WO2018169325A1 - Pharmaceutical composition for release control, comprising mirabegron or salt thereof - Google Patents
Pharmaceutical composition for release control, comprising mirabegron or salt thereof Download PDFInfo
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- WO2018169325A1 WO2018169325A1 PCT/KR2018/003043 KR2018003043W WO2018169325A1 WO 2018169325 A1 WO2018169325 A1 WO 2018169325A1 KR 2018003043 W KR2018003043 W KR 2018003043W WO 2018169325 A1 WO2018169325 A1 WO 2018169325A1
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- Prior art keywords
- pharmaceutical composition
- peo
- mirabegron
- present
- polyethylene oxide
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- 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 20
- 229960001551 mirabegron Drugs 0.000 title claims abstract description 19
- 150000003839 salts Chemical class 0.000 title claims abstract description 10
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 43
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000013270 controlled release Methods 0.000 claims description 8
- -1 aluminum silver Chemical group 0.000 claims description 7
- 239000003086 colorant Substances 0.000 claims description 4
- 229920003023 plastic Polymers 0.000 claims description 4
- 239000004033 plastic Substances 0.000 claims description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 3
- 239000011888 foil Substances 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 239000007935 oral tablet Substances 0.000 claims description 2
- 229940096978 oral tablet Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 12
- 239000002202 Polyethylene glycol Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229940068917 polyethylene glycols Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Natural products OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- 208000001718 Immediate Hypersensitivity Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- BVHLGVCQOALMSV-JEDNCBNOSA-N L-lysine hydrochloride Chemical compound Cl.NCCCC[C@H](N)C(O)=O BVHLGVCQOALMSV-JEDNCBNOSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 206010045240 Type I hypersensitivity Diseases 0.000 description 1
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000010216 atopic IgE responsiveness Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 235000012730 carminic acid Nutrition 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- FVTCRASFADXXNN-SCRDCRAPSA-N flavin mononucleotide Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O FVTCRASFADXXNN-SCRDCRAPSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229960005337 lysine hydrochloride Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 229950001574 riboflavin phosphate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 description 1
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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
Definitions
- the present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof.
- the present invention relates to a pharmaceutical composition for controlling release, including polyethylene oxide for controlling the release of Mirabegron as an active ingredient, which is harmless to the human body and is easy to prepare pharmaceutically.
- Mirabegron is a compound having the structure of Formula 1 below, and its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 '- ⁇ 2-[(2-hydroxy-2- Phenylethyl) amino] ethyl ⁇ acetanilide.
- Mirabegron or a pharmaceutically acceptable salt thereof has ⁇ 3 adrenergic receptor agonist action.
- Mira GRONLUND bay is used for the treatment of symptoms of urgency, frequency or urge incontinence, which can occur in patients with overactive bladder, it is commercially available in the name of Micah Beta ® sustained-release tablet in Korea.
- Miravegron relaxes the bladder in the storage phase, where urine fills the bladder, and this bladder relaxation effect improves the storage capacity of the bladder (Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8).
- studies using a mouse model of ischemia in the bladder have shown that mirabegron reduces bladder overactivity by protecting bladder function and morphology (Eur Urol 2013; 64: 664-71).
- Korean Patent No. 1524164 discloses a pharmaceutical composition for controlling release including Mirabegron, by including (a) a hydrophilic additive for infiltrating water into the formulation and (b) a polymer material forming a hydrogel.
- a formulation for controlled release is disclosed wherein the drug dissolution rate is 75% or less from the formulation at 1.5 hours and 75% or more and 100% or less at 7 hours.
- Korean Patent No. 507400 discloses a pharmaceutical composition with no change in drug dissolution upon storage under light irradiation, comprising: (a) a hydrophilic base, (b) polyethylene oxide having an average molecular weight of 2 million or more, and Disclosed is an oral pharmaceutical composition comprising.
- the above patents all include a hydrophilic base and use polyethylene glycol (PEG) as a representative material of the hydrophilic base.
- PEG polyethylene glycol
- polyethylene glycol as a hydrophilic base has been found to cause delayed and immediate hypersensitivity of polyethylene glycol (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology).
- polyethylene glycol is likely to cause changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance) (U.S. Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie).
- the inventors of the present invention have attempted to develop a pharmaceutical composition that is harmless to the human body and is stable in the preparation of a release-controlling formulation containing Mirabegron.
- Polyethyleneglycols are generally considered to be biologically inert and safe. However, it has the disadvantage of causing hypersensitivity to a small number of people and altering pharmacokinetic behavior.
- the present inventors have completed the present invention as a result of the development of a pharmaceutical composition and formulation which is safe and pharmaceutically easy to prepare without including a hydrophilic base such as polyethylene glycol.
- the present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and a polyethylene oxide (PEO) as a sustained release agent.
