroxy anisole and vitamin E. Preparing a eutectic mixture containing the mirabegron, the gelling agent, the gel reinforcing agent and the antioxidant under the protection of nitrogen, and crushing the eutectic mixture by using a water-cooling crusher to form particles with uniformly distributed active component mirabegron. The prepared sustained-release tablet has excellent sustained-release effect.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a mirabegron slow-release composition, and a preparation method and application thereof.
Background
The mirabegron belongs to an aromatic ethanolamine beta 3 adrenergic receptor stimulant, acts on a bladder detrusor smooth muscle beta 3 adrenergic receptor, relaxes the bladder, promotes the bladder filling, increases the urine storage capacity, can effectively reduce the urination frequency and improve the urine frequency caused by overactive bladder; the mirabegron slow release tablet has the advantages that the influence of food on the absorption of the mirabegron slow release tablet can be reduced, the mirabegron slow release tablet can be taken before and after meals, the long-time stable effective blood concentration can be maintained, the curative effect of the medicine is improved, only one tablet is needed in one day, the taking is convenient, the compliance of patients is improved, and therefore, the research on the novel mirabegron slow release tablet and the preparation method thereof has important significance.
The chemical name of mirabegron is: (R) -2- (2-amino-1, 3-thiazol-4-yl) -4' - [2- [ (2-hydroxy-2-phenylethyl) amino group]Ethyl radical]Phenylacetamide, molecular formula: c21H24N4O2S, molecular weight: 396.51, CAS: 223673-61-8, having the formula:
in recent years, with the progress of our country into an aging society and the increase of diabetes and nervous system impairment diseases, the incidence of overactive bladder, which is a secondary related disease, has also increased year by year. The data report that the total disease rate of the people over 18 years old of overactive bladder (OAB) is 6 percent, the disease rate of the people over 50 years old can reach 11.3 percent, and the life quality of people is seriously influenced.
The mirabegron sustained release tablet is different from the action mechanism of the current main clinical treatment medicines of antimuscarinic medicines (solifenacin, oxybutynin and tolterodine), is a selective beta-adrenoceptor agonist, can inhibit overactive bladder and simultaneously avoid the common adverse reactions of the antimuscarinic medicines, such as dry mouth, constipation, blurred vision and the like, and therefore becomes a potential OAB treatment new medicine.
However, the original ground medicament is prepared by crushing mirabegron, a framework material, an antioxidant and an adhesive, uniformly mixing, briquetting, crushing, wet granulation and dry granulation, adding a lubricant, uniformly mixing and tabletting to obtain the mirabegron sustained-release tablet. The process has certain defects: the preparation method adopts wet granulation and dry granulation, and the granulation operation is complicated; and the content uniformity of the active ingredients is a difficult point to control in the process. Therefore, it is an urgent need to provide a mirabegron sustained release preparation with uniform active ingredient content and excellent sustained release effect, and a preparation method which is simple and convenient to operate and easy to control the uniformity of the active ingredient.
Disclosure of Invention
The invention provides a mirabegron slow-release composition, which comprises the following components: active ingredients of mirabegron and pharmaceutic adjuvant;
the pharmaceutic adjuvant at least contains an antioxidant, and the antioxidant is selected from at least one of dibutyl hydroxy toluene, butyl hydroxy anisole and vitamin E, and is exemplified by dibutyl hydroxy toluene.
According to an embodiment of the invention, the composition comprises mirabegron 10-30 parts, such as 15-25 parts, further such as 16 parts, 18 parts, 20 parts, 22 parts, 22.5 parts, 24 parts by weight.
According to an embodiment of the invention, the pharmaceutical excipient further comprises a gelling agent. Preferably, the gelling agent is present in the composition in an amount of 25 to 55 parts, for example 30 to 50 parts, further such as 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 32 parts, 33 parts, 40 parts, 43.4 parts, 45 parts, 46.8 parts, 50 parts by weight.
