WO2024063734A1 - A tablet comprising mirabegron - Google Patents
A tablet comprising mirabegron Download PDFInfo
- Publication number
- WO2024063734A1 WO2024063734A1 PCT/TR2023/050936 TR2023050936W WO2024063734A1 WO 2024063734 A1 WO2024063734 A1 WO 2024063734A1 TR 2023050936 W TR2023050936 W TR 2023050936W WO 2024063734 A1 WO2024063734 A1 WO 2024063734A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polyethylene oxide
- film coated
- coated tablet
- mirabegron
- weight
- Prior art date
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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 48
- 229960001551 mirabegron Drugs 0.000 title claims abstract description 46
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 53
- 239000003826 tablet Substances 0.000 claims abstract description 30
- 239000007941 film coated tablet Substances 0.000 claims abstract description 24
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 38
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000007888 film coating Substances 0.000 claims description 15
- 238000009501 film coating Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 12
- 239000003795 chemical substances by application 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 10
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 239000003963 antioxidant agent Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 4
- 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 description 4
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 235000011010 calcium phosphates Nutrition 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 239000000728 ammonium alginate Substances 0.000 claims description 2
- 235000010407 ammonium alginate Nutrition 0.000 claims description 2
- KPGABFJTMYCRHJ-YZOKENDUSA-N ammonium alginate Chemical compound [NH4+].[NH4+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O KPGABFJTMYCRHJ-YZOKENDUSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 229960001021 lactose monohydrate Drugs 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 9
- 206010020853 Hypertonic bladder Diseases 0.000 description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 7
- 208000020629 overactive bladder Diseases 0.000 description 7
- 239000013543 active substance Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 206010004446 Benign prostatic hyperplasia 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010027566 Micturition urgency Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000007912 modified release tablet Substances 0.000 description 1
- HWMFFWCDLWDYGX-UHFFFAOYSA-N n-(4-aminophenyl)furan-2-carboxamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=CO1 HWMFFWCDLWDYGX-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229940114930 potassium stearate Drugs 0.000 description 1
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960001187 propiverine hydrochloride Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
Definitions
- the present invention relates to a film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 so the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile.
- the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the film coated tablet.
- Overactive bladder causes a frequent and sudden urge to urinate that may be difficult to control. You may feel like you need to pass urine many times during the day and night, and may also experience unintentional loss of urine.
- overactive bladder There are many options for treatment of overactive bladder such as; bladder training and drug therapy using anticholinergic substances such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, intractable cases and side effects could be occurred such as urinary dysfunction and dry mouth and, therefore, Mirabegron has been reported as one of the substance for the management of overactive bladder.
- Mirabegron is a beta-3 adrenergic agonist that is used for treatment of overactive bladder syndrome.
- the chemical designation of mirabegron is 2-(2-amino-1 ,3-thiazol-4-yl)-N-[4-[2- [[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl] acetamide, with the chemical structure illustrated below in Formula I.
- a mirabegron containing pharmaceutical product is approved under the brand name Betmiga® in the Ell and Mirbetriq® in the US as modified release tablets comprising 25 and 50 mg of mirabegron.
- Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and low permeability. It is known that the bioavailability of mirabegron is affected by the presence of food in the Gl tract. To prevent this food effect, modified release form is used.
- BCS Biopharmaceutical Classification System
- EP1559427 patent application was first disclosed a pharmaceutical composition comprising mirabegron that can be used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.
- overactive bladder such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.
- W02019072404 relates to a pharmaceutical composition for modified release comprising; mirabegron presenting 5-25 wt% to the total weight of the uncoated tablet, polyethylene oxide having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25°C and polyethylene glycol having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio polyethylene oxide to polyethylene glycol ranges from 1 :3 to 1 :4.5.
- WO2018169325 relates to a controlled release pharmaceutical composition
- a controlled release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and a polyethylene oxide as a sustained release agent.
- the main object of the present invention is to provide a film coating tablet comprising mirabegron with having desired level of dissolution rate which overcomes the above described problems in prior art and have additive advantages over them.
- Another object of the present invention is to provide a film coating tablet comprising mirabegron with improved homogenity, flowability and high stability.
- Another object of the present invention is to provide a film coating tablet comprising mirabegron prepared by simple, easy, time-saving and fast manufacturing methods.
- modified release refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period. In this invention, using release controlling (polyethylene oxide) agent provides modified release.
- a film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 .
- the amount of mirabegron is 15.0% to 25.0% by weight in the total composition. Preferably, it is between 18.0% to 22.0% by weight in the total formulation.
- the release controlling agent is polyethylene oxide.