- a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and a polyethylene oxide (PEO) as a sustained release agent.
- PEO polyethylene oxide
- the polyethylene oxide (PEO) of the present invention is very excellent in pharmacokinetics and dissolution rate to exhibit a continuous effect of the drug when it includes both PEO 300,000 and PEO 100 million.
- PEO polyethylene oxide
- the polyethylene oxide has an average molecular weight of about 300,000 or more.
- the average molecular weight of polyethylene oxide is preferably 1 million or less, but is not limited thereto.
- Suitable polyethylene oxides for use in the present invention are commercially available.
- Polyox WSR N-12K, Polyox N-60K, Polyox N-750, Polyox WSR 301 NF or Polyox WSR 303NF can be used in the dosage forms of the present invention. But it is not limited thereto.
- the present invention may be a pharmaceutical composition characterized by comprising less than 5% hydrophilic base.
- Hydrophilic bases include water-soluble polymers such as polyvinylpyrrolidone (PVP); Sugar alcohols such as D-mannitol, sorbitol and xylitol; Sugars such as lactose, white sugar, maltose anhydrous, D-fructose, dextran and glucose; Surfactant, such as polyoxyethylene hardened castor oil and polyoxyethylene sorbitan higher fatty acid ester; Salts such as sodium chloride and magnesium chloride; Organic acids such as citric acid and tartaric acid; Amino acids such as glycine, alanine, and lysine hydrochloride; Amino acid saccharides such as meglumine and the like.
- PVP polyvinylpyrrolidone
- Sugar alcohols such as D-mannitol, sorbitol and xylitol
- Sugars such as lactose, white sugar, maltose anhydrous, D-fructose, dextran and glucose
- the present invention may further comprise a colorant.
- the colorant may be carmine, caramel, ⁇ -carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, and the like, and preferably aluminum lake.
- the pharmaceutical composition of the present invention contains Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, and is a conventional agent in the pharmaceutical field, such as tablets, capsules, beads, beadlets, granules, pills, tro It may be formulated as an oral preparation such as a key preparation, a liquid preparation, a suspension, or a parenteral preparation, and in particular, may be a tablet for oral administration.
- the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary.
- a pH adjusting agent suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like.
- the content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.
- the formulation of the present invention may be packaged in a container, preferably packaged in an airtight package, and the container includes both an airtight container and a sealed container.
- the tablet for oral administration of the present invention is preferably packaged in aluminum silver foil (alu-alu) packaging container, but is not limited thereto.
- compositions comprising a mirabegron or a pharmaceutically acceptable salt thereof according to the present invention have the advantage of long-lasting pharmacological effects through control of release, harmless to the human body, and easy to manufacture pharmaceuticals.
- Figure 1 shows the dissolution test results by the paddle method (50rpm, 37 °C) in pH 6.8 eluate of Examples 1 to 5 and Comparative Examples.
- the present invention relates to a pharmaceutical composition for controlling release, comprising Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained release agent.
- the polyethylene oxide (PEO) of the present invention may include only one million PEO and only 30 PEO. It is preferable to include only 300,000 PEO and 100 million PEO in a weight ratio of 1: 0.1 to 1: 5.
- the average molecular weight of polyethylene oxide (PEO) is preferably 1 million or less.
- the present invention includes pharmaceutical compositions that do not contain at least 5% hydrophilic base.
- the present invention is characterized in that it does not contain polyethylene glycol (PEG) as a hydrophilic base.
- PEG polyethylene glycol
- the present invention includes an agent for controlling the release of the pharmaceutical composition is formulated, which may be an oral tablet, but is not limited thereto.
- the formulation may be packaged in a plastic container, with the plastic container being preferably aluminum silver foil (Alu-Alu).
- the sieved material was put into a mixer, the colloidal silicon dioxide and magnesium stearate were passed through a sieve, and then mixed to prepare a final mixture.
- the final mixture was compressed into tablets using an automatic tablet press (XP1, Korsh, Germany) to give a tablet of 250 mg in total weight.
- XP1 Korsh, Germany
- Example 2 Example 3
- Example 4 Example 5 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % 1T (mg) % mix Mirabegron 50.0 19.8 50.0 20.0 50.0 20.0 50.0 20.0 50.0 20.0 50.0 20.0 PEO 2,000,000 70.0 27.7 - - - - - - - - - - PEO 1,000,000 - - 187.1 74.8 153.5 61.4 117.5 47.0 92.5 37.0 67.1 26.8 PEO 300,000 - - - - 33.6 13.4 69.6 27.8 94.6 37.8 120.0 48.0 PEG 8,000 119.6 47.4 - - - - - - - - - - Binder ethanol 50.0 - 50.0 - 50.0 - 50.0 - 50.0 - BHT 0.4 0.2 0.4 0.2 0.4 0.4 0.4 0.4 0.4
- Dissolution test was performed at pH 6.8 (900 mL, 50 rpm) of the tablets prepared in Examples 1 to 5 and Comparative Examples, and the liquid chromatograph measuring method thereof is as follows.
