NZ752060B2 - Pharmaceutical compositions of 5-ht6 antagonist - Google Patents
Pharmaceutical compositions of 5-ht6 antagonist Download PDFInfo
- Publication number
- NZ752060B2 NZ752060B2 NZ752060A NZ75206017A NZ752060B2 NZ 752060 B2 NZ752060 B2 NZ 752060B2 NZ 752060 A NZ752060 A NZ 752060A NZ 75206017 A NZ75206017 A NZ 75206017A NZ 752060 B2 NZ752060 B2 NZ 752060B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- bromophenyl
- methoxy
- sulfonyl
- immediate release
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 55
- 229940124801 5-HT6 antagonist Drugs 0.000 title 1
- 239000003751 serotonin 6 antagonist Substances 0.000 title 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims abstract description 70
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- -1 methylpiperazinyl Chemical group 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 52
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 47
- 239000003085 diluting agent Substances 0.000 claims description 46
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 43
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
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- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
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- 208000035475 disorder Diseases 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
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- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
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- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
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- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
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- 239000004014 plasticizer Substances 0.000 description 1
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- 230000036515 potency Effects 0.000 description 1
- 229920003124 powdered cellulose Chemical group 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
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- TVRGPOFMYCMNRB-UHFFFAOYSA-N quinizarine green ss Chemical compound C1=CC(C)=CC=C1NC(C=1C(=O)C2=CC=CC=C2C(=O)C=11)=CC=C1NC1=CC=C(C)C=C1 TVRGPOFMYCMNRB-UHFFFAOYSA-N 0.000 description 1
- 239000004172 quinoline yellow Substances 0.000 description 1
- 235000012752 quinoline yellow Nutrition 0.000 description 1
- IZMJMCDDWKSTTK-UHFFFAOYSA-N quinoline yellow Chemical compound C1=CC=CC2=NC(C3C(C4=CC=CC=C4C3=O)=O)=CC=C21 IZMJMCDDWKSTTK-UHFFFAOYSA-N 0.000 description 1
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- 229920005989 resin Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 description 1
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Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/2004—Excipients; Inactive ingredients
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-
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
- A61K9/2004—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
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Abstract
The present invention relates to an immediate release (IR) pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-methyl-1-piperazinyl) methyl]- 1H-indole or pharmaceutically acceptable salt (s) and one or more pharmaceutically acceptable excipients. The present invention also relates to methods of preparation of said pharmaceutical compositions. also relates to methods of preparation of said pharmaceutical compositions.
Description
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PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written n of IPEA
There is a need to develop a suitable dosage form of the compound 1 to treat the
patients with AD and other disorders of memory and cognition like Attention deficient
hyperactivity, Parkinson’s disease, schizophrenia, lewy body dementia, vascular dementia or
frontotemporal dementia. In our present ion. we developed IR pharmaceutical
compositions of compound 1 having (1) excellent properties of tablet formation, (2)
excellent wetting, disintegration, rapid and te drug release propenies, (3) good purity
profile and (4) stable formulation for the ent of AD and other disorders of memory and
cognition like Attention deficient hyperactivity, Parkinson’s disease, schizophrenia, lewy
body dementia, vascular dementia or frontotemporal dementia.
Summagy of Invention
In one aspect, the present invention s to immediate release pharmaceutical
composition comprising l-[(2-bromophenyl)sulfonylj-S-methoxy[(4-methyl-lpiperazinyl
) j-lH-indolc or a pharmaceutically acceptable salt thereof and one or
more pharmaceutically acceptable excipients.
In another aspect, the present ion relates to immediate release pharmaceutical
ition comprising l-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-lpiperazinyl
) methyl]-lH-indole late monohydrate and one or more pharmaceutically
acceptable excipients.
In another . the present invention relates to immediate release pharmaceutical
composition comprising l-[(2-bromophenyl)sulfonylj-S-methoxy[(4-methyl
piperazinyl) methylj-lH-indole dimesylate monohydrate, wherein the pharmaceutical
composition comprises binder, diluent, lubricant, glidant, disintegrant and ying agent.
In yet another aspect, the present invention relates to immediate release
pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyIJ-IH-indole dimesylate drate, wherein said composition
comprises on a total of 100 % by :
(a) from about 2 % to about 60 % l—[(2—bromophenyl)sulfonyl]—5-meth0xy—3-[(4—
methyl—l—piperazinyl) methyl]— 1 H—indole dimesylate monohydrate,
3O (b) from about 36 % to about 97 % of one diluent or total of two diluents;
(c) from about 0.5 % to about 2 % lubricant;
(d) from about 0.5 % to about 1 % glidant;
(e) 0 % to about 10 % ;
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended ption filed in
In reply to n Opinion of IPEA
(f) 0 % to about 5 % disintegrant; and
(g) 0 % to about 2 % acidifying agent.
In yet another aspect, the present invention relates to immediate release
pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]methoxy[(4—methyl
piperazinyl) methyl]-1H-indole dimesylate monohydrate. wherein said composition
comprises on a total of 100 % by weight:
(a) from about 2 % to about 3 % 1—[(2—bromophenyl)sulfonle-5—methoxy—3—[(4—
methyl— 1 —piperazinyl) methyl]— 1 H—indole dimesylate monohydrate;
(b) about 95 % to about 97 % diluent;
(c) about 1 % lubricant; and
(d) about 0.5 % glidant.
In yet another aspect. the present invention relates to immediate release
pharmaceutical composition of bromophenyl)sulfonyl]methoxy[(4-methyl-l-
piperazinyl) methyl]-lH-indole late monohydrate, wherein said ition
comprises on a total of 100 % by weight:
(a) from about 11 % to about 38 % l-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl-l-pipcrazinyl) methyl]- 1 H-indole dimesylate monohydrate;
(b) from about 61 % to about 87 % of one t or total of two diluents;
(c) about 1 % lubricant;
((1) about 0.5 % t;
(e) about 2 % disintegrant; and
(I) about 1 % ying agent.
In yet another aspect, the present ion relates to immediate release
pharmaceutical composition of 1-[(2-bromophenyl)sulfonylJ-5—methoxy—3—[(4-methyl—1-
piperazinyl) methylj-IH-indole dimesylate monohydrate. wherein said composition
comprises on a total of 100 % by weight:
(a) from about 24 % to about 38 % 1—[(2—bromophenyl)sulfonyl]—5—methoxy—3—[(4-
methyl- l-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
(b) from about 61 % to about 72 % one diluent or total of two diluents;
(c) from about 1 % to about 1.25 % lubricant;
((1) about 0.5 % glidant; and
(e) about 2 % disintegrant.
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
In yet another aspect. the present invention relates to immediate release
pharmaceutical composition of bromophenyl)sulfonyl]methoxy—3-[(4-methyl
zinyl) methyl]-lH-indole dimesylate monohydrate. wherein said composition
comprises on a total of 100 % by :
(a) from about 37 % to about 51 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl- 1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
(b) from about 45 % to about 60 % diluent;
(c) about 1 % lubricant;
((1) about 0.5 % glidant;
(e) about 2 % of disintegrant; and
(1') about 1 % acidifying agent.
