CN115300471B - Orally disintegrating amisulpride tablet and preparation method thereof - Google Patents
Orally disintegrating amisulpride tablet and preparation method thereof Download PDFInfo
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- CN115300471B CN115300471B CN202211243975.8A CN202211243975A CN115300471B CN 115300471 B CN115300471 B CN 115300471B CN 202211243975 A CN202211243975 A CN 202211243975A CN 115300471 B CN115300471 B CN 115300471B
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- amisulpride
- orally disintegrating
- water
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- 229960003036 amisulpride Drugs 0.000 title claims abstract description 131
- NTJOBXMMWNYJFB-UHFFFAOYSA-N amisulpride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=C(N)C=C1OC NTJOBXMMWNYJFB-UHFFFAOYSA-N 0.000 title claims abstract description 131
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000007962 solid dispersion Substances 0.000 claims abstract description 50
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 28
- 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 abstract description 27
- 229930195725 Mannitol Natural products 0.000 claims abstract description 27
- 229920001531 copovidone Polymers 0.000 claims abstract description 27
- 239000000594 mannitol Substances 0.000 claims abstract description 27
- 235000010355 mannitol Nutrition 0.000 claims abstract description 27
- 239000006191 orally-disintegrating tablet Substances 0.000 claims abstract description 21
- SERLAGPUMNYUCK-YJOKQAJESA-N 6-O-alpha-D-glucopyranosyl-D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-YJOKQAJESA-N 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 239000000853 adhesive Substances 0.000 claims abstract description 8
- 230000001070 adhesive effect Effects 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 20
- 239000008187 granular material Substances 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 239000011812 mixed powder Substances 0.000 claims description 16
- 239000000905 isomalt Substances 0.000 claims description 13
- 235000010439 isomalt Nutrition 0.000 claims description 13
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 238000002844 melting Methods 0.000 claims description 10
- 230000008018 melting Effects 0.000 claims description 10
- 238000007873 sieving Methods 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 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 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 229940032147 starch Drugs 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 235000013355 food flavoring agent Nutrition 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 3
- 108010011485 Aspartame Proteins 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 3
- 229960004998 acesulfame potassium Drugs 0.000 claims description 3
- 239000000619 acesulfame-K Substances 0.000 claims description 3
- 239000000605 aspartame Substances 0.000 claims description 3
- 235000010357 aspartame Nutrition 0.000 claims description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 3
- 229960003438 aspartame Drugs 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000004376 Sucralose Substances 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 244000246386 Mentha pulegium Species 0.000 claims 1
- 235000016257 Mentha pulegium Nutrition 0.000 claims 1
- 235000004357 Mentha x piperita Nutrition 0.000 claims 1
- 235000001050 hortel pimenta Nutrition 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 13
- 239000003826 tablet Substances 0.000 abstract description 12
- 235000019640 taste Nutrition 0.000 abstract description 5
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000969 carrier Substances 0.000 description 10
- 238000007908 dry granulation Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 238000010298 pulverizing process Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 235000019658 bitter taste Nutrition 0.000 description 4
- 238000009474 hot melt extrusion Methods 0.000 description 4
- 235000015424 sodium Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 4
- 208000028017 Psychotic disease Diseases 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 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
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Neurology (AREA)
- Nutrition Science (AREA)
- Zoology (AREA)
- Physiology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an amisulpride oral disintegrating tablet and a preparation method thereof, and the amisulpride oral disintegrating tablet specifically comprises an amisulpride solid dispersoid, isomaltitol, a disintegrating agent and an adhesive; wherein the amisulpride solid dispersion comprises amisulpride and a water-soluble carrier; the water soluble carrier comprises copovidone and mannitol. The orally disintegrating tablet of amisulpride provided by the invention is fast in dissolution and good in taste, improves the medication compliance of patients, is smooth in preparation process, ensures the safety and effectiveness of patients in taking, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an orally disintegrating tablet of amisulpride and a preparation method thereof.
