WO2024023710A1 - Compositions pharmaceutiques de tafamidis - Google Patents
Compositions pharmaceutiques de tafamidis Download PDFInfo
- Publication number
- WO2024023710A1 WO2024023710A1 PCT/IB2023/057546 IB2023057546W WO2024023710A1 WO 2024023710 A1 WO2024023710 A1 WO 2024023710A1 IB 2023057546 W IB2023057546 W IB 2023057546W WO 2024023710 A1 WO2024023710 A1 WO 2024023710A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tablet
- pharmaceutical composition
- tafamidis
- free acid
- microcrystalline cellulose
- Prior art date
Links
- 229960001353 tafamidis Drugs 0.000 title claims abstract description 124
- TXEIIPDJKFWEEC-UHFFFAOYSA-N tafamidis Chemical compound O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 TXEIIPDJKFWEEC-UHFFFAOYSA-N 0.000 title claims abstract description 124
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 111
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 80
- 239000002253 acid Substances 0.000 claims abstract description 78
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229960000913 crospovidone Drugs 0.000 claims abstract description 58
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 58
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 58
- 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 abstract description 41
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 41
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 41
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 41
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 41
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 41
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 40
- 239000007884 disintegrant Substances 0.000 claims abstract description 22
- 239000003085 diluting agent Substances 0.000 claims abstract description 10
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000003826 tablet Substances 0.000 claims description 170
- 239000007888 film coating Substances 0.000 claims description 26
- 238000009501 film coating Methods 0.000 claims description 26
- 108010071690 Prealbumin Proteins 0.000 claims description 16
- 239000007941 film coated tablet Substances 0.000 claims description 16
- 102000009190 Transthyretin Human genes 0.000 claims description 14
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 11
- 229960001375 lactose Drugs 0.000 claims description 11
- 239000008101 lactose Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 201000007905 transthyretin amyloidosis Diseases 0.000 claims description 11
- 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 10
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 5
- 206010036105 Polyneuropathy Diseases 0.000 claims description 5
- 230000007824 polyneuropathy Effects 0.000 claims description 5
- 239000000203 mixture Substances 0.000 description 39
- 239000002775 capsule Substances 0.000 description 17
- 238000009472 formulation Methods 0.000 description 15
- DQJDBUPLRMRBAB-WZTVWXICSA-N tafamidis meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 DQJDBUPLRMRBAB-WZTVWXICSA-N 0.000 description 8
- 241000283690 Bos taurus Species 0.000 description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 5
- 238000007906 compression Methods 0.000 description 4
- 239000002706 dry binder Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940081715 tafamidis meglumine Drugs 0.000 description 4
- 230000006835 compression Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 229940126534 drug product Drugs 0.000 description 3
- 239000007935 oral tablet Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 101000772194 Homo sapiens Transthyretin Proteins 0.000 description 2
- 102100029290 Transthyretin Human genes 0.000 description 2
- 206010002022 amyloidosis Diseases 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960003194 meglumine Drugs 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000001049 Amyloid Human genes 0.000 description 1
- 108010094108 Amyloid Proteins 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010038748 Restrictive cardiomyopathy Diseases 0.000 description 1
- 229940121767 Transthyretin stabilizer Drugs 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- Transthyretin (ATTR) amyloidosis is rare, progressive disease characterized by the abnormal buildup of amyloid deposits composed of misfolded transthyretin protein in the body’s organs and tissues. ATTR amyloidosis can impact numerous organs and tissues in the body, including the peripheral nervous system, and organs such as the heart, kidneys, gastrointestinal tract and eyes.
- Transthyretin cardiomyopathy (ATTR- CM) and transthyretin polyneuropathy (ATTR-PN) are two presentations of the disease. ATTR-CM affects the heart and leads to restrictive cardiomyopathy and progressive heart failure.