In yet another aspect. the present invention relates to immediate release
pharmaceutical composition of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-l-
piperazinyl) methyl]-lH-indole dimesylate monohydrate, wherein said composition
comprises on a total of 100 % by weight:
(a) from about 36 % to about 60 % l-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl-l-pipcrazinyl) methyl]- 1 H-indole dimesylate drate;
(b) from about 36 % to about 62 % diluent;
(c) from about 0.5 % to about 1 % lubricant;
((1) about 0.5 % glidant; and
(e) about 2 % disintegrant.
In yet another aspect. the present ion relates to immediate release
pharmaceutical composition of bromophenyl)sulfonyl]methoxy[(4—methyl
zinyl) j-lH-indole dimesylate monohydrate. wherein said composition
comprises on a total of 100 % by :
(a) from about 11 % to about 38 % 1—[(2—bromophenyl)sulfonyl]—5—meth0xy—3-[(4-
methyl-l—pipcrazinyl) methyl]-1 H—indole dimesylate monohydrate;
(b) from about 61 % to about 72 % diluent;
(c) about 1 % lubricant;
(d) from about 2 % to about 10 % binder;
(e) about 0.5 % glidant; and
(I) from about 2 % to about 5 % disintegrant.
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
In yet another aspect, the present invention also relates to methods of preparation of
immediate release pharmaceutical compositions.
In yet another aspect the t ion relates to an immediate release tablet,
wherein said tablet comprises on a total of 100 % by weight:
(a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl- 1-piperazinyl) methy1]- lH-indole late monohydrate;
(b) from about 36 % to about 97 % of one diluent or total of two diluents;
(c) 0 % to about 10 % binder;
(d) from about 0.5 % to about 2 % lubricant;
(e) from about 0.5 % to about 1 % glidant;
(1') O % to about 5 % disintegrant; and
(g) 0 % to about 2 % acidifying agent.
In yet another aspect. the present invention relates to immediate release tablet,
wherein said tablet comprises on a total of 100 % by :
(a) from about 2 % to about 3 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
mcthyl-l-piperazinyl) methyl]- 1 H-indole dimesylate monohydrate;
(b) about 95 % to about 97 % diluent;
(c) about 1 % lubricant; and
((1) about 0.5 % t.
In yet another . the present invention relates to immediate release tablet,
wherein the said tablet comprises on a total of 100 % by weight:
(a) from about 11 % to about 38 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
- 1-piperazinyl) methyl]-1H-indole dimesylate monohydrate;
(b) from about 61 % to about 87 % of one t or total of two diluents;
(c) about 1 % lubricant;
((1) about 0.5 % glidant;
(e) about 2 % disintegrant; and
(I) about 1 % acidifying agent.
In yet another aspect, the present invention relates to immediate release tablet,
n said tablet ses on a total of 100 % by weight:
(a) from about 24 % to about 38 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl-l-piperazinyl) methyl]- 1 H-indole dimesylate monohydrate;
(b) from about 61 % to about 72 % one diluent or total of two diluents;
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended ption filed in
In reply to Written n of IPEA
(c) from about 1 % to about 1.25 % lubricant;
((1) about 0.5 % glidant; and
(e) about 2 % egrant.
In yet another aspect. the present invention relates to immediate release tablet,
wherein said tablet comprises on a total of 100 % by weight:
(a) from about 37 % to about 51 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl—l—piperazinyl) methylj—lH—indolc dimesylate monohydratc;
(b) from about 45 % to about 60 % diluent;
(c) about 1 % ant;
((1) about 0.5 % glidant;
(e) about 2 % of disintegrant; and
(I) about 1 % acidifying agent.
In yet another aspect. the present invention relates to immediate release tablet,
wherein said tablet comprises on a total of 100 % by weight:
(a) from about 36 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
mcthyl-l-piperazinyl) methyl]- 1 H-indole dimesylate monohydratc;
(b) from about 36 % to about 62 % t;
(c) from about 0.5 % to about 1 % ant;
((1) about 0.5 % glidant; and
(e) about 2 % disintegrant.
In yet another aspect, the present invention relates to immediate release tablet,
wherein said tablet comprises on a total of 100 % by weight:
(a) from about 11 % to about 38 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methylpiperazinyl) methyl]- 1 H—indole dimesylate monohydratc;
(b) from about 61 % to about 72 % diluent;
(0) about 1 % lubricant;
(d) from about 2 % to about 10 % binder;
(6) about 0.5 % glidant; and
(1) from about 2 % to about 5 % disintegrant.
In yet another aspect, the present invention relates to the immediate release
pharmaceutical ition of dose ranges from about 5 mg to about 200 mg.
AMENDED SHEET
238864NZPR
104785980
In yet another aspect, the present invention relates to the ate release
pharmaceutical composition, wherein the total weight of the immediate e tablet is from
about 100 mg to about 600 mg.
In yet another aspect, the present invention relates to the immediate e
pharmaceutical composition, wherein the immediate release pharmaceutical composition
comprises,
i) less than 0.5 % of chloro impurity;
ii) less than 0.5 % of unknown ty;
iii) less than 1 % of total impurity.
In yet another aspect, the present invention relates to the immediate release
pharmaceutical ition, wherein the purity of the 1-[(2-bromophenyl)sulfonyl]
methoxy[(4-methylpiperazinyl) methyl]-1H-indole dimesylate monohydrate is about
99.3 %.
In yet another aspect, the present ion relates to the immediate release
pharmaceutical composition, wherein the 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methylpiperazinyl) methyl]-1H-indole dimesylate monohydrate is released about 85 % to
about 100 % within 30 minutes.
In one particular aspect the present invention provides an immediate release
pharmaceutical composition on a total of 100% by weight comprising:
a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
piperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt
thereof;
b) from about 36 % to about 97 % diluent or total of two diluents; wherein the diluent
is selected from the group ting of microcrystalline cellulose, lactose
monohydrate, dibasic calcium ate, lactose, lactose hydrate, lactose anhydrate,
mannitol, starch and isomalt;
c) from about 0.5 % to about 2 % lubricant; wherein the lubricant is magnesium
stearate;
d) from about 0.5 % to about 1 % glidant; wherein the glidant is dal silicon
dioxide; e) 0 % to about 10 % binder; wherein the binder is ed from group
consisting of povidone or hydroxypropyl methylcellulose;
f) 0 % to about 5 % disintegrant; wherein the disintegrant is selected from
crospovidone, sodium starch glycolate and croscarmellose sodium; and
7 [followed by page 7A]
238864NZPR
104785980
g) 0 % to about 2 % acidifying agent; wherein the acidifying agent is citric acid.
Detailed ption of Invention
Unless otherwise stated, the following terms used in the specification and claims
have the meanings given below:
The term, “pharmaceutically acceptable excipients” as used herein refers to diluents,
disintegrants, binders, ants, glidants, rs, coating agents, solvents, co-solvents,
preservatives, wetting agents, thickening agents, antifoaming agents, sweetening agents,
flavouring agents, antioxidants, colorants, solubulizers, plasticizer or dispersing agents and
the like. The pharmaceutical itions of the present invention may be formulated in a
conventional manner using one or more pharmaceutically acceptable excipients.
