CN1921838A - Extended release pharmaceutical compositions of divalproex sodium - Google Patents
Extended release pharmaceutical compositions of divalproex sodium Download PDFInfo
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- CN1921838A CN1921838A CNA2005800054532A CN200580005453A CN1921838A CN 1921838 A CN1921838 A CN 1921838A CN A2005800054532 A CNA2005800054532 A CN A2005800054532A CN 200580005453 A CN200580005453 A CN 200580005453A CN 1921838 A CN1921838 A CN 1921838A
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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
- A61K9/2004—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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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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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
- A61K9/2004—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
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- 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
- A61P25/06—Antimigraine agents
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- 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
- A61P25/08—Antiepileptics; Anticonvulsants
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The present invention relates to a sustained release preparation comprising valproic acid and the pharmaceutical acceptable salt, ester or amide, or divalproex sodium, and a preparation method of the sustained release preparation.
Description
Technical field
The present invention relates to comprise valproic acid, and the slow releasing preparation of pharmaceutically acceptable salt, ester or amide or divalproex sodium (divalproex sodium) and preparation method thereof.
Background of invention
Valproic acid, 2-valproic acid and derivant thereof are widely used for treating mania, migraine and epilepsy.These chemical compounds become the valproic acid radical ion at the gastrointestinal tract internal disintegration.
Some physical propertys of valproic acid and derivant thereof have problems it when being mixed with dosage form.They are liquid or liquefaction rapidly, and have viscosity.And with regard to character, the extremely moisture absorption of most of valproic acids and derivant thereof.These physicochemical properties of valproic acid and derivant thereof make it have serious problems when making pharmaceutical composition.
In addition, the elimination half-life of valproic acid and derivant thereof is also shorter.For example, report that the half-life of valproic acid was 4-14 hour among the child among the adult between 6-17 hour.For keeping the plasma concentration of reasonably stability, need frequent drug administration.And this causes patient's inconvenience, and finally causes patient's poor compliance and plasma concentration fluctuation greatly.
United States Patent (USP) 6,419,953 disclose a kind of sustained-release matrix tablets, and it comprises the silicon dioxide of the about 1-10 micron of valproate chemical compound, hydroxypropyl emthylcellulose, lactose, microcrystalline Cellulose and mean diameter.This patent also discloses, and 1% silicon dioxide and/or 5% microcrystalline Cellulose is joined in this invention hydrophilic skeleton preparation tablet hardness is doubled.Yet, when using conventional grade of other silicon dioxide, still have problem of viscosity, and can only overcome by using particle mean size other silicon dioxide of a specific order (Syloid 244) less, that be about the 1-10 micron.
Summary of the invention
On the one hand, the invention provides a kind of sustained release pharmaceutical composition.Said composition comprises can decompose medicine, the high viscosity grade hydroxypropyl emthylcellulose of about 15-50 weight % and the low viscosity level hydroxypropyl emthylcellulose of about 0.1-10 weight % that produces the valproic acid radical ion.
The embodiment of this pharmaceutical composition comprises one or more following characteristics.For example, can decompose the medicine that produces the valproic acid radical ion can be valproic acid and pharmaceutically acceptable salt, ester and amide.Valproate can be a divalproex sodium, and content accounts for about 10-90 weight % of pharmaceutical composition gross weight.
Pharmaceutical composition of the present invention can be administration once a day.Pharmaceutical composition can be tablet or capsule.
The high viscosity grade hydroxypropyl emthylcellulose can be the sign viscosity of its 2% aqueous solution greater than about 10,000cP or indicate viscosity and be about 10,000-100, the high viscosity grade hydroxypropyl emthylcellulose of 000cP.The amount that the high viscosity grade hydroxypropyl emthylcellulose exists can be about 20-40 weight % of pharmaceutical composition gross weight.
Low viscosity level hydroxypropyl emthylcellulose can be the sign viscosity of its 2% aqueous solution less than about 1,000cP or indicate the low viscosity level hydroxypropyl emthylcellulose that viscosity is about 5-100cP.The amount that low viscosity level hydroxypropyl emthylcellulose exists can be about 1-5 weight % of pharmaceutical composition gross weight.
