CN102600132B - Oral preparation containing amisulpride - Google Patents
Oral preparation containing amisulpride Download PDFInfo
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- CN102600132B CN102600132B CN201210065170.9A CN201210065170A CN102600132B CN 102600132 B CN102600132 B CN 102600132B CN 201210065170 A CN201210065170 A CN 201210065170A CN 102600132 B CN102600132 B CN 102600132B
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- China
- Prior art keywords
- amisulpride
- granule
- cyclodextrin
- mix
- xanthan gum
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- 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 85
- 229960003036 amisulpride Drugs 0.000 title claims abstract description 85
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000008187 granular material Substances 0.000 claims abstract description 53
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 37
- 239000002775 capsule Substances 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 20
- 238000009472 formulation Methods 0.000 claims description 20
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 19
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-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)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 HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 19
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 239000003085 diluting agent Substances 0.000 claims description 15
- 239000000314 lubricant Substances 0.000 claims description 15
- 239000000230 xanthan gum Substances 0.000 claims description 15
- 229920001285 xanthan gum Polymers 0.000 claims description 15
- 235000010493 xanthan gum Nutrition 0.000 claims description 15
- 229940082509 xanthan gum Drugs 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 235000011837 pasties Nutrition 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000005516 engineering process Methods 0.000 claims description 11
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-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)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 GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 11
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 11
- 239000007779 soft material Substances 0.000 claims description 10
- 238000005507 spraying Methods 0.000 claims description 10
- 238000004806 packaging method and process Methods 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 8
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 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 6
- 229950005162 benexate Drugs 0.000 claims description 6
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 claims description 6
- 239000000084 colloidal system Substances 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 235000012239 silicon dioxide Nutrition 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 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
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract description 26
- 239000003814 drug Substances 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 8
- 235000019658 bitter taste Nutrition 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 22
- 238000012360 testing method Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- 239000011230 binding agent Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 239000012535 impurity Substances 0.000 description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- -1 hydroxypropyl Chemical group 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 5
- 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 4
- 208000028017 Psychotic disease Diseases 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229920001206 natural gum Polymers 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 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 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 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 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 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
- 229950005770 hyprolose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
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Abstract
The invention relates to an oral preparation containing amisulpride. The amisulpride which is active medicine is prepared into cyclodextrin inclusion compound, is sieved, is uniformly mixed with pharmaceutically acceptable auxiliary materials, and is granulated by a wet method or a dry method, obtained granules are squashed to form tablets, filled into capsules to form a capsule preparation or is directly separately packaged to obtain a granule preparation. The water solubility and the stability of the oral preparation containing the amisulpride can be strengthened, bitter taste of the amisulpride is covered, medication compliances of patients are improved, and bioavailability of the oral preparation is improved to a great extent.
Description
Technical field
The present invention relates to a kind of oral formulations that contains amisulpride, belong to pharmaceutical preparations technology field.
Background technology
Amisulpride is a kind of atypical antipsychotic drug, for class paranoia process schizophrenia, the psychotic treatment of acute absurd Rui type, also can be used for treating schizoid defect state, and remaining psychosis develops and with blunt inhibitory state.Amisulpride conventionally orally use take every tablet amounts as the tablet form of 100,200 and 400 milligrams (Vidal, edition2003, Solianmonograph, the 1736th and 1738 pages).But during acute psychotic episode, oral every daily dose of amisulpride often improves, and can reach 1200 mg/day.Therefore, use the patient of amisulpride treatment must swallow several pieces tablets every day.
Due to the special pathological state of patient, and active component amisulpride taste is very bitter, can meet difficulty, or even show significant being reticent to correctly taking a large amount of tablets in accordance with doctor's advice timing, affects patient's compliance; Therefore the sensory issues of amisulpride oral formulations in the urgent need to address.
Amisulpride is slightly soluble in water, but clinical requirement medicine Fast Stripping, onset rapidly, this just requires to adopt suitable prescription and technique to improve drug dissolution in preparation production.