The “binder” employed in a composition of the present invention is capable for
holding the ingredients together and forming the granules with required mechanical strength.
Example of binders includes without limitation, nylpyrrolidone (povidone (PVPK30)),
polyethlylene glycol (PEG), saccharides, gelatins, pregelatinized starches,
hydroxypropylcellulose, ypropyl cellulose (HPMC) and cellulose .
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The “diluent” employed in a composition of the present invention is e for
providing bulkiness to obtain a desired immediate e pharmaceutical composition.
Preferred diluents are inorganic phosphates such as c calcium phosphate, calcium
sulphate or dicalcium phosphate dihydrate; sugars such as lactose, lactose hydrate, lactose
monohydrate. lactose anhydrate. sucrose, dextrose, erythritol, lactilol. xylitol. sorbitol.
mannitol or malitol; cellulose or cellulose derivatives such as microcrystalline cellulose;
Avicel. Avicel PH 101. Avicel PH 102 or Avicel PH 103. maize starch. p—lSOO.
Starlac and isomalt.
The “disintegrant” employed in a composition of the present invention is e of
facilitating the breakup of an immediate release pharmaceutical composition prepared from
the composition when placed in contact with an aqueous medium. Preferred disintegrants are
alginic acid or sodium te; cellulose or cellulose tives such as
carboxymethylcellulose sodium. croscarmellose sodium, powdered cellulose or
croscarmellose; iron exchange resin such as ite, gums such as agar. locust bean,
karaya, pectin and tragacanth. crospovidone (cross-linked homopolymer of N-vinyl
pyrrolidinone, i.e., cross-linked 1-ethenylpyrrolidinone); sodium starch glycolate or
starch.
The “lubricant” employed in a composition of the present ion is capable of
preventing the ingredients from clumping together and from sticking to the apparatus on
which it is . for example. preventing adherence to the face of the upper punch
(picking) or lower punch (sticking) of a ssion machine. Preferred lubricants are fatty
acids or fatty acid derivatives such as calcium stearate, glyceryl monostearate. glyceryl
palmitostearate, talc. magnesium stearate, sodium lauryl sulfate. sodium stearyl fumarate,
zinc stearate, stearic acid or hydrogenated ble oil; kylene glycols such as
polyethylene glycol (PEG) or sodium benzoate and the like.
The “glidant” employed in a composition of the present invention is capable for
increase in flow. those selected from the group consisting of colloidal silicon dioxide
(Aerosil), higher fatty acids. the metal salts. talc. and the like or the mixtures thereof.
The fying agent” employed in a composition of the present ion is capable
to increase the acidity. those selected from the group consisting of citric acid. tartaric acid,
fumaric acid. hydrochloric acid, maleic acid, acetic acid, nitric acid and the like.
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended ption filed in
In reply to Written Opinion of IPEA
The “coloring agent” (or "colorant”) employed in a composition of the present ion may
be one or more compounds which impart a desired color to the composition. Addition of a coloring
agent may be used, for example. so that tablets of different potencies may be easily distinguished.
Example of coloring agent includes but not limited to beta-carotene, indigo cannine, sunset yellow
FCF. tartrazine. brilliant blue FCF. titanium dioxide, quinoline yellow, allura red AC, quinizarine
green SS and iron oxides. which are accepted universally.
The e ingredient” defined in this invention is 1-[(2-bromophenyl)sulfonyl]methoxy-
3—| (4-methyl— l -piperazinyl)methyl ]—l H-indolc dimesylate monohydrate.
The term “about” means within an able error range for the particular value as
determined by one of ordinary skill in the art, which will depend in part on how the value is
measured or determined, i.e., the limitations of the measurement system. The term ” as used
herein refers to a defined range of the value by i 10 %. For example, about 2 % means 1.8 % to 2.2
%, about 5 % means 4.5 % to 5.5 %, about 10 % means 9 % to 1] % and about 40 % means 36 % to
44 %.
The term, “pharmaceutically acceptable salt” as used herein refers to salts of the active
ingredient and are ed by reaction with the appropriate acid or acid derivative, depending on the
particular substitucnts found on the compounds described herein. The pharmaceutically acceptable
salt includes but not d to dimesylate monohydrate salt, dihydrochloride salt, oxalate salt,
tartrate salt and the like. Preferably, the pharmaceutically able salt is dimesylate monohydrate
salt and dihydrochloride salt. More preferably, the pharmaceutically acceptable salt is dimesylate
monohydrate salt.
The term, "patient” as used herein refers to an animal. Preferably the term nt” refers to
mammal. The term mammal includes animals such as mice, rats. dogs, rabbits. pigs, s. horses
and human. More preferably the patient is human.
The term. “immediate release composition" refers to a composition of an active ingredient which
disintegrates rapidly and releases greater than 85 % at 30 minutes.
The term ity” as used herein refers to any component of a drug substance that is not the
chemical entity defined as the drug nce and in addition. for a drug product. any component that is not a
formulation ingredient.
The immediate release pharmaceutical compositions of the present invention can be used for
treatment or prevention of Alzheimer's disease and other disorders of memory and cognition like
ion nt hyperactivity, Parkinson's disease, schizophrenia, lewy body dementia, vascular
dementia or frontotemporal dementia. The immediate release pharmaceutical composition of the
instant ion can be stered orally, in an effective amount, to a mammalian (especially
human) subject to treat or prevent the aforementioned disorders.
The effective dosage of the immediate release pharmaceutical composition
comprising l-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-l-piperazinyl) ]-
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
lH-indole dimesylate monohydratc is about 5 mg to about 200 mg. The immediate release
pharmaceutical composition can be administered 1 to 3 times per day. based on condition of the
patients. The total weight of ate e pharmaceutical ition of the present
invention is from about 100 mg to 600 mg.
The compound 1 belongs to class I as per BCS classification based on our
experimental results and hence particle size of the compound 1 does not effect in the
treatment of the patient.
In one embodiment the present invention relates to the immediate release
pharmaceutical ition comprising:
. Range Preferred Range
<%w/w> (W
Compound 1 10 — 50
2 _ 60
(Active in redient)
36—97 40-90
m_-u-
In yet another embodiment, the present ion relates to the immediate release
ceutical composition comprises about 2 % to about 3 % by weight of l-[(2-
bromophenyl)sulfonyl]methoxy[(4-methyl-1 -piperazinyl)methyl]-1H-indole
dimesylate monohydrate.
In yet another embodiment. the present invention relates to the immediate release
pharmaceutical composition ses about 10 % to about 40 % by weight of 1—[(2—
bromophenyl)sulfonlemethoxy[(4—methyl—1-piperazinyl) methyl]-1 H-indole
dimesylate monohydrate.
