CA3078568A1 - Modified release tablet composition comprising mirabegron - Google Patents
Modified release tablet composition comprising mirabegron Download PDFInfo
- Publication number
- CA3078568A1 CA3078568A1 CA3078568A CA3078568A CA3078568A1 CA 3078568 A1 CA3078568 A1 CA 3078568A1 CA 3078568 A CA3078568 A CA 3078568A CA 3078568 A CA3078568 A CA 3078568A CA 3078568 A1 CA3078568 A1 CA 3078568A1
- Authority
- CA
- Canada
- Prior art keywords
- tablet
- modified release
- mirabegron
- composition according
- release tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 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 50
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- 229960001551 mirabegron Drugs 0.000 title claims abstract description 38
- 239000007912 modified release tablet Substances 0.000 title claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 43
- 239000003826 tablet Substances 0.000 claims description 43
- 239000002202 Polyethylene glycol Substances 0.000 claims description 31
- 229920001223 polyethylene glycol Polymers 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 238000009826 distribution Methods 0.000 claims description 4
- 238000007908 dry granulation Methods 0.000 claims description 4
- 239000008187 granular material Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000002245 particle Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000009491 slugging Methods 0.000 claims description 2
- 229960003855 solifenacin Drugs 0.000 claims description 2
- FBOUYBDGKBSUES-VXKWHMMOSA-N solifenacin Chemical compound C1([C@H]2C3=CC=CC=C3CCN2C(O[C@@H]2C3CCN(CC3)C2)=O)=CC=CC=C1 FBOUYBDGKBSUES-VXKWHMMOSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 239000007916 tablet composition Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 6
- 239000008108 microcrystalline cellulose Substances 0.000 description 6
- 229940120393 myrbetriq Drugs 0.000 description 6
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 5
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010020853 Hypertonic bladder Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 208000020629 overactive bladder Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 230000009246 food effect Effects 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- VIAMIUDTTIDZCA-TYYBGVCCSA-N (e)-but-2-enedioic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.OC(=O)\C=C\C(O)=O VIAMIUDTTIDZCA-TYYBGVCCSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940124225 Adrenoreceptor agonist Drugs 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
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 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-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027566 Micturition urgency Diseases 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 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
- 239000002775 capsule Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000020937 fasting conditions Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- -1 for example Substances 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 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
- 125000006353 oxyethylene group Chemical group 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
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012602 primary packaging material Substances 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960002613 tamsulosin Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 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 description 1
- 208000022934 urinary frequency Diseases 0.000 description 1
- 230000036318 urination frequency Effects 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a pharmaceutical composition, particularly a modified release tablet composition comprising mirabegron or a pharmaceutically acceptable salt thereof and to a process for preparing such a composition
Description
MODIFIED RELEASE TABLET COMPOSITION COMPRISING
MIRABEGRON
BACKGROUND OF THE PRESENT INVENTION
The present invention relates to a pharmaceutical composition, particularly a modified release tablet composition comprising mirabegron or a pharmaceutically acceptable salt thereof and to a process for preparing such a composition.
Mirabegron and the pharmaceutically acceptable salts thereof were first disclosed in (International Publication No.) WO 99/20607 (Example 41).
A mirabegron containing pharmaceutical product is approved in many countries all over the world under the brand name Betmiga@ in the EU, Myrbetriq@ in the US
US and Betanis@ in Japan as modified release tablets comprising 25 and 50 mg of mirabegron.
Mirabegron is the generic name of (R)-2-(2-aminothiazol-4-y1)-4'42-[(2-hydroxy-
MIRABEGRON
BACKGROUND OF THE PRESENT INVENTION
The present invention relates to a pharmaceutical composition, particularly a modified release tablet composition comprising mirabegron or a pharmaceutically acceptable salt thereof and to a process for preparing such a composition.
Mirabegron and the pharmaceutically acceptable salts thereof were first disclosed in (International Publication No.) WO 99/20607 (Example 41).
A mirabegron containing pharmaceutical product is approved in many countries all over the world under the brand name Betmiga@ in the EU, Myrbetriq@ in the US
US and Betanis@ in Japan as modified release tablets comprising 25 and 50 mg of mirabegron.