According to an embodiment of the present invention, the gelling agent may be selected from at least one of polyoxyethylene, methylcellulose, hydroxypropylmethylcellulose, sodium hydroxymethylcellulose, and povidone, illustratively polyoxyethylene.
According to an embodiment of the invention, the polyoxyethylene has a number average molecular weight of from 100 to 300, for example from 150 to 250, further for example 160, 180, 200, 220, 240.
According to an embodiment of the invention, the pharmaceutical excipient further comprises a gel enhancer. Preferably, the gel enhancer is present in the composition in an amount of 35 to 70 parts, for example 40 to 60 parts, further for example 42 parts, 44 parts, 45 parts, 46 parts, 48 parts, 49 parts, 50 parts, 54.4 parts, 55 parts, 56.8 parts, 60 parts by weight.
According to an embodiment of the present invention, the gel enhancer may be selected from one of polyethylene glycol and polyvinylpyrrolidone. Preferably polyethylene glycol.
According to an embodiment of the invention, the polyethylene glycol has a number average molecular weight of 5000-.
According to an embodiment of the invention, the antioxidant is present in the composition in an amount of 0.05 to 0.5 parts, such as 0.1 to 0.3 parts, further such as 0.1 parts, 0.12 parts, 0.14 parts, 0.15 parts, 0.17 parts, 0.18 parts, 0.19 parts, 0.2 parts, 0.25 parts, 0.3 parts by weight. Antioxidants can prevent gelling agents, such as polyoxyethylene, from oxidizing during storage.
According to an embodiment of the invention, the pharmaceutical excipient further comprises a binder. Preferably, the binder is present in the composition in an amount of 1.5 to 5 parts, for example 2 to 4 parts, further such as 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, by weight.
According to an embodiment of the present invention, the binder may be selected from at least one of hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC-Na), copovidone (Kolidon VA64), methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, exemplarily hydroxypropyl cellulose. Preferably, the hydroxypropyl cellulose is SL-type hydroxypropyl cellulose.
According to an embodiment of the invention, the pharmaceutical excipient further comprises a glidant. Preferably, the glidant is present in the composition in an amount of 0.5 to 2 parts, for example 0.8 to 1.6 parts, such as 1 part, 1.2 parts, 1.25 parts, 1.5 parts, 1.7 parts, 1.9 parts.
According to an embodiment of the present invention, the glidant may be selected from at least one of aerosil and talc, exemplified by aerosil.
According to an embodiment of the invention, the pharmaceutical excipient further comprises a lubricant. Preferably, the lubricant is present in the composition in an amount of 0.5 to 2 parts, for example 0.8 to 1.6 parts, such as 1 part, 1.2 parts, 1.25 parts, 1.5 parts, 1.7 parts, 1.9 parts.
According to an embodiment of the present invention, the lubricant may be selected from at least one of magnesium stearate, calcium stearate, glyceryl behenate and hydrogenated vegetable oil, exemplified by magnesium stearate.
According to an embodiment of the invention, the composition comprises, in parts by weight: 15-25 parts of mirabegron, 30-50 parts of polyoxyethylene, 40-60 parts of polyethylene glycol, 1.5-5 parts of hydroxypropyl cellulose, 0.1-0.3 part of butylated hydroxytoluene, 0.5-2 parts of superfine silica gel powder and 0.5-2 parts of magnesium stearate.
According to an exemplary embodiment of the invention, the composition comprises, in parts by weight: 22.5 parts of mirabegron, 46.8 parts of polyoxyethylene, 49 parts of polyethylene glycol, 1.5 parts of hydroxypropyl cellulose, 0.25 part of butylated hydroxytoluene, 1.25 parts of aerosil and 1.25 parts of magnesium stearate.