CN1842331A discloses a kind of amisulpride solid composite medicament, comprises by the coated amisulpride granule of the coating of lipid-coated and polymer coating and is suitable for disperseing a pharmaceutically acceptable excipient for administration to form in mouth with at least one.Amisulpride pharmaceutical composition prepared by the method is that the granule containing amisulpride is wrapped up, and specification is very large, is made mouthful interior dispersible tablet difficulty very large, is difficult to reach the effect of Fast Stripping, rapid onset.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of energy Fast Stripping, onset rapidly, can cover again the amisulpride oral formulations of its bitterness.The present invention also provides a kind of preparation method of described amisulpride oral formulations.
Term explanation:
Related substance: impurity is generally divided into organic impurities, inorganic impurity and residual solvent according to physicochemical property.Organic impurities comprises impurity and the catabolite etc. in technique, introduced, may be known or unknown, volatile or fixedness; Because the chemical constitution of this class impurity is general and active component is similar or tool origin relation, therefore conventionally can be described as again related substance.
Technical scheme of the present invention is as follows:
A kind of amisulpride oral formulations, the cyclodextrin that contains active drug amisulpride, enclose active drug and pharmaceutically acceptable excipient; Wherein, amisulpride exists with cyclodextrin clathrate form, and the mass ratio of amisulpride and cyclodextrin is 1: (0.5～4).
According to the present invention, preferred, the mass ratio of described amisulpride and cyclodextrin is 1: (1～3.5).Further preferably the mass ratio of amisulpride and cyclodextrin is 1: (2～3.5)
According to the present invention, described cyclodextrin is selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin; Preferably alpha-cyclodextrin, beta-schardinger dextrin-; Most preferably beta-schardinger dextrin-.
According to the present invention, preferred described excipient comprises diluent, disintegrating agent, binding agent and/or lubricant.
According to the present invention, preferably scheme is, a kind of amisulpride oral formulations is made up of the composition of following mass ratio:
Amisulpride 10%-50%, diluent 10%-50%, disintegrating agent 1%-10%, binding agent 0.5%-5%, lubricant 1%-5%, each composition sum is 100%; The amount of additional cyclodextrin is that the mass ratio of amisulpride and cyclodextrin is 1: (0.5～4).Wherein, preferably the mass ratio of amisulpride and cyclodextrin is 1: (1～3.5).Further preferably the mass ratio of amisulpride and cyclodextrin is 1: (2～3.5)
According to the present invention, described diluent is preferably 15%-45%, and disintegrating agent is preferably 3.0-5.0%, and binding agent is preferably 0.5-3.0%, and lubricant is preferably 1.5-5.0%.
According to the present invention, the adjuvants such as described diluent, disintegrating agent, binding agent, lubricant are by state of the art.The present invention is preferably as follows:
Described diluent is selected from one or more in microcrystalline Cellulose, lactose, mannitol, pregelatinized Starch.
Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose.
Described binding agent is selected from the mixture of synthetic copolymer or natural gum or synthetic copolymer and natural gum; Described synthetic copolymer is copolyvidone, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl emthylcellulose; Described natural gum is Radix Acaciae senegalis or xanthan gum.Preferably, binding agent is made into aqueous solution or hydrous ethanol solution adds.
Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, silicon dioxide.
The preferred version one according to the present invention, described amisulpride oral formulations, write out a prescription composed as follows:
Amisulpride 100g,
Beta-schardinger dextrin-350g,
Microcrystalline Cellulose 63g,
Polyvinylpolypyrrolidone 18g,
Polyvinylpyrrolidone 16g, is mixed with 10wt% polyvinylpyrrolidone aqueous solution and adds,
Magnesium stearate 6g,
Silicon dioxide 3g,
Make altogether 1000 units.