- Mobile phase A To 900 mL of water add 8.7 mL of perchloric acid (70%) and 3.0 g of sodium hydroxide, adjust the pH to 2.0 mL with 0.1 N aqueous sodium hydroxide solution and adjust to 1000 mL.
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Abstract
The present invention relates to a pharmaceutical composition for release control, comprising mirabegron or a pharmaceutically acceptable salt thereof. Particularly, the present invention relates to a pharmaceutical composition for release control, which comprises polyethylene oxide for controlling the release of mirabegron as an active ingredient and is harmless to the human body and easy to pharmaceutically prepare.
Description
본 발명은 미라베그론(mirabegron) 또는 이의 약제학적으로 허용가능한 염을 포함하는 방출조절용 약제학적 조성물에 관한 것이다. 구체적으로, 활성성분으로 미라베그론의 방출조절을 위하여 폴리에틸렌옥사이드를 포함하여, 인체에 무해하고 제제학적으로 제조하기 용이한 방출조절용 약제학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a pharmaceutical composition for controlling release, including polyethylene oxide for controlling the release of Mirabegron as an active ingredient, which is harmless to the human body and is easy to prepare pharmaceutically.
미라베그론은 하기 화학식 1의 구조를 갖는 화합물로, 이의 화학명은 (R)-2-(2-아미노티아졸-4-일)-4'-{2-[(2-히드록시-2-페닐에틸)아미노]에틸}아세트아닐리드이다. Mirabegron is a compound having the structure of Formula 1 below, and its chemical name is (R) -2- (2-aminothiazol-4-yl) -4 '-{2-[(2-hydroxy-2- Phenylethyl) amino] ethyl} acetanilide.
[화학식 1][Formula 1]
미라베그론 또는 그의 약제학적으로 허용가능한 염은 β3 아드레날린 수용체 아고니스트 작용을 갖고 있다. 미라베그론은 과민성 방광 환자에서 발생할 수 있는 절박뇨, 빈뇨 또는 절박요실금의 증상의 치료를 위해 사용되고 있으며, 한국에서 베타미가서방정®의 제품명으로 시판되고 있다.Mirabegron or a pharmaceutically acceptable salt thereof has β3 adrenergic receptor agonist action. Mira GRONLUND bay is used for the treatment of symptoms of urgency, frequency or urge incontinence, which can occur in patients with overactive bladder, it is commercially available in the name of Micah Beta ® sustained-release tablet in Korea.
미라베그론은 방광에 소변이 차오르는 저장기(storage phase)에 방광을 이완시키고, 이러한 방광 이완 효과로 인해 방광의 저장 능력을 향상시킨다(Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8). 또한, 방광에 허혈이 발생한 쥐 모델을 이용해 연구를 진행한 결과, 미라베그론은 방광기능 및 형태를 보호하여 방광의 과활동성을 감소시킨다고 밝혀졌다(Eur Urol 2013; 64: 664-71).Miravegron relaxes the bladder in the storage phase, where urine fills the bladder, and this bladder relaxation effect improves the storage capacity of the bladder (Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 71-8). In addition, studies using a mouse model of ischemia in the bladder have shown that mirabegron reduces bladder overactivity by protecting bladder function and morphology (Eur Urol 2013; 64: 664-71).
미라베그론의 이러한 약물학적 효과를 최대한 발현하기 위해서, 방출조절용 제제의 개발이 필요하였다. In order to maximize the pharmacological effects of Mirabegron, it was necessary to develop an agent for controlling release.
한국등록특허 제1524164호는 미라베그론을 포함하는 방출제어용 의약 조성물을 제공하기 위하여, (a) 제제 내부에 물을 침입시키기 위한 친수성 첨가제 및 (b) 하이드로겔을 형성하는 고분자 물질을 포함함으로써, 1.5시간에 제제로부터 약물 용출률이 75% 이하, 7시간에 75% 이상 100% 이하인 방출제어용 제제를 개시한다.Korean Patent No. 1524164 discloses a pharmaceutical composition for controlling release including Mirabegron, by including (a) a hydrophilic additive for infiltrating water into the formulation and (b) a polymer material forming a hydrogel. A formulation for controlled release is disclosed wherein the drug dissolution rate is 75% or less from the formulation at 1.5 hours and 75% or more and 100% or less at 7 hours.