- Polyethylene oxide is a very hydrophilic polymer. It is available in several different grades that vary in viscosity profiles in aqueous isopropyl alcohol solutions.
- the amount of polyethylene oxide is 30.0% to 60.0% by weight in the total composition.
- the amount is important because the rapid or extra slow release of mirabegron can cause some problems, for example; dissolution profile and stability and half-life of the drug. Also, it was observed that tablet breaking force/tablet hardness was increased on using PEO, this indicates that polyethylene oxide powder has good compatibility.
- the release controlling agent is polyethylene oxide WSR 205 or polyethylene oxide WSR N-60K or mixtures thereof.
- Polyethylene oxide suitable for use in the present invention is commercially available.
- Polyethylene oxide WSR N-60K has a molecular weight of 2,000,000 with viscosity of 2,000 to 4,000 cP at low addition levels.
- Polyethylene oxide WSR 205 is a non-ionic, water-soluble polyethylene oxide) polymer with a molecular weight of 600,000 with viscosity 4,500 to 8,800 cP. Both of them are a water insoluble hydrophilic excipients within the tablet core has shown good results in the achievement of the desired dissolution profile.
- the amount of polyethylene oxide WSR 205 is 20.0% to 35.0% by weight in the total composition and the amount of polyethylene oxide WSR N-60K is 5.0% to 15.0% by weight in the total composition.
- the weight ratio of PEO polyethylene oxide WSR N-60K and polyethylene oxide WSR 205) to mirabegron ranges from 1 :1 to 3.3:1 , preferably ranges from 1.4:1 to 2:1.
- the amount of polyethylene oxide WSR 205 is 45.0% to 60.0% by weight in the total composition.
- the weight ratio of PEO (polyethylene oxide WSR 205) to mirabegron ranges from 1 .8:1 to 4:1 , preferably ranges from 2:1 to 3:1 .
- the film coating tablet comprises;
- the film coating tablet comprises;
- excipients provided in a composition may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, stability, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a composition is developed. If active agent is incompatible of excipients, stability and psychochemical problems may be during or after the process.
- the tablet should have no physicochemical incompatibility between the active agent and the excipients.
- the film coated tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising diluents, antioxidants, lubricants or mixtures thereof.
- Suitable diluents are selected from the group comprising microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, ethylcellulose, lactose, mannitol, magnesium carbonate, medium chain triglycerides, polyvinylpyrrolidone, sodium alginate, sodium chloride, sucrose, sugar spheres, or mixtures thereof.
- the diluent is microcrystalline cellulose. It gives volume to tablet and enables mirabegron to be dispersed homogeneously in the tablet.
- the amount of microcrystalline cellulose is 22.0% to 55.0% by weight in the total composition.
- Suitable antioxidants are selected from the group comprising BHT (butylated hydroxy toluene), propyl gallate, BHA (butylated hydroxy anisole), monothioglycerol or mixtures thereof.
- the antioxidant is BHT (butylated hydroxy toluene). It helps to provide stability of tablet.
- the amount of butylated hydroxitoluen is 0.05% to 1 .5% by weight in the total composition.
- Suitable lubricant is selected from the group comprising magnesium stearate, polyoxyl 40 stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, high melting point waxes, sodium chloride, sodium benzoate, sodium acetate, sodium oleate or mixtures thereof.
- the lubricant is magnesium stearate. It enhances product flow by reducing inter particulate friction. According to an embodiment of the present invention, the amount of magnesium stearate is 0.1% to 2.0% by weight in the total composition.
- the film coating tablet comprises;
- the film coating tablet is obtained by using dry granulation or direct compression and therefore a simple and low-cost production method was employed.
- a process for the preparation of the film coated tablet comprising mirabegron comprising the following steps:
- a process for the preparation of the film coated tablet comprising mirabegron comprising the following steps:
- Example 1 Coating the tablets with film coating agent.
- Example 2 Example 3: Example 4:
Abstract
The present invention relates to a film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 so the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the film coated tablet.
Description
A TABLET COMPRISING MIRABEGRON
Field of the Invention
The present invention relates to a film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 so the tablet provides the desired stability and pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the film coated tablet.
Background of the Invention
Overactive bladder causes a frequent and sudden urge to urinate that may be difficult to control. You may feel like you need to pass urine many times during the day and night, and may also experience unintentional loss of urine.
There are many options for treatment of overactive bladder such as; bladder training and drug therapy using anticholinergic substances such as propiverine hydrochloride and oxybutynin hydrochloride have been mostly used at present. However, intractable cases and side effects could be occurred such as urinary dysfunction and dry mouth and, therefore, Mirabegron has been reported as one of the substance for the management of overactive bladder.