Described sustained release pharmaceutical composition also can comprise one or more pharmaceutically inert adjuvants.These one or more pharmaceutically inert adjuvant can be one or more fluidizer, lubricant, diluent and binding agent.
Described sustained release pharmaceutical composition can not contain microcrystalline Cellulose.
On the other hand, the invention provides the method for preparing sustained release pharmaceutical composition.This method comprises: mixing can be decomposed medicine, the high viscosity grade hydroxypropyl emthylcellulose of about 15-50 weight % and the low viscosity level hydroxypropyl emthylcellulose of about 0.1-10 weight % that produces the valproic acid radical ion, to form mixture; Randomly with this mixture pelleting; Lubricated this mixture; With the compacting or be filled in the solid dosage forms of suitable size.
The embodiment of described method comprises one or more following characteristics.For example, for example, can decompose the medicine that produces the valproic acid radical ion can be valproic acid and pharmaceutically acceptable salt, ester and amide, or divalproex sodium.
Pharmaceutical composition can be tablet or capsule.
Can carry out pelletize by wet granulation, non-slurry pelletizing or extrusion by melting.
On the other hand, the invention provides the method for in the patient of this treatment of needs, treating mania, migraine and epilepsy.This method comprises the sustained release pharmaceutical composition of the low viscosity level hydroxypropyl emthylcellulose that comprises the high viscosity grade hydroxypropyl emthylcellulose that can decompose the medicine that produces the valproic acid radical ion, about 15-50 weight % and about 0.1-10 weight %.
Detailed Description Of The Invention
The inventor has now developed a kind of pharmaceutical composition for oral administration, and said composition comprises can decompose medicine, high viscosity grade hydroxypropyl emthylcellulose and the low viscosity level hydroxypropyl emthylcellulose that produces the valproic acid radical ion.The inventor finds that low viscosity level hydroxypropyl emthylcellulose helps to keep the skeleton integrity, thereby plays an important role from the release of skeleton at the control medicine.
Once a day after the administration, sustained release pharmaceutical composition prolong the time ask and discharge medicine in the scope, so that lasting drug plasma concentration to be provided.
Term " pharmaceutical composition " comprises all solids dosage form as used herein, as tablet, capsule, pill etc.Tablet can prepare by methods known in the art, comprises the valproate chemical compound for the treatment of effective dose.Can use by these technology and form necessary one or more acceptable accessories of tablet.Also can prepare tablet and pill, to reach the acid protection, purpose such as to swallow easily with enteric coating and other controlled release coat.
Term " the internal energy decomposition of gastrointestinal tract produces the medicine of valproic acid radical ion " is included in and decomposes the chemical compound that produces the valproic acid radical ion in the intestines and stomach, comprises the salt of valproic acid, valproic acid sodium salt, divalproex sodium, following any valproic acid and the prodrug of following any valproic acid.
Known valproic acid has the activity as the epilepsy chemical compound, as at " doctor's desk reference " (Physician Desk Reference), and the 52nd edition, the 422nd page, described in 1998.During orally ingestible, acid moieties is decomposed to form carboxylate part (being the valproic acid radical ion) in intestines and stomach.
The also known sodium salt of valproic acid in this area is as Anti-epileptics.Also known is sodium valproate, and at MerckIndex, the 12nd volume is described in detail in the 1691st page (1996).
Divalproex sodium (two valproic acid hydrogen sodium) is effective Anti-epileptics, also can be used for migraine and two-phase sexual disorders.Be similar to valproic acid, it also can decompose the generation valerate ion in gastrointestinal tract.It is a kind of stable coordination compound, comprises 1: the sodium valproate of l and valproic acid, and with forming in the 0.5 Equivalent Hydrogen sodium oxide part and during valproic acid.The amount of medicine can change between about 10-90 weight % of pharmaceutical composition gross weight.