또한, 한국등록특허 제507400호는 광조사 하에 저장시 약물 용출에 변화가 없는 의약 조성물을 제공하기 위하여, (a) 친수성 기제, (b) 평균분자량이 200만 이상인 폴리에틸렌 옥사이드 및 (c) 산화철을 포함하는 경구용 의약 조성물을 개시한다.In addition, Korean Patent No. 507400 discloses a pharmaceutical composition with no change in drug dissolution upon storage under light irradiation, comprising: (a) a hydrophilic base, (b) polyethylene oxide having an average molecular weight of 2 million or more, and Disclosed is an oral pharmaceutical composition comprising.
상기 등록특허는 모두 친수성 기제를 포함하고, 친수성 기제의 대표적인 물질로 폴리에틸렌글리콜(PEG)를 사용한다.The above patents all include a hydrophilic base and use polyethylene glycol (PEG) as a representative material of the hydrophilic base.
그러나, 친수성 기제로 폴리에틸렌글리콜을 사용할 경우, 폴리에틸렌글리콜이 지연된 또는 즉각적인 과민반응(delayed and immediate hypersensitivity)을 유발하는 사례들이 발견되었다(Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology). 이와 더불어 폴리에틸렌글리콜은 ABC Phenomenon(accelerated blood clearance)으로 인한 약동학적 거동의 변화를 유발할 가능성이 있다(U.S. Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie).However, the use of polyethylene glycol as a hydrophilic base has been found to cause delayed and immediate hypersensitivity of polyethylene glycol (Sapna Shah MD, et al., Hypersensitivity to Polyethylene Glycols, The Journal of Clinical Pharmacology). In addition, polyethylene glycol is likely to cause changes in pharmacokinetic behavior due to ABC Phenomenon (accelerated blood clearance) (U.S. Schuber et al., Polyethylene glycol in Drug delivery, Angewandte chemie).
따라서, 본 발명자들은 미라베그론을 포함하는 방출조절용 제제의 제조시, 인체에 무해하고 안정한 약제학적 조성물을 개발하고자 하였다.Therefore, the inventors of the present invention have attempted to develop a pharmaceutical composition that is harmless to the human body and is stable in the preparation of a release-controlling formulation containing Mirabegron.
폴리에틸렌글리콜은 일반적으로 생물학적으로 비활성이고 안전하다고 간주된다. 그러나 소수의 사람들에게 과민반응을 유발하며, 약동학적 거동을 변화시키는 단점을 가진다. Polyethyleneglycols are generally considered to be biologically inert and safe. However, it has the disadvantage of causing hypersensitivity to a small number of people and altering pharmacokinetic behavior.
따라서, 본 발명자들은 폴리에틸렌글리콜과 같은 친수성 기제를 포함하지 않으면서, 안전하고 제제학적으로 제조하기 용이한 약제학적 조성물 및 제제를 개발한 결과, 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention as a result of the development of a pharmaceutical composition and formulation which is safe and pharmaceutically easy to prepare without including a hydrophilic base such as polyethylene glycol.
본 발명은 활성성분으로 미라베그론 또는 이의 약제학적으로 허용가능한 염을 포함하고 서방화기제로 폴리에틸렌옥사이드(polyethylene oxide, PEO)를 포함하는 방출조절용 약제학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for controlled release comprising a mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and a polyethylene oxide (PEO) as a sustained release agent.
바람직하게, 본 발명의 폴리에틸렌옥사이드(PEO)는 PEO 30만 및 PEO 100만을 모두 포함할 때, 약물의 지속적인 효과를 나타내기 위한 약물동태 및 용출률이 매우 우수하다. 또한, PEO 30만 및 PEO 100만을 1:0.1 내지 1:5의 중량비로 포함하는 것이 바람직하나, 이에 한정되지 않는다.Preferably, the polyethylene oxide (PEO) of the present invention is very excellent in pharmacokinetics and dissolution rate to exhibit a continuous effect of the drug when it includes both PEO 300,000 and PEO 100 million. In addition, it is preferable to include only 300,000 PEO and 100 million PEO in a weight ratio of 1: 0.1 to 1: 5, but is not limited thereto.
상기 폴리에틸렌옥사이드는 약 30만 이상의 평균 분자량을 갖는다. 또한, 폴리에틸렌옥사이드의 평균분자량이 100만 이하인 것이 바람직하나, 이에 한정되지 않는다.The polyethylene oxide has an average molecular weight of about 300,000 or more. In addition, the average molecular weight of polyethylene oxide is preferably 1 million or less, but is not limited thereto.
본 발명에 사용하기에 적합한 폴리에틸렌옥사이드는 상업적으로 입수가능하다. 예를 들면, Polyox WSR N-12K, Polyox N-60K, Polyox N-750, Polyox WSR 301 NF 또는 Polyox WSR 303NF가 본 발명의 투여 제형에 사용될 수 있다. 그러나 이에 제한하는 것은 아니다.Suitable polyethylene oxides for use in the present invention are commercially available. For example, Polyox WSR N-12K, Polyox N-60K, Polyox N-750, Polyox WSR 301 NF or Polyox WSR 303NF can be used in the dosage forms of the present invention. But it is not limited thereto.