According to an exemplary embodiment of the invention, the composition comprises, in parts by weight: 22.5 parts of mirabegron, 43.4 parts of polyoxyethylene, 54.4 parts of polyethylene glycol, 2 parts of hydroxypropyl cellulose, 0.25 part of butylated hydroxytoluene, 1.25 parts of silica gel micropowder and 1.25 parts of magnesium stearate.
According to an exemplary embodiment of the invention, the composition comprises, in parts by weight: 22.5 parts of mirabegron, 40 parts of polyoxyethylene, 56.8 parts of polyethylene glycol, 3.5 parts of hydroxypropyl cellulose, 0.25 part of butylated hydroxytoluene, 1.25 parts of silica gel micropowder and 1.25 parts of magnesium stearate.
The invention also provides application of the composition in preparing a medicinal preparation for treating overactive bladder. For example, the pharmaceutical formulation is a sustained release formulation. More preferably, the sustained release agent is a sustained release tablet.
The invention also provides a sustained-release tablet which contains the composition.
According to an embodiment of the invention, the sustained release tablet comprises a tablet core and a coating coated on the surface of the tablet core; the tablet core contains active ingredients of mirabegron, antioxidant and gumCoagulant, gel enhancer, binder, glidant and lubricant; the coating contains hypromellose, a gel enhancer, and optionally a colorant, with or without. For example, the coating is a coating agent
03F42192。
Preferably, the mirabegron, antioxidant, gelling agent, gel enhancer, binder, glidant, lubricant are in the amounts and selections as described above.
According to an embodiment of the invention, the coating is present in the sustained release tablet in an amount of 3 to 10 parts, such as 4 to 8 parts, exemplarily 4 parts, 5 parts, 6 parts, 6.44 parts, 6.5 parts, 7 parts by weight.
According to an embodiment of the invention, the sustained release tablet comprises a tablet core and a coating coated on the surface of the tablet core;
the tablet core comprises, by weight, 15-25 parts of mirabegron, 30-50 parts of polyoxyethylene, 40-60 parts of polyethylene glycol, 1.5-5 parts of hydroxypropyl cellulose, 0.1-0.3 part of butylated hydroxytoluene, 0.5-2 parts of aerosil and 0.5-2 parts of magnesium stearate; and 4-8 parts of a coating.
According to an embodiment of the invention, the sum of the parts by weight of the components of the core in the above composition and/or sustained release tablet is 100 parts.
The invention also provides a preparation method of the sustained release tablet, which comprises the following steps:
(1) under the protection of inert gas, heating the gelling agent and the gel reinforcing agent to be molten to form a eutectic body;
(2) and adding mirabegron and an antioxidant into the eutectic, mixing and cooling to obtain a solid.
The preparation method according to the invention further comprises the following steps:
(3) crushing the solid obtained in the step (2) into powder, mixing the powder with a binder, and sieving and grading the mixture;
(4) mixing the granules obtained in the step (3) with a flow aid and a lubricant, and tabletting to obtain a tablet core;
the preparation method according to the invention further comprises the following steps:
(5) and coating the tablet core by adopting a coating agent to obtain the sustained-release tablet.
According to an embodiment of the invention, the above components are used in the amounts and in the choices as described above.
According to an embodiment of the invention, in step (1), the heating is at a temperature of 60 to 80 ℃, such as 65 to 75 ℃, exemplary 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃. Preferably, the heating is water bath heating.
According to an embodiment of the invention, the inert gas in step (1) is nitrogen.
According to an embodiment of the present invention, in the step (2), the cooling is cooling to room temperature.
According to an embodiment of the invention, in step (3), the temperature of the comminution is controlled below 20 ℃, such as below 18 ℃, such as below 15 ℃. For example, the temperature of comminution may be controlled by an ice water bath. For example, the pulverization is carried out by a water-cooled pulverizer.
According to an embodiment of the present invention, in the step (3), D of the pulverized powder90The particle size is 400-560 μm, such as 450-560 μm, and exemplary are 500 μm, 506 μm, 518 μm, 520 μm, 540 μm.
