WO2023281089A4 - Pharmaceutical composition comprising naproxen and paracetamol - Google Patents
Pharmaceutical composition comprising naproxen and paracetamol Download PDFInfo
- Publication number
- WO2023281089A4 WO2023281089A4 PCT/EP2022/069158 EP2022069158W WO2023281089A4 WO 2023281089 A4 WO2023281089 A4 WO 2023281089A4 EP 2022069158 W EP2022069158 W EP 2022069158W WO 2023281089 A4 WO2023281089 A4 WO 2023281089A4
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- multilayer tablet
- layer
- paracetamol
- naproxen
- tablet according
- Prior art date
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract 72
- 229960005489 paracetamol Drugs 0.000 title claims abstract 72
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 title claims abstract 57
- 229960002009 naproxen Drugs 0.000 title claims abstract 57
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 title claims abstract 57
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract 20
- 239000007884 disintegrant Substances 0.000 claims abstract 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract 9
- 238000005550 wet granulation Methods 0.000 claims abstract 5
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 18
- 208000002193 Pain Diseases 0.000 claims 15
- 229960000913 crospovidone Drugs 0.000 claims 14
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 14
- 229940069328 povidone Drugs 0.000 claims 14
- 229920000881 Modified starch Polymers 0.000 claims 12
- 229920002472 Starch Polymers 0.000 claims 12
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 12
- 239000008107 starch Substances 0.000 claims 12
- 229940032147 starch Drugs 0.000 claims 12
- 235000019698 starch Nutrition 0.000 claims 12
- 239000011230 binding agent Substances 0.000 claims 10
- 239000003085 diluting agent Substances 0.000 claims 10
- 239000000314 lubricant Substances 0.000 claims 10
- 235000019359 magnesium stearate Nutrition 0.000 claims 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims 8
- 239000000194 fatty acid Substances 0.000 claims 8
- 229930195729 fatty acid Natural products 0.000 claims 8
- 229920001223 polyethylene glycol Polymers 0.000 claims 8
- 229960003940 naproxen sodium Drugs 0.000 claims 7
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 claims 7
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 4
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 4
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 4
- 239000002202 Polyethylene glycol Substances 0.000 claims 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims 4
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 4
- 239000011575 calcium Substances 0.000 claims 4
- 229910052791 calcium Inorganic materials 0.000 claims 4
- 229960005069 calcium Drugs 0.000 claims 4
- 150000001719 carbohydrate derivatives Chemical class 0.000 claims 4
- 150000001720 carbohydrates Chemical class 0.000 claims 4
- 235000014633 carbohydrates Nutrition 0.000 claims 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 4
- 229950008138 carmellose Drugs 0.000 claims 4
- 229920001531 copovidone Polymers 0.000 claims 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims 4
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims 4
- -1 fatty acid esters Chemical class 0.000 claims 4
- 150000004665 fatty acids Chemical class 0.000 claims 4
- 150000002191 fatty alcohols Chemical class 0.000 claims 4
- 229940049654 glyceryl behenate Drugs 0.000 claims 4
- 238000005469 granulation Methods 0.000 claims 4
- 230000003179 granulation Effects 0.000 claims 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 4
- 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 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims 4
- 229910052751 metal Inorganic materials 0.000 claims 4
- 239000002184 metal Chemical class 0.000 claims 4
- 229920000609 methyl cellulose Polymers 0.000 claims 4
- 239000001923 methylcellulose Substances 0.000 claims 4
- 235000010981 methylcellulose Nutrition 0.000 claims 4
- 239000002480 mineral oil Substances 0.000 claims 4
- 235000019426 modified starch Nutrition 0.000 claims 4
- 229960005455 polacrilin Drugs 0.000 claims 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims 4
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims 4
- 150000004760 silicates Chemical class 0.000 claims 4
- 239000001632 sodium acetate Substances 0.000 claims 4
- 235000017281 sodium acetate Nutrition 0.000 claims 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims 4
