CN109674758A - A kind of Divalproex sodium sustained-release tablet and preparation method thereof for treating epilepsy - Google Patents
A kind of Divalproex sodium sustained-release tablet and preparation method thereof for treating epilepsy Download PDFInfo
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- CN109674758A CN109674758A CN201910136073.6A CN201910136073A CN109674758A CN 109674758 A CN109674758 A CN 109674758A CN 201910136073 A CN201910136073 A CN 201910136073A CN 109674758 A CN109674758 A CN 109674758A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention discloses a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, it is characterized in that, being made of the raw material of following parts by weight: 40-50 parts of divalproex sodium, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer double 15-20 parts of valproate, 3-5 parts of pore-foaming agent, 3-8 parts of filler, 1-4 parts of glycerol, 1-3 parts of lubricant, 5-10 parts of water.The invention also discloses the preparation methods of the Divalproex sodium sustained-release tablet.Divalproex sodium sustained-release tablet therapeutic effect disclosed by the invention is good, and curative effect stabilization, persistent, convenient drug administration, sustained release performance are good, and preparation process is simple, raw material sources are abundant, medication compliance is good, toxic side effect is small, and use is safe.
Description
Technical field
The present invention relates to technical field of medicine more particularly to a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy
And preparation method thereof.
Background technique
Epilepsy is a kind of recurrent exerbation, protracted course, the chronic disease of paroxysmal cerebral dysfunction.It is characterized in that brain mind
It discharges through first paroxysmal abnormality high-frequency and is spread to surrounding.Epilepsy is most ancient one of the disease of the mankind, according to electric discharge nerve
The difference at position, clinical manifestation are also not quite similar where first, and seizure types are divided into partial seizures, Generalized seizure, Quan Mianqiang
Straight Myoclonic seizures.It belongs to central nervous system disease, is a kind of chronic disease, as long as several years, even many decades can be delayed,
Can thus serious adverse effect be caused to patient body, spirit, marriage and socio-economic status etc., give patient and its family
Front yard brings great pain.Therefore, the world of medicine needs to develop a kind of drug for treating epileptics, reduces patient and its family with this
The pain in front yard.
Divalproex sodium is a kind of for treating epilepsy, bipolar disorder and the drug of migraine, is by equimolar ratio
Valproic acid and sodium vedproate composition oligomer, which not only has identical with valproic acid and sodium vedproate therapeutic
Can, and valproic acid and sodium vedproate are overcome as disadvantage possessed by classical antiepileptic: valproic acid is at normal temperature
Liquid is not easy that the solid pharmaceutical preparation of convenient oral is made；The stability of sodium vedproate easy to absorb moisture, manufactured pharmaceutical preparation is poor.But
It is that divalproex sodium is easy to assemble, easily agglomerates during long-term placement, while divalproex sodium fusing point is 90~100
DEG C, easily sticking during tabletting causes to be difficult to continuous production；On the other hand, due to divalproex sodium general formulation
Rate of releasing drug is too fast to keep peak plasma concentrations higher, is also easy to produce side effect, especially most commonly seen with gastrointestinal reaction；Due to main
Medication crowd is epileptic, and patient tends not to fine self-contr ol and takes medicine on time, and general formulation usually occurs in administration
Situations such as missing is so that therapeutic effect decline or unobvious.
In order to delay drug from the rate of release in medicament, the absorption rate that drug enters body is reduced, is played preferably
Therapeutic effect, currently, clinically main treated by Divalproex sodium sustained-release tablet.Currently, Divalproex sodium sustained-release tablet mostly uses
Wet granulation technology adds calcium monohydrogen phosphate, lactose, magnesium stearate, talcum powder using hydroxypropyl methyl cellulose as framework material
Deng using high concentration ethanol as wetting agent granulation.But the raw material of the Divalproex sodium sustained-release tablet and technique make granulation and
Drying time is longer, and hydroxypropyl methyl cellulose can become very sticky thick, easy agglomeration, the particle after drying after meeting water or alcohol
It is very rigid, it is not easy to whole grain；Divalproex sodium sustained-release tablet obtained will appear color spot and point, appearance are poor, influence market
It promotes.In addition, hydroxypropyl methyl cellulose is expensive, these defects hinder the further hair of Divalproex sodium sustained-release tablet
Exhibition.