- ATTR-CM There are two sub-types of ATTR-CM: hereditary, which is caused by a mutation in the transthyretin gene and can occur in people as early as their 50s and 60s; or the wild-type form which is associated with aging, and is thought to be more common, usually affecting men after age 60. Often ATTR-CM is diagnosed only after symptoms have become severe. ATTR-PN results from a genetic mutation of the transthyretin gene causing amyloid fibrils to form in the peripheral and autonomic nerves. ATTR-PN typically occurs during active adult years with onset as early as the 30s in some patients, followed by disease progression that may reach the terminal stage in approximately 10 years on average from disease onset.
- Tafamidis sold under the brand names Vyndaqel® and Vyndamax®, is an oral transthyretin stabilizer medication used for the treatment of adults with certain forms of transthyretin amyloidosis.
- Tafamidis can be used to treat both hereditary forms as well as wild-type transthyretin amyloidosis.
- Tafamidis works by selectively binding to transthyretin and stabilizes the quaternary structure of the tetrameric transthyretin protein and slowing the formation of amyloid.
- Tafamidis free acid can be prepared by methods such as those described in US Patent 7,214,695, WO 04056315, US 9,770,441 and WO 2016/038500.
- the present invention provides oral pharmaceutical compositions comprising tafamidis free acid.
- the oral pharmaceutical compositions comprise tafamidis free acid in an oral tablet dosage form.
- the present invention particularly provides immediate release tablet formulations of tafamidis free acid wherein the tablet may be film-coated.
- Tafamidis is formulated as a common blend to make immediate release tablet cores, which can then be film-coated to make film-coated tablets, such as 12.2 mg tafamidis free acid and 61 mg tafamidis free acid tablet drug products.
- the tafamidis 12.2 mg and 61 mg film-coated tablets have been formulated for immediate release for the oral treatment of transthyretin amyloidosis diseases such as ATTR-CM and ATTR-PN.
- the tablet cores are made from a common blend using a dry granulation process and can then be film-coated by a batch process to provide the film- coated tablet drug product.
- E1 is a pharmaceutical composition which is a tablet comprising tafamidis free acid, one or more diluents, 7-9% (w/w%) disintegrant and a lubricant.
- E2 is the pharmaceutical composition of E1 which is a tablet wherein the disintegrant is crospovidone.
- E3 is the pharmaceutical composition of E1 or E2 which is a tablet wherein the disintegrant is crospovidone type b.
- E4 is the pharmaceutical composition of any one of E1 to E3 which is a tablet wherein the one or more diluents are selected from microcrystalline cellulose and lactose monohydrate.
- E5 is the pharmaceutical composition of any one of E1 to E4 which is a tablet wherein the lubricant is magnesium stearate.
- E6 is the pharmaceutical composition of any one of E1 to E5 which is a tablet comprising about 8% (w/w%) crospovidone type b.
- E7 is the pharmaceutical composition of any one of E1 to E6 which is a tablet comprising about 11.6% (w/w%) tafamidis free acid.
- E8 is the pharmaceutical composition of any one of E1 to E7 which is a tablet comprising 12.2 mg tafamidis free acid.
- E9 is the pharmaceutical composition of any one of E1 to E7 which is a tablet comprising 61 mg tafamidis free acid.
- E10 is the pharmaceutical composition of any one of E1 to E9 which is a tablet comprising about 79.65% (w/w%) of one or more diluents which are selected from microcrystalline cellulose and lactose monohydrate.
- E11 is the pharmaceutical composition of any one of E1 to E10 which is a tablet comprising about 53.1% (w/w%) microcrystalline cellulose and about 26.55% lactose monohydrate.
- E12 is the pharmaceutical composition of any one of E1 to E11 which is a tablet comprising about 0.75% (w/w%) of magnesium stearate.
- E13 is the pharmaceutical composition of any one of E1 to E12 wherein the tablet is film coated.
- E14 is the pharmaceutical composition of E13 wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.
- E15 is the pharmaceutical composition of E13 or E14 wherein the tablet film coating is about 4% (w/w) of the overall weight of the film coated tablet.
- E16 is a pharmaceutical composition which is a tablet comprising about 11.6% (w/w%) tafamidis free acid; about 53.1% (w/w%) microcrystalline cellulose; about 26.55% (w/w%) lactose monohydrate; about 8.0% (w/w%) crospovidone type b and about 0.75% (w/w%) magnesium stearate.