- 239000004299 sodium benzoate Substances 0.000 claims 4
- 235000010234 sodium benzoate Nutrition 0.000 claims 4
- 239000011780 sodium chloride Substances 0.000 claims 4
- 235000002639 sodium chloride Nutrition 0.000 claims 4
- 239000008109 sodium starch glycolate Substances 0.000 claims 4
- 229920003109 sodium starch glycolate Polymers 0.000 claims 4
- 229940079832 sodium starch glycolate Drugs 0.000 claims 4
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims 4
- 208000001294 Nociceptive Pain Diseases 0.000 claims 3
- 235000010980 cellulose Nutrition 0.000 claims 2
- 229920002678 cellulose Polymers 0.000 claims 2
- 239000001913 cellulose Substances 0.000 claims 2
- 239000007788 liquid Substances 0.000 claims 2
- 229940057948 magnesium stearate Drugs 0.000 claims 2
- 229940079502 naproxen 500 mg Drugs 0.000 claims 2
- 239000008363 phosphate buffer Substances 0.000 claims 2
- 208000008035 Back Pain Diseases 0.000 claims 1
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 208000005171 Dysmenorrhea Diseases 0.000 claims 1
- 206010016059 Facial pain Diseases 0.000 claims 1
- 206010019233 Headaches Diseases 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 206010065390 Inflammatory pain Diseases 0.000 claims 1
- 208000000112 Myalgia Diseases 0.000 claims 1
- 208000036992 Psychogenic pain disease Diseases 0.000 claims 1
- 206010037660 Pyrexia Diseases 0.000 claims 1
- 208000005298 acute pain Diseases 0.000 claims 1
- 206010003246 arthritis Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 208000035475 disorder Diseases 0.000 claims 1
- 231100000869 headache Toxicity 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 208000004296 neuralgia Diseases 0.000 claims 1
- 208000021722 neuropathic pain Diseases 0.000 claims 1
- 230000001575 pathological effect Effects 0.000 claims 1
- 239000002831 pharmacologic agent Substances 0.000 claims 1
- 239000000049 pigment Substances 0.000 claims 1
- 230000001107 psychogenic effect Effects 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 208000004371 toothache Diseases 0.000 claims 1
- 208000009935 visceral pain Diseases 0.000 claims 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
- A61K9/2072—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
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
Abstract
The invention relates to a multilayer tablet comprising (i) a naproxen layer containing naproxen or a physiologically acceptable salt thereof and providing immediate release of the naproxen or the physio- logically acceptable salt thereof; and (ii) a paracetamol layer containing paracetamol and providing im- mediate release of the paracetamol. The multilayer tablet is preferably prepared by wet granulation such that the naproxen layer and the paracetamol layer both comprise an extragranular phase and an intragranular phase. Preferably, both extragranular phases contain microcrystalline cellulose. Preferably, the intragranular phase and the extragranular phase of the paracetamol layer both contain a disintegrant, whereas the naproxen layer does not contain disintegrant in any phase. The total content of excipients in both intragranular phases is particularly low.
Claims
AMENDED CLAIMS received by the International Bureau on 15 february 2023 (15.03.2023) A multilayer tablet comprising
- a naproxen layer containing naproxen or a physiologically acceptable salt thereof and providing immediate release of the naproxen or the physiologically acceptable salt thereof, wherein the naproxen layer comprises no disintegrant; and
- a paracetamol layer containing paracetamol and providing immediate release of the paracetamol. The multilayer tablet according to claim 1 , which is a bilayer tablet. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose. The multilayer tablet according to claim 3, wherein the amount of diluent, preferably microciys- talline cellulose, in the naproxen layer is in the range of 1 to 20 %, preferably 5 to 15 %, and most preferably 6 to 12 % by weight of the naproxen layer. The multilayer tablet according to any of the preceding claims, wherein the naproxen comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone. The multilayer tablet according to claim 5, wherein the amount of binder, preferably povidone, in the naproxen layer is in the range of 1 to 10 %, preferably 1 to 5 %, and most preferably 2 to 4 % by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate.