The preferred version two according to the present invention, described amisulpride oral formulations, write out a prescription composed as follows:
Amisulpride 100g,
Gamma-cyclodextrin 250g,
Lactose 137g,
Microcrystalline Cellulose 80g,
Carboxymethyl starch is received 24g,
Xanthan gum 3g, is mixed with 2wt% xanthan gum solution and adds,
Magnesium stearate 9g,
Make altogether 1000 units.
The preferred version three according to the present invention, described amisulpride oral formulations, write out a prescription composed as follows:
Amisulpride 100g,
Alpha-cyclodextrin 200g,
Pregelatinized Starch 240g,
Carboxymethyl starch is received 30g,
Hydroxypropyl cellulose 5g, is made into containing the solution of 5wt% hydroxypropyl cellulose and adds with the ethanol of concentration 75wt%,
Pulvis Talci 30g,
Make altogether 1000 units.
Above-mentioned raw materials of the present invention all can be bought in market.
In order further to improve the dissolution of active component in preparation, the invention provides a kind of preparation method of above-mentioned amisulpride oral formulations, comprise the steps:
(1) cyclodextrin of recipe quantity is made to 50-60 ℃ of saturated aqueous solution, then in blender, stirred, rotating speed is 750 revs/min-1500 revs/min; The amisulpride of recipe quantity is dissolved in appropriate ethanol, then be added drop-wise in the cyclodextrin saturated aqueous solution being stirred, control rate of addition is 1-3ml/ minute, after being added dropwise to complete, maintaining the temperature at 750 revs/min-1500 revs/min of 50-60 ℃, rotating speed continues to stir 4 hours, stop stirring, spraying is dry, makes amisulpride cyclodextrin clathrate; Or,
The cyclodextrin of recipe quantity is added to suitable quantity of water and be developed into pasty state, pour in colloid mill, grind; The amisulpride of recipe quantity is dissolved in appropriate ethanol, is then added drop-wise in ground pasty state cyclodextrin, control rate of addition is 2-4ml/ minute, continues to grind 30-45 minute, and spraying is dry, makes cyclodextrin clathrate;
(2) the amisulpride cyclodextrin clathrate making is crossed to 100 mesh sieves, then add diluent, disintegrating agent, binding agent soft material processed, cross 12-28 mesh sieve and make wet granular, wet granular is fully dry in 50-70 ℃, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix.
(3) will always mix gained granule and carry out that tabletting obtains tablet, filled capsules obtains capsule or direct packaging obtains granule.
Preferably, the binding agent described in above-mentioned steps (2) is made into aqueous solution or hydrous ethanol solution adds.In above-mentioned preparation method, be not particularly limited all by state of the art.
The present invention is surprised to find that and principal agent amisulpride is wrapped up with cyclodextrin, produce beat all excellent results, amisulpride exists and can either make medicine energy Fast Stripping, onset rapidly with cyclodextrin clathrate form, can cover again its bitterness, is beneficial to patient's medication.
The inventor is surprised to find that, adopts cyclodextrin inclusion compound amisulpride to prepare oral formulations, not to the utmost principal agent has been played to coating function, has also improved the stability of oral formulations.Compared with the amisulpride oral formulations of preparing according to common process, there is following excellent results:
1, can be good at covering the bitterness of amisulpride, increased insane medication compliance;
2, the related substance in preparation significantly reduces, and has improved medicine stability;
3, can significantly improve the water solublity of principal agent, be conducive to medicine Fast Stripping in gastrointestinal tract, improve bioavailability;
4, preparation technology is simple, is applicable to large-scale industrial and produces.
The specific embodiment
Below in conjunction with embodiment, the present invention will be further described.It will be appreciated that; for those skilled in the art; in an embodiment of the present invention, clearly and can be easy to make and not deviate from other embodiment and the modification of scope and the aim of the invention described above, be all included in protection scope of the present invention.Therefore the scope that, should not be construed as claims is limited in following examples.
For the ease of contrast, the formula ratio in following examples and comparative example is the amount of 1000 preparation units, and tablet is 1000, and capsule is 1000, and granule is 1000 bags.