- E17 is a pharmaceutical composition which is a tablet comprising 11.6% ⁇ 0.1% (w/w%) tafamidis free acid; 53.1% ⁇ 0.1% (w/w%) microcrystalline cellulose; 26.55% ⁇ 0.1% (w/w%) lactose monohydrate; 8.0% ⁇ 0.1% (w/w%) crospovidone type b and 0.75% ⁇ 0.1% (w/w%) magnesium stearate.
- E18 is the pharmaceutical composition of E16 or E17 wherein the tablet is film coated.
- E19 is the pharmaceutical composition of any one of E16 to E18 wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.
- E20 is the pharmaceutical composition of E18 or E19 wherein the tablet film coating is 4.0% ⁇ 0.1% (w/w%) of the overall weight of the film coated tablet.
- E21 is a pharmaceutical composition which is a tablet comprising about 12.20 mg tafamidis free acid, about 55.85 mg microcrystalline cellulose, about 27.92 mg lactose monohydrate, about 8.42 mg crospovidone type b and about 0.79 mg magnesium stearate.
- E22 is the pharmaceutical of E21 which is a tablet comprising 12.20 mg tafamidis free acid, 55.85 mg microcrystalline cellulose, 27.92 mg lactose monohydrate, 8.42 mg crospovidone type b and 0.79 mg magnesium stearate.
- E23 is the pharmaceutical composition of E21 or E22 wherein the tablet is film coated.
- E24 is the pharmaceutical composition of E23 wherein tablet film coating comprises hydroxypropyl methylcellulose and lactose.
- E25 is the pharmaceutical composition of E23 or E24 wherein the tablet film coating weighs 4.21 mg.
- E26 is a pharmaceutical composition which is a tablet comprising about 61.00 mg tafamidis free acid, about 279.25 mg microcrystalline cellulose, about 139.6 mg lactose monohydrate, about 42.10 mg crospovidone type b and about 2.95 mg magnesium stearate.
- E27 is the pharmaceutical composition of E26 which is a tablet comprising 61.00 mg tafamidis free acid, 279.25 mg microcrystalline cellulose, 139.6 mg lactose monohydrate, 42.10 mg crospovidone type b and 2.95 mg magnesium stearate.
- E28 is the pharmaceutical composition of E26 or E27 wherein the tablet is film coated.
- E29 is the pharmaceutical composition of E28 wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.
- E30 is the pharmaceutical composition of E28 or E29 wherein the tablet film coating weighs 21.05 mg.
- E31 is the pharmaceutical composition of any one of E1 to E7 which is a tablet comprising about 13.0 mg, about 13.5 mg, about 14.0 mg, about 14.5 mg, about 15.0 mg, about 15.5 mg, about 59.0 mg, about 60.0 mg or about 62 mg tafamidis free acid.
- E32 is the pharmaceutical composition of E31 which is a tablet comprising 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 59.0 mg, 60.0 mg or 62.0 mg of tafamidis free acid.
- E33 is the pharmaceutical composition of E32 which is a tablet comprising 13.0 mg tafamidis free acid.
- E34 is the pharmaceutical composition of E33 which is a tablet comprising 13.0 mg tafamidis free acid, 59.51 mg microcrystalline cellulose, 29.75 mg lactose monohydrate, 8.98 mg crospovidone type b and 0.85 mg magnesium stearate.
- E35 is the pharmaceutical composition of E32 which is a tablet comprising 13.5 mg tafamidis free acid.
- E36 is the pharmaceutical composition of E35 which is a tablet comprising 13.5 mg tafamidis free acid, 61.80 mg microcrystalline cellulose, 30.89 mg lactose monohydrate, 9.32 mg crospovidone type b and 0.88 mg magnesium stearate.
- E37 is the pharmaceutical composition of E32 which is a tablet comprising 14.0 mg tafamidis free acid.