1
AMENDED SHEET (ARTICLE 19)
. The multilayer tablet according to claim 7, wherein the amount of lubricant, preferably magnesium stearate, in the naproxen layer is in the range of 0.1 to 5 %, preferably 0.25 to 3 %, and most preferably 0.25 to 1 .5 % by weight of the naproxen layer. . cancelled 0. The multilayer tablet according to any of the preceding claims, which comprises from 220 mg to 660 mg of naproxen or a physiologically acceptable salt thereof; preferably naproxen sodium; more preferably 220 mg, 275 mg, 375 mg, 440 mg, 550 mg or 660 mg of naproxen sodium. 1 . The multilayer tablet according to any of the preceding claims, wherein the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the naproxen layer is in the range of 75±15 %, preferably 75±10 %, and most preferably 75±5 %, by weight of the naproxen layer. . The multilayer tablet according to any of the preceding claims, wherein the amount of naproxen or the physiologically acceptable salt thereof, preferably naproxen sodium, in the multilayer tablet is in the range of 25±15 %, preferably 25±10 %, and most preferably 25±5 %, by weight of the multilayer tablet. . The multilayer tablet according to any of the preceding claims, wherein the naproxen layer has been prepared by wet granulation. . The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the naproxen or physiologically acceptable salt thereof, preferably naproxen sodium, within 50 minutes, preferably within 45 minutes, more preferably within 40 minutes, still more preferably within 35 minutes, yet more preferably within 30 minutes, even more preferably within 25 minutes, most preferably within 20 minutes, and in particular within 15 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C. 5. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer comprises essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the multilayer tablet. . The multilayer tablet according to any of the preceding claims, wherein the naproxen layer has been prepared by granulation, preferably by wet granulation, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extragranular phase.
2
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to claim 16, wherein essentially the total amount of the naproxen or the physiologically acceptable salt thereof that is contained in the naproxen layer is contained in the intragranular phase of the naproxen layer. The multilayer tablet according to claim 16 or 17, wherein the intragranular phase of the naproxen layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone. The multilayer tablet according to claim 18, wherein the amount of binder, preferably povidone, in the intragranular phase of the naproxen layer is in the range of 9.0±8.0 %, preferably 9.0±5.0 %, and most preferably 9.0±2.0 % by weight of the naproxen layer. cancelled The multilayer tablet according to any of claims 16 to 20, wherein the total amount of all excipients in the intragranular phase of the naproxen layer is at most 15 %, preferably at most 13 %, and most preferably at most 1 1 % by weight of the intragranular phase of the naproxen layer. The multilayer tablet according to any of claims 16 to 21, wherein the total amount of all excipients in the intragranular phase of the naproxen layer is at most 14 %, preferably at most 12 %, and most preferably at most 10 % by weight of the naproxen layer. The multilayer tablet according to any of claims 16 to 22, wherein the total amount of all excipients in the intragranular phase of the naproxen layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet. The multilayer tablet according to any of claims 16 to 23, wherein the intragranular phase of the naproxen layer essentially consists of the naproxen or physiologically acceptable salt thereof, the binder, and optionally a pigment. The multilayer tablet according to any of claims 16 to 24, wherein the extragranular phase of the naproxen layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microciystalline cellulose.
3
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to claim 25, wherein the amount of diluent, preferably microcrystalline cellulose, in the extragranular phase of the naproxen layer is in the range of 8.0±7.0 %, preferably 8.0±5.0 %, and most preferably 8.0±3.0 % by weight of the naproxen layer. The multilayer tablet according to any of claims 16 to 26, wherein the extragranular phase of the naproxen layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate. The multilayer tablet according to claim 27, wherein the amount of lubricant, preferably magnesium stearate, in the extragranular phase of the naproxen layer is in the range of 1 ,0±0.9 %, preferably 1 .0±0.6 %, and most preferably 1 ,0±0.3 % by weight of the naproxen layer. cancelled The multilayer tablet according to any of claims 16 to 29, wherein the extragranular phase of the naproxen layer essentially consists of the diluent and the lubricant. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose. The multilayer tablet according to claim 31 , wherein the amount of diluent, preferably microcrystalline cellulose, in the paracetamol layer is in the range of 10 to 30 %, preferably 15 to 25 %, and most preferably 18 to 22 % by weight of the paracetamol layer. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone.