Embodiment 1: amisulpride oral formulations prescription:
Supplementary material title consumption
Amisulpride 100g,
Beta-schardinger dextrin-350g,
Microcrystalline Cellulose 63g,
Polyvinylpolypyrrolidone 18g,
Polyvinylpyrrolidone 16g, is made into 10wt% polyvinylpyrrolidone aqueous solution and adds,
Magnesium stearate 6g,
Silicon dioxide 3g,
Make altogether 1000 units.
Preparation technology:
1) make 50 ℃ of saturated aqueous solutions by taking beta-schardinger dextrin-350g, then put in homogenizer, open and stir, rotating speed is 1000 revs/min; Get amisulpride 100g and be dissolved in 3000ml ethanol, be then added drop-wise in the beta-schardinger dextrin-saturated aqueous solution being stirred, rate of addition is 2ml/ minute, and constant temperature stirs 1 hour; Stop heating and continue to be stirred to room temperature, stop stirring after 3 hours, spraying is dry, makes Benexate Hydrochloride;
2) Benexate Hydrochloride making is crossed to 100 mesh sieves, then with after diluents microcrystalline cellulose, disintegrating agent polyvinylpolypyrrolidone mix homogeneously use 10wt% polyvidone aqueous solution (binding agent) soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add magnesium stearate lubricant and silicon dioxide always to mix;
3) will always mix gained granule carries out tabletting and obtains tablet;
Or, will always mix the particles filled capsule of gained and obtain capsule, or direct packaging obtains granule.
Embodiment 2: amisulpride oral formulations prescription:
Supplementary material title consumption
Amisulpride 100g,
Beta-schardinger dextrin-250g,
Lactose 199g,
Cross-linked carboxymethyl cellulose is received 21g,
Hydroxypropyl emthylcellulose 3g, is made into 2wt% hydroxypropyl emthylcellulose aqueous solution and adds,
Pulvis Talci 30g,
Make altogether 1000 units.
Preparation technology
1) take beta-schardinger dextrin-by recipe quantity and make 50 ℃ of saturated aqueous solutions, then put in homogenizer, open and stir, rotating speed is 1500 revs/min; The amisulpride of recipe quantity is dissolved in 3000ml ethanol, is then added drop-wise in the beta-schardinger dextrin-saturated aqueous solution being stirred, speed is 2ml/ minute, and constant temperature stirs 30 minutes.Stop heating and continue to be stirred to room temperature, stop stirring after 2.5 hours, spraying is dry, makes Benexate Hydrochloride;
2) Benexate Hydrochloride making is crossed to 100 mesh sieves, then with diluent, disintegrating agent mix homogeneously after with 2% hypromellose aqueous solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting obtains tablet, filled capsules obtains capsule or direct packaging obtains granule.
Embodiment 3: supplementary material title consumption
Amisulpride 100g,
Alpha-cyclodextrin 200g,
Pregelatinized Starch 240g,
Carboxymethyl starch is received 30g,
Hydroxypropyl cellulose 5g, is made into containing the solution of 5wt% hydroxypropyl cellulose and adds with the ethanol of concentration 75wt%,
Pulvis Talci 30g,
Make altogether 1000 units.
Preparation technology
1) take alpha-cyclodextrin by recipe quantity and add suitable quantity of water and be ground to pasty state, pour in colloid mill, open machine; The amisulpride of recipe quantity is dissolved in 3000ml ethanol, is then added drop-wise in ground pasty state alpha-cyclodextrin, speed is 3ml/ minute, continues to grind 30 minutes, and spraying is dry, makes alpha-cyclodextrin clathrate;
2) the alpha-cyclodextrin clathrate making is crossed to 100 mesh sieves, then after mixing homogeneously with diluent, disintegrating agent, use the 75% alcoholic solution soft material processed containing 5wt% hyprolose, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting obtains tablet, filled capsules obtains capsule or direct packaging obtains granule.