- E38 is the pharmaceutical composition of E37 which is a tablet comprising 14.0 mg tafamidis free acid, 64.09 mg microcrystalline cellulose, 32.04 mg lactose monohydrate, 9.66 mg crospovidone type b and 0.91 mg magnesium stearate.
- E39 is the pharmaceutical composition of E32 which is a tablet comprising 14.5 mg tafamidis free acid.
- E40 is the pharmaceutical composition of E39 which is a tablet comprising 14.5 mg tafamidis free acid, 66.38 mg microcrystalline cellulose, 33.18 mg lactose monohydrate, 10.00 mg crospovidone type b and 0.94 mg magnesium stearate.
- E41 is the pharmaceutical composition of E32 which is a tablet comprising 15.0 mg tafamidis free acid.
- E42 is the pharmaceutical composition of E41 which is a tablet comprising 15.0 mg tafamidis free acid, 68.69 mg microcrystalline cellulose, 34.33 mg lactose monohydrate, 10.36 mg crospovidone type b and 0.97 mg magnesium stearate.
- E43 is the pharmaceutical composition of E32 which is a tablet comprising 15.5 mg tafamidis free acid.
- E44 is the pharmaceutical composition of E43 which is a tablet comprising 15.5 mg tafamidis free acid, 70.96 mg microcrystalline cellulose, 35.47 mg lactose monohydrate, 10.70 mg crospovidone type b and 1.00 mg magnesium stearate.
- E45 is the pharmaceutical composition of E32 which is a tablet comprising 59.0 mg tafamidis free acid.
- E46 is the pharmaceutical composition of E45 which is a tablet comprising 59.0 mg tafamidis free acid, 270.09 mg microcrystalline cellulose, 135.02 mg lactose monohydrate, 40.72 mg crospovidone type b and 3.82 mg magnesium stearate.
- E47 is the pharmaceutical composition of E32 which is a tablet comprising 60.0 mg tafamidis free acid.
- E48 is the pharmaceutical composition of E47 which is a tablet comprising 60.0 mg tafamidis free acid, 274.67 mg microcrystalline cellulose, 137.31 mg lactose monohydrate, 41.40 mg crospovidone type b and 3.89 mg magnesium stearate.
- E49 is the pharmaceutical composition of E32 which is a tablet comprising 62.0 mg tafamidis free acid.
- E50 is the pharmaceutical composition of E49 which is a tablet comprising 62.0 mg tafamidis free acid, 283.83 mg microcrystalline cellulose, 141.89 mg lactose monohydrate, 42.80 mg crospovidone type b and 4.01 mg magnesium stearate.
- E51 is the pharmaceutical composition of any one of E31 to E50 wherein the tablet is film coated.
- E52 is the pharmaceutical composition of E51 wherein the tablet film coating comprises hydroxypropyl methylcellulose and lactose.
- E53 is the pharmaceutical composition of E52 wherein the tablet film coating is about 4% (w/w) of the overall weight of the film coated tablet.
- E54 is a method of treating transthyretin amyloidosis in a patient comprising administering a pharmaceutical composition according to any one of E1 to E53 to the patient.
- E55 is the method of claim 54 wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).
- TRR-CM transthyretin cardiomyopathy
- ATTR-PN transthyretin polyneuropathy
- E56 is the use of a pharmaceutical composition according to any one of E1 to E53 for treatment of transthyretin amyloidosis.
- E57 is the use according to E56 wherein the transthyretin amyloidosis is transthyretin cardiomyopathy (ATTR-CM) or transthyretin polyneuropathy (ATTR-PN).
- TRR-CM transthyretin cardiomyopathy
- ATTR-PN transthyretin polyneuropathy
- Figure 1 Flow Diagram of Manufacturing Process for Tafamidis 12.2 mg and 61.0 mg Film-Coated Tablets.
- the excipients used in the tafamidis tablet or film-coated tablet are globally acceptable and all but crospovidone are present at precedented levels in the formulation.
- the amount of tablet ingredients can be expressed as weight percent of the tablet (i.e. w/w%). It is to be used that the term about can be plus or minus 0.2% or alternatively 0.1% (i.e. ⁇ 0.2% or ⁇ 0.1%).
