CN117752819A - Sand-fenamide mesylate composition and preparation method and application thereof - Google Patents
Sand-fenamide mesylate composition and preparation method and application thereof Download PDFInfo
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- CN117752819A CN117752819A CN202311778204.3A CN202311778204A CN117752819A CN 117752819 A CN117752819 A CN 117752819A CN 202311778204 A CN202311778204 A CN 202311778204A CN 117752819 A CN117752819 A CN 117752819A
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 239000000203 mixture Substances 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000000314 lubricant Substances 0.000 claims abstract description 17
- 239000000945 filler Substances 0.000 claims abstract description 16
- -1 mesylate amide Chemical class 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 claims abstract description 14
- 229950002652 safinamide Drugs 0.000 claims abstract description 14
- 239000004576 sand Substances 0.000 claims abstract description 13
- 239000000796 flavoring agent Substances 0.000 claims abstract description 12
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 9
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 9
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 9
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 9
- 229960004853 betadex Drugs 0.000 claims abstract description 9
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 230000001070 adhesive effect Effects 0.000 claims abstract description 8
- 239000008187 granular material Substances 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 26
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 25
- 238000007873 sieving Methods 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 15
- 239000002775 capsule Substances 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
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- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000004537 pulping Methods 0.000 claims description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000005550 wet granulation Methods 0.000 claims description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011248 coating agent Substances 0.000 claims description 5
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- 239000003814 drug Substances 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000811 xylitol Substances 0.000 claims description 3
- 235000010447 xylitol Nutrition 0.000 claims description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 3
- 229960002675 xylitol Drugs 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 210000000214 mouth Anatomy 0.000 abstract description 4
- 210000004400 mucous membrane Anatomy 0.000 abstract description 4
- 230000007794 irritation Effects 0.000 abstract description 3
- 210000003928 nasal cavity Anatomy 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 6
- 102000010909 Monoamine Oxidase Human genes 0.000 description 4
- 108010062431 Monoamine oxidase Proteins 0.000 description 4
- 238000007599 discharging Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002492 water-soluble polymer binding agent Substances 0.000 description 1
Abstract
The invention provides a sand fenamide mesylate composition, a preparation method and application thereof, and relates to the technical field of pharmaceutical preparations. The invention provides a shafen mesylate amide composition, which comprises 11-40 parts of shafen mesylate amide (10 parts of shafen mesylate amide, 1-30 parts of inclusion compound), 5-30 parts of filler, 0.5-10 parts of disintegrating agent, 0.1-5 parts of adhesive, 0.1-5 parts of glidant, 0.1-5 parts of lubricant and 0-1 part of flavoring agent; the inclusion of the sand fenamide mesylate comprises; the inclusion compound comprises beta-cyclodextrin. In the shafen mesylate composition provided by the invention, the shafen mesylate is included in the inclusion compound, has no irritation to the oral cavity, mucous membrane and nasal cavity, has good taste, is suitable for different people to take, is convenient to swallow, and obviously improves the compliance of patients to take. Furthermore, the safinamide mesylate composition provided by the invention has excellent stability and is convenient to carry and store.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a sand fenamide mesylate composition, a preparation method and application thereof.
Background
The methanesulfonic acid sand fenamide (safinamide mesilate) is a parkinsonism treatment drug which is a third generation monoamine oxidase B (MAO-B) inhibitor, has the characteristics of high efficiency, reversibility and strong specificity, has an action mechanism of inhibiting MAO-B (type B monoamine oxidase), has the additional function of inhibiting glutamic acid release, has high tolerance, has small adverse reaction, has the characteristics of neuroprotection and the like.
Chinese patent CN104546747a discloses a pharmaceutical composition containing salfenamide mesylate, which comprises salfenamide mesylate, a water-soluble excipient, a water-soluble polymer binder, a disintegrating agent and a lubricant, wherein the solid pharmaceutical dosage forms comprise a common tablet, an orally disintegrating tablet, a dispersible tablet, a coated tablet, a capsule and a granule. However, the above pharmaceutical composition containing the salfenamide mesylate has a strong irritation to the oral cavity and mucous membrane because the raw material of the salfenamide mesylate is not coated.