Embodiment 4: amisulpride oral formulations prescription:
Supplementary material title consumption
Amisulpride 200g,
Alpha-cyclodextrin 100g,
Pregelatinized Starch 120g,
Microcrystalline Cellulose 150g,
Polyvinylpolypyrrolidone 21g,
Xanthan gum 3g, is mixed with 2wt% xanthan gum solution and adds,
Magnesium stearate 9g,
Make altogether 1000 units.
Preparation technology
1) take alpha-cyclodextrin by recipe quantity and add suitable quantity of water and be ground to pasty state, pour in colloid mill, open machine; The amisulpride of recipe quantity is dissolved in 6000ml ethanol, is then added drop-wise in ground pasty state alpha-cyclodextrin, speed is 3ml/ minute, continues to grind 30 minutes, and spraying is dry, makes alpha-cyclodextrin clathrate;
2) the alpha-cyclodextrin clathrate making is crossed to 100 mesh sieves, then with diluent, disintegrating agent mix homogeneously after with 2% xanthan gum solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting obtains tablet, filled capsules obtains capsule or direct packaging obtains granule.
Embodiment 5: supplementary material title consumption
Amisulpride 100g,
Gamma-cyclodextrin 250g,
Lactose 137g,
Microcrystalline Cellulose 80g,
Carboxymethyl starch is received 24g,
Xanthan gum 3g, is made into 2wt% xanthan gum solution and adds,
Magnesium stearate 9g,
Make altogether 1000 units.
Preparation technology
1) take gamma-cyclodextrin by recipe quantity and add suitable quantity of water and be ground to pasty state, pour in colloid mill, open machine; The amisulpride of recipe quantity is dissolved in 3000ml ethanol, is then added drop-wise in ground pasty state gamma-cyclodextrin, speed is 3ml/ minute, continues to grind 30 minutes, and spraying is dry, makes alpha-cyclodextrin clathrate;
2) the gamma-cyclodextrin clathrate making is crossed to 100 mesh sieves, then with diluent, disintegrating agent mix homogeneously after with 2% xanthan gum solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting and obtain tablet, or filled capsules obtains capsule, or direct packaging obtains granule.
Comparative example 1: supplementary material title consumption
Amisulpride 100g,
Lactose 120g,
Microcrystalline Cellulose 63.5g,
Carboxymethyl starch is received 12g,
Hydroxypropyl emthylcellulose 1g, is made into 2wt% hydroxypropyl emthylcellulose aqueous solution and adds,
Magnesium stearate 4.5g,
Make altogether 1000 units.
Step of preparation process is as follows:
1) 50-70 ℃ of amisulpride and other adjuvant is dried to moisture < 3.0%, crosses 100 mesh sieves for subsequent use.
2) take amisulpride, diluent, disintegrating agent by recipe quantity and put in Quick-stirring granulator after mix homogeneously, with 2% hydroxypropyl emthylcellulose aqueous solution soft material processed, 24 mesh sieves are granulated.
3) wet granular put in drying baker 50-70 ℃ dry, 20 mesh sieve granulate must be done granule, add lubricant always to mix, and gained granule is carried out to tabletting and obtain tablet.
Further illustrate effect of the present invention below by experiment:
Test example 1: the comparison of amisulpride cyclodextrin clathrate dissolubility in aqueous solution
Embodiment 1-5 step 1) the amisulpride cyclodextrin clathrate and the each 50mg of reference substance amisulpride raw material that prepare, put in 50ml volumetric flask, be diluted with water to scale, jolting 1 hour under room temperature, measure respectively dissolubility with ultraviolet spectrophotometry, result is as shown in table 1 below:
The different embodiment of table 1. and reference substance solubility results in water
Result of the test can find out, after cyclodextrin inclusion compound, amisulpride dissolubility in water improves about 22-34 doubly.