In yet another embodiment, the present ion relates to the immediate release
pharmaceutical composition ses about 20 % to about 40 % by weight of 1—[(2—
bromophenyl)sulfonyl]methoxy[(4-methy1-1 -piperazinyl) methyl]- lH-indole
dimesylate monohydrate.
In yet another embodiment, the present invention relates to the immediate release
pharmaceutical composition comprises about 30 % to about 50 % by weight of 1-[(2-
bromophenyl)sulfonyl]methoxy-3—[(4-methyl-l -piperazinyl) methyl]- 1 H-indole
dimesylate monohydrate.
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
In yet another embodiment, the present invention relates to the immediate release
pharmaceutical composition comprises about 30 % to about 60 % by weight of 1-[(2-
bromophenyl)sulfonyl]methoxy[(4-methyl- l -piperazinyl) methyl]-1H-indole
dimesylate monohydrate.
In yet another embodiment. the present invention s to the immediate release
pharmaceutical composition sing; about 40 % to about 80 % by weight of diluent
In yet another embodiment, the present invention relates to the immediate release
pharmaceutical composition comprising about 70 % to about 90 % by weight of t.
In yet another ment, the present invention s to the immediate release
pharmaceutical composition comprising about 20 % to about 40 % by weight of diluent.
In yet r embodiment. the present invention relates to immediate release
pharmaceutical composition in the form of tablet or capsule.
In yet another embodiment, the present invention relates to an immediate release
tablet, n the tablet comprises,
(a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-
methyl-l-piperazinyl) methyl]- 1 H-indole dimesylate monohydrate;
(b) from about 36 % to about 97 % of rystalline cellulose;
(c) from about 0.5 % to about 2 % magnesium stearate;
(d) from about 0.5 % to about 1 % colloidal silicon dioxide;
(e) 0 % to about 5 % crospovidone; and
(f) 0 % to about 2 % citric acid.
In yet another ment. the present invention relates to an immediate release
, wherein the tablet comprises,
(a) from about 2 % to about 60 % l—[(2-bromophenyl)sulfonyl]—5-methoxy-3—[(4-
methyl— 1—piperazinyl) methyl]— 1 H—indole dimesylate monohydrate;
(b) from about 36 % to about 97 % of microcrystalline cellulose;
(c) from about 0.5 % to about 2 % magnesium stearate;
(d) from about 0.5 % to about 1 % colloidal silicon dioxide;
(e) 0 % to about 10 % povidone;
(D 0 % to about 5 % crospovidone; and
(g) 0 % to about 2 % citric acid.
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended ption filed in
In reply to n Opinion of IPEA
In yet another embodiment, the present ion relates to the immediate release
pharmaceutical composition comprises about 40 % to about 80 % by weight of
microcrystalline cellulose.
In yet another embodiment. the present invention relates to the immediate release
pharmaceutical composition comprises about 70 % to about 90 % by weight of
microcrystalline cellulose.
In yet another ment, the present invention relates to the immediate release
pharmaceutical composition comprises about 20 % to about 40 % by weight of
microcrystalline cellulose.
In yet another embodiment, the present ion relates to the immediate release
pharmaceutical composition comprises about 2 % by weight of crospovidone.
In yet another embodiment. the present invention relates to the immediate release
pharmaceutical composition comprises about 1 % by weight of citric acid.
In yet r embodiment, the present invention relates to the immediate release
pharmaceutical composition comprises about 4 % by weight of povidone.
In other aspect, the present invention relates to the use of the immediate release
pharmaceutical composition comprising 1-[(2—bromophcnyl)sulfonyl]methoxy[(4-
methyl-l-piperazinyl) methyll-lH-indole or a pharmaceutically acceptable salt thereof and
one or more pharmaceutically acceptable excipients for the treatment of Alzheimer's disease,
memory and cognition disorders selected from Attention nt hyperactivity disorder.
Parkinson’s disease, schizophrenia, lewy body dementia. vascular dementia or
frontotemporal dementia.
In yet another . the instant invention relates to the method of treatment of
Alzheimer‘s disease, memory and ion disorders selected from Attention deficient
hyperactivity disorder, Parkinson’s disease, schizophrenia. lewy body dementia. vascular
dementia or temporal ia comprising stering to a patient a therapeutically
effective amount of the immediate release ceutical composition comprising 1-[(2—
bromophenyl)sulfonyl]methoxy[(4-methylpiperazinyl) methyIJ-lH-indole or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable
excipients.
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Methods of preparation of immediate release pharmaceutical composition
In another aspect. the instant invention relates to the process for the preparation of
the immediate release pharmaceutical composition comprising 1-[(2-bromophenyl)sulfonyl]-
-methoxy[(4-methylpiperazinyl) methyl]-lH-indole or a pharmaceutically acceptable
salt f.
The preparation of the ate release ceutical composition includes two
methods. a) direct compression method and b) wet granulation method.
In one embodiment, the preparation of immediate release pharmaceutical
composition using direct compression method comprises the following steps:
a) weighing the active ingredient and one or two diluent (s) and sieving through sieve
number 40;
b) mixing the sieved active ingredient and one or two diluent (s);
c) weighing the ant. glidant, egrant and acidifying agent and sieving through
sieve number 40;
(1) adding the mixture obtained in step (c) into step (b) and ng the mixture for 5-20
minutes to form homogenous mixture; and
e) compressing the lubricated blend to obtain the required dosage form.
The above obtained dosage forms can be optionally coated with rs, solvents and
coloring agents by methods known in the art.
In another embodiment. the preparation of immediate release pharmaceutical
composition using wet granulation method ses the following steps:
a) weighing the active ingredient. diluents and super disintegrant;
b) g the weighed materials through sieve number 40;
c) blending the sieved active ingredient. diluents and super disintegrant for 10 minutes in
an octagonal blender;
d) weighing the binder and dissolve in required quantity of purified water;
e) erring the active ingredient. diluents and super disintegrant into RMG;
1") adding binder on dropwise to RMG to form cohesive mass;
g) drying the blend in a tray drier at 50 °C;
h) passing the blend through # 18 mesh to form granules;
i) weighing the ant and t and pass through sieve number 40;
j) adding the mixture obtained in step (h) to step (i) and blend for 10 minutes in an
octagonal blender; and
AMENDED SHEET
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In reply to Written Opinion of IPEA
k) ssing the lubricated blend to obtain the required dosage form.
The above obtained dosage forms can be optionally coated with polymers. solvents and
coloring agents by methods known in the art.
Abbreviations:
AUC : Area under the curve
Cum : Maximum plasma concentration
HDPE : High density polyethylene
HPMC : Hydroxypropyl methylcellulose
HPLC : High performance liquid chromatography
kg : Kilogram
LC-MS/MS : Liquid tography/ Tandem mass spectrometry
mg : Milligram
mL : Milliliter
ng : Nanogram
N : Normality
rpm : Rotation per minute
RMG : Rapid mixer granulator
T"m : Time of maximum plasma tration
Tl/z : ife
°C : Degree Celsius
% W/W : t weight/weight
UV : Ultra violet
Examples
The following Examples are provided to illustrate preferred embodiments of the
invention and are not intended to limit the scope of the present invention.