Background
Amisulpride is an atypical antipsychotic drug used for the treatment of paranoid progressive schizophrenia, acute empty psychosis, and for the treatment of defective states of schizophrenia, residual psychotic development and depressive states associated with dullness. During an acute psychotic episode, oral daily doses of amisulpride can often reach 1200mg/day. Thus, patients treated with amisulpride must ingest several tablets per day.
Amisulpride, chemical name of which is 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-ethylsulfonyl-2-methoxybenzamide, has a structural formula:
due to the particular pathological state of the patient and the extremely bitter taste of the active ingredient amisulpride, the patient suffers from difficulty in regularly taking a large number of tablets in proper compliance with medical advice or even shows significant silent gossypies, which affects the medication compliance of the patient; therefore, the problem of the mouthfeel of oral amisulpride preparations is urgently needed to be solved.
Amisulpride is poor in solubility, almost insoluble in water and poor in flowability and formability, but the drug is clinically required to be rapidly dissolved and take effect rapidly, so that the drug dissolution rate is required to be improved by adopting a proper formula and a proper process in preparation production.
In the prior art, CN1842331A discloses an amisulpride solid pharmaceutical composition, comprising amisulpride granules coated with a coating of a lipid and a polymer coating and at least one pharmaceutically acceptable excipient suitable for orodispersible administration. The amisulpride medicinal composition prepared by the method wraps granules containing amisulpride, has large specification, has large difficulty in preparing the amisulpride medicinal composition into an oral dispersible tablet, and is difficult to achieve the effects of quick dissolution and quick response.
Therefore, further research is needed to obtain orally disintegrating amisulpride tablets which are quickly dissolved out, have good mouthfeel and improve the compliance of patients.
Disclosure of Invention
In view of this, the invention provides orally disintegrating tablets of amisulpride, which aim to solve the problems of poor solubility, poor fluidity and bitter taste of amisulpride raw material medicines. The oral disintegrating tablet of amisulpride provided by the invention is quick to dissolve out, good in taste, smooth in preparation process, and suitable for industrial large-scale production, and the administration compliance of patients is improved, so that the oral disintegrating tablet of amisulpride is safe and effective for patients to take.
The invention provides an orally disintegrating tablet of amisulpride, which comprises an amisulpride solid dispersoid, isomalt, a disintegrating agent and an adhesive; the amisulpride solid dispersion comprises amisulpride and a water-soluble carrier, wherein the water-soluble carrier comprises copovidone and mannitol.
Amisulpride is poorly soluble and hardly soluble in water, and the inventors prepared amisulpride and a water-soluble carrier into a solid dispersion in order to enhance dissolution of amisulpride. The amisulpride is prepared into the solid dispersion, so that disintegration and dissolution of the amisulpride can be improved, and the problem of poor fluidity of the amisulpride can be solved. The inventor examines the types of water-soluble carriers and finds that when the water-soluble carriers are copovidone and mannitol, the obtained amisulpride solid dispersion can improve the solubility of amisulpride and further increase the disintegration and dissolution of amisulpride orally disintegrating tablets. In order to promote the rapid disintegration of the oral amisulpride disintegrating tablet in the oral cavity and have good mouthfeel and improve the medication compliance of patients, the inventor develops the matching of the solid amisulpride dispersion, isomaltitol, a disintegrating agent and a binder to obtain the oral amisulpride disintegrating tablet, and the oral amisulpride disintegrating tablet has the effects of rapid disintegration, good mouthfeel, improvement of the medication compliance of patients and smooth preparation process.
In the orally disintegrating tablet of amisulpride, the mass and dosage ratio of the copovidone to the mannitol is 1-3.
In the orally disintegrating tablet of amisulpride, the mass dosage ratio of amisulpride to the water-soluble carrier is 1:1.5-3.
In the orally disintegrating tablet of amisulpride, the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
In the orally disintegrating tablet of amisulpride, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and povidone.
The orally disintegrating tablet of amisulpride also comprises a flavoring agent, wherein the flavoring agent is one or more of sucralose, acesulfame potassium, mint essence and aspartame.