Disclosure of Invention
In view of the above, the present invention aims to provide a safinamide mesylate composition and a preparation method thereof. The present invention provides a safinamide mesylate composition that is non-irritating to the oral cavity and mucous membranes.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a sand-fenamide mesylate composition which comprises the following components in parts by mass: 11-40 parts of inclusion methanesulfonic acid sand fenamide, 5-30 parts of filler, 0.5-10 parts of disintegrating agent, 0.1-5 parts of adhesive, 0.1-5 parts of glidant, 0.1-5 parts of lubricant and 0-1 part of flavoring agent;
the inclusion compound comprises 10 parts of the shafen mesylate amide and 1-30 parts of the inclusion compound; the inclusion compound comprises beta-cyclodextrin.
Preferably, the filler comprises one or more of mannitol, xylitol, corn starch, microcrystalline cellulose, lactose and sucrose.
Preferably, the disintegrating agent comprises one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low substituted hydroxypropyl cellulose.
Preferably, the glidant comprises one or more of colloidal silicon dioxide, silicon dioxide powder and talcum powder.
Preferably, the lubricant comprises one or more of stearic acid, magnesium stearate and sodium hard fumarate.
Preferably, the formulation of the sandfenamide mesylate composition comprises a tablet, a granule or a capsule.
The invention provides a preparation method of the sandifenamide mesylate composition in the technical scheme, which comprises the following steps:
granulating and sieving the methanesulfonic acid salfenamide and the inclusion compound to obtain inclusion methanesulfonic acid salfenamide;
premixing inclusion methanesulfonic acid sand-fenamide, a filler and a disintegrating agent, adding an aqueous solution of a binding agent for pulping, granulating, wet finishing and sieving to obtain mixture wet granules;
drying the mixture wet particles, and then drying, granulating and sieving to obtain mixture dry particles;
the wet mixture particles are mixed with glidants, lubricants and flavoring agents to obtain the shafen mesylate amide composition.
Preferably, the mass content of the aqueous binder solution is 1-15%;
the conditions of the granulating and sieving include: the rotating speed is 100-1000 rpm, and the aperture of the screen is 0.5mm;
the speed of the premixing is 150-450 rpm, and the time is 5-15 min;
the slurry adding is carried out under the stirring condition, the stirring speed is 100-450 rpm, and the slurry adding time is 30-300 s;
the aperture of the screen mesh with the size of the screen mesh for wet granulation and sieving is 2-4 mm;
the granulating conditions include: the stirring speed is 100-450 rpm, the rotating speed of the cutter is 1000-2500 rpm, and the time is 30-180 s;
the temperature of the dried air inlet is 40-75 ℃, the temperature of the dried material is 40-50 ℃, and the water content of the dry particles of the mixture is 0.5-5%;
the conditions of the dry granulation and sieving include: the rotating speed is 100-1000 rpm, and the aperture of the screen is 0.5-2 mm.
Preferably, the preparation method further comprises: tabletting the mixture obtained by the total mixing to obtain tablets of the sandifenamide mesylate composition;
or coating the mixture obtained by the total mixing by using a capsule material to obtain the capsule of the sandifenamide mesylate composition.
The invention also provides the application of the salfenamide mesylate composition in preparing the medicine for treating the Parkinson's disease.
The invention provides a sand-fenamide mesylate composition which comprises the following components in parts by mass: 11-40 parts of inclusion methanesulfonic acid sand fenamide, 5-30 parts of filler, 0.5-10 parts of disintegrating agent, 0.1-5 parts of adhesive, 0.1-5 parts of glidant, 0.1-5 parts of lubricant and 0-1 part of flavoring agent; the inclusion compound comprises 10 parts of the shafen mesylate amide and 1-30 parts of the inclusion compound; the inclusion compound comprises beta-cyclodextrin. In the shafen mesylate composition provided by the invention, the shafen mesylate is included in the inclusion compound, so that the shafen mesylate has no irritation to the oral cavity, mucous membrane and nasal cavity, has good taste, is suitable for different people to take, is convenient to swallow, and obviously improves the compliance of patients to take medicines. In addition, the raw material of the shafen mesylate has poor fluidity, and the shafen mesylate amide composition provided by the invention can improve the fluidity of the raw material of the shafen mesylate, so that the shafen mesylate is convenient to prepare into a uniform preparation; the safinamide mesylate composition provided by the invention also has excellent stability, and is convenient to carry and store.