- Crospovidone is typically used at a 1-5% (w/w %) level and an advantageous embodiment of the tafamidis common blend used to prepare the tablet core of the present invention contains 8% crospovidone.
- Crospovidone was evaluated at 4, 6, 8 and 10% (w/w%) levels during development and the microcrystalline cellulose/lactose monohydrate diluents were adjusted accordingly to manage the tablet core weight.
- Crospovidone is included in the tablet core formulation as a disintegrant in the oral tablets. Adding the disintegrant promotes tablet disintegration and adding in the extra-granular portion after roller compaction is completed acts as a disintegrant as well as a dry binder.
- Magnesium stearate is included in the tablet core formulation as a lubricant in the tablets. Magnesium stearate is used as a lubricant in the tablet core formulation to aid in tablet compression.
- Opadry® II yellow and Opadry® II white are proprietary film coating systems used for the 12.2 mg and 61 mg tablets, respectively.
- Table A Estimated Cmax and ALICinf ratio of dose-adjusted tafamidis free acid tablet (test) to 20 mg meglumine capsule (reference) calculated by clinical data observed in B3461103.
- the potential dose adjustment range for low dose tafamidis FA tablet (equivalent to 20 mg tafamidis MS capsule) is estimated to be 12.2 mg to 16 mg as the estimated Cmax and ALICinf ratios are within 0.8-1.25. A more conservative estimate would set the dose range between 13 mg to 15.5 mg as the estimated Cmax and ALICinf ratios would be within 0.85-1.20.
- the estimated Cmax and ALICinf ratios can be calculated using the clinical data obtained in Study B3461030 (48.8 mg tafamidis FA tablet vs 4 x 20 mg tafamidis MS capsules) and Study B3461051 (48.8 mg tafamidis FA tablet or 58 mg tafamidis free acid tablet vs. 4 x 20 mg tafamidis MS capsules).
- the estimated Cmax and ALICinf ratios of tafamidis FA tablet with various strengths to 4 x 20 mg tafamidis MS capsules are listed in Table B.
- the dose adjustment range for high dose tafamidis FA tablet (equivalent to 4 x 20 mg meglumine salt capsule) is estimated to be 51 mg to 70 mg as the estimated Cmax and ALICinf ratios are within 0.8 - 1.25.
- the dose adjustment range is estimated to be 53 mg to 67 mg using the observed rBA data of the 48.8 mg tafamidis FA tablet in Study B3461051 (Table B2), and 56 mg to 65 mg using the observed rBA data of the 58 mg tafamidis FA tablet in Study B3461051 (Table B3).
- the acceptance criteria of Cmax and ALICinf ratios can be set at 0.85 - 1.20.
- the potential dose adjustment range is estimated to be 51 - 67 mg using the 48.8 mg tafamidis FA tablet rBA data from Study B3461030 (Table B), 56 - 64 mg using the 48.8 mg tafamidis FA tablet rBA data from Study B3461051 (Table B2), and 59 - 62 mg using the 58 mg tafamidis FA tablet rBA data from study B3461051 (Table B3).
- this dose adjustment range could be preferable.
- the observed clinical data suggests that the dose adjustment range of high dose tafamidis FA tablet is likely between 51 mg to 70 mg.
- This dose range include all the estimated ranges calculated by the methods described above. Within this dose adjustment range, 59 mg to 62 mg is preferable because it is the intersection of all the estimated ranges.
- Table B Estimated Cmax and ALICinf ratio between dose-adjusted tafamidis free acid tablet (test) and 4 x 20 mg meglumine capsules (reference).
- Table B2 Cmax and ALICinf ratio calculated using rBA data between 48.8 mg tafamidis free acid tablet and 4 x 20 mg tafamidis meglumine salt capsules in study 1051
- Table B3 Cmax and ALICinf ratio calculated using rBA data between 58 mg tafamidis free acid tablet and 4 x 20 mg tafamidis meglumine salt capsules in study 1051
- Formulation Tafamidis is formulated as a common blend to make immediate release tablet cores such as 12.2 mg and 61 mg immediate release tablet cores.