The orally disintegrating tablet of amisulpride also comprises a lubricant, wherein the lubricant is one or more of talcum powder, magnesium stearate and sodium stearyl fumarate.
In the orally disintegrating tablet of amisulpride, the dosage of each component is as follows by mass: 100-200 parts of amisulpride, 75-200 parts of copovidone, 50-100 parts of mannitol, 75-135 parts of isomalt, 3-10 parts of disintegrant and 4-10 parts of adhesive.
The invention provides the preparation method of the amisulpride solid dispersion, the solid dispersion is prepared by a solvent method or a hot-melt extrusion method, the preparation method is convenient, easy and controllable, large-scale production can be realized, the prepared solid dispersion has better powder flowability and compressibility, better solubility can be ensured, and the amisulpride solid dispersion is favorable for further preparing amisulpride orally disintegrating tablets.
The preparation method of the solid dispersion by the hot-melt extrusion method provided by the invention comprises the following steps:
a. uniformly mixing amisulpride and a water-soluble carrier to obtain a mixture, heating and melting, and cooling;
b. and crushing and sieving the cooled mixture to obtain the amisulpride solid dispersion.
The solvent method for preparing the solid dispersion comprises the following steps:
1) Dissolving or dispersing amisulpride and a water-soluble carrier in an organic solvent;
2) The organic solvent was removed to obtain a solid dispersion.
The invention also provides a preparation method of the orally disintegrating tablet containing amisulpride, which comprises the following steps:
(1) Uniformly mixing the amisulpride solid dispersion, isomalt, a disintegrating agent and an adhesive to prepare mixed powder;
(2) Performing dry granulation on the mixed powder in the step (1) to obtain medicine granules;
(3) Tabletting the drug granules obtained in the step (2).
Compared with the prior art, the invention has the following beneficial effects:
1. the amisulpride solid dispersion is prepared from the amisulpride, the copovidone and the water-soluble carrier of the mannitol, and the bitter taste of the amisulpride can be well covered by matching the amisulpride solid dispersion with the isomaltitol, so that the medication compliance of patients with mental diseases is improved.
2. The amisulpride solid dispersion is prepared from amisulpride, copovidone and a water-soluble carrier of mannitol, and the amisulpride solid dispersion can be matched with isomaltitol, a disintegrating agent and an adhesive to remarkably improve disintegration and dissolution of amisulpride in oral cavity, improve bioavailability and quickly exert drug effect.
3. The invention prepares the amisulpride, the copovidone and the mannitol water-soluble carrier into the solid dispersion, can solve the technical problem of poor fluidity of the amisulpride, ensures the process smoothness in the preparation process, and is suitable for industrial production.
Detailed Description
1. Effect of different classes of Water-soluble Carriers on solubility of amisulpride
1.1 Hot melt extrusion method
With amisulpride: the mass ratio of the water-soluble carriers is 1, 2, respectively selecting different water-soluble carriers, including mannitol, copovidone, a combination of mannitol and copovidone, polyethylene glycol 6000, lactose and povidone K30, mixing amisulpride and water-soluble carrier materials, heating for melting, cooling, crushing, sieving with a 60-mesh sieve to obtain amisulpride solid dispersions, respectively measuring the solubility of the amisulpride solid dispersions, taking 2g of samples, placing the amisulpride solid dispersions in a 50ml volumetric flask, adding water for diluting to a scale, shaking for 1 hour at room temperature, calculating according to a solubility calculation formula, converting the amisulpride solid dispersions into g/100ml units, detecting the wavelength of the amisulpride solid dispersions by using a four-part ultraviolet-visible spectrophotometry method of 2020 edition of Chinese pharmacopoeia, wherein the detection wavelength is 225nm, and respectively measuring the amisulpride solubility, and the specific data are as follows:
1.2 solvent method
With amisulpride: the mass ratio of the water-soluble carriers is 1, 2, respectively selecting different water-soluble carriers, including mannitol, copovidone, a combination of mannitol and copovidone, polyethylene glycol 6000, lactose and povidone K30, dissolving amisulpride and water-soluble carrier materials in ethanol, carrying out vacuum drying to obtain amisulpride solid dispersoids, respectively measuring the solubility of the amisulpride solid dispersoids, taking 2g of samples, placing the samples in a 50ml volumetric flask, adding water to dilute the samples to a scale, shaking the samples at room temperature for 1 hour, calculating according to a solubility calculation formula, converting the obtained solution into g/100ml units, detecting the wavelength of the amisulpride solid dispersions at 225nm by using a four-part 0401 ultraviolet-visible spectrophotometry method of the 2020 edition of Chinese pharmacopoeia, and respectively measuring the solubility of the amisulpride, wherein the specific data are as follows:
from the above data, it can be seen that the solid dispersion prepared by combining mannitol and copovidone in a plurality of carriers significantly increases the solubility of amisulpride under the condition that the mass using ratio of amisulpride to the water-soluble carrier is the same.