The invention provides a preparation method of the sandifenamide mesylate composition. The preparation method provided by the invention comprises the steps of mixing, granulating, drying and finishing, does not need coating operation, has simple process, low preparation cost and is suitable for industrial production.
Detailed Description
The invention provides a sand-fenamide mesylate composition which comprises the following components in parts by mass: 11-40 parts of inclusion methanesulfonic acid sand fenamide, 5-30 parts of filler, 0.5-10 parts of disintegrating agent, 0.1-5 parts of adhesive, 0.1-5 parts of glidant, 0.1-5 parts of lubricant and 0-1 part of flavoring agent;
the inclusion compound comprises 10 parts of the shafen mesylate amide and 1-30 parts of the inclusion compound; the inclusion compound comprises beta-cyclodextrin.
In the present invention, materials and equipment used are commercially available in the art unless otherwise specified.
The invention provides a safinamide mesylate composition which comprises 10 parts of safinamide mesylate by mass.
The shafen mesylate amide composition provided by the invention comprises 1-30 parts, preferably 5-25 parts, more preferably 10-20 parts, particularly preferably 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts or 30 parts of inclusion compound by mass. In the present invention, the inclusion compound includes beta-cyclodextrin.
The composition comprises, by mass, 5-30 parts of filler, preferably 10-25 parts, more preferably 15-20 parts, and particularly preferably 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts or 30 parts. In the present invention, the filler preferably includes one or more of mannitol, xylitol, corn starch, microcrystalline cellulose, lactose and sucrose.
The composition comprises 0.5-10 parts, preferably 1-9 parts, more preferably 2-8 parts, particularly preferably 0.5 part, 1 part, 1.5 part, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts, 5 parts, 5.5 parts, 6 parts, 6.5 parts, 7 parts, 7.5 parts, 8 parts, 8.5 parts, 9 parts, 9.5 parts or 10 parts of disintegrating agent by mass part. In the present invention, the disintegrant preferably includes one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low substituted hydroxypropylcellulose.
The composition of the present invention comprises 0.1 to 5 parts, preferably 1 to 4 parts, more preferably 2 to 3 parts, particularly preferably 0.1 part, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts or 5 parts of the binder, based on the parts by mass of the shafen mesylate. In the present invention, the binder preferably includes one or more of povidone, hydroxypropyl cellulose, and hypromellose.
The composition comprises 0.1-5 parts, preferably 1-4 parts, more preferably 2-3 parts, particularly preferably 0.1 part, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts or 5 parts of glidant by mass part of the shafen mesylate. In the present invention, the glidant preferably includes one or more of colloidal silicon dioxide, silicon dioxide powder and talcum powder.
The shafen mesylate amide composition provided by the invention comprises 0.1-5 parts, preferably 1-4 parts, more preferably 2-3 parts, particularly preferably 0.1 part, 0.5 part, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, 4 parts, 4.5 parts or 5 parts of lubricant by mass part. In the present invention, the lubricant preferably includes one or more of stearic acid, magnesium stearate and sodium hard fumarate.
The shafen mesylate amide composition provided by the invention comprises 0-1 part, preferably 0.1-0.9 part, more preferably 0.2-0.8 part, particularly preferably 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part or 1 part of a flavoring agent based on the mass parts of the shafen mesylate amide. The flavoring agent is not particularly limited, and a pharmaceutically acceptable flavoring agent known to those skilled in the art may be used.
In the present invention, the formulation of the shafen mesylate composition preferably comprises a tablet, a granule or a capsule.
The invention provides a preparation method of the sandifenamide mesylate composition in the technical scheme, which comprises the following steps:
granulating and sieving the methanesulfonic acid salfenamide and the inclusion compound to obtain inclusion methanesulfonic acid salfenamide;
premixing inclusion methanesulfonic acid sand-fenamide, a filler and a disintegrating agent, adding an aqueous solution of a binding agent for pulping, granulating, wet finishing and sieving to obtain mixture wet granules;
drying the mixture wet particles, and then drying, granulating and sieving to obtain mixture dry particles;
the wet mixture particles are mixed with glidants, lubricants and flavoring agents to obtain the shafen mesylate amide composition.
The invention carries out granule finishing and sieving on the methanesulfonic acid salfenamide and the inclusion compound to obtain the inclusion methanesulfonic acid salfenamide.