According to an embodiment of the present invention, in the step (3), the sieving is a 20-mesh sieving.
According to an embodiment of the present invention, in the step (4), the compressed tablet may be compressed using a rotary tablet press.
According to an embodiment of the present invention, in step (5), the coating agent is 5 to 10 wt% of the aqueous dispersion, preferably 10 wt% of the aqueous dispersion.
According to an embodiment of the present invention, the above mixing is stirring mixing or vibration mixing, preferably stirring mixing. For example, the mixing time is 5-20min, such as 10-15 min.
According to an exemplary embodiment of the present invention, the method for preparing the sustained-release tablet comprises the steps of:
(1) under the protection of nitrogen, heating polyoxyethylene and polyethylene glycol to melt to form a eutectic body;
(2) adding mirabegron and dibutyl hydroxy toluene into the eutectic, mixing uniformly and cooling to form a solid;
(3) pulverizing the solid into powder, mixing with hydroxypropyl cellulose, sieving, and grading;
(4) mixing the granules obtained in the step (3) with aerosil and magnesium stearate, and tabletting to obtain a tablet core;
(5) coating the tablet core by adopting the coating composition to obtain the sustained-release tablet.
The invention also provides application of the composition and/or the sustained-release tablet in preventing and/or treating frequent micturition, urgency of micturition, urinary incontinence and the like caused by overactive bladder.
The invention has the beneficial effects that:
the invention provides the mirabegron sustained release tablet which is qualified and stable in quality, the release of the active ingredients can reach uniform release speed and high release degree, and the effect of the mirabegron sustained release tablet is not different from the sustained release effect of the original ground product. Specifically, the release amount of the active ingredients in 1.5 hours is 20-45%, the release amount of the active ingredients in 2.5 hours is 45-70%, and the release amount of the active ingredients in 4.5 hours is more than 80%. The release result can well meet the clinical requirement.
The invention also provides a preparation method of the mirabegron sustained release tablet, which comprises the steps of fully and uniformly mixing the mirabegron, the gelling agent, the gel reinforcing agent and the antioxidant in a molten state under the protection of nitrogen to form a eutectic mixture, crushing the eutectic mixture by using a water-cooling crusher to form particles with uniformly distributed active ingredient mirabegron, and then performing dry granulation. Compared with the preparation process in the prior art, the method reduces the complicated granulation operation and material loss caused by the granulation and crushing process, reduces the requirement on the particle size of raw and auxiliary materials required by the mixing requirement, can achieve the effect consistent with the slow release effect of the original ground product, can fully ensure the content uniformity of the mirabegron in the preparation on the premise of safe process operation, and achieves good batch reproducibility in production. Simple operation, suitability for industrial production and great practical value.
Drawings
FIG. 1 shows the cumulative release of active ingredient results for examples 1 to 3, comparative examples 1 to 2 and the original product.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
The formula of the mirabegron sustained release tablet comprises the following components:
the preparation method of the mirabegron sustained release tablet comprises the following steps:
(1) and sieving hydroxypropyl cellulose, aerosil and magnesium stearate with a 60-mesh sieve for later use.
(2) Under the protection of nitrogen, 468g of polyoxyethylene and 490g of polyethylene glycol 8000 are heated in a water bath (60 ℃ to 80 ℃) and stirred until the mixture is melted.
(3) 225g of mirabegron and 2.5g of butylated hydroxytoluene are added into the eutectic, stirred for 10min and mixed uniformly. Left to cool to room temperature and become a solid.
(4) Pulverizing the above solid with water-cooled pulverizer (equipped with 20 mesh sieve), controlling pulverizing temperature below 20 deg.C with ice water bath, measuring particle diameter after pulverizing, and measuring D90And was 506 μm.
(5) The pulverized material and 15g of hydroxypropylcellulose were mixed in a mixer for 10 minutes.