Except these concrete chemical compounds, those of ordinary skills understand that easily the carboxylic moiety of valproate compound can be functionalized in every way.This comprises and forms easily the chemical compound that metabolism in vivo produces valproate such as valproic acid amide, and other pharmaceutically acceptable amide and ester (being prodrug) that should acid.Also comprise various pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable base addition salts includes but not limited to: based on the cation of alkali metal or alkaline-earth metal, comprise lithium, sodium, potassium, calcium, magnesium and aluminum salt; Non-toxicity quaternary ammonium and amine cation comprise ammonium, tetramethylammonium, etamon, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine and ethamine.Other representative organic amines that are used to form base addition salts comprise ethylenediamine, ethanolamine, diethanolamine, piperidines and piperazine.
Other possible chemical compounds comprise pharmaceutically acceptable amide and ester." pharmaceutically acceptable ester " refer to when ester linkage hydrolyzing, keeps biological effectiveness and carboxylic acid character and those esters of undesirable character or other undesirable character biologically not.The alcohol moiety of ester generally comprises (i) C
2-C
12Aliphatic alcohol can have the carbon that one or more pairs of keys also can have side chain; Or (ii) C
7-C
12Aromatic alcohol or heteroaromatic alcohols.The present invention also considers to use to be ester and to be those compositionss of its pharmaceutically acceptable salt simultaneously.
" pharmaceutically acceptable amide " refer to when the amido link hydrolysis, keeps biological effectiveness and carboxylic acid character and those amide of undesirable character or other undesirable character biologically not.The present invention also considers to use to be above-mentioned amide and to be those compositionss of its pharmaceutically acceptable salt simultaneously.
Term " sustained release pharmaceutical composition " comprises any pharmaceutical composition that can slowly discharge medicine in the time cycle that prolongs here, comprises the compositions that prolongs release and sustained release.
The sign viscosity that term " high viscosity grade hydroxypropyl emthylcellulose " comprises its 2 weight % aqueous solution here is greater than about 10, the hydroxypropyl emthylcellulose rank of 000cP.
The sign viscosity that term " low viscosity level hydroxypropyl emthylcellulose " comprises its 2 weight % aqueous solution here is less than about 1, the hydroxypropyl emthylcellulose rank of 000cP.
Also can use the hydroxypropyl methyl cellulose polymers of hydrophilic, different viscosities level, comprise available from the Methocel TM of DowChemical company with available from the Metolose of Shin Etsu Ltd..The example of high viscosity hydroxypropyl methyl cellulose polymers comprises Methocel K15M, Methocel K100M, Methocel E10M, Metolose 90SH 15000 and Metolose 90SH 39000, its 2 weight % viscosity in aqueous solution is respectively 15,000cP, 100,000cP, 10,000cP, 15,000cP and 39,000cP.The working concentration of high viscosity grade hydroxypropyl methyl cellulose polymers is about 15-50 weight %, especially is about 20-40 weight %.
Low viscosity level hydroxypropyl methyl cellulose polymers comprises Methocel E5, Methocel E-15LV, MethocelE50LV, Methocel K100LV, Methocel F50LV, Methocel E6LV, MethocelA15LV and Metolose 60SH 50, and its 2 weight % viscosity in aqueous solution is respectively 5cP, 15cP, 50cP, 100cP, 50cP, 6cP, 15cP and 50cP.The working concentration of low viscosity level hydroxypropyl methyl cellulose polymers is about 0.1-10 weight %, especially is about 1-5 weight %.
Can pass through methods known in the art, for example, pulverize, mix, pelletize, fusing, screening is filled, and drying is molded, dipping, coating, one or more in the compacting prepare sustained release pharmaceutical composition.
Can prepare sustained release pharmaceutical composition by wet granulation.This method comprises: will in gastrointestinal tract, can decompose the medicine that produces the valproic acid radical ion and one or more release polymer and randomly one or more pharmacy inert excipients mix; With mixture and granulation liquid, or binder solution/dispersion liquid carries out pelletize; Drying and screening granule; Choose wantonly with the outer adjuvant of the inert granule of one or more pharmacy and mix; Lubricated granules/mixture; Lubricated mixture/granule is pressed into sizeable tablet; Randomly use one or more film forming polymers and coating additive coating.
Also can prepare sustained release pharmaceutical composition by non-slurry pelletizing.This method comprises: will in gastrointestinal tract, can decompose the medicine that produces the valproic acid radical ion and one or more release polymer and randomly one or more pharmacy inert excipients mix; By roller type press or slugging with the mixture non-slurry pelletizing; Lubricated granules/mixture; Lubricated mixture/granule is pressed into sizeable tablet; Randomly use one or more film forming polymers and coating additive coating.