In the invention, the conditions of the granule finishing and sieving include: the rotation speed is preferably 100 to 1000rpm, more preferably 200 to 800rpm, still more preferably 300 to 500rpm; the mesh size is preferably 0.5mm and the undersize fraction is taken for use.
After the inclusion shafen mesylate is obtained, premixing the inclusion shafen mesylate, a filler and a disintegrating agent, adding an aqueous solution of a binding agent for pulping, granulating, wet granulating, and sieving to obtain mixture wet granules.
In the present invention, the rotational speed of the premixing is preferably 150 to 450rpm, more preferably 200 to 400rpm, still more preferably 250 to 300rpm; the premixing time is preferably 5 to 15 minutes, more preferably 8 to 12 minutes, and still more preferably 10 minutes.
In the present invention, the mass content of the aqueous binder solution is preferably 1 to 15%, more preferably 5 to 12%, and even more preferably 8 to 10%.
In the present invention, the sizing is preferably performed under stirring conditions, and the stirring speed is preferably 100 to 450rpm, more preferably 200 to 400rpm, and still more preferably 250 to 300rpm; the time for the sizing is preferably 30 to 300 seconds, more preferably 50 to 250 seconds, and still more preferably 100 to 200 seconds.
In the present invention, the granulating conditions include: the stirring speed is preferably 100 to 450rpm, more preferably 200 to 400rpm, still more preferably 250 to 300rpm; the cutter rotation speed is preferably 1000 to 2500rpm, more preferably 1500 to 2200rpm, still more preferably 1800 to 2000rpm; the time is preferably 30 to 180 seconds, more preferably 50 to 150 seconds, and still more preferably 100 seconds. In the present invention, the premixing and granulating are preferably performed in a wet granulation kettle.
In the present invention, the wet-granulation sieved mesh size is preferably 2 to 4mm, more preferably 2.5 to 3.5mm, still more preferably 3mm in mesh size, and the undersize fraction is taken out for use.
After the mixture wet particles are obtained, the mixture wet particles are dried, granulated and sieved to obtain the mixture dry particles.
In the invention, the inlet air temperature for drying is preferably 40-75 ℃, more preferably 45-70 ℃, further preferably 50-70 ℃, and most preferably 60 ℃; the temperature of the dried material (i.e., the dry particles of the mixture) is preferably 40 to 50 ℃, more preferably 42 to 48 ℃, still more preferably 45 to 46 ℃; the drying time is not particularly limited, and the drying may be carried out until the water content of the dry mixture particles is 0.5 to 5%, and the water content of the dry mixture particles is more preferably 1 to 4%, and still more preferably 2 to 3%. In the present invention, the drying is preferably performed in a fluidized bed.
In the present invention, the conditions of the dry granulation and sieving include: the rotation speed is preferably 100 to 1000rpm, more preferably 200 to 800rpm, still more preferably 300 to 500rpm; the mesh size is preferably 0.5 to 2mm, more preferably 1 to 1.5mm, and the undersize fraction is taken for use.
In the present invention, D of the mixture dry particles 90 Preferably 50 to 1000. Mu.m, more preferably 200 to 800. Mu.m, still more preferably 400 to 500. Mu.m.
After the dry mixture particles are obtained, the wet mixture particles are mixed with a glidant, a lubricant and a flavoring agent in total to obtain the sand-fenamide mesylate composition (granules).
In the present invention, the rotational speed of the total mixture is preferably 5 to 20rpm, more preferably 5 to 15rpm, still more preferably 10rpm; the total mixing time is preferably 5 to 30 minutes, more preferably 5 to 15 minutes, and still more preferably 10 minutes.
In the present invention, the preparation method preferably further comprises: tabletting the mixture obtained by the total mixing to obtain tablets of the sandifenamide mesylate composition. The present invention is not particularly limited to the above-mentioned tabletting, and tabletting conditions well known to those skilled in the art may be employed.
In the present invention, the preparation method preferably further comprises: and coating the mixture obtained by the total mixing by using a capsule material to obtain the capsule of the safinamide mesylate composition. The capsule material and coating of the present invention are not particularly limited, and the preparation conditions of the capsule, which are well known to those skilled in the art, may be employed.
The invention also provides the application of the salfenamide mesylate composition in preparing the medicine for treating the Parkinson's disease.