Mirabegron is the generic name of (R)-2-(2-aminothiazol-4-y1)-4'42-[(2-hydroxy-
2-phenylethyl)amino]ethyl]acetic acid anilide, OH
known as a selective P3 adrenoreceptor agonist and 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.
Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and SUBSTITUTE SHEET (RULE 26) low permeability. Based on the assessment report of Betmiga published by the European Medicines Agency, mirabegron is soluble in water between neutral to acidic pH.
It is known that the bioavailability of mirabegron is affected by the presence of food in the GI tract. To prevent this food effect, the commercially available pharmaceutical formulation of mirabegron is in the form of a modified-release (MR) tablet formulation based on an orally controlled absorption system (OCAS ) tablet formulation.
The OCAS is described in W09406414 (Al). W09406414 (Al) describes a hydrogel-type sustained-release preparation comprising (1) at least one drug (tamsulosine as one of the examples), (2) an additive which insures penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.
Further, the concept of using a sustained release pharmaceutical composition for reducing or avoiding the changes in pharmacokinetics such as AUC or Cmax accompanied by food intake is known. It was first disclosed in W003039531 (Al) and was applied to tamsulosin.
The application of the OCAS system to mirabegron is described in W02010038690 (Al). It specifically describes a tablet formulation comprising mirabegron or a pharmaceutically acceptable salt thereof, an additive which ensures penetration of water into the pharmaceutical composition, and a polymer which forms a hydrogel.
Due to the use of said additive the preparation undergoes a substantially complete gelation in the upper part of the GI tract, namely stomach and small intestine. The formed gel matrix is then maintained in the hydrated state during the passage through the GI tract for 4 hours or more maintaining a constant release and thus reducing the effects by food, because SUBSTITUTE SHEET (RULE 26) the drug release from the formulation becomes the rate-limiting step for absorption. This results in a uniform, sustained release of the drug throughout the entire GI
tract independently of the presence of food. The 4 hours release period has been selected to simply avoid the effect of food since on the basis of the elimination half-life (T1/2) of mirabegron, which is known to be approximately 18 to 24 hours, a sustained release per se is not needed.
However, we have discovered in our laboratories that not all the formulations encompassed in W02010038690 (Al) provide the desired release profile for mirabegron and/or show sufficient stability.
There is still a need for a stable pharmaceutical composition of mirabegron or a pharmaceutically acceptable salt thereof having a drug release profile bioequivalent to the commercially available product Betmiga , Myrbetriq or Betanis and that is obtainable by a straight forward and economical process.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a modified release tablet composition comprising:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5.
known as a selective P3 adrenoreceptor agonist and 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.
Mirabegron is considered to be a Class III compound according to the Biopharmaceutical Classification System (BCS). That means that it has high solubility and SUBSTITUTE SHEET (RULE 26) low permeability. Based on the assessment report of Betmiga published by the European Medicines Agency, mirabegron is soluble in water between neutral to acidic pH.
It is known that the bioavailability of mirabegron is affected by the presence of food in the GI tract. To prevent this food effect, the commercially available pharmaceutical formulation of mirabegron is in the form of a modified-release (MR) tablet formulation based on an orally controlled absorption system (OCAS ) tablet formulation.
The OCAS is described in W09406414 (Al). W09406414 (Al) describes a hydrogel-type sustained-release preparation comprising (1) at least one drug (tamsulosine as one of the examples), (2) an additive which insures penetration of water into the core of the preparation and (3) a hydrogel-forming polymer, wherein said preparation is capable of undergoing substantially complete gelation during its stay in the upper digestive tract including stomach and small intestine and is capable of releasing the drug in the lower digestive tract including colon.
Further, the concept of using a sustained release pharmaceutical composition for reducing or avoiding the changes in pharmacokinetics such as AUC or Cmax accompanied by food intake is known. It was first disclosed in W003039531 (Al) and was applied to tamsulosin.
The application of the OCAS system to mirabegron is described in W02010038690 (Al). It specifically describes a tablet formulation comprising mirabegron or a pharmaceutically acceptable salt thereof, an additive which ensures penetration of water into the pharmaceutical composition, and a polymer which forms a hydrogel.