(6) After finishing the granules with a 20-mesh sieve, 12.5g of aerosil and 12.5g of magnesium stearate are added and mixed in a mixer for 10 min.
(7) Tabletting with a rotary tablet machine to obtain the mirabegron tablets.
(8) Preparing a film coating agent with a concentration of 10% w/v: weighing
And putting 64.4g of 03F42192 coating powder into 640ml of purified water, stirring for 1 hour, uniformly mixing, and sieving by using a 100-mesh sieve to obtain the coating.
(9) The obtained mirabegron tablet is sprayed with water dispersion of coating film coating agent by a high-efficiency coating machine to obtain the mirabegron sustained release tablet with the weight of about 257.5 mg.
Example 2
The formula of the mirabegron sustained release tablet comprises the following components:
the preparation method of the mirabegron sustained release tablet comprises the following steps:
(1) and sieving hydroxypropyl cellulose, aerosil and magnesium stearate with a 60-mesh sieve for later use.
(2) Under the protection of nitrogen, 434g of polyoxyethylene and 544g of polyethylene glycol 8000 are heated in a water bath (60-80 ℃) and stirred until the polyoxyethylene and the polyethylene glycol are melted.
(3) 225g of mirabegron and 2.5g of butylated hydroxytoluene are added into the eutectic, stirred for 10min and mixed uniformly. Left to cool to room temperature and become a solid.
(4) Pulverizing the above solid with water-cooled pulverizer (equipped with 20 mesh sieve), controlling pulverizing temperature below 20 deg.C with ice water bath, measuring particle diameter after pulverizing, and measuring D90Is 500 μm.
(5) The pulverized material and 20g of hydroxypropylcellulose were mixed in a mixer for 10 minutes.
(6) After finishing the granules with a 20-mesh sieve, 12.5g of aerosil and 12.5g of magnesium stearate are added and mixed in a mixer for 10 min.
(7) Tabletting with a rotary tablet machine to obtain the mirabegron tablets.
(8) Preparing a film coating agent with a concentration of 10% w/v: weighing
And putting 64.4g of 03F42192 coating powder into 640ml of purified water, stirring for 1 hour, uniformly mixing, and sieving by using a 100-mesh sieve to obtain the coating.
(9) The obtained mirabegron tablet is sprayed with water dispersion of coating film coating agent by a high-efficiency coating machine to obtain the mirabegron sustained release tablet with the weight of about 257.5 mg.
Example 3
The formula of the mirabegron sustained release tablet comprises the following components:
the preparation method of the mirabegron sustained release tablet comprises the following steps:
(1) and sieving hydroxypropyl cellulose, aerosil and magnesium stearate with a 60-mesh sieve for later use.
(2) Under the protection of nitrogen, 400g of polyoxyethylene and 568g of polyethylene glycol 8000 are heated in a water bath (60-80 ℃) and stirred until being melted.
(3) 225g of mirabegron and 2.5g of butylated hydroxytoluene are added into the eutectic, stirred for 10min and mixed uniformly. Left to cool to room temperature and become a solid.
(4) Pulverizing the above solid with water-cooled pulverizer (equipped with 20 mesh sieve), controlling pulverizing temperature below 20 deg.C with ice water bath, measuring particle diameter after pulverizing, and measuring D90It was 518 μm.
(5) The pulverized material and 35g of hydroxypropylcellulose were mixed in a mixer for 10 minutes.
(6) After finishing the granules with a 20-mesh sieve, 12.5g of aerosil and 12.5g of magnesium stearate are added and mixed in a mixer for 10 min.
(7) Tabletting with a rotary tablet machine to obtain the mirabegron tablets.
(8) Preparing a film coating agent with a concentration of 10% w/v: weighing
03F42192 coating powder 64.4g is put into 640ml of purified water and stirred for 1 hourAnd sieving with 100 mesh sieve after mixing uniformly.