For further explanation of the present invention, the following describes the safinamide mesylate composition and the process for preparing it in detail with reference to the examples, but they should not be construed as limiting the scope of the invention.
Example 1
The raw materials for the preparation of the shafen mesylate composition are shown in table 1.
Table 1 raw materials for preparing the shafen mesylate composition
The preparation method of the methanesulfonic acid safinamide composition comprises the following steps:
1) Sieving the methanesulfonic acid sand-fenamide and beta-cyclodextrin together, and finishing the granules by a screen with the diameter of 1.5mm at the rotating speed of 300rpm;
2) Adding the inclusion methanesulfonic acid sand fenamide, the filler and the disintegrating agent prepared in the step 1) into a wet granulation pot, and premixing for 5min under the condition of 400 rpm;
3) Setting the stirring speed to be 150rpm, adding the aqueous solution of the adhesive into a granulating pan, and finishing pulping within 240 seconds;
4) Setting stirring speed to be 400rpm and cutter speed to be 2000rpm after the slurry adding is completed, and continuously granulating for 90s in a granulating pot;
5) Discharging, namely sieving wet particles with a 3X 3mm screen to obtain granules;
6) Drying the wet particles to water of 2.0wt% by adopting a fluidized bed, wherein the temperature of the drying inlet air is 65 ℃, and the temperature of the material is 45 ℃;
7) Drying and granulating the dried granules by a 0.5mm screen;
8) Adding the flow aid and the lubricant in the prescription amount for total mixing, wherein the mixing speed is 10rpm, and the mixing time is 10min;
9) And (5) sub-packaging the total mixed granules into granules for granulation.
Example 2
The raw materials for the preparation of the shafen mesylate composition are shown in table 2.
TABLE 2 preparation of the compositions of salfenamide mesylate
The preparation method of the methanesulfonic acid safinamide composition comprises the following steps:
1) Sieving the methanesulfonic acid sand-fenamide and beta-cyclodextrin together, and finishing the granules by a screen with the diameter of 1.5mm at the rotating speed of 300rpm;
2) Adding the inclusion methanesulfonic acid sand fenamide, the filler and the disintegrating agent prepared in the step 1) into a wet granulation pot, and premixing for 5min under the condition of 400 rpm;
3) Setting the stirring speed to be 250rpm, adding the aqueous solution of the adhesive into a granulating pan, and finishing pulping within 300 seconds;
4) Setting the stirring speed to be 450rpm and the cutter speed to be 2000rpm after the slurry adding is completed, and continuously granulating for 90 seconds in a granulating pot;
5) Discharging, namely sieving wet particles with a 3X 3mm screen to obtain granules;
6) Drying the wet particles to water of 2.0wt% by adopting a fluidized bed, wherein the temperature of the drying inlet air is 65 ℃, and the temperature of the material is 45 ℃;
7) Drying and granulating the dried granules by a 0.5mm screen;
8) Adding the flow aid and the lubricant in the prescription amount for total mixing, wherein the mixing speed is 10rpm, and the mixing time is 10min;
9) And (5) sub-packaging the total mixed granules into granules for granulation.
Example 3
The raw materials for the preparation of the shafen mesylate composition are shown in table 3.
TABLE 3 preparation of the compositions of salfenamide mesylate
The preparation method of the methanesulfonic acid safinamide composition comprises the following steps:
1) Sieving the methanesulfonic acid sand-fenamide and beta-cyclodextrin together, and finishing the granules by a screen with the diameter of 1.5mm at the rotating speed of 300rpm;
2) Adding the inclusion methanesulfonic acid sand fenamide, the filler and the disintegrating agent prepared in the step 1) into a wet granulation pot, and premixing for 5min under the condition of 400 rpm;
3) Setting the stirring speed to be 150rpm, adding the aqueous solution of the adhesive into a granulating pan, and finishing pulping within 240 seconds;
4) Setting stirring speed to be 400rpm and cutter speed to be 2000rpm after the slurry adding is completed, and continuously granulating for 90s in a granulating pot;
5) Discharging, namely sieving wet particles with a 3X 3mm screen to obtain granules;
6) Drying the wet particles to water of 2.0wt% by adopting a fluidized bed, wherein the temperature of the drying inlet air is 65 ℃, and the temperature of the material is 45 ℃;
7) Drying and granulating the dried granules by a 0.5mm screen;
8) Adding the flow aid and the lubricant in the prescription amount for total mixing, wherein the mixing speed is 10rpm, and the mixing time is 10min;
9) And (5) sub-packaging the total mixed granules into granules for granulation.