4
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to claim 33, wherein the amount of binder, preferably povidone, in the paracetamol layer is in the range of 1 to 10 %, preferably 1 to 5. %, and most preferably 2 to 4 % by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate. The multilayer tablet according to claim 35, wherein the amount of lubricant, preferably magnesium stearate, in the paracetamol layer is in the range of 0.1 to 5 %, preferably 0.25 to 3 %, and most preferably 0.25 to 1.5 % by weight of the paracetamol layer. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone. The multilayer tablet according to claim 37, wherein the amount of disintegrant, preferably crospovidone, in the paracetamol layer is in the range of 1 to 10 %, preferably 1 to 5 % and most preferably 2 to 4 % by weight of the paracetamol layer. The multilayer tablet according to any of the preceding claims, which comprises from 100 mg to 1000 mg of paracetamol; preferably 275 mg, 300 mg, 500 mg or 750 mg of paracetamol. The multilayer tablet according to any of the preceding claims, wherein the amount of paracetamol in the paracetamol layer is in the range of 70±l 5 %, preferably 70±10 %, and most preferably 70±5 %, by weight of the paracetamol layer. The multilayer tablet according to any of the preceding claims, wherein the amount of paracetamol in the multilayer tablet is in the range of 45±15 %, preferably 45±10 %, and most preferably 45±5 %, by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer has been prepared by wet granulation.
5
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C. The multilayer tablet according to any of the preceding claims, wherein the tablet releases at least 75% of the paracetamol within 45 minutes, preferably within 40 minutes, more preferably within 35 minutes, still more preferably within 30 minutes, yet more preferably within 25 minutes, even more preferably within 20 minutes, most preferably within 15 minutes, and in particular within 10 minutes, when determined with USP I (basket) apparatus at 100 rpm in 900 mL phosphate buffer pH 6.8 at 37 °C. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer comprises essentially the total amount of the paracetamol that is contained in the multilayer tablet. The multilayer tablet according to any of the preceding claims, wherein the paracetamol layer has been prepared by granulation, preferably by wet granulation, more preferably with an aqueous granulation liquid, and comprises an intragranular phase and an extragranular phase. The multilayer tablet according to claim 46, wherein essentially the total amount of the paracetamol that is contained in the paracetamol layer is contained in the intragranular phase of the paracetamol layer. The multilayer tablet according to claim 46 or 47, wherein the intragranular phase of the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of cro- spovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone. The multilayer tablet according to claim 48, wherein the amount of disintegrant, preferably crospovidone, in the intragranular phase of the paracetamol layer is in the range of 2.0±l .5 %, preferably 2.0±l .0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer.
AMENDED SHEET (ARTICLE 19)
0. The multilayer tablet according to any of claims 46 to 49, wherein the extragranular phase of the paracetamol layer comprises a disintegrant; preferably selected from the group consisting of cro- spovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone. 1 . The multilayer tablet according to claim 50, wherein the amount of disintegrant, preferably crospovidone, in the extragranular phase of the paracetamol layer is in the range of 2.0±l .5 %, preferably 2.0±l .0 % and most preferably 2.0±0.5 % by weight of the paracetamol layer. . The multilayer tablet according to any of claims 46 to 51 , wherein the intragranular phase as well as the extragranular phase of the paracetamol layer comprises a disintegrant; preferably independently selected from the group consisting of crospovidone, starch, pregelatinized starch, croscarmellose sodium, carmellose sodium, carmellose calcium, low substituted hydroxypropyl cellulose, sodium starch glycolate, salts of polacrilin, silicate derivatives, and combinations thereof; more preferably crospovidone. . The multilayer tablet according to claim 52, wherein the total amount of disintegrant, preferably crospovidone, in the extragranular phase and the intragranular phase of the paracetamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±l .0 % by weight of the paracetamol layer. . The multilayer tablet according to any of claims 46 to 53, wherein the intragranular phase of the paracetamol layer comprises a binder; preferably selected from the group consisting of povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, polyvinyl alcohol, polyethylene glycol, starch, pregelatinized starch, and combinations thereof; more preferably povidone. . The multilayer tablet according to claim 54, wherein the amount of binder, preferably povidone, in the intragranular phase of the paracetamol layer is in the range of 4.0±3.0 %, preferably 4.0±2.0 % and most preferably 4.0±l .0 % by weight of the paracetamol layer. . The multilayer tablet according to any of claims 46 to 55, wherein the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 12 %, preferably at most 10 %, and most preferably at most 8 % by weight of the intragranular phase of the paracetamol layer.