Example 1: Pharmaceutical composition of Compound 1 IR tablets.
By using range of ingredients (% w/w) in below mentioned table and procedures
explained in above mentioned ation methods. the IR tablets of l-[(2-
bromophenyl)sulfonyl]methoxy—3-[(4-methylpipera7.inyl)methyl]-lH-indolc
dimesylate monohydrate are prepared.
AMENDED SHEET
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In reply to Written Opinion of IPEA
Ingredient Range (% w/w)
Compound 1 2 — 60
Binder 0 — 5
Diluent 36 - 97
Disintegrant 0 — 4
Acidifying agent
Example 2:
Preparation of IR tablet using direct ssion method:
ition of 5 mg dose IR :
Communal
Microcrystalline cellulose 96.03 288.09
(Avicel PH 102)
iumsme [-—
Colloidal silicon dioxide 0.5 1.5
(Aerosil®)
# equivalent
to 5 mg of l-[(2-bromopheny1)sulfonyl]methoxy[(4-methyl-l-piperazinyl)
methyIJ-IH-indole (free base compound).
Method of preparing IR tablet:
All the ingredients were accurately weighed (Compound 1 of 2.47 %, Avicel PH 102
of 96.03 %) and sieved using sieve number 40. The sieved compound 1 and Avicel PH 102
were blended for 10 minutes in an octagonal r. The mixture obtained was added to
ium stearate (1%) and aerosil (0.5 %) and blended for 10 minutes in an octagonal
blender. The lubricated blend was compressed using 9 mm round concave punches and dies
on rotary ssion machine to obtain 300 mg tablet.
The examples 3 to 52 are prepared by following the method of preparation of
example 2 by using appropriate amount of active ingredient, diluent(s). disintegrant,
lubricant and with/without acidifying agent.
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Examples 3 to 16:
Compositions of 25 mg dose IR tablets:
Example 3 e 4
Ingredient (% w/w) mg/tablet (% w/w) mg/tablet
Compound 1 12.34 37.02 14.81 37.02
Microcrystalline cellulose 86.16 258.48 83.69 209.23
(Avicel PH 102)
Colloidal silicon dioxide 0.5 1.5 0.5 1.25
(Aerosil®)
—---I11-
equivalent to 25 mg of l-[(2-bromophenyl)sulfonylJmethoxy-3—[(4-methyl
piperazinyl) methyl]- lH-indole (free base compound)
(% w/w) mg/tablet (% w/w) mg/tablet
Compound 1 37.03 37.03 12.42 37.26
Microcrystalline ose 61.47 61.47 84.08 252.24
l PH 102)
Colloidal silicon e 0.5 0.5 0.5 1.5
il®)
—---_
“mm-
equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
pipcrazinyl) methyll-lH-indole (free base compound)
‘ ’
Compound 1 16.93 37.25 16.93 37.25
Microcrystalline cellulose 79.57 175.05 81.57 179.45
(Avicel PH 102)
Colloidal silicon dioxide 0.5 1.1 0.5 1.1
(Aerosil®)
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
—---
—--m
equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]—5-methoxy[(4-methyl-1—
piperazinyl) methyl]-1H-indole (free base compound)
Compound 1 16.93 37.25 16.93 37.25
Microcrystalline cellulose 40.78 89.72
(Avicel PH 102)
Lactose Monohydrate 40.79 89.73 --
Dibasic calcium phosphate 81.57 179.45
dihydrate
—--—_
Colloidal n e 0.5 0.5
(Aerosil®)
—--“
equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]-lH-indole (free base compound)
Compound 1 16.93 37.25 16.93 37.25
Microcrystalline cellulose 40.78 89.72 40.78 89.72
(Avicel PH 102)
—--—-
—---
—---
Colloidal silicon dioxide 0.5 1.1 0.5 1.1
(Aerosil®)
—---I1i-
equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-l-
piperazinyl) j-lH-indolc (free base compound)
AMENDED SHEET
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SUV-PCT0764 Clean copy of Amended Description filed in
In reply to n Opinion of IPEA
e 13 Example 14
Ingredient (% w/w) mg/tablet (% w/w) mg/tablet
Compound 1 16.93 37.25 16.93 37.25
Microcrystalline cellulose 40.78 89.72 81.57 179.45
(Avicel PH 102)
Starch (Starlac) 40.79 89.73
Magnesium stearate 1 2.2 2.2
Colloidal silicon dioxide 0.5 1.1 0.5
(Aerosil®)
equivalent to 25 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]-lH-indole (free base compound)
Compound 1 16.93 37.25 16.93 37.25
rystalline cellulose 80.57 177.25
(Avicel PH 102)
—-—--
—---I-
“IA'l
—----
—---I1_
equivalent to 25 mg of 1—[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-1—
piperazinyl) methle—lH—indole (free base compound)
Examples 17 to 38:
Compositions of 50 mg dose IR tablets:
(% w/w) mg/tablet (% w/w) let
Microcrystalline cellulose 66.63 166.58
(Avicel PH 102)
—---
AMENDED SHEET
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In reply to Written Opinion of IPEA
—--—_
Colloidal n dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
—----
lcnt to 50 mg of 1—[(2—bromophenyl)sulfonyl]-5—methoxy—3—[(4-methyl—l—
piperazinyl) methyl]— 1 H—indole (free base compound)
—----
Microcrystalline cellulose 69.45 173.63
(Avicel PH 113)
—---I-
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]- 1 H-indole (free base compound)
(% w/w) mg/tablet (% w/w) mg/tablet
nd 1 29.62 74.05
Microcrystalline cellulose 69.45 173.63
(Avicel PH 102)
—--—-
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
equivalent to 50 mg of l-[(2-bromophenyl)su1fonyl]methoxy[(4-methyl-l-
piperazinyl) methyl]-lH-indole (free base nd)
AMENDED SHEET
PCT/IB 2017/056 009 - 2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Compound 1 29.62 74.05
Starch (Starcap 1500) 68.63 171.58 --
Microcrystalline cellulose 69.45 173.63
(Avicel PH 101)
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
—---I11-
equivalent to 50 mg of l-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl-l-
pipcrazinyl) mcthyl]-1H-indolc(free base compound)
—----
—-—-
—--—I-
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
—---m-
lent to 50 mg of 1-[(2-bromophenyl)sulfony1]—5—methoxy—3—[(4-methyl-1—
piperazinyl) j—lH-indole (free base compound)
Compound 1 37.03 74.06 29.62 74.05
-----Microcrystalline cellulose 61.47 122.94
-----Dicalcium phosphate 68.63 171.58
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Colloidal silicon dioxide 0.5 1 0.5 1.25
(Aerosil®)
—--Ifi--Total100 200 250
equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]~1H—indole (free base nd)