Due to the use of said additive the preparation undergoes a substantially complete gelation in the upper part of the GI tract, namely stomach and small intestine. The formed gel matrix is then maintained in the hydrated state during the passage through the GI tract for 4 hours or more maintaining a constant release and thus reducing the effects by food, because SUBSTITUTE SHEET (RULE 26) the drug release from the formulation becomes the rate-limiting step for absorption. This results in a uniform, sustained release of the drug throughout the entire GI
tract independently of the presence of food. The 4 hours release period has been selected to simply avoid the effect of food since on the basis of the elimination half-life (T1/2) of mirabegron, which is known to be approximately 18 to 24 hours, a sustained release per se is not needed.
However, we have discovered in our laboratories that not all the formulations encompassed in W02010038690 (Al) provide the desired release profile for mirabegron and/or show sufficient stability.
There is still a need for a stable pharmaceutical composition of mirabegron or a pharmaceutically acceptable salt thereof having a drug release profile bioequivalent to the commercially available product Betmiga , Myrbetriq or Betanis and that is obtainable by a straight forward and economical process.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a modified release tablet composition comprising:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5.
3 SUBSTITUTE SHEET (RULE 26)
4 The present invention also relates to a dry granulation process to prepare such a modified release composition and to a multilayer tablet comprising such a modified release tablet composition.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a modified release tablet composition comprising:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5.
The modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a dissolution study in 250 ml phosphate buffer (pH 6.8) using a USP apparatus 3 at 20 rpm at 37 C.
The term "stable" as used herein means that tablets comply with the dissolution specification when subjected to a 6 months stability study at the accelerated stability conditions of 40 C and 75% RH.
The term "total weight" refers to the total weight of the uncoated tablet.
Modified release hydrogel tablets based on polyethylene oxide tend to suffer changes in their dissolution release profile when exposed to oxygen or UV light not complying with the SUBSTITUTE SHEET (RULE 26) dissolution specifications during the stability study. This is relevant since it may cause loss of the desired therapeutic control of the modified release tablets. Particularly the weight ratio of polyethylene oxide in the tablet and the average molecular weight of the polyethylene oxide may affect the stability of the tablets and their dissolution profile when exposed to a 6 months stability study at the accelerated stability conditions of 40 C and 75% RH.
Preferably the pharmaceutical tablet composition of the present invention is stabilized by an oxygen and UV light barrier like for example a primary packaging material like Aluminium/Aluminium blister foil or a light resistant HDPE container.
The modified release tablet composition of the present invention is described in further detail hereinafter.
A therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof is present at a weight ratio of 5 to 25% in the tablet with respect to the total weight of the uncoated tablet. In a particular embodiment mirabegron or a pharmaceutically acceptable salt thereof has a particle size distribution of D90 between 5 and 150 iLtm.
Preferably the D90 is between 10 and 60 iLtm.
The modified release tablet composition of the present invention further comprises PEO
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 PEG having an average molecular weight of approximately 6000 to 10000, preferably 8000.
Polyethylene oxide is a nonionic homopolymer of ethylene oxide, represented by the formula [(OCH2CH2)n], in which n represents the average number of oxyethylene groups and varies from about 2,000 to 160,000; the molecular weights range from about 100,000 to 7 million. Polyethylene oxide occurs as a white to off-white, free-flowing powder. It is available in different grades that vary in viscosity profiles in aqueous isopropyl alcohol
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a modified release tablet composition comprising:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5.
The modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a dissolution study in 250 ml phosphate buffer (pH 6.8) using a USP apparatus 3 at 20 rpm at 37 C.
The term "stable" as used herein means that tablets comply with the dissolution specification when subjected to a 6 months stability study at the accelerated stability conditions of 40 C and 75% RH.
The term "total weight" refers to the total weight of the uncoated tablet.