(9) The obtained mirabegron tablet is sprayed with water dispersion of coating film coating agent by a high-efficiency coating machine to obtain the mirabegron sustained release tablet with the weight of about 257.5 mg.
Comparative example 1
The formula of the mirabegron sustained release tablet comprises the following components:
the preparation method of the mirabegron sustained release tablet comprises the following steps:
(1) and sieving hydroxypropyl cellulose, aerosil and magnesium stearate with a 60-mesh sieve for later use.
(2) The polyoxyethylene, the polyethylene glycol 8000, the mirabegron and the dibutyl hydroxy toluene are sieved by a sieve of 80 meshes for standby.
(3) 400g of polyoxyethylene 200 ten thousand, 568g of polyethylene glycol 8000, 225g of mirabegron, 2.5g of dibutylhydroxytoluene and 35g of hydroxypropylcellulose are mixed in a mixer for 10 minutes.
(4) After finishing the granules with a 20-mesh sieve, 12.5g of aerosil and 12.5g of magnesium stearate are added and mixed in a mixer for 10 min.
(5) Tabletting with a rotary tablet machine to obtain the mirabegron tablets.
(6) Preparing a film coating agent with a concentration of 10% w/v: weighing
And putting 64.4g of 03F42192 coating powder into 640ml of purified water, stirring for 1 hour, uniformly mixing, and sieving by using a 100-mesh sieve to obtain the coating.
(7) The obtained tablet was spray coated with an aqueous dispersion of a film coating agent using a high-efficiency coating machine to obtain a mirabegron sustained release tablet having a tablet weight of about 257.5 mg.
Comparative example 2
The formula of the mirabegron sustained release tablet comprises the following components:
the preparation method of the mirabegron sustained release tablet comprises the following steps:
(1) and sieving hydroxypropyl cellulose, aerosil and magnesium stearate with a 60-mesh sieve for later use.
(2) Pulverizing 400g polyoxyethylene, 568g polyethylene glycol 8000, 225g mirabegron and 2.5g dibutyl hydroxy toluene with water-cooled pulverizer (20 mesh sieve), controlling pulverizing temperature below 20 deg.C with ice water bath, determining particle diameter after pulverizing, and measuring D90And 560 μm.
(3) The pulverized material and 35g of hydroxypropylcellulose were mixed in a mixer for 10 minutes.
(4) After finishing the granules with a 20-mesh sieve, 12.5g of aerosil and 12.5g of magnesium stearate are added and mixed in a mixer for 10 min.
(5) Tabletting with a rotary tablet machine to obtain the mirabegron tablets.
(6) Preparing a film coating agent with a concentration of 10% w/v: weighing
And putting 64.4g of 03F42192 coating powder into 640ml of purified water, stirring for 1 hour, uniformly mixing, and sieving by using a 100-mesh sieve to obtain the coating.
(9) The obtained tablet was spray coated with an aqueous dispersion of a film coating agent using a high-efficiency coating machine to obtain a mirabegron sustained release tablet having a tablet weight of about 257.5 mg.
Test example 1
Dissolution test
The sustained release tablets prepared in examples 1-3 and comparative examples 1-2, and the original research products (Betameli BETMIGA, 50mg specification) of different lots were subjected to dissolution test in 900mL of phosphate buffer at 37 ℃ and pH 6.8 by 200 rpm paddle according to the Chinese pharmacopoeia dissolution test method, and the liquid chromatography measurement method thereof was as follows.
A detection instrument: an ultraviolet detector (measurement wavelength: 250 nm);
a chromatographic column: c18(4.6 mm. times.150 mm, 5 μm);
mobile phase: the buffer (3 g of sodium hydroxide, placed in 1000ml of 0.9% aqueous perchloric acid and adjusted to pH 2.0 with 0.1N aqueous sodium hydroxide) and acetonitrile were mixed in a volume ratio of 7: 3.