본 발명은 친수성 기제를 5% 미만으로 포함하는 것을 특징으로 하는 약제학적 조성물일 수 있다.The present invention may be a pharmaceutical composition characterized by comprising less than 5% hydrophilic base.
친수성 기제는 폴리비닐피롤리돈(PVP) 등의 수용성 고분자; D-만니톨, 소르비톨, 자일리톨 등의 당알코올류; 젖당, 백당, 무수 말토오스, D-프럭토오스, 덱스트란, 포도당 등의 당류; 폴리옥시에틸렌 경화 피마자유, 폴리옥시에틸렌소르비탄 고급 지방산 에스테르 등의 계면활성제; 염화나트륨, 염화마그네슘 등의 염류; 시트르산, 타르타르산 등의 유기산; 글리신, 알라닌, 염산리신 등의 아미노산류; 메글루민 등의 아미노산 당류 등을 포함한다. Hydrophilic bases include water-soluble polymers such as polyvinylpyrrolidone (PVP); Sugar alcohols such as D-mannitol, sorbitol and xylitol; Sugars such as lactose, white sugar, maltose anhydrous, D-fructose, dextran and glucose; Surfactant, such as polyoxyethylene hardened castor oil and polyoxyethylene sorbitan higher fatty acid ester; Salts such as sodium chloride and magnesium chloride; Organic acids such as citric acid and tartaric acid; Amino acids such as glycine, alanine, and lysine hydrochloride; Amino acid saccharides such as meglumine and the like.
본 발명은 착색제를 추가로 포함할 수 있다. 상기 착색제는 카르민, 카라멜, β-카로틴, 산화티탄, 탈크, 인산리보플라빈나트륨, 황색 알루미늄레이크 등일 수 있으며, 바람직하게는 알루미늄레이크일 수 있다.The present invention may further comprise a colorant. The colorant may be carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, yellow aluminum lake, and the like, and preferably aluminum lake.
본 발명의 약제학적 조성물은 미라베그론 또는 이의 약제학적으로 허용가능한 염을 활성성분으로 함유하고, 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 비드, 비들렛, 과립, 환제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화될 수 있으며, 특히 경구투여용 정제일 수 있다.The pharmaceutical composition of the present invention contains Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient, and is a conventional agent in the pharmaceutical field, such as tablets, capsules, beads, beadlets, granules, pills, tro It may be formulated as an oral preparation such as a key preparation, a liquid preparation, a suspension, or a parenteral preparation, and in particular, may be a tablet for oral administration.
이 밖에도, 본 발명의 약제학적 제제는 필요에 따라 pH 조절제, 현탁화제, 보존제, 착향제, 착색제, 감미제, 흡착제 등을 더 포함할 수 있다. 이러한 첨가제의 함량은 본 발명에서 특별히 제한되지 않고 필요에 따라 적절히 조절될 수 있다.In addition, the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary. The content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.
본 발명의 제제는 용기에 포장될 수 있으며, 기밀 포장체에 포장되는 것이 바람직하며, 상기 용기는 기밀용기 및 밀봉용기를 모두 포함한다.The formulation of the present invention may be packaged in a container, preferably packaged in an airtight package, and the container includes both an airtight container and a sealed container.
또한, 본 발명의 상기 경구투여용 정제는 알루미늄은박(alu-alu) 포장 용기로 포장되는 것이 바람직하나, 이에 한정되지 않는다.In addition, the tablet for oral administration of the present invention is preferably packaged in aluminum silver foil (alu-alu) packaging container, but is not limited thereto.
본 발명에 따른 미라베그론 또는 이의 약제학적으로 허용가능한 염을 포함하는 약제학적 조성물은, 방출제어를 통해 약효를 오랫동안 지속시키고, 인체에 무해하며, 제제학적으로 제조하기 용이한 장점을 갖는다.Pharmaceutical compositions comprising a mirabegron or a pharmaceutically acceptable salt thereof according to the present invention have the advantage of long-lasting pharmacological effects through control of release, harmless to the human body, and easy to manufacture pharmaceuticals.
도 1은 실시예 1 내지 5 및 비교예의 pH 6.8 용출액에서 패들법(50rpm, 37℃)으로 용출 시험 결과를 나타낸다.Figure 1 shows the dissolution test results by the paddle method (50rpm, 37 ℃) in pH 6.8 eluate of Examples 1 to 5 and Comparative Examples.