(% w/w) mg/tablet (% w/w) mg/tablet
Compound 1 29.62 74.05: 29.62 74.05"
-----Microcrystalline ose 68.63 171.58
—--—-
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
—-—--
equivalcnt to 50 mg of 1-[(2-bromophenyl)sulfonyl]mcthoxy[(4-methyl-lpiperazinyl
) methyl]- 1 H-indole (free base compound)
(% w/w) mg/tablet (% w/w) mg/tablet
nd] 29.62 74.05 29.62 74.05
Starch 66.63 166.58
(Starcap 1500)
Dicalcium ate dihydrate 66.63 166.58 --
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Acrosil®)
# equivalent to 50 mg of l-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]-lH-indole (free base compound)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of d Description filed in
In reply to Written Opinion of IPEA
(% w/w) mg/tablet (% w/w) mg/tablct
nd 1 29.62 74.05 29.62 74.05
Lactose Monohydrate 66.63 166.58 --
Microcrystalline cellulose 66.63 166.58
(Avicel 101)
Colloidal silicon dioxide 0.5 1.25 0.5 1.25
(Aerosil®)
# equivalent to 50 mg of 1-[(2-bromopheny])sulfonyl]methoxy[(4-methyl
piperazinyl) methyIJ-IH-indole (free base compound)
(% w/w) mg/tablet (% w/w) let
Compound 1 24.83 33.86
Microcrystalline ose 71.67 215 62.64 137.8
(Avicel PH 102)
Colloidal silicon dioxide 0.5 1.5 0.5 1.1
(Aerosil®)
—---_
# equivalent to 50 mg of 1-[(2-bromopheny1)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]~1H—indole (free base compound)
(% w/w) mg/tablet (% w/w) mg/tablet
Microcrystalline cellulose 84.15 504.9 49.83 70.24
(Avicel PH 102)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of d Description filed in
In reply to Written Opinion of IPEA
—-__-
Colloidal silicon dioxide 0.5 3 0.5 0.75
(Aerosil®)
—-—E1
equivalent to 50 mg of 1-[(2-bromophenyl)sulfonyl]—5—methoxy—3-[(4-mcthy1—l—
zinyl) methyl]~1H—indole (free base compound)
Example 39 to 43:
Composition of 75 mg dose IR tablets:
(% w/w) mg/tablet (% w/w) mg/tablct
Compoundl 37.25 111.75 50.79 111.74
Microcrystallinecellulose 59.25 177.75 45.71 100.56
(Avicel PH 102)
_--I--
Colloidal silicon dioxide 0.5 1.5 0.5
(Aerosil®)
—--—_
—---I1_
equivalent to 75 mg of bromophenyl)sulfonyl]methoxy[(4-mcthyl
piperazinyl) methyl]- 1 H-indolc (free base compound)
(% w/w) mg/tablet (% w/w) mg/tablet
Compoundl 111.76 111.76
Microcrystalline cellulose 46.7 102.74 47.7 104.94
(Aviccl PH 102)
Colloidal n dioxide 0.5 1.1 0.5 1.1
(Aerosil®)
—--——
equivalent to 75 mg of 1-[(2-bromopheny])sulfonylJmethoxy[(4-methy1
pipcrazinyl) methyl]-1H-indolc(frec base compound)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Colloidal silicon dioxide 0.5 1.1
(Acrosil®)
equivalent to 75 mg of bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]- lH-indolc (free base compound)
Examples 44 to 50:
Composition of 100 mg dose IR tablets:
(% w/w) mg/tablct (% w/w) mg/tablct
Compound 1 49.36 148.08 49.37 148.1 1
Microcrystalline cellulose 49.14 147.42 49.13 147.39
(Avicel PH 102)
dal n dioxide 0.5 1.5 0.5 1.5
(Acrosil®)
—---n1-
equivalent to 100 mg of bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]-1H-indole (free base compound)
(% w/w) mg/tablct (% w/w) mg/tablct
Compound 1 59.24 148.1’ 37.03 148.12
Microcrystalline cellulose 39.26 98.15 61.47 245.88
(Avicel PH 102)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of d Description filed in
In reply to Written Opinion of IPEA
_---—
—---m-
equivalent to 100 mg of l-[(2-bromophenyl)sulfonyl]~5-methoxy-3—[(4-methyl
piperazinyl) methyl]-1H-indole (free base compound)
(% w/w) lct (% w/w) mg/tablct
Compound 1 49.67 149.01
Microcrystalline cellulose 47.33 141.99 36.9 92.25
(Avicel PH 102)
—-—-I-
Colloidal silicon dioxide 0.5 1.5 0.5 1.25
(Acrosil®)
equivalent to 100 mg of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyl]-lH-indole (free base compound)
Compound 1 148.2
Microcrystalline cellulose 71.8 430.8
(Avicel PH 102)
Magnesium stearate
Colloidal silicon dioxide 0.5
(Aerosil®)
vidone
Total 100
equivalent to 100 mg of 1-[(2—bromophenyl)sulfonyl]methoxy[(4—mcthyl
zinyl) methyIJ-lH-indolc (free base compound)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to Written n of IPEA
Examples 51-52:
Composition of 150 mg and 200 mg dose IR tablets:
Compound 1 49.67 223.52 49.67 298.02
Microcrystalline cellulose 46.83 210.73 46.83 280.98
(Avicel PH 102)
Colloidal silicon dioxide 0.5 2.25 0.5 3
(Aerosil®)
—---_
—-Ifi-E_
equivalent to 150 mg of bromophenyl)sulfonylj-S-methoxy[(4-methyl
pipcrazinyl) methyl]- 1 H-indole (free base compound)
# equivalent
to 200 mg of bromophcnyl)sulfonyl]methoxy[(4-methyl
piperazinyl) methyIJ-lH-indole (free base compound)
Example 53:
Preparation of IR tablet using wet granulation method
Composition of 50 mg IR tablet:
mg/tablet
Compound 1 24.67
rystalline cellulose 200.5
66 83
(Avicel PH 102) ' ”
dal silicon dioxide 1.5
(Aerosil®) 0 5‘
#equivalcnt to 50 mg of 1-[(2-bromophenyl)sulfonyl]—5—methoxy-3—[(4-methyl—1—
piperazinyl) methyll-lH-indole (free base compound)
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean copy of Amended Description filed in
In reply to n Opinion of IPEA
Method of preparing IR tablet:
All the ingredients were accurately weighed (Compound 1 of 24.67%, Avicel PH 102
of 66.83% and crospovidone of 3%) and sieved using sieve number 40. The sieved
compound 1. Avicel PH 102 and crospovidone were blended for 10 minutes in an octagonal
blender. The mixture obtained was transferred into RMG and added povidone binder
solution (povidone (4 %) was dissolved in purified water) dropwise to RMG to form
cohesive mass. The blend obtained was dried in a tray drier at 50 °C. Dried blend was passed
through # 18 mesh to form granules. The granules obtained were mixed with magnesium
stearate and l and the mixture was blended for 10 minutes in an octagonal blender. The
lubricated blend was compressed using 9 mm round concave s and dies on rotary
ssion e to obtain 300 mg tablet.