Also can prepare sustained release pharmaceutical composition by straight pressing.This method comprises: will in gastrointestinal tract, can decompose the medicine that produces the valproic acid radical ion and one or more release polymer and randomly one or more pharmacy inert excipients mix; Lubrication mixture; Lubricated mixture directly is pressed into sizeable tablet; Randomly use one or more film forming polymers and coating additive coating.
Can prepare sustained release pharmaceutical composition by extrusion by melting.This method comprises: will in gastrointestinal tract, can decompose the medicine that produces the valproic acid radical ion and one or more release polymer and randomly one or more pharmacy inert excipients mix; Behind the molten mixture, it is cured as DB; Broken this DB forms granule; Randomly mix with the outer adjuvant of one or more pharmacy inert particles; Lubricated granules/mixture; Lubricated mixture/granule is pressed into sizeable tablet; Randomly use one or more film forming polymers and coating additive coating.
Term " pharmaceutically acceptable inert excipients " comprises all adjuvants that use in the solid dosage forms manufacturing field as used herein.Example comprises one or more in binding agent, diluent, surfactant, lubricants, coloring agent and composition thereof.
The suitable bonding example comprises: methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, gelatin, arabic gum, ethyl cellulose, polyvinyl alcohol, amylopectin, pregelatinised starch, agar, Calculus Bovis from Northwest of China are had a liking for one or more in glue, sodium alginate, propylene glycol and composition thereof.
Suitable diluent comprises: calcium carbonate, secondary calcium phosphate (calcium phosphate-dibasic), tertiary calcium phosphate (calcium phosphate-tribasic) but, in calcium sulfate, microcrystalline Cellulose, cellulose powder, dextrates, dextrin, glucose adjuvant, fructose, Kaolin, lactose, lactose, mannitol, Sorbitol, starch, pregelatinized starch, sucrose pressing sugar, confection and composition thereof one or more.
Surfactant comprises nonionic and ion (cation, anion and the both sexes) surfactant that is applicable to pharmaceutical dosage form.These comprise: polyethoxylated fatty acid and derivant thereof, for example, PEG400 distearate, Polyethylene Glycol 20-dioleate, the single dilaurate of Polyethylene Glycol 4-150, Polyethylene Glycol-20 tristerin; Alcohol-oily anti-esterification mixture, for example, Polyethylene Glycol-6 Semen Maydis oil; The bound to polyglycerol fatty acid, for example, polyglyceryl-6 five oleate; Methyl glycol fatty acid ester, for example, Capryol 90; List and two glycerol, for example, castor oil acid glyceride; Sterol and sterol derivative; Sorbitan fatty acid esters and derivant thereof, for example, Polyethylene Glycol-20 dehydrated sorbitol mono-fatty acid ester, sorbitan monolaurate; Polyethylene glycol alkyl ether or phenol, for example, Polyethylene Glycol-20 cetyl ether, Polyethylene Glycol-10-100 nonyl phenol; Sugar esters, for example, sucrose palmitic acid ester; Polyox-yethylene-polyoxypropylene block copolymer, be called " poloxamer "; Ionic surfactant, for example, Sodium caproate, NaGC, soybean lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl group disodium sulfosuccinate, palmitoyl carnitine etc.
Examples of suitable lubricants/incremental dose comprises: one or more in the sucrose ester of silica sol, stearic acid, magnesium stearate, calcium stearate, Talcum, castor oil hydrogenated, fatty acid, microwax, yellow beeswax, cera alba and composition thereof.
Coloring agent comprises any color that the FDA approval orally uses.
If desired, pharmaceutical composition can randomly have and comprises the functional of film forming polymer and/or non-functional layer coating.
Suitable film forming polymer comprises: ethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, cellulose acetate, Hydroxypropyl Methylcellulose Phathalate, Cellacefate, acetic acid trihemellitic acid cellulose; Wax, as Polyethylene Glycol; Among methacrylate polymer such as Eudragit R1 and RS and composition thereof one or more.Perhaps, also can use with multiple trade name such as Opadry commercially available coated composition that sell, that comprise film forming polymer.