2. Effect of different amounts of Water-soluble Carrier on solubility of amisulpride
2.1 Hot melt extrusion method
Taking a combination of copovidone and mannitol as a water-soluble carrier, mixing the medicine and the water-soluble carrier according to different mass dosage ratios of the medicine and the water-soluble carrier, heating for melting, cooling, crushing, sieving by a 60-mesh sieve to obtain amisulpride solid dispersions, respectively measuring the solubility of the amisulpride solid dispersions, taking 2g of samples, placing the samples in a 50ml volumetric flask, adding water for diluting to a scale, shaking for 1 hour at room temperature, calculating according to a solubility calculation formula, converting the amisulpride solid dispersions into g/100ml units, and respectively measuring the amisulpride solubility by using a four-part ultraviolet-visible spectrophotometry 0401 method of the 2020 edition of Chinese pharmacopoeia, wherein the detection wavelength is 225nm, and the specific data are as follows:
2.2 solvent method
Taking a combination of copovidone and mannitol as a water-soluble carrier, dissolving amisulpride and the water-soluble carrier material in ethanol according to different mass and dosage ratios of a drug to the water-soluble carrier, drying in vacuum to obtain amisulpride solid dispersions, respectively measuring the solubility of the amisulpride solid dispersions, taking 2g of samples, placing the samples in a 50ml volumetric flask, adding water to dilute the samples to the scales, shaking the samples at room temperature for 1 hour, calculating according to a solubility calculation formula, converting the samples into g/100ml units, and respectively measuring the amisulpride solubility by using a four-part 0401 ultraviolet-visible spectrophotometry method in 2020 edition of Chinese pharmacopoeia, wherein the detection wavelength is 225nm, and the specific data are as follows:
from the data, the obtained amisulpride solid dispersion has obviously increased solubility of amisulpride by combining the amisulpride and a water-soluble carrier (copovidone and mannitol).
Example 1
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride with copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing the amisulpride solid dispersion, isomalt, sodium carboxymethyl starch and povidone to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) Tabletting the drug granules obtained in the step (4).
Example 2
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride with copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing the amisulpride solid dispersion, isomalt, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) Tabletting the drug granules obtained in the step (4).
Example 3
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride with copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing amisulpride solid dispersion, isomalt, croscarmellose sodium and hydroxypropyl methylcellulose to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) Tabletting the drug granules obtained in the step (4).
Example 4
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride, copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing the amisulpride solid dispersion, isomalt, crospovidone, sodium carboxymethylcellulose and aspartame to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) And (4) uniformly mixing the medicine granules obtained in the step (4) and magnesium stearate, and tabletting.
Example 5
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride with copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing the amisulpride solid dispersion, isomalt, sodium carboxymethyl starch, crospovidone and povidone to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) And (4) uniformly mixing the medicine granules obtained in the step (4), talcum powder and sodium stearyl fumarate, and tabletting.