Test example 2: tablet stripping feature prepared by amisulpride cyclodextrin clathrate is investigated
Adopt dissolution method (two appendix XC the second methods of Chinese Pharmacopoeia version in 2010), take water as solvent, rotating speed is 50 revs/min, temperature is 37.0 ± 0.5 ℃ of operations in accordance with the law, in the time of 10,15,20,30,45 minutes, taking liquid 10ml supplements the water of equivalent simultaneously respectively, the membrane filtration of medicinal liquid being crossed to 0.45 μ m, ultraviolet spectrophotometry is measured.
Conventional tablet prepared by the tablet of preparing in embodiment 1-5 and comparative example 1 carries out the investigation of stripping feature as stated above, and its stripping curve is shown in Fig. 1.From figure, we can find out, amisulpride sheet of the present invention and amisulpride ordinary tablet (comparative example 1) accumulation dissolution in the time of 30 minutes is all greater than 80%, meets the stripping requirement of tablet, and tablet stripping prepared by the present invention is steady, fast.Stripping completely substantially in 20 minutes.This feature shows that tablet prepared by the present invention can make medicine steadily discharge fast in vivo, not only makes curative effect of medication performance fast, and has effectively avoided medicine peak valley phenomenon, reduces the untoward reaction causing because blood drug level is too high.
Test example 3: the investigation of tablet related substance (total impurities) prepared by amisulpride cyclodextrin clathrate
(1) influence factor's test
Get amisulpride tablet in embodiment 1-5, put respectively under illumination (4500LX ± 500LX), high temperature (60 ℃), high humidity (92.5%) condition and place, detect related substance result respectively at sampling in the 5th day, 10 days as shown in table 2:
Table 2. embodiment 1-5 and comparative example 1 influence factor test and detect related substance (%)
(2) accelerated test
Amisulpride sheet in embodiment 1-5 and comparative example 1 amisulpride sheet are put to 40 ℃ of temperature by commercially available back, in the climatic chamber of relative humidity 75%, place 6 months, and sampling detects related substance 1,2,3,6 the end of month, result is as shown in table 3:
The different embodiment of table 3. and comparative example accelerated test related substance comparison (%)
| Time (moon) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Comparative example 1 |
| 0 | 0.17 | 0.16 | 0.16 | 0.17 | 0.16 | 0.17 |
| 1 | 0.18 | 0.19 | 0.16 | 0.18 | 0.17 | 0.28 |
| 2 | 0.17 | 0.18 | 0.19 | 0.20 | 0.18 | 0.34 |
| 3 | 0.19 | 0.20 | 0.19 | 0.22 | 0.19 | 0.42 |
| 6 | 0.22 | 0.23 | 0.25 | 0.27 | 0.23 | 0.48 |
In amisulpride sheet influence factor test and accelerated test, character and the content of tablet do not change substantially, can be found out by the result of the test of table 2 and table 3, and amisulpride sheet related substance of the present invention is far below comparative example.Illustrate that the prepared granule of the present invention can improve the stability of medicine, extend the storage life of preparation.
Claims (1)
1. an amisulpride oral formulations, is characterized in that, is made up of following composition:
Amisulpride 100g,
Beta-schardinger dextrin-350g,
Microcrystalline Cellulose 63g,
Polyvinylpolypyrrolidone 18g,
Polyvinylpyrrolidone 16g, is made into 10wt% polyvinylpyrrolidone aqueous solution and adds,
Magnesium stearate 6g,
Silicon dioxide 3g,
Make altogether 1000 units;
Preparation technology is as follows:
1) take beta-schardinger dextrin-350g by recipe quantity and make 50 ℃ of saturated aqueous solutions, then put in homogenizer, open and stir, rotating speed is 1000 revs/min; Get amisulpride 100g and be dissolved in 3000ml ethanol, be then added drop-wise in the beta-schardinger dextrin-saturated aqueous solution being stirred, rate of addition is 2ml/ minute, and constant temperature stirs 1 hour; Stop heating and continue to be stirred to room temperature, stop stirring after 3 hours, spraying is dry, makes Benexate Hydrochloride;
2) Benexate Hydrochloride making is crossed to 100 mesh sieves, then with after diluents microcrystalline cellulose, disintegrating agent polyvinylpolypyrrolidone mix homogeneously use 10wt% polyvidone aqueous solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ to be fully dried, cross 10-24 mesh sieve granulate and must do granule, add magnesium stearate lubricant and silicon dioxide always to mix;
3) will always mix gained granule carries out tabletting and obtains tablet;
Or, will always mix the particles filled capsule of gained and obtain capsule, or direct packaging obtains granule.