Examples 54-55:
The following examples are prepared by following the method of preparation of
example 53.
ition of 50 mg IR tablets:
Compound 1 24.67 24.67
Microcrystalline cellulose
65.83 197.5 64.83 194.5
(Avicel PH 102)
Povidone
4.0 12
(PVP K30)
—---
—----
—--_-
—--_j_5
equivalent to 50mg of 1—[(2——bromophenyl)sulfonyl]——5-m-e-thoxy--3 thyl- 1—
piperazinyl) methyl]- 1 H—indole (free Base compound)
AMENDED SHEET
PCT/IB 2017/056 009 - 2018
SUV-PCT0764 Clean copy of Amended ption filed in
In reply to Written Opinion of IPEA
Example 56:
Dissolution studies of IR tablets
The dissolution studies were ted for the immediate release tablets of the
instant invention to demonstrate the % release of active ingredient at different time intervals.
Protocol:
Dissolution was carried out in accordance with the United States pharmacopeia
general procedures using dissolution apparatus 11 (paddle method). The IR tablet was placed
in 900 mL of simulated gastric fluid (pH 1.2), 0.1N hydrochloric acid or water at 37 °C with
a paddle speed of 50 rpm/ 100 rpm and measuring the amount of active ingredient dissolved
(especially. using UV at 255 nm or using HPLC, ngth 220 nm) at 15 and 30 minutes.
Results:
The ution studies data of the IR tablets are tabulated below.
% of % of
Time Active Time Active
Examples 8' No Examples
(minutes) ingredient (minutes) ient
release release
Example 2 Example 25
--—-m_p‘
Example 26
—-m_
--_—--—-i_- ~ —-m-
E 112—_24“mpe E 133——WP —-m-
. —m_
Examp'e”
Em EBP
_-i_
26 Exam 1638P '
~ 28 -—-m_
—-m_
n-—-m_ Example42 —-m_—-m-
E ,17--30"ampe —-m- E. .43_-m_“m“ _-m_
=E 11831Xamt’e —m_ E 147——“mp6
E 119mp _“32 E 148——”m“
—-m-
Examp‘e” —-m
Examplezo
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean co of Amended Descri tion filed in
In re 1 to n 0 inion of IPEA
% of % of
Time Active Time Active
Examples‘ Examples
es) ingredient (minutes) ingredient
release release
-—_—-——_
I Exampne21--- Examp'e”_“_— —m-15
33 _— Examplefl
EXflmPle 22__
I 15
3—m- Example 54
W23 '
'3- 35_-‘5.m-
Example 24 105
Example 57:
Stability study of IR tablets
The stability study was conducted to assess the stability of the immediate release
tablets and the impurity profile of the instant invention under different storage conditions.
The ity studies were carried out at ambient temperature. 40 °C / 75 % RH and
60 °C oven for 6 months.
Protocol:
The immediate release s are packed in HDPE bottles with hylene liners
with desiccant for a period of 6 months at different storage conditions. The samples were
analyzed for purity using HPLC.
Results:
ution:
The dissolution data of examples for different time points at accelerated storage
conditions are tabulated below.
' % of Active ingredient release
S. No Examples .
-—----m
-—--“n
—m-n-
-—--“n
[mm-m
Elm-film“
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
SUV-PCT0764 Clean co of Amended Descri tion filed in
In re 1 to Written 0 inion of IPEA
Conclusion:
We observed no significant variation in dissolution of the IR tablets after storing for
6 months at accelerated storage conditions (Le, temperature 40 i 2 °C at 75 i 5 % relative
humidity (RH)).
Purity:
The purity of IR tablet on day 1 is ted below.
l2”S. No Example '
. Chloro Maximum Other Total
impurity unknown unknown impurities
impurity impurities (%)
The purity of IR tablets under different storage conditions at the end of 6 months is
tabulated below.
Maximum
Other Total
e ‘
.‘ e n
im Untlesp lm
number impurity PUritles conditions
(’0o ()%
In...“-°C 99.38 0.21 0.32 062
IHI40 °C / 75 99.63
% R. I““--
flfl-3 20 75 40 °C / 75 99.64 0.36
III-II-I-4 22 75 60 °C 99.37 0.20 0.08 0.35 0.63
I-I5 22 75 40 °C / 75 99.62 0.20 0.12 0.38
% .. II“.-
Conclusion:
We observed no significant variation in purity of the active ingredient under different
storage conditions. As evident from the above stability data the active ingredient in
immediate release s of instant invention is stable at least six months under accelerated
storage condition.
AMENDED SHEET
PCT/IB 2017/056 009 - 30.10.2018
T0764 Clean copy of Amended Description filed in
In reply to Written Opinion of IPEA
Example 58:
In-vivo pharmacokinetic study of IR tablets
The dog pharmacokinetic study is ted to confirm the dissolution data of
Compound 1.
Experimental procedure of dog pharmacokinetic study
Male beagle dogs (10 i 2 kg) were used as experimental animals. Each dog was
housed in individual cages. Animals were fasted over night before oral dosing (p.0) and food
s were allowed 2 hours post dosing. Two beagle dogs (~11 mg/kg) were dosed orally
with IR tablets prepared by pharmaceutical compositions disclosed in Example 48.
At each time point, blood (0.5 mL) was collected through cephalic vein. Collected
blood was transferred into a labeled eppendroff tube containing 10 “L of heparin as
anticoagulant. Typically blood samples were collected at following time : Pre dose,
0.25, 0.5, 1, 1.5, 2, 3. 5. 7. 12, 24, 30 and 48 hours post dose (n=2). Blood was centrifuged
at 4000 rpm for 10 minutes. Plasma was separated and stored at -20 °C until is. The
concentrations of active ingredient were fied in plasma by validated LC-MS/MS
method using suitable extraction technique. The active ingredient was quantified in the
calibration range around 0.2-200 ng/mL.
Pharmacokinetic parameters Cum, Tmax, AUCm and Tm were calculated by using
standard non-compartmental model Phoenix WinNonlin 6.2 version Software package.
The results of this study are tabulated below.