Mirabegron is a beta-3 adrenergic agonist that is used for treatment of overactive bladder syndrome. The chemical designation of mirabegron is 2-(2-amino-1 ,3-thiazol-4-yl)-N-[4-[2- [[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl] acetamide, with the chemical structure illustrated below in Formula I.
Formula I
A mirabegron containing pharmaceutical product is approved under the brand name Betmiga® in the Ell and Mirbetriq® in the US as modified release tablets comprising 25 and 50 mg of mirabegron.
Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and low permeability. It is known that the bioavailability of mirabegron is affected by the presence of food in the Gl tract. To prevent this food effect, modified release form is used.
EP1559427 patent application was first disclosed a pharmaceutical composition comprising mirabegron that can be used as a therapeutic agent for overactive bladder, such as overactive bladder accompanied by prostatic hyperplasia, or overactive bladder accompanied by urinary urgency, urinary incontinence, and urinary frequency.
W02019072404 relates to a pharmaceutical composition for modified release comprising; mirabegron presenting 5-25 wt% to the total weight of the uncoated tablet, polyethylene oxide having an average molecular weight of approximately 7,000,000 or a viscosity of 7500 to 10000 cps at a 1% aqueous solution at 25°C and polyethylene glycol having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio polyethylene oxide to polyethylene glycol ranges from 1 :3 to 1 :4.5.
WO2018169325 relates to a controlled release pharmaceutical composition comprising mirabegron or a pharmaceutically acceptable salt thereof and a polyethylene oxide as a sustained release agent.
In prior art, there are also several patents which disclose a composition comprising mirabegron. However, despite the dissolution profile and stability problems of compositions comprising mirabegron, an effective formulation and method has not been disclosed.
There still remains a need in the art to provide an improved film coating tablet formulation of mirabegron, having high solubility, dissolution rate, and excellent pharmacotechnical properties such as flowability, compressibility and homogeneity.
Detailed Description of the Invention
The main object of the present invention is to provide a film coating tablet comprising mirabegron with having desired level of dissolution rate which overcomes the above described problems in prior art and have additive advantages over them.
Another object of the present invention is to provide a film coating tablet comprising mirabegron with improved homogenity, flowability and high stability.
Another object of the present invention is to provide a film coating tablet comprising mirabegron prepared by simple, easy, time-saving and fast manufacturing methods.
The term “modified release” refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period. In this invention, using release controlling (polyethylene oxide) agent provides modified release.
According to an embodiment of the present invention, a film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 .
We have surprisingly found that when the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 . This specific weight ratio has shown good results in the achievement of the desired dissolution profile and compliance to the dissolution specification during the stability testing.
According to an embodiment of the present invention, the amount of mirabegron is 15.0% to 25.0% by weight in the total composition. Preferably, it is between 18.0% to 22.0% by weight in the total formulation.
According to an embodiment of the present invention, the release controlling agent is polyethylene oxide. Polyethylene oxide is a very hydrophilic polymer. It is available in several different grades that vary in viscosity profiles in aqueous isopropyl alcohol solutions.
According to an embodiment of the present invention, the amount of polyethylene oxide is 30.0% to 60.0% by weight in the total composition. The amount is important because the rapid or extra slow release of mirabegron can cause some problems, for example; dissolution profile and stability and half-life of the drug. Also, it was observed that tablet breaking force/tablet hardness was increased on using PEO, this indicates that polyethylene oxide powder has good compatibility.
According to an embodiment of the present invention, the release controlling agent is polyethylene oxide WSR 205 or polyethylene oxide WSR N-60K or mixtures thereof.
Polyethylene oxide suitable for use in the present invention is commercially available. Polyethylene oxide WSR N-60K has a molecular weight of 2,000,000 with viscosity of 2,000 to 4,000 cP at low addition levels. Polyethylene oxide WSR 205 is a non-ionic, water-soluble polyethylene oxide) polymer with a molecular weight of 600,000 with viscosity 4,500 to 8,800 cP. Both of them are a water insoluble hydrophilic excipients within the tablet core has shown good results in the achievement of the desired dissolution profile.
According to an embodiment of the present invention, the amount of polyethylene oxide WSR 205 is 20.0% to 35.0% by weight in the total composition and the amount of polyethylene oxide WSR N-60K is 5.0% to 15.0% by weight in the total composition.
According to an embodiment of the present invention, using both of them as release controlling agents in a tablet, the weight ratio of PEO (polyethylene oxide WSR N-60K and polyethylene oxide WSR 205) to mirabegron ranges from 1 :1 to 3.3:1 , preferably ranges from 1.4:1 to 2:1.