Modified release hydrogel tablets based on polyethylene oxide tend to suffer changes in their dissolution release profile when exposed to oxygen or UV light not complying with the SUBSTITUTE SHEET (RULE 26) dissolution specifications during the stability study. This is relevant since it may cause loss of the desired therapeutic control of the modified release tablets. Particularly the weight ratio of polyethylene oxide in the tablet and the average molecular weight of the polyethylene oxide may affect the stability of the tablets and their dissolution profile when exposed to a 6 months stability study at the accelerated stability conditions of 40 C and 75% RH.
Preferably the pharmaceutical tablet composition of the present invention is stabilized by an oxygen and UV light barrier like for example a primary packaging material like Aluminium/Aluminium blister foil or a light resistant HDPE container.
The modified release tablet composition of the present invention is described in further detail hereinafter.
A therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof is present at a weight ratio of 5 to 25% in the tablet with respect to the total weight of the uncoated tablet. In a particular embodiment mirabegron or a pharmaceutically acceptable salt thereof has a particle size distribution of D90 between 5 and 150 iLtm.
Preferably the D90 is between 10 and 60 iLtm.
The modified release tablet composition of the present invention further comprises PEO
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 PEG having an average molecular weight of approximately 6000 to 10000, preferably 8000.
Polyethylene oxide is a nonionic homopolymer of ethylene oxide, represented by the formula [(OCH2CH2)n], in which n represents the average number of oxyethylene groups and varies from about 2,000 to 160,000; the molecular weights range from about 100,000 to 7 million. Polyethylene oxide occurs as a white to off-white, free-flowing powder. It is available in different grades that vary in viscosity profiles in aqueous isopropyl alcohol
5 SUBSTITUTE SHEET (RULE 26) solutions. Polyethylene oxide may degrade by oxidation and commercially available polyethylene oxide may therefore contain a suitable antioxidant.
Polyethylene oxide is a very hydrophilic polymer. Upon contact with an aqueous medium, it hydrates rapidly to form a gel layer to support the release of the active. Typically the drug release occurs by combination of two mechanisms; diffusion and erosion. For a water soluble drug substance as mirabegron, diffusion of the active through the gel layer is the dominant mechanism but gradual erosion of the gel, exposing fresh surfaces containing drug to the dissolution media, may also take place.
Different ratios of polyethylene oxide 7,000,000 (e.g. Polyethylene oxide 20 NF or Polyox WSR 303 NF) and PEG having an average molecular weight of approximately to 10000 were evaluated in order to study its influence on drug dissolution.
The inventors have surprisingly found that when the weight ratio PEO to PEG ranges from 1:3 to 1:4.5, preferably from 1:3 to 1:4, more preferably from 1:3.2 to 1:3.8 the mirabegron formulation is bioequivalent to the commercial Betmiga , Myrbetriq or Betanis . 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.
Figure 1 shows the dissolution profile of a formulation with a weight ratio PEO having an average molecular weight of approximately 7,000,000 and PEG having an average molecular weight of approximately 8000, with respect to the total weight of the uncoated tablet in comparison to the reference product Mirbetriq .
The qualitative and quantitative compositions of the tested tablet are disclosed in Table 1.
Polyethylene oxide having an average molecular weight of 7,000,000 forms a high viscosity matrix typically leading to a decrease in the diffusion of the drug, slowing excessively the dissolution rate. However, we have found that PEO with an average
Polyethylene oxide is a very hydrophilic polymer. Upon contact with an aqueous medium, it hydrates rapidly to form a gel layer to support the release of the active. Typically the drug release occurs by combination of two mechanisms; diffusion and erosion. For a water soluble drug substance as mirabegron, diffusion of the active through the gel layer is the dominant mechanism but gradual erosion of the gel, exposing fresh surfaces containing drug to the dissolution media, may also take place.
Different ratios of polyethylene oxide 7,000,000 (e.g. Polyethylene oxide 20 NF or Polyox WSR 303 NF) and PEG having an average molecular weight of approximately to 10000 were evaluated in order to study its influence on drug dissolution.
The inventors have surprisingly found that when the weight ratio PEO to PEG ranges from 1:3 to 1:4.5, preferably from 1:3 to 1:4, more preferably from 1:3.2 to 1:3.8 the mirabegron formulation is bioequivalent to the commercial Betmiga , Myrbetriq or Betanis . 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.