Strain/ Dose Dosage form Cmax Tum AUCO. Tm
Gender (mg/kg) (ng/mL) (hours) (ng.hour/mL) )
Beagle
Tablet 60 i 16 12510.35 251 i 27 5.97i0.40
AMENDED SHEET
238864NZPR
104785980
Claims (12)
1. An immediate release ceutical composition on a total of 100% by weight comprising: a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- 5 methylpiperazinyl) methyl]-1H-indole or a pharmaceutically acceptable salt thereof; b) from about 36 % to about 97 % diluent or total of two diluents; wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose drate, c calcium phosphate, lactose, lactose hydrate, lactose anhydrate, 10 mannitol, starch and isomalt; c) from about 0.5 % to about 2 % lubricant; wherein the lubricant is magnesium stearate; d) from about 0.5 % to about 1 % glidant; n the glidant is colloidal silicon dioxide; e) 0 % to about 10 % binder; wherein the binder is selected from group 15 consisting of povidone or hydroxypropyl methylcellulose; f) 0 % to about 5 % disintegrant; wherein the disintegrant is selected from crospovidone, sodium starch glycolate and croscarmellose sodium; and g) 0 % to about 2 % acidifying agent; n the acidifying agent is citric acid. 20
2. The immediate release pharmaceutical ition as claimed in claim 1, wherein said ition comprises on a total of 100 % by weight: (a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- methylpiperazinyl) methyl]-1H-indole dimesylate monohydrate; (b) from about 36 % to about 97 % of one diluent or total of two ts; where in 25 the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, lactose, lactose hydrate, lactose anhydrate, ol, starch and isomalt; (c) from about 0.5 % to about 2 % lubricant; wherein the ant is magnesium stearate; 30 (d) from about 0.5 % to about 1 % glidant; wherein the glidant is colloidal silicon dioxide; (e) 0 % to about 10 % ; where in the binder is selected from group consisting of povidone or hydroxypropyl methylcellulose; 238864NZPR 104785980 (f) 0 % to about 5 % disintegrant; wherein the disintegrant is selected from crospovidone, sodium starch glycolate and croscarmellose sodium and (g) 0 % to about 2 % acidifying agent; wherein the acidifying agent is citric acid. 5
3. The immediate e pharmaceutical compositions as claimed in claim 1 or claim 2, wherein the composition on a total of 100 % by weight is ed from the group consisting of: 1) (a) from about 2 % to about 3 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl- 1-piperazinyl) methyl]-1H-indole dimesylate drate, (b) from about 95 % to about 10 97 % diluent, (c) about 1 % lubricant and (d) about 0.5 % glidant; 2) (a) from about 11 % to about 38 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl- 1-piperazinyl) methyl]-1H-indole dimesylate monohydrate, (b) from about 61 % to about 87 % of one diluent or total of two diluents, (c) about 1% lubricant, (d) about 0.5 % glidant, (e) about 2 % disintegrant and (f) about 1 % acidifying agent; 15 3) (a) from about 24 % to about 38 % bromophenyl)sulfonyl]methoxy[(4-methyl- 1-piperazinyl) ]-1H-indole dimesylate monohydrate (b) from about 61 % to about 72 % one diluent or total of two ts, (c) from about 1 % to about 1.25 % lubricant, (d) about 0.5 % glidant and (e) about 2 % disintegrant; 4) (a) from about 37 % to about 51 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- 20 methylpiperazinyl) methyl]-1H-indole dimesylate monohydrate, (b) from about 45 % to about 60 % diluent, (c) about 1 % lubricant, (d) about 0.5 % glidant, (e) about 2 % of disintegrant and (f) about 1 % acidifying agent; 5) (a) from about 36 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- methylpiperazinyl) methyl]-1H-indole late monohydrate, (b) from about 36 % 25 to about 62 % t, (c) from about 0.5 % to about 1 % lubricant, (d) about 0.5 % glidant and (e) about 2 % disintegrant; and 6) (a) from about 11 % to about 38 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- methylpiperazinyl) methyl]-1H-indole dimesylate monohydrate; (b) from about 61 % to about 72 % diluent; (c) from about 2 % to about 5 % binder; (d) about 1 % lubricant; 30 (d) about 0.5 % glidant and e) from about 2 % to about 4 % disintegrant.
4. The immediate release pharmaceutical composition as claimed in any one of the claims 1 to 3, wherein the dosage of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl 238864NZPR 104841967 piperazinyl)methyl]-1H-indole or a pharmaceutically acceptable salt thereof is about 5 mg to about 200 mg.
5. The immediate release pharmaceutical composition as claimed in any one of the claims 1 5 to 4, wherein the ition is in the form of tablet or capsule.
6. The immediate release ceutical composition as claimed in any one of the claims 1 to 3, wherein the composition has: i) less than 0.5 % of chloro impurity; 10 ii) less than 0.5 % of unknown impurity; iii) less than 1 % of total impurity.
7. The immediate e pharmaceutical composition as claimed in any one of the claims 1 to 3, wherein the purity of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl 15 piperazinyl) methyl]-1H-indole dimesylate monohydrate is about 99.3 %.
8. The immediate release pharmaceutical composition as claimed in any one of the claims 1 to 3, wherein the composition has: i) about 99.3 % purity of 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methyl 20 zinyl) methyl]-1H-indole dimesylate drate; ii) less than 0.5 % of chloro impurity; iii) less than 0.5 % of unknown impurity; iv) less than 1 % of total impurity. 25
9. The immediate release pharmaceutical composition as claimed in any one of the claims 1 to 3, wherein the 1-[(2-bromophenyl)sulfonyl]methoxy[(4-methylpiperazinyl) ]-1H-indole dimesylate monohydrate is released about 85 % to about 100 % within 30 minutes when tested with the ng paddle at 100 rpm with 900 mL of dissolution media, 01N hydrochloric acid or water at 37°C.
10. The immediate release pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of a tablet and said composition on a total of 100% by weight comprises: 238864NZPR (a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(4- piperazinyl) methyl]-1H-indole dimesylate monohydrate; (b) from about 36 % to about 97 % of one diluent or total of two diluents; where in the t is selected from the group consisting of microcrystalline cellulose, lactose 5 monohydrate, dibasic calcium phosphate, lactose, lactose hydrate, lactose anhydrate, ol, starch and isomalt; (c) from about 0.5 % to about 2 % lubricant; n the lubricant is magnesium stearate; (d) from about 0.5 % to about 1 % glidant; wherein the glidant is colloidal silicon 10 dioxide; (e) 0 % to about 10 % binder; where in the binder is selected from group consisting of povidone or hydroxypropyl methylcellulose; (f) 0 % to about 5 % disintegrant; wherein the disintegrant is selected from crospovidone, sodium starch glycolate and croscarmellose sodium; and 15 (g) 0 % to about 2 % acidifying agent; wherein the acidifying agent is citric acid.
11. The immediate release tablet composition as claimed in claim 10, wherein the composition on a total of 100% by weight comprises: (a) from about 2 % to about 60 % 1-[(2-bromophenyl)sulfonyl]methoxy[(41-piperazinyl) methyl]-1H-indole dimesylate monohydrate; (b) from about 36 % to about 97 % of microcrystalline ose; (c) from about 0.5 % to about 2 % magnesium stearate; (d) from about 0.5 % to about 1 % colloidal silicon dioxide; (e) 0 % to about 5 % ne; 25 (f) 0 % to about 4 % crospovidone; and (g) 0 % to about 2 % citric acid.
12. The immediate release tablet composition as claimed in claim 10 or claim 11, wherein the total weight of immediate release tablet is from about 100 mg to 600 mg.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201641033741 | 2016-10-03 | ||
| IN201641033741 | 2016-10-03 | ||
| PCT/IB2017/056009 WO2018065869A1 (en) | 2016-10-03 | 2017-09-29 | Pharmaceutical compositions of 5-ht6 antagonist |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ752060A NZ752060A (en) | 2020-09-25 |
| NZ752060B2 true NZ752060B2 (en) | 2021-01-06 |
Family
ID=
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