- the formulation provided in Table 1 , is composed of microcrystalline cellulose and lactose monohydrate (diluents), crospovidone (disintegrant), and magnesium stearate (lubricant).
- Commercial tafamidis tablet cores are manufactured using a dry granulation manufacturing platform followed by a film coating step. Tablets are film coated with an appropriate coating.
- the tablets can be coated with hydroxypropyl methylcellulose I lactose based Opadry® II formulation with yellow color for the 12.2 mg tablets and white color for the 61 mg tablets.
- the preceding procedure is used in an analogous manner to prepare the tablet cores which contain 13.0 mg, 13.5 mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 59.0 mg, 60 mg or 62.0 mg of tafamidis and to coat those cores with 4% by weight of film coating.
- Examples 1 and 2 were prepared using the General Procedure for Tablet Preparation as described above. Table 1: Examples 1 and 2 - Composition of Tafamidis 12.2 mg and 61 mg Film-Coated
- the above tablet was prepared in a manner analogous to the General Method described above for Examples 1 and 2. In studies this formulation failed to exhibit equivalent properties to the 20 mg tafamidis meglumine gel capsule and therefore was determined to be not viable as a commercially acceptable formulation.
- Table 1A Examples 3 and 4 - Composition of Tafamidis 13.0 mg and 13.5 mg Film- Coated Tablets using 8% (w/w) Disintegrant Crospovidone Type B a Intra-granular b Extra-granular c non-bovine
- Table 1B Examples 5 and 6 - Composition of Tafamidis 14.0 mg and 14.5 mg Film- Coated Tablets using 8% (w/w) Disintegrant Crospovidone Type B a Intra-granular b Extra-granular c non-bovine Table 1C: Examples 7 and 8 - Composition of Tafamidis 15.0 mg and 15.5 mg Film-
Abstract
La présente invention concerne une composition pharmaceutique qui est un comprimé comprenant de l'acide libre de tafamidis, un ou plusieurs diluants, de 7 à 9 % (p/p %) de délitant et un lubrifiant. Un exemple représentatif est un comprimé comprenant environ 11,6 % (p/p %) d'acide libre de tafamidis ; environ 53,1 % (p/p %) de cellulose microcristalline ; environ 26,55 % 5 (p/p %) de monohydrate de lactose ; environ 8,0 % (p/p %) de crospovidone de type b et environ 0,75 % (p/p %) de stéarate de magnésium.
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US20230149366A1 (en) * | 2021-11-18 | 2023-05-18 | Nuray Chemicals Private Limited | Solid dosage forms of tafamidis |
WO2023091534A1 (fr) * | 2021-11-17 | 2023-05-25 | Teva Pharmaceuticals International Gmbh | Forme à l'état solide de tafamidis |
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WO2004056315A2 (fr) | 2002-12-19 | 2004-07-08 | The Scripps Research Institute | Compositions et methodes permettant de stabiliser la transthyretine et d'inhiber un mauvais repliement de la transthyretine |
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US20210363116A1 (en) * | 2019-11-15 | 2021-11-25 | Crystal Pharmaceutical (Suzhou) Co., Ltd. | Crystal form of tafamidis and preparation method therefor and use thereof |
WO2023091534A1 (fr) * | 2021-11-17 | 2023-05-25 | Teva Pharmaceuticals International Gmbh | Forme à l'état solide de tafamidis |
US11523993B1 (en) * | 2021-11-18 | 2022-12-13 | Nuray Chemicals Private Limited | Dosage forms of tafamidis and its pharmaceutically acceptable salt thereof |
US20230149365A1 (en) * | 2021-11-18 | 2023-05-18 | Nuray Chemicals Private Limited | Dosage forms of tafamidis and its pharmaceutically acceptable salt thereof |
US20230149366A1 (en) * | 2021-11-18 | 2023-05-18 | Nuray Chemicals Private Limited | Solid dosage forms of tafamidis |
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