본 발명은 활성성분으로 미라베그론 또는 이의 약제학적으로 허용가능한 염을 포함하고 서방화기제로 폴리에틸렌옥사이드(PEO)를 포함하는 방출조절용 약제학적 조성물에 관한 것이다. 또한, 본 발명의 폴리에틸렌옥사이드(PEO)는 PEO 100만 및 PEO 30만을 동시에 포함할 수 있다. PEO 30만 및 PEO 100만을 1:0.1 내지 1:5의 중량비로 포함하는 것이 바람직하다. The present invention relates to a pharmaceutical composition for controlling release, comprising Mirabegron or a pharmaceutically acceptable salt thereof as an active ingredient and polyethylene oxide (PEO) as a sustained release agent. In addition, the polyethylene oxide (PEO) of the present invention may include only one million PEO and only 30 PEO. It is preferable to include only 300,000 PEO and 100 million PEO in a weight ratio of 1: 0.1 to 1: 5.
또한, 폴리에틸렌옥사이드(PEO)의 평균분자량이 100만 이하인 것이 바람직하다.In addition, the average molecular weight of polyethylene oxide (PEO) is preferably 1 million or less.
본 발명은 친수성 기제를 5% 이상 포함하지 않는 약제학적 조성물을 포함한다.The present invention includes pharmaceutical compositions that do not contain at least 5% hydrophilic base.
특히 본 발명은 친수성 기제로 폴리에틸렌글리콜(PEG)을 포함하지 않는 것을 특징으로 한다.In particular, the present invention is characterized in that it does not contain polyethylene glycol (PEG) as a hydrophilic base.
본 발명은 상기 약제학적 조성물이 제제화되는 방출조절용 제제를 포함하며, 이는 경구투여용 정제일 수 있으나, 이에 한정되지 않는다. 상기 제제는 플라스틱 용기로 포장될 수 있고, 플라스틱 용기가 알루미늄은박(Alu-Alu)인 것이 바람직하다.The present invention includes an agent for controlling the release of the pharmaceutical composition is formulated, which may be an oral tablet, but is not limited thereto. The formulation may be packaged in a plastic container, with the plastic container being preferably aluminum silver foil (Alu-Alu).
이하, 실시예를 통하여 본 발명을 더욱 구체적으로 설명한다. 그러나 이들 실시예는 본 발명에 대한 이해를 돕기 위해 예시의 목적으로만 제공된 것일 뿐, 본 발명의 범위가 하기 실시예에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are provided only for the purpose of illustration in order to help the understanding of the present invention, the scope of the present invention is not limited by the following examples.
[실시예 1 내지 5, 및 비교예][Examples 1 to 5 and Comparative Examples]
하기 표 1에 나타낸 바와 같이, 실시예 1 내지 5, 및 비교예에 사용된 폴리에틸렌 옥사이드의 분자량을 변화시켜 약제학적 제제를 아래와 같은 제조방법으로 제조하였다.As shown in Table 1 below, by changing the molecular weight of the polyethylene oxide used in Examples 1 to 5, and Comparative Examples, a pharmaceutical formulation was prepared by the following preparation method.
과립의 조제Preparation of granules
미라베그론과 폴리에틸렌 옥사이드(Polyox® WSR N-12K)을 균질하게 혼합한 후, 에탄올에 히드록시프로필셀롤로오스와 디부틸히드록시톨루엔이 용해된 결합액을 넣어 연합하여 제립, 건조하고 정립하였다.After homogeneously mixing Mirabegron and polyethylene oxide (Polyox® WSR N-12K), the combined solution of hydroxypropyl cellulose and dibutyl hydroxytoluene was added to ethanol to form granules, dried and established. .
최종혼합Final mixing
상기 정립물을 혼합기에 넣고 콜로이드성 이산화규소 및 스테아르산마그네슘을 체과하여 투입한 후, 혼합을 진행하여 최종 혼합물을 제조하였다.The sieved material was put into a mixer, the colloidal silicon dioxide and magnesium stearate were passed through a sieve, and then mixed to prepare a final mixture.
타정Tableting
상기 최종 혼합물을 자동 타정기(XP1, Korsh, 독일)을 이용하여 타정하여 총 중량 250mg의 정제를 수득하였다.The final mixture was compressed into tablets using an automatic tablet press (XP1, Korsh, Germany) to give a tablet of 250 mg in total weight.