Test example 1
Stability test: the sample is placed in a stability experiment box, the temperature is set to 40+/-2 ℃, and the humidity is 75+/-5% RH for accelerating experiment investigation for 6 months. The results are shown in Table 4.
Table 4 stability test results of the shafen mesylate amide composition
The structural formula of the impurity I isThe structural formula of the impurity II isImpurity III is shown in formula->
As can be seen from Table 4, the safinamide mesylate composition prepared in the present invention has more excellent stability performance.
While the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments of the invention can be made and still fall within the scope of the invention without undue effort.
Claims (10)
1. The sand-fenpyrad mesylate composition is characterized by comprising the following components in parts by mass: 11-40 parts of inclusion methanesulfonic acid sand fenamide, 5-30 parts of filler, 0.5-10 parts of disintegrating agent, 0.1-5 parts of adhesive, 0.1-5 parts of glidant, 0.1-5 parts of lubricant and 0-1 part of flavoring agent;
the inclusion compound comprises 10 parts of the shafen mesylate amide and 1-30 parts of the inclusion compound; the inclusion compound comprises beta-cyclodextrin.
2. The sand fenamide mesylate composition according to claim 1, wherein the filler comprises one or more of mannitol, xylitol, corn starch, microcrystalline cellulose, lactose and sucrose.
3. The sandfenamide mesylate composition according to claim 1, wherein the disintegrant comprises one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium and low substituted hydroxypropyl cellulose.
4. The sand fenamide mesylate composition of claim 1, wherein the glidant comprises one or more of colloidal silicon dioxide, silicon dioxide powder and talc.
5. The safinamide mesylate composition according to claim 1, wherein the lubricant comprises one or more of stearic acid, magnesium stearate and sodium hard fumarate.
6. The salfenamide mesylate composition according to any one of claims 1 to 5, wherein the formulation of the salfenamide mesylate composition comprises a tablet, a granule or a capsule.
7. A process for the preparation of a sandfenamide mesylate composition according to any one of claims 1 to 6, comprising the steps of:
granulating and sieving the methanesulfonic acid salfenamide and the inclusion compound to obtain inclusion methanesulfonic acid salfenamide;
premixing inclusion methanesulfonic acid sand-fenamide, a filler and a disintegrating agent, adding an aqueous solution of a binding agent for pulping, granulating, wet finishing and sieving to obtain mixture wet granules;
drying the mixture wet particles, and then drying, granulating and sieving to obtain mixture dry particles;
the wet mixture particles are mixed with glidants, lubricants and flavoring agents to obtain the shafen mesylate amide composition.
8. The preparation method according to claim 7, wherein the mass content of the aqueous binder solution is 1 to 15%;
the conditions of the granulating and sieving include: the rotating speed is 100-1000 rpm, and the aperture of the screen is 0.5mm;
the speed of the premixing is 150-450 rpm, and the time is 5-15 min;
the slurry adding is carried out under the stirring condition, the stirring speed is 100-450 rpm, and the slurry adding time is 30-300 s;
the aperture of the screen mesh with the size of the screen mesh for wet granulation and sieving is 2-4 mm;
the granulating conditions include: the stirring speed is 100-450 rpm, the rotating speed of the cutter is 1000-2500 rpm, and the time is 30-180 s;
the temperature of the dried air inlet is 40-75 ℃, the temperature of the dried material is 40-50 ℃, and the water content of the dry particles of the mixture is 0.5-5%;
the conditions of the dry granulation and sieving include: the rotating speed is 100-1000 rpm, and the aperture of the screen is 0.5-2 mm.
9. The production method according to claim 7 or 8, characterized in that the production method further comprises: tabletting the mixture obtained by the total mixing to obtain tablets of the sandifenamide mesylate composition;
or coating the mixture obtained by the total mixing by using a capsule material to obtain the capsule of the sandifenamide mesylate composition.
10. Use of a salfenamide mesylate composition according to any one of claims 1 to 6 or a salfenamide mesylate composition prepared by a method according to any one of claims 7 to 9 in the manufacture of a medicament for the treatment of parkinson's disease.
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