The results of the cumulative release of mirabegron over time are shown in figure 1 and table 1.
TABLE 1
| Time (h) | 0.5 | 1.5 | 2.5 | 4.5 | 6 | 8 |
| Example 1 | 7.5％ | 32.4％ | 53.8％ | 91.3％ | 94.8％ | 97.2％ |
| Example 2 | 8.0％ | 31.9％ | 52.6％ | 90.6％ | 95.5％ | 99.8％ |
| Example 3 | 9.8％ | 32.3％ | 55.7％ | 89.7％ | 95.1％ | 98.5％ |
| Comparative example 1 | 5.4％ | 28.4％ | 40.8％ | 73.3％ | 88.4％ | 89.2％ |
| Comparative example 2 | 7.5％ | 25.4％ | 42.3％ | 76.1％ | 86.1％ | 88.4％ |
| Original product 1 | 8.1％ | 33.5％ | 54.7％ | 91.5％ | 96.3％ | 99.9％ |
| Original |
9.5％ | 31.5％ | 53.2％ | 90.7％ | 95.8％ | 99.2％ |
The data in figure 1 and table 1 show that the mirabegron in the products prepared by the examples can be released relatively gently within a specified time, the in-vitro release effect of the original product can be achieved, and the release effect of each example in each time period is not obviously different. In the comparative example, because the eutectic body is not prepared before dry granulation, under the condition that other process parameters are not changed, because the mirabegron and the auxiliary materials are not uniformly dispersed in the tablet, a proper slow release system is not formed among the auxiliary materials, the slow release effect of the mirabegron is poor. Therefore, the technical scheme of the invention achieves the aim of the invention.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A mirabegron sustained release composition characterized in that said composition comprises: active ingredients of mirabegron and pharmaceutic adjuvant;
the pharmaceutic adjuvant at least contains an antioxidant, and the antioxidant is selected from at least one of dibutyl hydroxy toluene, butyl hydroxy anisole and vitamin E.
2. Composition according to claim 1, characterized in that it contains mirabegron 10-30 parts, such as 15-25 parts, by weight.
3. The composition of claim 1 or 2, wherein the pharmaceutical excipient further comprises a gelling agent. Preferably, the gelling agent is present in the composition in an amount of 25 to 55 parts, for example 30 to 50 parts, by weight.
Preferably, the gelling agent is selected from at least one of polyoxyethylene, methylcellulose, hydroxypropylmethylcellulose, sodium hydroxymethylcellulose, and povidone.
Preferably, the polyoxyethylene has a number average molecular weight of from 100 to 300, for example from 150 to 250, ten thousand.
4. The composition of any one of claims 1-3, wherein the pharmaceutical excipient further comprises a gel enhancer. Preferably, the gel enhancer is present in the composition in an amount of 35 to 70 parts, for example 40 to 60 parts, by weight.
Preferably, the gel enhancer may be selected from at least one of polyethylene glycol and polyvinylpyrrolidone, preferably polyethylene glycol.
Preferably, the number average molecular weight of the polyethylene glycol is 5000-.
5. Composition according to any one of claims 1 to 4, characterized in that the antioxidant is present in the composition in an amount of 0.05 to 0.5 parts, such as 0.1 to 0.3 parts, by weight.
Preferably, the antioxidant is dibutylhydroxytoluene.
6. The composition of any one of claims 1-5, wherein the pharmaceutical excipient further comprises a binder. Preferably, the binder is present in the composition in an amount of 1.5 to 5 parts, for example 2 to 4 parts, by weight.
Preferably, the binder is selected from at least one of hydroxypropyl cellulose, sodium carboxymethyl cellulose (CMC-Na), copovidone, methyl cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, exemplarily hydroxypropyl cellulose. Preferably, the hydroxypropyl cellulose is SL-type hydroxypropyl cellulose.
Preferably, the pharmaceutical excipients further comprise a glidant. Preferably, the glidant is selected from at least one of aerosil and talc.