| 구분division | 비교예Comparative example | 실시예 1Example 1 | 실시예 2Example 2 | 실시예 3Example 3 | 실시예 4Example 4 | 실시예 5Example 5 | |||||||
| 1T1T (mg)(mg) | %% | 1T1T (mg)(mg) | %% | 1T1T (mg)(mg) | %% | 1T1T (mg)(mg) | %% | 1T1T (mg)(mg) | %% | 1T1T (mg)(mg) | %% | ||
| 혼합mix | 미라베그론Mirabegron | 50.050.0 | 19.819.8 | 50.050.0 | 20.020.0 | 50.050.0 | 20.020.0 | 50.050.0 | 20.020.0 | 50.050.0 | 20.020.0 | 50.050.0 | 20.020.0 |
| PEO PEO 2,000,0002,000,000 | 70.070.0 | 27.727.7 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | |
| PEO PEO 1,000,0001,000,000 | -- | -- | 187.1187.1 | 74.874.8 | 153.5153.5 | 61.461.4 | 117.5117.5 | 47.047.0 | 92.592.5 | 37.037.0 | 67.167.1 | 26.826.8 | |
| PEO PEO 300,000300,000 | -- | -- | -- | -- | 33.633.6 | 13.413.4 | 69.669.6 | 27.827.8 | 94.694.6 | 37.837.8 | 120.0120.0 | 48.048.0 | |
| PEG PEG 8,0008,000 | 119.6119.6 | 47.447.4 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | |
| 결합액Binder | 에탄올ethanol | 50.050.0 | -- | 50.050.0 | -- | 50.050.0 | -- | 50.050.0 | -- | 50.050.0 | -- | 50.050.0 | -- |
| BHTBHT | 0.40.4 | 0.20.2 | 0.40.4 | 0.20.2 | 0.40.4 | 0.20.2 | 0.40.4 | 0.20.2 | 0.40.4 | 0.20.2 | 0.40.4 | 0.20.2 | |
| HPC-LHPC-L | 7.57.5 | 3.03.0 | 7.57.5 | 3.03.0 | 7.57.5 | 3.03.0 | 7.57.5 | 3.03.0 | 7.57.5 | 3.03.0 | 7.57.5 | 3.03.0 | |
| 최총Maximum 혼합mix | Mg. StearateMg. Stearate | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 |
| Aerosil 200Aerosil 200 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | 2.52.5 | 1.01.0 | |
| 중량weight | 252.5252.5 | 100.0100.0 | 250.0250.0 | 100.0100.0 | 250.0250.0 | 100.0100.0 | 250.0250.0 | 100.0100.0 | 250.0250.0 | 100.0100.0 | 250.0250.0 | 100.0100.0 | |
[시험예 1] [Test Example 1]
용출시험Dissolution Test
실시예 1 내지 5, 및 비교예에서 제조된 정제를 pH 6.8(900mL, 50rpm)에서 용출시험을 수행하였고, 이의 액체크로마토그래프 측정방법은 다음과 같다. Dissolution test was performed at pH 6.8 (900 mL, 50 rpm) of the tablets prepared in Examples 1 to 5 and Comparative Examples, and the liquid chromatograph measuring method thereof is as follows.
- 검출기 : 자외부흡광광도계 (측정파장 : 250 nm)-Detector: ultraviolet absorption photometer (wavelength: 250 nm)
- 칼럼 : C18 (4.6 mm × 150 mm, 5 μm)Column: C18 (4.6 mm × 150 mm, 5 μm)
- 이동상 : 이동상 A와 B를 7:3 비율로 혼화하여 사용한다.-Mobile phase: Use mobile phases A and B in a 7: 3 ratio.
· 이동상 A : 물 900 mL에 8.7 mL의 과염소산(70%)과 3.0g의 수산화나트륨을 첨가한 후, 0.1 N 수산화나트륨 수용액으로 pH 2.0을 조정한 다음 1000 mL로 맞춘다.Mobile phase A: To 900 mL of water add 8.7 mL of perchloric acid (70%) and 3.0 g of sodium hydroxide, adjust the pH to 2.0 mL with 0.1 N aqueous sodium hydroxide solution and adjust to 1000 mL.
· 이동상 B : 아세토니트릴Mobile phase B: acetonitrile
- 유속 : 4분에 미라베그론이 검출되도록 유속을 조절-Flow rate: Adjust the flow rate so that Mirabegron can be detected in 4 minutes
- 컬럼온도 : 40 ℃-Column temperature: 40 ℃
그 결과를 도 1 및 표 2에 나타내었으며, 용출률을 확인하였다. 즉, PEO 100만을 단독으로 사용하는 것보다, PEO 100만과 PEO 30만을 혼합하여 사용하는 경우 더 우수한 용출률을 나타내었다. The results are shown in Figure 1 and Table 2, the dissolution rate was confirmed. That is, when only PEO 100 and PEO 30 were mixed and used, the dissolution rate was better than using only PEO 100 alone.