Figure 1 shows the dissolution profile of a formulation with a weight ratio PEO having an average molecular weight of approximately 7,000,000 and PEG having an average molecular weight of approximately 8000, with respect to the total weight of the uncoated tablet in comparison to the reference product Mirbetriq .
The qualitative and quantitative compositions of the tested tablet are disclosed in Table 1.
Polyethylene oxide having an average molecular weight of 7,000,000 forms a high viscosity matrix typically leading to a decrease in the diffusion of the drug, slowing excessively the dissolution rate. However, we have found that PEO with an average
6 SUBSTITUTE SHEET (RULE 26) molecular weight of 7,000,000 can be used minimising this behaviour by using it in combination with PEG having an average molecular weight of approximately 6000 to 10000 in the specific weight ratio of the invention. When the weight ratio PEO to PEG ranges from 1:3 to 1:4.5, preferably from 1:3 to 1:4, more preferably from 1:3.2 to 1:3.8, it decreases the gel viscosity on the surface of the tablet which accelerates the diffusion of the drug from the gel layer. Additionally, using the weight ratio of the invention results in less stability problems, when compared with the examples provided in W02010038690 (Al).
The PEO 7M has a tendency to oxidise. When the PEO oxidises, it becomes less viscous, accelerating the dissolution. Optionally to further diminish the oxidation, the modified release tablet of the present invention can additionally comprise an antioxidant. A
preferred antioxidant is butylated hydroxytoluene (BHT).
Additionally the present invention may comprise other pharmaceutically acceptable excipients, for example, binders, diluents, lubricants, and glidants.
Binders which are suitable for use in accordance with the present invention include hydroxypropyl cellulose, povidone, dihydroxy propylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used in an amount of from 1 to 5 wt%
with respect to the total weight of the uncoated tablet. A preferred binder is hydroxypropylcellulose.
Diluents are fillers which are used to increase the bulk volume of a tablet or capsule.
Generally, by combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling.
Diluents give volume to low active dose tablets. The present invention may comprise one or more diluents. Suitable examples of diluents to be used in accordance with the present invention include starch, pregelatinized starch, microcrystalline cellulose (MCC), calcium phosphate, lactose, sorbitol, mannitol. In a preferred embodiment one of the diluents is MCC. In a more preferred embodiment the amount of MCC is 5 to 25% with respect to the total weight of the uncoated
The PEO 7M has a tendency to oxidise. When the PEO oxidises, it becomes less viscous, accelerating the dissolution. Optionally to further diminish the oxidation, the modified release tablet of the present invention can additionally comprise an antioxidant. A
preferred antioxidant is butylated hydroxytoluene (BHT).
Additionally the present invention may comprise other pharmaceutically acceptable excipients, for example, binders, diluents, lubricants, and glidants.
Binders which are suitable for use in accordance with the present invention include hydroxypropyl cellulose, povidone, dihydroxy propylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used in an amount of from 1 to 5 wt%
with respect to the total weight of the uncoated tablet. A preferred binder is hydroxypropylcellulose.
Diluents are fillers which are used to increase the bulk volume of a tablet or capsule.
Generally, by combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling.
Diluents give volume to low active dose tablets. The present invention may comprise one or more diluents. Suitable examples of diluents to be used in accordance with the present invention include starch, pregelatinized starch, microcrystalline cellulose (MCC), calcium phosphate, lactose, sorbitol, mannitol. In a preferred embodiment one of the diluents is MCC. In a more preferred embodiment the amount of MCC is 5 to 25% with respect to the total weight of the uncoated
7 SUBSTITUTE SHEET (RULE 26) tablet. Most preferably, the amount of MCC is 8 to 20% with respect to the total weight of the uncoated tablet.
The tablet composition of the invention may also contain a lubricant.
Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet's surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate. The tablet composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interparticulate friction. A
.. suitable example is colloidal silicon dioxide.
Lubricants and glidants preferably are used in a total amount of from 0.05 to 5 wt%
with respect to the total weight of the uncoated tablet.
In a preferred embodiment, the tablet composition of the present invention comprises the following ingredients, based on the total weight of the composition:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
3. A binder in an amount of from 1% to 5wt% with respect to the total weight of the uncoated tablet;
The tablet composition of the invention may also contain a lubricant.
Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet's surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and glycerine fumarate. The tablet composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interparticulate friction. A
.. suitable example is colloidal silicon dioxide.
Lubricants and glidants preferably are used in a total amount of from 0.05 to 5 wt%
with respect to the total weight of the uncoated tablet.
In a preferred embodiment, the tablet composition of the present invention comprises the following ingredients, based on the total weight of the composition:
1. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
2. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
3. A binder in an amount of from 1% to 5wt% with respect to the total weight of the uncoated tablet;
8 SUBSTITUTE SHEET (RULE 26) 4. A lubricant in an amount from 0.05% to 5wt% with respect to the total weight of the uncoated tablet; and 5. Optionally, MCC, preferably in an amount 5 to 25% with respect to the total weight of the uncoated tablet.
In one embodiment of the present invention, the therapeutically effective dose of mirabegron is 25 mg or 50 mg.
The pharmaceutical composition of the present invention can be used in combination with another API to form a multilayer tablet. A preferred API to be used in combination with mirabegron is solifenacin or an acceptable salt thereof.
The present invention further relates to a tablet composition as described hereinabove, prepared by a dry-granulation process by slugging or roller compaction.
Said process comprises the steps of:
1. Mixing mirabegron, polyethylene oxide, polyethylene glycol and one or more further pharmaceutically acceptable excipients to form a mixture;
2. Compacting the resulting mixture;
3. Further mixing the obtained granulate with one or more further pharmaceutically acceptable excipients to form a further mixture;
4. Compressing the mixture obtained in step (3) into a tablet;, 5. Optionally, coating the tablet.
The granules of the present invention typically have a particle size distribution D90 equal or less than 1 mm. The pharmaceutical compositions described herein can be made using conventional methods and equipment well-known in the art.
The modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a
In one embodiment of the present invention, the therapeutically effective dose of mirabegron is 25 mg or 50 mg.
The pharmaceutical composition of the present invention can be used in combination with another API to form a multilayer tablet. A preferred API to be used in combination with mirabegron is solifenacin or an acceptable salt thereof.
The present invention further relates to a tablet composition as described hereinabove, prepared by a dry-granulation process by slugging or roller compaction.
Said process comprises the steps of:
1. Mixing mirabegron, polyethylene oxide, polyethylene glycol and one or more further pharmaceutically acceptable excipients to form a mixture;
2. Compacting the resulting mixture;
3. Further mixing the obtained granulate with one or more further pharmaceutically acceptable excipients to form a further mixture;
4. Compressing the mixture obtained in step (3) into a tablet;, 5. Optionally, coating the tablet.
The granules of the present invention typically have a particle size distribution D90 equal or less than 1 mm. The pharmaceutical compositions described herein can be made using conventional methods and equipment well-known in the art.
The modified release tablet compositions of the present invention are stable and show an in vitro dissolution profile wherein mirabegron is released 15-35% within 1 hour, at least 50% within 2 hours and at least 90% within 3 hours when the composition is subjected to a
9 SUBSTITUTE SHEET (RULE 26) dissolution study in 250 ml phosphate buffer (pH 6.8) using a USP apparatus 3 at 20 rpm at 37 C.
Figure 1 shows the in vitro dissolution profile of tablet composition in accordance with the present invention compared to commercially available tablets.
The present invention is illustrated by the following Examples.
EXAMPLES
Table 1 - Qualitative and quantitative formula examplel Components mg/tablet %
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 41.25 16.50 Polyethylene glycol 8,000 P 148.35 59.34 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:3.60 Table 2 - Qualitative and quantitative formula comparative example 2 Components mg/tablet %
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 31.30 12.64 Polyethylene glycol 8,000 P 158.40 63.36 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:5.01
Figure 1 shows the in vitro dissolution profile of tablet composition in accordance with the present invention compared to commercially available tablets.
The present invention is illustrated by the following Examples.