2
.a kind of amisulpride oral formulations, is characterized in that, is made up of following composition:
Amisulpride 100g,
Gamma-cyclodextrin 250g,
Lactose 137g,
Microcrystalline Cellulose 80g,
Carboxymethyl starch sodium 24g,
Xanthan gum 3g, is mixed with 2wt% xanthan gum solution and adds,
Magnesium stearate 9g,
Make altogether 1000 units;
Preparation technology is as follows:
1) take gamma-cyclodextrin by recipe quantity and add suitable quantity of water and be ground to pasty state, pour in colloid mill, open machine; The amisulpride of recipe quantity is dissolved in 3000ml ethanol, is then added drop-wise in ground pasty state gamma-cyclodextrin, speed is 3ml/ minute, continues to grind 30 minutes, and spraying is dry, makes gamma-cyclodextrin clathrate;
2) the gamma-cyclodextrin clathrate making is crossed to 100 mesh sieves, then with diluent, disintegrating agent mix homogeneously after with 2% xanthan gum solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ and is fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting and obtain tablet, or filled capsules obtains capsule, or direct packaging obtains granule.
3
.a kind of amisulpride oral formulations, is characterized in that, is made up of following composition:
Amisulpride 200g,
Alpha-cyclodextrin 100g,
Pregelatinized Starch 120g,
Microcrystalline Cellulose 150g,
Polyvinylpolypyrrolidone 21g,
Xanthan gum 3g, is mixed with 2wt% xanthan gum solution and adds,
Magnesium stearate 9g,
Make altogether 1000 units;
Preparation technology is as follows:
1) take alpha-cyclodextrin by recipe quantity and add suitable quantity of water and be ground to pasty state, pour in colloid mill, open machine; The amisulpride of recipe quantity is dissolved in 6000ml ethanol, is then added drop-wise in ground pasty state alpha-cyclodextrin, speed is 3ml/ minute, continues to grind 30 minutes, and spraying is dry, makes alpha-cyclodextrin clathrate;
2) the alpha-cyclodextrin clathrate making is crossed to 100 mesh sieves, then with diluent, disintegrating agent mix homogeneously after with 2% xanthan gum solution soft material processed, cross 12-28 mesh sieve wet granular processed, granule is put to 50-70 ℃ and is fully dried, cross 10-24 mesh sieve granulate and must do granule, add lubricant always to mix;
3) gained granule is carried out to tabletting obtains tablet, filled capsules obtains capsule or direct packaging obtains granule.
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| JP2021505595A (en) | 2017-12-05 | 2021-02-18 | サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | Crystal form and its manufacturing method |
| EP3720434A4 (en) | 2017-12-05 | 2021-09-01 | Sunovion Pharmaceuticals Inc. | NON-RACEMIC MIXTURES AND THEIR USE |
| CA3142355A1 (en) | 2019-06-04 | 2020-12-10 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| CN111821337B (en) * | 2020-08-30 | 2022-05-17 | 扬子江药业集团广州海瑞药业有限公司 | Process for preparing pharmaceutical composition |
| CN115300471B (en) * | 2022-10-12 | 2022-12-23 | 则正(济南)生物科技有限公司 | Orally disintegrating amisulpride tablet and preparation method thereof |
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| DE102005041860A1 (en) * | 2005-09-02 | 2007-03-08 | Schering Ag | Nano-particle embedded- and charged-complex, useful for the production of a pharmaceutical composition, comprises two complex partners, where the complex partner is an embedded anionic and a cationic active substance |
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