7
AMENDED SHEET (ARTICLE 19)
7. The multilayer tablet according to any of claims 46 to 56, wherein the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 1 1 %, preferably at most 9.0 %, and most preferably at most 7.0 % by weight of the paracetamol layer. 8. The multilayer tablet according to any of claims 46 to 57, wherein the total amount of all excipients in the intragranular phase of the paracetamol layer is at most 8.0 %, preferably at most 6.0 %, and most preferably at most 4.0 % by weight of the multilayer tablet. 9. The multilayer tablet according to any of claims 46 to 58, wherein the intragranular phase of the paracetamol layer essentially consists of the paracetamol, the disintegrant and the binder. 0. The multilayer tablet according to any of claims 46 to 59, wherein the extragranular phase of the paracetamol layer comprises a diluent; preferably selected from the group consisting of starch, starch derivatives, cellulose, microcrystalline cellulose, carbohydrates, carbohydrate derivatives, metal salts of phosphoric acid, and combinations thereof; more preferably microcrystalline cellulose. 1 . The multilayer tablet according to claim 60, wherein the amount of diluent, preferably microcrystalline cellulose, in the extragranular phase of the paracetamol layer is in the range of 20± l 5 %, preferably 20±10 %, and most preferably 20±5 % by weight of the paracetamol layer. . The multilayer tablet according to any of claims 46 to 61 , wherein the extragranular phase of the paracetamol layer comprises a lubricant; preferably selected from the group consisting of metallic stearates, fatty acid esters, fatty acids, fatty alcohols, glyceryl behenate, mineral oils, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols, metallic lauryl sulfates, sodium chloride, sodium benzoate, sodium acetate, and combinations thereof; more preferably magnesium stearate. . The multilayer tablet according to claim 62, wherein the amount of lubricant, preferably magnesium stearate, in the extragranular phase of the paracetamol layer is in the range of 0.5±0.4 %, preferably 0.5±0.3 %, and most preferably 0.5±0.2 % by weight of the naproxen layer. . The multilayer tablet according to any of claims 46 to 63, wherein the extragranular phase of the naproxen layer essentially consists of the disintegrant, the diluent and the lubricant.
8
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to any of claims 46 to 64, wherein the extragranular phase of the naproxen layer and the extragranular phase of the paracetamol layer both contain microcrystalline cellulose. The multilayer tablet according to any of claims 46 to 65, wherein the intragranular phase of the paracetamol layer and the extragranular phase of the paracetamol layer both contain a disinte- grant, whereas the naproxen layer does not contain a disintegrant in any phase. The multilayer tablet according to any of claims 16 to 66, wherein the total amount of all excipients contained in the intragranular phase of the naproxen layer arid in the intragranular phase of the paracetamol layer is at most 10 %, more preferably at most 9.0 %, still more preferably at most 8.0 % by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, which besides the naproxen or the physiologically acceptable salt thereof and the paracetamol contains no additional pharmacologically active ingredient. The multilayer tablet according to any of the preceding claims, which comprises 275 mg of naproxen sodium and 500 mg of paracetamol. The multilayer tablet according to any of the preceding claims, wherein the naproxen layer and the paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate; and wherein the paracetamol layer comprises crospovidone. The multilayer tablet according to any of the preceding claims,
- wherein the multilayer tablet is a bilayer tablet;
- which releases at least 75% of the paracetamol within 45 minutes, when determined with USP 1 (basket) apparatus at 100 rpm in 900 mL 0.1 M hydrochloric acid at 37 °C;
- wherein the tablet comprises 275 mg of naproxen sodium and 500 mg of paracetamol,
- wherein the naproxen layer and the paracetamol layer comprise microcrystalline cellulose, povidone and magnesium stearate; and
- wherein the paracetamol layer comprises crospovidone. The multilayer tablet according to any of the preceding claims, wherein the amount of the naproxen layer in the multilayer tablet is in the range of 33±15 %, preferably 33±10 %, and most preferably 33±5 %, by weight of the multilayer tablet.