Example 6
The preparation method comprises the following steps:
(1) Uniformly mixing amisulpride with copovidone and mannitol to obtain a mixture, heating and melting, and cooling;
(2) Pulverizing the cooled mixture, and sieving to obtain solid dispersion;
(3) Uniformly mixing amisulpride solid dispersion, isomalt, sodium carboxymethyl starch, povidone, sodium carboxymethyl cellulose and acesulfame potassium to prepare mixed powder;
(4) Performing dry granulation on the mixed powder in the step (3) to obtain medicine granules;
(5) Tabletting the medicine granules obtained in the step (4).
Comparative example
The preparation method is the same as example 1.
And (3) taste test investigation:
samples of examples and comparative examples were taken, tested by 3 experimenters, and the bitterness was classified as: 1 is clearly bitter, 2 is slightly bitter but acceptable, 3 is not bitter, 4 is slightly sweet and 5 is clearly five types of sweet, the experimental results are as follows:
the taste tests of the samples in the examples and the comparative examples prove that the sample obtained by adding the isomaltitol in the example has good taste and is easily accepted by patients, and the medication compliance of the patients is improved.
Dissolution study
Taking the samples obtained in the examples and the comparative examples, according to the dissolution rate and the dissolution rate determination method (second method) of 0931 in the four parts of the 2020 edition of Chinese pharmacopoeia, taking a phosphate buffer solution with pH of 6.8 as a dissolution medium, and measuring the dissolution rate (%) of amisulpride at 5min, 10min, 15min and 30min at the rotating speed of 75 rpm. The results obtained are given in the following table:
according to the experimental results, the dissolution rate of the orally disintegrating amisulpride tablet can be improved by using the copovidone and the mannitol as water-soluble carriers to prepare the amisulpride solid dispersion and matching with the isomalt, the disintegrant and the binder. In contrast, in comparative examples 1 to 4, although amisulpride solid dispersion was prepared using copovidone and mannitol as water-soluble carriers, the dissolution effect of the prepared samples was poor without adding isomalt.
Claims (7)
1. An orally disintegrating tablet of amisulpride, which comprises an amisulpride solid dispersion, isomalt, a disintegrating agent and a binder; wherein the amisulpride solid dispersion comprises amisulpride and a water-soluble carrier; the water soluble carrier comprises copovidone and mannitol; the disintegrating agent is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and povidone; the dosage of each component is calculated by mass portion: 100-200 parts of amisulpride, 75-200 parts of copovidone, 50-100 parts of mannitol, 75-135 parts of isomalt, 3-10 parts of disintegrant and 4-10 parts of adhesive.
2. The orally disintegrating tablet of amisulpride according to claim 1, wherein the mass ratio of copovidone to mannitol is 1-3.
3. The orally disintegrating tablet of amisulpride according to claim 1 or 2, wherein the mass ratio of amisulpride to the water-soluble carrier is 1:1.5-3.
4. The orally disintegrating tablet of amisulpride according to claim 1, further comprising a flavoring agent, wherein the flavoring agent is one or more of sucralose, acesulfame potassium, peppermint essence, and aspartame.
5. The orally disintegrating tablet of amisulpride according to claim 1, further comprising a lubricant, wherein the lubricant is one or more of talc, magnesium stearate and sodium stearyl fumarate.
6. A method for preparing an orally disintegrating tablet of amisulpride according to claim 1, wherein the method for preparing the solid dispersion of amisulpride comprises the steps of:
a. uniformly mixing amisulpride and a water-soluble carrier to obtain a mixture, heating and melting, and cooling;
b. and crushing and sieving the cooled mixture to obtain the amisulpride solid dispersion.
7. A process for the preparation of orally disintegrating tablets of amisulpride according to claim 6, comprising the steps of:
(1) Uniformly mixing the amisulpride solid dispersoid, isomaltitol, a disintegrating agent and an adhesive to prepare mixed powder;
(2) Dry granulating the mixed powder in the step (1) to obtain medicine granules;
(3) Tabletting the drug granules obtained in the step (2).
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