EXAMPLES
Table 1 - Qualitative and quantitative formula examplel Components mg/tablet %
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 41.25 16.50 Polyethylene glycol 8,000 P 148.35 59.34 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:3.60 Table 2 - Qualitative and quantitative formula comparative example 2 Components mg/tablet %
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 31.30 12.64 Polyethylene glycol 8,000 P 158.40 63.36 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:5.01
10 SUBSTITUTE SHEET (RULE 26) Table 3¨ Qualitative and quantitative formula comparative example 3 Components mg/tablet %
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 60.00 24 Polyethylene glycol 8,000 P 129.60 51.84 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:2.16
Intragranular Mirabegron 50.00 20.00 PEO 7,000,000 (PEO-20NF) 60.00 24 Polyethylene glycol 8,000 P 129.60 51.84 Hydroxypropyl cellulose (Klucel EXF) 7.50 3.00 BHT 0.40 0.16 Magnesium stearate 1.25 0.50 Extragranular Magnesium stearate 1.25 0.50 Core weight 250.00 100.0 Opadry Yellow 03F220071 7.50 -Final weight 257.50 Weight ratio PEO 7,000,000 to Polyethylene glycol 8,000 P 1:2.16
11 SUBSTITUTE SHEET (RULE 26) The tablets of example 1, comparative example 2 and comparative example 3 were made according to the process depicted in the following scheme:
12 SUBSTITUTE SHEET (RULE 26) In vivo Bioequivalence study In a single dose bioavailability study of mirabegron, modified release tablets produced according to example 1 and comparative example 2 and 3 were compared with that of Myrbetriq / Betmiga 50 mg in healthy adult volunteers subjects under fasting conditions.
Table 1: Comparative pharmacokinetic parameters of present invention vs commercial Myrbetriq Betmiga 50 mg Examples Ratio PEG/PEO T/R T/R
Cmax(%) AUCt(%) 1 3.60 100.19 97.3 Comparative 2 5.01 173.45 129.63 Comparative 3 2.16 56.01 63.03 Figure 1 shows the in vitro dissolution profiles of 50 mg mirabegron modified release tablets prepared following example 1 in accordance with the present invention as compared to commercially available Myrbetriq 50 mg tablets.
Table 1: Comparative pharmacokinetic parameters of present invention vs commercial Myrbetriq Betmiga 50 mg Examples Ratio PEG/PEO T/R T/R
Cmax(%) AUCt(%) 1 3.60 100.19 97.3 Comparative 2 5.01 173.45 129.63 Comparative 3 2.16 56.01 63.03 Figure 1 shows the in vitro dissolution profiles of 50 mg mirabegron modified release tablets prepared following example 1 in accordance with the present invention as compared to commercially available Myrbetriq 50 mg tablets.
13 SUBSTITUTE SHEET (RULE 26)
Claims (11)
1. A modified release tablet composition comprising:
a. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
b. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
a. 5 to 25 wt% with respect to the total weight of the uncoated tablet of a therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof;
b. polyethylene oxide (PEO) 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 (PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
2. A modified release tablet composition according to claim 1 wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.
3. A modified release tablet composition according to claim 1 or 2 further comprising MCC.
4. A modified release tablet composition according to any one of the claims 1 to 3 wherein mirabegron has a particle size distribution of D90 between 10 and 60 µm.
5. A modified release tablet composition according to any one of claims 1 to 4 comprising the following ingredients:
a. A therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof in an amount of from 5 to 25 wt % with respect to the total weight of the uncoated tablet;
b. polyethylene oxide (PEO) 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(PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
c. A binder in an amount of from 1 to 5 wt % with respect to the total weight of the uncoated tablet;
d. A lubricant in an amount from 0.05% to 5 wt% with respect to the total weight of the uncoated tablet;
e. Optionally MCC .
a. A therapeutically effective dose of mirabegron or a pharmaceutically acceptable salt thereof in an amount of from 5 to 25 wt % with respect to the total weight of the uncoated tablet;
b. polyethylene oxide (PEO) 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(PEG) having an average molecular weight of approximately 6000 to 10000, preferably 8000, wherein the weight ratio PEO to PEG ranges from 1:3 to 1:4.5;
c. A binder in an amount of from 1 to 5 wt % with respect to the total weight of the uncoated tablet;
d. A lubricant in an amount from 0.05% to 5 wt% with respect to the total weight of the uncoated tablet;
e. Optionally MCC .