|
시간(hour) |
22 | 66 | 88 | 1010 | 1212 |
| 비교예Comparative example | 22.622.6 | 66.666.6 | 84.084.0 | 92.592.5 | 95.295.2 |
| 실시예 1Example 1 | 11.611.6 | 47.047.0 | 62.662.6 | 74.574.5 | 82.782.7 |
| 실시예 2Example 2 | 14.314.3 | 54.654.6 | 73.873.8 | 87.887.8 | 94.494.4 |
| 실시예 3Example 3 | 14.314.3 | 54.954.9 | 74.674.6 | 87.887.8 | 94.994.9 |
| 실시예 4Example 4 | 18.818.8 | 67.467.4 | 85.385.3 | 95.795.7 | 99.399.3 |
| 실시예 5Example 5 | 14.714.7 | 61.061.0 | 80.780.7 | 93.493.4 | 96.096.0 |
Claims (10)
- 활성성분으로 미라베그론 또는 이의 약제학적으로 허용 가능한 염을 포함하고 서방화기제로 폴리에틸렌 옥사이드(PEO)를 포함하는 방출조절용 약제학적 조성물.A pharmaceutical composition for controlled release comprising an active ingredient Mirabegron or a pharmaceutically acceptable salt thereof and a polyethylene oxide (PEO) as a sustained release agent.
- 제1항에 있어서, 폴리에틸렌 옥사이드(PEO)는 PEO 100만 및 PEO 30만을 포함하는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the polyethylene oxide (PEO) comprises only 1 million PEO and 30 only PEO.
- 제2항에 있어서, PEO 30만 및 PEO 100만을 1:0.1 내지 1:5의 중량비로 포함하는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 2 comprising only 300,000 PEO and 100 million PEO in a weight ratio of 1: 0.1 to 1: 5.
- 제1항에 있어서, 폴리에틸렌 옥사이드(PEO)의 평균분자량이 100만 이하인 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition according to claim 1, wherein the average molecular weight of polyethylene oxide (PEO) is 1 million or less.
- 제1항에 있어서, 친수성 기제를 5% 미만으로 추가로 포함하는 것을 특징으로 하는 약제학적 조성물. The pharmaceutical composition of claim 1, further comprising less than 5% hydrophilic base.
- 제1항에 있어서, 착색제로 알루미늄레이크를 추가로 포함하는 약제학적 조성물.The pharmaceutical composition of claim 1, further comprising aluminum lake as colorant.
- 제1항에 따른 조성물이 제제화되는 방출조절용 제제.An agent for controlled release, wherein the composition according to claim 1 is formulated.
- 제7항에 있어서, 상기 제제가 경구투여용 정제인 방출조절용 제제.The agent for controlled release according to claim 7, wherein the agent is an oral tablet.
- 제7항에 있어서, 상기 제제는 플라스틱 용기로 포장되는 방출조절용 제제.8. A formulation for controlled release according to claim 7, wherein said formulation is packaged in a plastic container.
- 제9항에 있어서, 상기 플라스틱 용기가 알루미늄은박(Alu-Alu)인 것을 특징으로 하는 방출조절용 제제.10. The controlled release formulation of claim 9, wherein the plastic container is aluminum silver foil (Alu-Alu).
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| CN201880018616.8A CN110446490B (en) | 2017-03-17 | 2018-03-15 | Pharmaceutical composition for modified release comprising mirabegron or its salt |
| JP2019548680A JP2020510679A (en) | 2017-03-17 | 2018-03-15 | Pharmaceutical composition for modified release containing mirabegron or a salt thereof |
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| KR1020170033944A KR102051132B1 (en) | 2017-03-17 | 2017-03-17 | Pharmaceutical composition for controlled release comprising Mirabegron or its salts |
| KR10-2017-0033944 | 2017-03-17 |
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| JP (2) | JP2020510679A (en) |
| KR (1) | KR102051132B1 (en) |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4338729A1 (en) | 2022-09-19 | 2024-03-20 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A tablet comprising mirabegron |
| WO2024144207A1 (en) * | 2022-12-26 | 2024-07-04 | Rexpharmtech Co., Ltd | Sustained-release tablet comprising apixaban |
| EP4410279A1 (en) | 2023-01-25 | 2024-08-07 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A film tablet comprising mirabegron |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021069944A1 (en) * | 2019-10-09 | 2021-04-15 | Alvogen Korea Co., Ltd. | Pharmaceutical composition comprising mirabegron and process for manufacturing the same |
| KR102546923B1 (en) | 2020-03-03 | 2023-06-26 | 동광제약 주식회사 | Controlled-released dosage form comprising mirabegron as an active ingredient |
| WO2023022520A1 (en) * | 2021-08-18 | 2023-02-23 | 주식회사 삼양홀딩스 | Oral tablet composition of ruxolitinib and method for preparing same |
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| EP4410279A1 (en) | 2023-01-25 | 2024-08-07 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A film tablet comprising mirabegron |
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| CN110446490A (en) | 2019-11-12 |
| KR102051132B1 (en) | 2019-12-02 |
| JP2020510679A (en) | 2020-04-09 |
| JP2021185139A (en) | 2021-12-09 |
| KR20180106185A (en) | 2018-10-01 |
| CN110446490B (en) | 2023-04-04 |
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