Therefore, it is good to develop a kind of therapeutic effect, curative effect stabilization, persistent, convenient drug administration, sustained release performance are good, prepare work
The Divalproex sodium sustained-release tablet that skill is simple, raw material sources are abundant, medication compliance is good, toxic side effect is small is imperative.
Summary of the invention
In order to overcome the defects of the prior art, the present invention provides a kind of divalproex sodium sustained release for treating epilepsy
Piece, the Divalproex sodium sustained-release tablet therapeutic effect is good, and curative effect stabilization, persistent, convenient drug administration, sustained release performance are good, prepares work
Skill is simple, raw material sources are abundant, medication compliance is good, toxic side effect is small, and use is safe.
To achieve the above object of the invention, the technical solution adopted by the present invention is that: it is a kind of for treating double valproic acids of epilepsy
Sodium sustained release tablets are made of the raw material of following parts by weight: 40-50 parts of divalproex sodium, ionization Tanabe Seiyoku base vinylpyridine
Pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer double the third penta
15-20 parts of hydrochlorate, 3-5 parts of pore-foaming agent, 3-8 parts of filler, 1-4 parts of glycerol, 1-3 parts of lubricant, 5-10 parts of water.
Further, the pore-foaming agent is selected from one or more of povidone, starch, microcrystalline cellulose, sucrose.
Further, the filler is selected from one of ethyl cellulose, lactose, calcium monohydrogen phosphate, calcium phosphate dibasic anhydrous
Or it is several.
Further, the lubricant is selected from one of magnesium stearate, silica, superfine silica gel powder, talcum powder or several
Kind.
Further, the ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate two
The preparation method of the double valproates of sodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex in anhydrous pyridine, then 3 are added thereto, 4- epoxy fourth
Base-beta- cellobioside and basic catalyst are stirred to react 8-10 hours at 80-90 DEG C, and anhydrous pyrrole is evaporated off in back spin
Pyridine, then crude product is poured into acetone, after the solid of precipitation is washed with water 3-5 times, finally at 70-80 DEG C of vacuum oven
Drying obtains intermediate product to constant weight；
II by the intermediate product being prepared by step I, acrylic acid chloroethene ester adding into dichloromethane, at room temperature
It is stirred to react 6-8 hours, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose, vinyl alcohol acid, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydro
Quinoline is added in tetrahydrofuran, after be stirred to react at 30-40 DEG C 18-22 hours, solvent is evaporated off in back spin, uses methylene chloride
It washes 3-5 times, methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
It IV by be prepared by step II ionization Tanabe Seiyoku, the vinyl alcohol that is prepared by step III
Sour modified amido hydroxy propyl cellulose, n-vinyl pyrrolidone, oleamide MEA sulfosuccinate disodium, initiator add
Enter into high boiling solvent, be stirred to react at nitrogen or 65-80 DEG C of atmosphere of inert gases 4-6 hours, after settle out in acetone,
It is placed at 70-80 DEG C of vacuum oven and is dried to constant weight again, obtain copolymer；
V is added to the water the copolymer, the divalproex sodium that are prepared by step IV, stirs at 70-80 DEG C anti-
It answers 10-12 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfo group amber
The double valproates of amber acid esters disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
Preferably, single (6- amino -6- deoxidation) betadex, anhydrous pyridine, 3,4- epoxybutyl-described in step I
Beta- cellobioside, basic catalyst mass ratio be (3-5): (10-15): 1:0.6.
Preferably, the basic catalyst is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or several
Kind.
Preferably, intermediate product described in step II, acrylic acid chloroethene ester, methylene chloride mass ratio be 2:1:(10-
15)。
Preferably,-the 2- of 3- amino described in step III hydroxy propyl cellulose, vinyl alcohol acid, 2- ethyoxyl -1- ethoxy
Carbonic acyl radical -1,2- dihydroquinoline, tetrahydrofuran mass ratio be 1:2:0.3:(10-15).
Preferably, described in step IV ionization Tanabe Seiyoku, vinyl alcohol acid modified amido hydroxy propyl cellulose,
N-vinyl pyrrolidone, oleamide MEA sulfosuccinate disodium, initiator, high boiling solvent mass ratio be 1:1:1:
2:0.05:(15-20)。
Preferably, the initiator is selected from least one of azodiisobutyronitrile, azobisisoheptonitrile；The higher boiling
Solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, N-Methyl pyrrolidone；The inert gas choosing
From one of helium, neon, argon gas.