According to an embodiment of the present invention, the amount of polyethylene oxide WSR 205 is 45.0% to 60.0% by weight in the total composition.
According to an embodiment of the present invention, using only PEO WSR 205 as release controlling agent in a tablet, the weight ratio of PEO (polyethylene oxide WSR 205) to mirabegron ranges from 1 .8:1 to 4:1 , preferably ranges from 2:1 to 3:1 .
According to an embodiment of the present invention, the film coating tablet comprises;
15.0% and 25.0% by weight of Mirabegron
- 20.0% and 35.0% by weight of Polyethylene oxide WSR 205 5.0% and 15.0% by weight of Polyethylene oxide WSR N-60K
According to an embodiment of the present invention, the film coating tablet comprises;
15.0% and 25.0% by weight of Mirabegron
- 45.0% and 60.0% by weight of Polyethylene oxide WSR 205
In general terms, excipients provided in a composition may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, stability, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a composition is developed. If active agent is incompatible of excipients, stability and psychochemical
problems may be during or after the process. The tablet should have no physicochemical incompatibility between the active agent and the excipients.
According to one embodiment of the present invention, the film coated tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising diluents, antioxidants, lubricants or mixtures thereof.
Suitable diluents are selected from the group comprising microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, ethylcellulose, lactose, mannitol, magnesium carbonate, medium chain triglycerides, polyvinylpyrrolidone, sodium alginate, sodium chloride, sucrose, sugar spheres, or mixtures thereof.
According to an embodiment of the present invention, the diluent is microcrystalline cellulose. It gives volume to tablet and enables mirabegron to be dispersed homogeneously in the tablet.
According to an embodiment of the present invention, the amount of microcrystalline cellulose is 22.0% to 55.0% by weight in the total composition.
Suitable antioxidants are selected from the group comprising BHT (butylated hydroxy toluene), propyl gallate, BHA (butylated hydroxy anisole), monothioglycerol or mixtures thereof.
According to an embodiment of the present invention, the antioxidant is BHT (butylated hydroxy toluene). It helps to provide stability of tablet.
According to an embodiment of the present invention, the amount of butylated hydroxitoluen is 0.05% to 1 .5% by weight in the total composition.
Suitable lubricant is selected from the group comprising magnesium stearate, polyoxyl 40 stearate, calcium stearate, sodium stearyl fumarate, potassium stearate, stearic acid, high melting point waxes, sodium chloride, sodium benzoate, sodium acetate, sodium oleate or mixtures thereof.
According to an embodiment of the present invention, the lubricant is magnesium stearate. It enhances product flow by reducing inter particulate friction.
According to an embodiment of the present invention, the amount of magnesium stearate is 0.1% to 2.0% by weight in the total composition.
According to an embodiment of the present invention, the film coating tablet comprises;
Mirabegron
Polyethylene oxide WSR 205 or Polyethylene oxide WSR N-60K or mixtures thereof
Microcrystalline cellulose pH102
Magnesium stearate
Butylated Hydroxytoluene.
Furthermore, the film coating tablet is obtained by using dry granulation or direct compression and therefore a simple and low-cost production method was employed.
According to an embodiment of the present invention, a process for the preparation of the film coated tablet comprising mirabegron comprising the following steps:
- Mixing mirabegron, microcrystalline cellulose, polyethylene oxide(s) and at least one antioxidant,
- Adding the half of at least one lubricant and then mixing,
Compressing the mixture and sieving into 0.85,
Adding the remaining of at least one and then mixing,
- Compressing the mixture into the tablet,
- Coating the tablets with film coating agent.
According to an embodiment of the present invention, a process for the preparation of the film coated tablet comprising mirabegron comprising the following steps:
- Mixing mirabegron, at least one diluent, at least one release controlling agent and Butylated Hydroxitoluen,
- Adding the half of magnesium stearate and then mixing,
Compressing the mixture and sieving into 0.85,
Adding the remaining of magnesium sterate and then mixing,
- Compressing the mixture into the tablet,
- Coating the tablets with film coating agent.
Example 1 :
Example 2:
Example 3:
Example 4:
A process for example 1 or 2 or 3 or 4;
- Mixing mirabegron, microcrystalline cellulose, polyethylene oxide(s) and Butylated Hydroxitoluen,
- Adding the half of magnesium stearate and then mixing, Compressing the mixture and sieving into 0.85,
Adding the remaining of magnesium stearate and then mixing,
- Compressing the mixture into the tablet, - Coating the tablets with film coating agent.