Preferably, the pharmaceutical excipient further comprises a lubricant. Preferably, the lubricant is selected from at least one of magnesium stearate, calcium stearate, glyceryl behenate and hydrogenated vegetable oil.
7. The composition according to any one of claims 1 to 6, characterized in that it comprises, in parts by weight: 15-25 parts of mirabegron, 30-50 parts of polyoxyethylene, 40-60 parts of polyethylene glycol, 1.5-5 parts of hydroxypropyl cellulose, 0.1-0.3 part of butylated hydroxytoluene, 0.5-2 parts of superfine silica gel powder and 0.5-2 parts of magnesium stearate.
8. Use of a composition according to any one of claims 1 to 7 for the preparation of a pharmaceutical formulation for the treatment of overactive bladder. For example, the pharmaceutical formulation is a sustained release formulation. More preferably, the sustained release agent is a sustained release tablet.
9. An extended release tablet comprising the composition of any one of claims 1 to 7.
Preferably, the sustained release tablet comprises a tablet core and a coating coated on the surface of the tablet core; the tablet core contains active ingredients of mirabegron, antioxidant, gelling agent, gel enhancer, adhesive, glidant and lubricant; the coating contains hypromellose, a gel enhancer, and optionally a colorant, with or without. For example, the coating is a coating agent
03F42192。
Preferably, the mirabegron, antioxidants, gelling agents, gel enhancers, binders, glidants, lubricants are in an amount and selected according to any one of claims 1 to 7.
Preferably, the coating is present in the sustained release tablet in an amount of 3 to 10 parts, for example 4 to 8 parts, by weight.
Preferably, the sustained release tablet comprises a tablet core and a coating coated on the surface of the tablet core;
the tablet core comprises, by weight, 15-25 parts of mirabegron, 30-50 parts of polyoxyethylene, 40-60 parts of polyethylene glycol, 1.5-5 parts of hydroxypropyl cellulose, 0.1-0.3 part of butylated hydroxytoluene, 0.5-2 parts of aerosil and 0.5-2 parts of magnesium stearate; and 4-8 parts of a coating.
10. A process for preparing a sustained-release tablet according to claim 9, which comprises the steps of:
(1) under the protection of inert gas, heating the gelling agent and the gel reinforcing agent to be molten to form a eutectic body;
(2) and adding mirabegron and an antioxidant into the eutectic, mixing and cooling to obtain a solid.
Preferably, it further comprises the following steps:
(3) crushing the solid obtained in the step (2) into powder, mixing the powder with a binder, and sieving and grading the mixture;
(4) mixing the granules obtained in the step (3) with a flow aid and a lubricant, and tabletting to obtain a tablet core;
preferably, it further comprises the following steps:
(5) and coating the tablet core by adopting a coating agent to obtain the sustained-release tablet.
Preferably, in step (1), the heating is at a temperature of from 60 to 80 ℃, such as from 65 to 75 ℃, exemplary 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃. Preferably, the heating is water bath heating.
Preferably, the inert gas in step (1) is nitrogen.
Preferably, in the step (2), the cooling is cooling to room temperature.
Preferably, in step (3), the temperature of the pulverization is controlled to be below 20 ℃, for example below 18 ℃, and further for example below 15 ℃. For example, the temperature of comminution may be controlled by an ice water bath. For example, the pulverization is carried out by a water-cooled pulverizer.
Preferably, in the step (3), D is a powder obtained by pulverizing90Particle sizes of 400-560 μm, e.g., 450-560 μm, illustratively 500 μm, 506 μm, 518 μm,520μm，540μm。
preferably, in the step (3), the sieving is 20-mesh sieving.
Preferably, in the step (4), the tabletting can be performed by using a rotary tabletting machine.
Preferably, in step (5), the coating agent is 5-10 wt% of aqueous dispersion, preferably 10 wt% of aqueous dispersion.
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