Preferably, copolymer described in step V, divalproex sodium, water mass ratio be 1:0.3:(20-30).
Further, described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy including as follows
Step: being mixed to get mixture for raw material in proportion, then adds mixture into mixed method granulator and mix well, and carries out high speed system
Grain, wet granular obtained is dry, according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
The beneficial effects of adopting the technical scheme are that
(1) Divalproex sodium sustained-release tablet provided by the invention, preparation method is simple, and raw material is easy to get, cheap, faces
Bed is practical.
(2) Divalproex sodium sustained-release tablet provided by the invention, therapeutic effect is good, and curative effect stabilization, gives prescription at persistent
Just, sustained release performance is good, and preparation process is simple, raw material sources are abundant, medication compliance is good, toxic side effect is small, and use is safe, can have
Effect reduces administration number of times, keeps drug effect concentration long-term and stably.
(3) Divalproex sodium sustained-release tablet provided by the invention, addition ionization Tanabe Seiyoku base vinyl pyrrolidone-
The double valproates of oleamide MEA sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer, respectively
Ingredient and structurally reasonable prescription compatibility, the structure of formation is hydrophobic alternate with hydrophilic radical, has both been conducive to preparations shaping and divided dose is quasi-
Really, the rate of release of divalproex sodium is reduced indirectly to the affinity of aqueous solution by reducing material in preparation, pass through ion
Key introduces double valproic acid roots, further increases slow release effect；Material of main part biodegradable properties are good, are used conveniently and safely；Point
Oleamide MEA sulfosuccinate disodium, vinyl pyrrolidone, vinyl alcohol acid modified amido hydroxypropyl are introduced in subchain
The double valproate structures of cellulose copolymer, so that advantage of the sustained release tablets with these three substances, can effectively improve its enteric
Property, bond properties, emulsifying effectiveness is good, to ensure that slow release effect, this polymer molecular structure is three-dimensional net structure, has
Effect improves its comprehensive performance.
(4) Divalproex sodium sustained-release tablet provided by the invention, not only solve that particle in wet-granulation process bonds asks
Topic, and resulting sample size is uniform, and avoiding leads to drug formulation release rate substantially because bulk pharmaceutical chemicals mixing is uneven
Fluctuation, it is ensured that process stabilizing advantageously ensures that the safety of preparation clinical application.
(5) Divalproex sodium sustained-release tablet provided by the invention does not use traditional hydroxypropyl for relying primarily on external import
Ylmethyl cellulose, reduces costs, and sustained release tablets good biocompatibility can effectively improve the convenience of clinical application, not need
Package enteric coating can accurately realize enteron aisle positioning release, reduce the irritation to stomach, be suitable for different age people
Intestines peristalsis and pH environment and it can be avoided the influence to drug release such as diet.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, and make features described above of the invention,
Purpose and advantage are more clear understandable, and the present invention will be further explained with reference to the examples below.Embodiment is only used for
It is bright the present invention rather than limit the scope of the invention.
Raw material described in the following embodiments of the present invention is from upper Haiquan sunrise foreign trade Co., Ltd.
Embodiment 1
It is a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, be made of the raw material of following parts by weight: divalproex sodium
40 parts, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid change
Property hydroxy amino propyl cellulose copolymer double 15 parts of valproates, 3 parts of povidone, 3 parts of ethyl cellulose, 1 part of glycerol, stearic
1 part of sour magnesium, 5 parts of water.
The ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-ethylene second
The preparation method of the double valproates of alkyd modified hydroxy amino propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex 30g in anhydrous pyridine 100g, then 3 are added thereto,
4- epoxybutyl-beta- cellobioside 10g and sodium hydroxide 6g, are stirred to react 8 hours, nothing is evaporated off in back spin at 80 DEG C
Water pyridine, then crude product is poured into acetone, after the solid of precipitation is washed with water 3 times, finally at 70 DEG C of vacuum oven
Drying obtains intermediate product to constant weight；
The intermediate product 20g, the acrylic acid chloroethene ester 10g that are prepared by step I are added to methylene chloride 100g by II
In, reaction 6 hours is stirred at room temperature, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose 10g, vinyl alcohol acid 20g, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,
2- dihydroquinoline 3g is added in tetrahydrofuran 100g, after be stirred to react at 30 DEG C 18 hours, solvent is evaporated off in back spin, with two
Chloromethanes is washed 3 times, and methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV by the ionization being prepared by step II Tanabe Seiyoku 10g, the ethylene that is prepared by step III
Glycolic modified amido hydroxy propyl cellulose 10g, n-vinyl pyrrolidone 10g, oleamide MEA sulfosuccinate disodium
20g, azodiisobutyronitrile 0.5g are added in dimethyl sulfoxide 150g, are stirred to react at 65 DEG C of nitrogen atmosphere 4 hours, after third
It settles out in ketone, then is placed at 70 DEG C of vacuum oven and dries to constant weight, obtain copolymer；
V is added to the copolymer 1 0g, the divalproex sodium 3g that are prepared by step IV in water 200g, at 70 DEG C
It is stirred to react 10 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulphur
The double valproates of base succinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
It is described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy, include the following steps: raw material
It is mixed to get mixture in proportion, then adds mixture into mixed method granulator and mixes well, carries out high speed granulation, it will be obtained
Wet granular is dry, and according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
Embodiment 2
It is a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, be made of the raw material of following parts by weight: divalproex sodium
43 parts, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid change
Property hydroxy amino propyl cellulose copolymer double 16 parts of valproates, 4 parts of starch, 4 parts of lactose, 2 parts of glycerol, 2 parts of silica,
6 parts of water.
The ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-ethylene second
The preparation method of the double valproates of alkyd modified hydroxy amino propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex 35g in anhydrous pyridine 110g, then 3 are added thereto,
4- epoxybutyl-beta- cellobioside 10g and potassium hydroxide 6g, are stirred to react 8.5 hours, back spin is evaporated off at 82 DEG C
Anhydrous pyridine, then crude product is poured into acetone, after the solid of precipitation is washed with water 4 times, finally at 73 DEG C of vacuum oven
Lower drying obtains intermediate product to constant weight；
The intermediate product 20g, the acrylic acid chloroethene ester 10g that are prepared by step I are added to methylene chloride 110g by II
In, reaction 6.5 hours is stirred at room temperature, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose 10g, vinyl alcohol 20g acid, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,
2- dihydroquinoline 3g is added in tetrahydrofuran 110g, after be stirred to react at 32 DEG C 19 hours, solvent is evaporated off in back spin, with two
Chloromethanes is washed 4 times, and methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV by the ionization being prepared by step II Tanabe Seiyoku 10g, the ethylene that is prepared by step III
Glycolic modified amido hydroxy propyl cellulose 10g, n-vinyl pyrrolidone 10g, oleamide MEA sulfosuccinate disodium
20g, azobisisoheptonitrile 0.5g are added in n,N-Dimethylformamide 160g, are stirred to react 4.5 at 68 DEG C of helium atmosphere
Hour, after settle out in acetone, then be placed at 72 DEG C of vacuum oven dry to constant weight, obtain copolymer；
V is added to the copolymer 1 0g, the divalproex sodium 3g that are prepared by step IV in water 230g, at 73 DEG C
It is stirred to react 10.5 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA
The double valproates of sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
It is described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy, include the following steps: raw material
It is mixed to get mixture in proportion, then adds mixture into mixed method granulator and mixes well, carries out high speed granulation, it will be obtained
Wet granular is dry, and according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
Embodiment 3
It is a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, be made of the raw material of following parts by weight: divalproex sodium
45 parts, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid change
Property hydroxy amino propyl cellulose copolymer double 18 parts of valproates, 4 parts of microcrystalline cellulose, 5 parts of calcium monohydrogen phosphate, 3 parts of glycerol, micro-
2 parts of powder silica gel, 7 parts of water.
The ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-ethylene second
The preparation method of the double valproates of alkyd modified hydroxy amino propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex 40g in anhydrous pyridine 130g, then 3 are added thereto,
4- epoxybutyl-beta- cellobioside 10g and sodium carbonate 6g, are stirred to react 9 hours, back spin is evaporated off anhydrous at 86 DEG C
Pyridine, then crude product is poured into acetone, after the solid of precipitation is washed with water 4 times, finally done at 76 DEG C of vacuum oven
It is dry to constant weight, obtain intermediate product；
The intermediate product 20g, the acrylic acid chloroethene ester 10g that are prepared by step I are added to methylene chloride 130g by II
In, reaction 7 hours is stirred at room temperature, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose 10g, vinyl alcohol acid 20g, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,
2- dihydroquinoline 3g is added in tetrahydrofuran 120g, after be stirred to react at 35 DEG C 20 hours, solvent is evaporated off in back spin, with two
Chloromethanes is washed 4 times, and methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV by the ionization being prepared by step II Tanabe Seiyoku 10g, the ethylene that is prepared by step III
Glycolic modified amido hydroxy propyl cellulose 10g, n-vinyl pyrrolidone 10g, oleamide MEA sulfosuccinate disodium
20g, azodiisobutyronitrile 0.5g are added in N-Methyl pyrrolidone 180g, are stirred to react at 75 DEG C of neon atmosphere 5 hours,
It settles out in acetone afterwards, then is placed at 75 DEG C of vacuum oven and dries to constant weight, obtain copolymer；
V is added to the copolymer 1 0g, the divalproex sodium 3g that are prepared by step IV in water 260g, at 76 DEG C
It is stirred to react 11 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulphur
The double valproates of base succinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
It is described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy, include the following steps: raw material
It is mixed to get mixture in proportion, then adds mixture into mixed method granulator and mixes well, carries out high speed granulation, it will be obtained
Wet granular is dry, and according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
Embodiment 4
It is a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, be made of the raw material of following parts by weight: divalproex sodium
48 parts, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid change
Property hydroxy amino propyl cellulose copolymer double 19 parts of valproate, 5 parts of pore-foaming agent, 7 parts of filler, 3 parts of glycerol, lubricant 3
Part, 9 parts of water.
The pore-foaming agent is the mixing that povidone, starch, microcrystalline cellulose, sucrose 1:2:3:2 in mass ratio are mixed
Object；The filler is that ethyl cellulose, lactose, calcium monohydrogen phosphate, calcium phosphate dibasic anhydrous are mixed by weight 3:1:2:4
Mixture；The lubricant be magnesium stearate, silica, superfine silica gel powder, talcum powder mass ratio mixed for 2:3:5:2
Mixture.
The ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-ethylene second
The preparation method of the double valproates of alkyd modified hydroxy amino propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex 45g in anhydrous pyridine 145g, then 3 are added thereto,
4- epoxybutyl-beta- cellobioside 10g and basic catalyst 6g, are stirred to react 9.5 hours, back spin is evaporated off at 88 DEG C
Remove anhydrous pyridine, then crude product be poured into acetone, after the solid of precipitation is washed with water 5 times, finally in vacuum oven 78
It dries at DEG C to constant weight, obtains intermediate product；The basic catalyst be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate by
The mixture that mass ratio 1:2:2:1 is mixed；
The intermediate product 20g, the acrylic acid chloroethene ester 10g that are prepared by step I are added to methylene chloride 145g by II
In, reaction 7.8 hours is stirred at room temperature, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose 10g, vinyl alcohol acid 20g, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,
2- dihydroquinoline 3g is added in tetrahydrofuran 145g, after be stirred to react at 38 DEG C 21 hours, solvent is evaporated off in back spin, with two
Chloromethanes is washed 5 times, and methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV by the ionization being prepared by step II Tanabe Seiyoku 10g, the ethylene that is prepared by step III
Glycolic modified amido hydroxy propyl cellulose 10g, n-vinyl pyrrolidone 10g, oleamide MEA sulfosuccinate disodium
20g, initiator 0.5g are added in high boiling solvent 195g, are stirred to react at 78 DEG C of argon atmosphere 5.5 hours, after in acetone
In settle out, then be placed at 78 DEG C of vacuum oven dry to constant weight, obtain copolymer；The initiator be azodiisobutyronitrile,
Azobisisoheptonitrile 3:5 in mass ratio is mixed；The high boiling solvent is dimethyl sulfoxide, N,N-dimethylformamide, N-
Methyl pyrrolidone 1:3:4 in mass ratio is mixed；
V is added to the copolymer 1 0g, the divalproex sodium 3g that are prepared by step IV in water 290g, at 78 DEG C
It is stirred to react 11.5 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA
The double valproates of sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
It is described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy, include the following steps: raw material
It is mixed to get mixture in proportion, then adds mixture into mixed method granulator and mixes well, carries out high speed granulation, it will be obtained
Wet granular is dry, and according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
Embodiment 5
It is a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, be made of the raw material of following parts by weight: divalproex sodium
50 parts, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid change
Property hydroxy amino propyl cellulose copolymer double 20 parts of valproate, 5 parts of sucrose, 8 parts of calcium phosphate dibasic anhydrous, 4 parts of glycerol, talcum
3 parts of powder, 10 parts of water.
The ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-ethylene second
The preparation method of the double valproates of alkyd modified hydroxy amino propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex 50g in anhydrous pyridine 150g, then 3 are added thereto,
4- epoxybutyl-beta- cellobioside 10g and potassium carbonate 6g, are stirred to react 10 hours, back spin is evaporated off anhydrous at 90 DEG C
Pyridine, then crude product is poured into acetone, after the solid of precipitation is washed with water 5 times, finally done at 80 DEG C of vacuum oven
It is dry to constant weight, obtain intermediate product；
The intermediate product 20g, the acrylic acid chloroethene ester 10g that are prepared by step I are added to methylene chloride 150g by II
In, reaction 8 hours is stirred at room temperature, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose 10g, vinyl alcohol acid 20g, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,
2- dihydroquinoline 3g is added in tetrahydrofuran 150g, after be stirred to react at 40 DEG C 22 hours, solvent is evaporated off in back spin, with two
Chloromethanes is washed 5 times, and methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV by the ionization being prepared by step II Tanabe Seiyoku 10g, the ethylene that is prepared by step III
Glycolic modified amido hydroxy propyl cellulose 10g, n-vinyl pyrrolidone 10g, oleamide MEA sulfosuccinate disodium
20g, azobisisoheptonitrile 0.5g are added in N-Methyl pyrrolidone 200g, are stirred to react at 80 DEG C of nitrogen atmosphere 6 hours,
It settles out in acetone afterwards, then is placed at 80 DEG C of vacuum oven and dries to constant weight, obtain copolymer；
V is added to the copolymer 1 0g, the divalproex sodium 3g that are prepared by step IV in water 300g, at 80 DEG C
It is stirred to react 12 hours, water is evaporated off in back spin, obtains ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulphur
The double valproates of base succinate disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
It is described a kind of for treating the preparation method of the Divalproex sodium sustained-release tablet of epilepsy, include the following steps: raw material
It is mixed to get mixture in proportion, then adds mixture into mixed method granulator and mixes well, carries out high speed granulation, it will be obtained
Wet granular is dry, and according to inspection result tabletting, Divalproex sodium sustained-release tablet is made.
Comparative example
Commercially available Divalproex sodium sustained-release tablet is purchased from Abbott, the U.S., specification 500mg, lot number 1019635.
The slow release effect of sustained release agent composition obtained by sustained release tablets and comparative example to above-described embodiment 1-5 is tested,
Test result is shown in Table 1, and test method is as follows: Example 1-5 and comparative example respectively, with 0.1mol/L hydrochloric acid solution
500ml, revolving speed are 100 turns per minute, are operated according to methods, and after 45min, filtering changes acid solution in cup into phosphate rapidly and delays
Solution (pH5.5) 900ml is rushed, continues to dissolve out 3h, 9h, 12h with for 24 hours, takes solution appropriate respectively, and mend in process container immediately
The phosphate buffer of equivalent is filled, is filtered, is measured as test solution.Each group Divalproex sodium sustained-release tablet is in USP device II
Under middle 100rpm, there is following dissolution feature:
Table 1
As it can be seen from table 1 Divalproex sodium sustained-release tablet slow release effect disclosed by the embodiments of the present invention can reach it is commercially available into
Mouthful liquid medicine is flat, since its is cheap, the value for clinical application that has had.
The basic principles, main features and advantages of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and what is described in the above embodiment and the description is only the present invention
Principle, various changes and improvements may be made to the invention without departing from the spirit and scope of the present invention, these variation and
Improvement is both fallen in the range of claimed invention.The present invention claims protection scope by appended claims and its
Equivalent defines.
Claims (10)
1. a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that be made of the raw material of following parts by weight: double
40-50 parts of sodium vedproate, ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-second
Alkene glycolic modified amido hydroxy propyl cellulose copolymer double 15-20 parts of valproates, 3-5 parts of pore-foaming agent, filler 3-8
Part, 1-4 parts of glycerol, 1-3 parts of lubricant, 5-10 parts of water.
2. according to claim 1 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that the cause
Hole agent is selected from one or more of povidone, starch, microcrystalline cellulose, sucrose；The filler is selected from ethyl cellulose, cream
One or more of sugar, calcium monohydrogen phosphate, calcium phosphate dibasic anhydrous；The lubricant is selected from magnesium stearate, silica, micro mist silicon
One or more of glue, talcum powder.