Film coating
Claims
1. A film coated tablet comprising mirabegron, polyethylene oxide and at least one pharmaceutically acceptable excipient wherein the weight ratio of polyethylene oxide to mirabegron ranges from 1 :1 to 4:1 .
2. The film coated tablet according to claim 1 , wherein the amount of mirabegron is 15.0% to 25.0% by weight in the total composition.
3. The film coated tablet according to claim 1 , wherein the amount of polyethylene oxide is 30.0% to 60.0% by weight in the total composition.
4. The film coated tablet according to claim 1 , wherein the polyethylene oxide is polyethylene oxide WSR 205 or polyethylene oxide WSR N-60K or mixtures thereof.
5. The film coated tablet according to claim 4, wherein the amount of polyethylene oxide WSR 205 is 20.0% to 35.0% by weight in the total composition and the amount of polyethylene oxide WSR N-60K is 5.0% to 15.0% by weight in the total composition.
6. The film coated tablet according to claim 4, wherein the amount of polyethylene oxide WSR 205 is 45.0% to 60.0% by weight in the total composition.
7. The film coated tablet according to claim 4, wherein the film coating tablet comprises;
15.0% and 25.0% by weight of Mirabegron
- 20.0% and 35.0% by weight of Polyethylene oxide WSR 205
5.0% and 15.0% by weight of Polyethylene oxide WSR N-60K
8. The film coated tablet according to claim 4, wherein the film coating tablet comprises;
15.0% and 25.0% by weight of Mirabegron
- 45.0% and 60.0% by weight of Polyethylene oxide WSR 205
9. The film coated tablet according to claim 1 , wherein the film coated tablet comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising diluents, antioxidants, lubricants or mixtures thereof.
10. The film coated tablet according to claim 9, wherein diluents are selected from the group comprising microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, ethylcellulose, lactose,
mannitol, magnesium carbonate, medium chain triglycerides, polyvinylpyrrolidone, sodium alginate, sodium chloride, sucrose, sugar spheres, or mixtures thereof.
11. The film coated tablet according to claim 10, wherein the diluent is microcrystalline cellulose.
12. The film coated tablet according to claim 9, wherein antioxidants are selected from the group comprising BHT (butylated hydroxy toluene), propyl gallate, BHA (butylated hydroxy anisole), monothioglycerol or mixtures thereof.
13. The film coated tablet according to claim 12, wherein the antioxidant is BHT (butylated hydroxy toluene).
14. The film coated tablet according to claim 1 , wherein the tablet comprises;
Mirabegron
Polyethylene oxide WSR 205 or Polyethylene oxide WSR N-60K or mixtures thereof Microcrystalline cellulose pH102
Magnesium stearate
Butylated Hydroxytoluene.
15. A process for the preparation of the film coated tablet comprising mirabegron comprising the following steps:
- Mixing mirabegron, microcrystalline cellulose, polyethylene oxide(s) and at least one antioxidant,
- Adding the half of at least one lubricant and then mixing, Compressing the mixture and sieving into 0.85, Adding the remaining of at least one and then mixing,
- Compressing the mixture into the tablet,
- Coating the tablets with film coating agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2022014389 | 2022-09-19 | ||
| TR2022/014389 | 2022-09-19 |
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| Publication Number | Publication Date |
|---|---|
| WO2024063734A1 true WO2024063734A1 (en) | 2024-03-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2023/050936 WO2024063734A1 (en) | 2022-09-19 | 2023-09-11 | A tablet comprising mirabegron |
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| Country | Link |
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| WO (1) | WO2024063734A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180106924A (en) * | 2017-03-17 | 2018-10-01 | 주식회사 네비팜 | Controlled-release pharmaceutical composition |
| EP3653202A2 (en) * | 2017-07-14 | 2020-05-20 | Daewoong Pharmaceutical Co., Ltd. | Pharmaceutical preparation and preparation method therefor |
| WO2021069944A1 (en) * | 2019-10-09 | 2021-04-15 | Alvogen Korea Co., Ltd. | Pharmaceutical composition comprising mirabegron and process for manufacturing the same |
-
2023
- 2023-09-11 WO PCT/TR2023/050936 patent/WO2024063734A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180106924A (en) * | 2017-03-17 | 2018-10-01 | 주식회사 네비팜 | Controlled-release pharmaceutical composition |
| EP3653202A2 (en) * | 2017-07-14 | 2020-05-20 | Daewoong Pharmaceutical Co., Ltd. | Pharmaceutical preparation and preparation method therefor |
| WO2021069944A1 (en) * | 2019-10-09 | 2021-04-15 | Alvogen Korea Co., Ltd. | Pharmaceutical composition comprising mirabegron and process for manufacturing the same |
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