9
AMENDED SHEET (ARTICLE 19)
The multilayer tablet according to any of the preceding claims, wherein the amount of the paracetamol layer in the multilayer tablet is in the range of 67±15 %, preferably 67±10 %, and most preferably 67±5 %, by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, which has a total weight of at most 1200 mg, preferably at most 1 150 mg, more preferably at most 1 100 mg. The multilayer tablet according to any of the preceding claims, wherein the total amount of all excipients is at most 35 %, preferably at most 30 % by weight of the multilayer tablet. The multilayer tablet according to any of the preceding claims, which is film coated. The multilayer tablet according to any of the preceding claims, which is a scored tablet. The multilayer tablet according to any of the preceding claims for use in the treatment of a condition or disorder selected from pain, fever and inflammation. The multilayer tablet for use according to claim 78, wherein the pain is selected from nociceptive pain, inflammatory pain, pathological pain, neuropathic pain, idiopathic pain, chronic pain, acute pain, subacute pain, thermal pain, mechanical pain, chemical pain, visceral pain, deep somatic pain, superficial somatic pain, somatoform pain, psychogenic pain, and psychalgia pain; preferably from arthritis pain, rheumatoid pain, muscular pain, back pain, menstrual pain, headache, orofacial pain, tooth pain. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered once daily. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered twice daily. The multilayer tablet for use according to claim 78 or 79, wherein the multilayer tablet is orally administered thrice daily or more frequently.
10
AMENDED SHEET (ARTICLE 19)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SIP-202100137 | 2021-07-08 | ||
| SI202100137 | 2021-07-08 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2023281089A2 WO2023281089A2 (en) | 2023-01-12 |
| WO2023281089A3 WO2023281089A3 (en) | 2023-03-16 |
| WO2023281089A4 true WO2023281089A4 (en) | 2023-05-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2022/069158 WO2023281089A2 (en) | 2021-07-08 | 2022-07-08 | Pharmaceutical composition comprising naproxen and paracetamol |
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| WO (1) | WO2023281089A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114796142A (en) * | 2022-04-08 | 2022-07-29 | 黄山学院 | Naproxen gastric floating tablet and preparation method thereof |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU528532B2 (en) | 1978-12-18 | 1983-05-05 | Mcniel Laboratories | Acetaminophen analgesic potentiation |
| PL1781277T3 (en) | 2004-07-07 | 2012-07-31 | Aft Pharmaceuticals Ltd | A combination composition comprising ibuprofen and paracetamol |
| PL1799195T3 (en) | 2004-08-12 | 2016-09-30 | Granules comprising paracetamol, an nsaid and a sugar alcohol made by melt extrusion | |
| US20080166407A1 (en) | 2005-07-29 | 2008-07-10 | Shalaby Shalaby W | Solid oral formulations for combination therapy |
| GB0519350D0 (en) | 2005-09-22 | 2005-11-02 | Boots Healthcare Int Ltd | Therapeutic agents |
| AU2007309281B2 (en) | 2006-10-20 | 2013-10-31 | Johnson & Johnson Consumer Inc. | Acetaminophen / ibuprofen combinations |
| US20090264530A1 (en) | 2008-04-16 | 2009-10-22 | Nickell Robert P | Combined nsaid and acetaminophen formulation and method |
| MX340662B (en) | 2008-10-14 | 2016-07-20 | Aft Pharmaceuticals Ltd | A medicinal product and treatment. |
| WO2010138441A1 (en) * | 2009-05-28 | 2010-12-02 | Aptapharma, Inc. | Multilayer oral tablets containing a non-steroidal anti-inflammatory drug and/or acetaminophen |
| WO2012005605A1 (en) | 2010-07-07 | 2012-01-12 | Aft Pharmaceuticals Limited | A combination composition comprising ibuprofen and paracetamol |
| LT2635269T (en) | 2010-11-04 | 2019-09-10 | Aft Pharmaceuticals Limited | A combination composition |
| MX2014008985A (en) | 2014-07-24 | 2016-01-25 | Liomont S A De C V Lab | Pharmaceutical composition of sodic naproxene, paracetamol and pamabrom, for the treatment of pains related to dysmenorrhoea and/or premenstrual syndrome. |
| AU2016218950C1 (en) | 2015-02-13 | 2022-11-03 | Anlar Pty Ltd | Analgesic formulation |
| CN110354111A (en) | 2019-07-18 | 2019-10-22 | 上海臣邦医药科技股份有限公司 | A kind of compound and its pharmaceutical composition and application |
| EP4076427A4 (en) * | 2019-12-19 | 2023-11-22 | Bayer Healthcare LLC | Oral tablets comprising roller-compacted granules of naproxen sodium, methods of preparing thereof, and methods of using thereof |
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| WO2023281089A3 (en) | 2023-03-16 |
| WO2023281089A2 (en) | 2023-01-12 |
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