3. according to claim 1 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that it is described from
Sonization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinate disodium-vinyl alcohol acid modified amido hydroxyl
The preparation method of the double valproates of base propyl cellulose copolymer, includes the following steps:
I is added to single (6- amino -6- deoxidation) betadex in anhydrous pyridine, then 3 are added thereto, 4- epoxybutyl -
Beta- cellobioside and basic catalyst are stirred to react 8-10 hours at 80-90 DEG C, and anhydrous pyridine is evaporated off in back spin, then
Crude product is poured into acetone, after the solid of precipitation is washed with water 3-5 times, it is finally dry at 70-80 DEG C of vacuum oven
To constant weight, intermediate product is obtained；
II, by the intermediate product being prepared by step I, acrylic acid chloroethene ester adding into dichloromethane, is stirred at room temperature
Reaction 6-8 hours, methylene chloride is evaporated off in back spin, obtains ionization Tanabe Seiyoku；
III by 3- amino -2- hydroxy propyl cellulose, vinyl alcohol acid, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline
Be added in tetrahydrofuran, after be stirred to react at 30-40 DEG C 18-22 hours, solvent is evaporated off in back spin, washes 3- with methylene chloride
5 times, methylene chloride is evaporated off in back spin, obtains vinyl alcohol acid modified amido hydroxy propyl cellulose；
IV changes the ionization Tanabe Seiyoku being prepared by step II, the vinyl alcohol acid being prepared by step III
Property hydroxy amino propyl cellulose, n-vinyl pyrrolidone, oleamide MEA sulfosuccinate disodium, initiator are added to
In high boiling solvent, be stirred to react at nitrogen or 65-80 DEG C of atmosphere of inert gases 4-6 hours, after settle out in acetone, then set
It dries at 70-80 DEG C of vacuum oven to constant weight, obtains copolymer；
V is added to the water the copolymer, the divalproex sodium that are prepared by step IV, is stirred to react at 70-80 DEG C
10-12 hours, water was evaporated off in back spin, obtained ionization Tanabe Seiyoku base vinyl pyrrolidone-oleamide MEA sulfosuccinic
The double valproates of acid esters disodium-vinyl alcohol acid modified amido hydroxy propyl cellulose copolymer.
4. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that step I
Described in single (6- amino -6- deoxidation) betadex, anhydrous pyridine, 3,4- epoxybutyl-beta- cellobioside, alkalinity
The mass ratio of catalyst is (3-5): (10-15): 1:0.6；The basic catalyst is selected from sodium hydroxide, potassium hydroxide, carbonic acid
One or more of sodium, potassium carbonate.
5. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that step II
Described in intermediate product, acrylic acid chloroethene ester, methylene chloride mass ratio be 2:1:(10-15).
6. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that step III
Described in 3- amino -2- hydroxy propyl cellulose, vinyl alcohol acid, 2- ethyoxyl -1- ethoxy carbonic acyl radical -1,2- dihydroquinoline,
The mass ratio of tetrahydrofuran is 1:2:0.3:(10-15).
7. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that step IV
Described in ionization Tanabe Seiyoku, vinyl alcohol acid modified amido hydroxy propyl cellulose, n-vinyl pyrrolidone, oleoyl
Amine MEA sulfosuccinate disodium, initiator, high boiling solvent mass ratio be 1:1:1:2:0.05:(15-20).
8. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that described to draw
It sends out agent and is selected from least one of azodiisobutyronitrile, azobisisoheptonitrile；The high boiling solvent is selected from dimethyl sulfoxide, N, N-
One or more of dimethylformamide, N-Methyl pyrrolidone；The inert gas is in helium, neon, argon gas
It is a kind of.
9. according to claim 3 a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy, which is characterized in that step V
Described in copolymer, divalproex sodium, water mass ratio be 1:0.3:(20-30).
10. -9 is described in any item a kind of for treating the Divalproex sodium sustained-release tablet of epilepsy according to claim 1, feature exists
In, the preparation method of the Divalproex sodium sustained-release tablet includes the following steps: for raw material to be mixed to get mixture in proportion, then
It adds mixture into mixed method granulator and mixes well, carry out high speed granulation, wet granular obtained is dry, according to inspection result
Divalproex sodium sustained-release tablet is made in tabletting.
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