6. A modified release tablet composition according to any one of claims 1 to 5 prepared by a dry-granulation process, which process comprises:
a. Mixing mirabegron, polyethylene oxide, polyethylene glycol and one or more further pharmaceutically acceptable excipients to form a mixture;
b. Compacting the resulting mixture;
c. Further mixing the obtained granulate with one or more further pharmaceutically acceptable excipients to form a further mixture;
d. Compressing the mixture obtained in step (c) into a tablet;
e. Optionally, coating the tablet.
a. Mixing mirabegron, polyethylene oxide, polyethylene glycol and one or more further pharmaceutically acceptable excipients to form a mixture;
b. Compacting the resulting mixture;
c. Further mixing the obtained granulate with one or more further pharmaceutically acceptable excipients to form a further mixture;
d. Compressing the mixture obtained in step (c) into a tablet;
e. Optionally, coating the tablet.
7. A modified release tablet composition according to claim 6, wherein the process of dry granulation is performed by slugging or by a roller compactor.
8. A modified release tablet composition according to claim 6 or 7, wherein the granules have a particle size distribution D90 equal or less than 1 mm.
9. A multilayer tablet comprising the modified release tablet composition according to any one of claims 1 to 8.
10. The multilayer tablet according to claim 9, which is a bilayer tablet.
11. The multilayer tablet according to claim 9 or 10 further comprising solifenacin.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15/730,988 US10478399B2 (en) | 2017-10-12 | 2017-10-12 | Modified release tablet composition comprising mirabegron |
| US15/730,988 | 2017-10-12 | ||
| EP17196234.3 | 2017-10-12 | ||
| EP17196234.3A EP3292864A1 (en) | 2017-10-12 | 2017-10-12 | Modified release tablet composition comprising mirabegron |
| PCT/EP2017/082896 WO2019072404A1 (en) | 2017-10-12 | 2017-12-14 | Modified release tablet composition comprising mirabegron |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3078568A1 true CA3078568A1 (en) | 2019-04-18 |
Family
ID=60702778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3078568A Abandoned CA3078568A1 (en) | 2017-10-12 | 2017-12-14 | Modified release tablet composition comprising mirabegron |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP3694492A1 (en) |
| CA (1) | CA3078568A1 (en) |
| WO (1) | WO2019072404A1 (en) |
Families Citing this family (2)
| 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 |
| EP4410279A1 (en) | 2023-01-25 | 2024-08-07 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A film tablet comprising mirabegron |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0661045T3 (en) | 1992-09-18 | 2002-10-28 | Yamanouchi Pharma Co Ltd | Delayed release hydrogel preparation |
| JP3193706B2 (en) | 1997-10-17 | 2001-07-30 | 山之内製薬株式会社 | Amide derivative or salt thereof |
| DE20220415U1 (en) | 2001-11-07 | 2003-10-09 | Synthon Bv | Tamsulosin tablets |
| TWI478712B (en) * | 2008-09-30 | 2015-04-01 | Astellas Pharma Inc | Pharmaceutical composition for modified release |
| EP2832730A4 (en) * | 2012-03-30 | 2015-09-09 | Astellas Pharma Inc | Mirabegron-containing pharmaceutical composition |
| CN104352475A (en) * | 2014-12-05 | 2015-02-18 | 安徽联创生物医药股份有限公司 | Mirabegron sustained release tablet and preparation method thereof |
-
2017
- 2017-12-14 WO PCT/EP2017/082896 patent/WO2019072404A1/en unknown
- 2017-12-14 EP EP17816802.7A patent/EP3694492A1/en not_active Withdrawn
- 2017-12-14 CA CA3078568A patent/CA3078568A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
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| EP3694492A1 (en) | 2020-08-19 |
| WO2019072404A1 (en) | 2019-04-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20200406 |
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| EEER | Examination request |
Effective date: 20200406 |
|
| FZDE | Discontinued |
Effective date: 20220830 |
|
| FZDE | Discontinued |
Effective date: 20220830 |