Following embodiment has further described the present invention, embodiment be illustrative purpose and should not be construed as by any way and limit the scope of the invention.
Embodiment 1
In the rapid mixing comminutor, mix divalproex sodium, lactose, Methocel K-15M CR and MethocelE-5.By granulation liquid (purified water) being joined in drug/polymer/milk-sugar mixture the preparation granule.Dry gained granule in fluid bed dryer is by suitable screen cloth screening.Dried granules is mixed with Pulvis Talci, silica sol and magnesium stearate, be pressed into the tablet of suitable size, and with PEG 400 and Opadry aqueous liquid dispersion coating.
Table 1: the composition of divalproex sodium slow releasing tablet
| Composition | Weight/sheet (mg) embodiment 1 |
| Divalproex sodium | 542.3 |
| Lactose | 90.0 |
| Methocel K-15M CR | 320.0 |
| Methocel E-5 | 20.0 |
| Water | In right amount |
| Magnesium stearate | 5.0 |
| Pulvis Talci | 8.0 |
| Silica sol | 17.0 |
External dissolution test
Adopt USP II type device, oar rotating speed 100rpm contains in the phosphate buffer (pH6.8) of 1% sodium laurylsulfate at 900ml, and the divalproex sodium slow releasing tablet of forming shown in embodiment 1 is carried out external dissolution test, and slow releasing tablet is placed the sedimentation basket No. 10.The result is as shown in table 2.
Table 2: the drug release profile of slow releasing preparation
| Time (hour) | Medicine is from the cumulative percentage rate of the preparation release of embodiment 1 |
| 1 | 16 |
| 2 | 27 |
| 4 | 35 |
| 8 | 53 |
| 12 | 69 |
| 16 | 78 |
| 20 | 92 |
| 24 | 102 |
Though above described concrete preparation, should understand, do not deviate from the scope of spirit of the present invention and can carry out various improvement and combination the preparation that this paper describes in detail.For example, can change the concentration of high viscosity grade and low viscosity level polymer, as shown in table 3.
Table 3: the composition of divalproex sodium slow releasing tablet
| Composition | Weight/sheet (mg) embodiment 2 | Weight/sheet (mg) embodiment 3 | Weight/sheet (mg) embodiment 4 |
| Divalproex sodium | 542.3 | 542.3 | 538.1 |
| Lactose | 90.0 | 90.0 | 68.6 |
| Methocel K-15M CR | 310.0 | 330.0 | 360.0 |
| Methocel E-5 | 30.0 | 12.0 | 8.0 |
| Water | In right amount | In right amount | In right amount |
| Magnesium stearate | 5.0 | 5.0 | 3.0 |
| Pulvis Talci | 8.0 | 8.0 | 7.3 |
| Silica sol | 17.0 | 17.0 | 15.0 |
Following examples have been described employing embodiment 1 described method, comprise the preparation of the divalproex sodium that is equivalent to the 750mg valproic acid.
Embodiment 5
| Composition | Weight/sheet (mg) embodiment 5 |
| Divalproex sodium | 807.15 |
| Lactose | 18.90 |
| Methocel K-100MCR | 254.0 |
| Methocel E-5 | 6.0 |
| Water | In right amount |
| Magnesium stearate | 3.0 |
| Pulvis Talci | 10.95 |
| Silica sol | 22.5 |
Therefore, sustained-release tablet preparation of the present invention provides a kind of effective delivery system, and the patient who is used for once a day needs being treated gives valproic acid (divalproex sodium).
Though described specific embodiment more of the present invention, some improves and the equivalent form of value it will be apparent to those skilled in the art that, and is included in the scope of the present invention.
Claims (21)
1. sustained release pharmaceutical composition, described pharmaceutical composition comprises:
A) can decompose the medicine that produces the valproic acid radical ion;
B) the high viscosity grade hydroxypropyl emthylcellulose of about 15-50 weight %; With
C) the low viscosity level hydroxypropyl emthylcellulose of about 0.1-10 weight %.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the described medicine that produces the valproic acid radical ion that can decompose comprises valproic acid and pharmaceutically acceptable salt, ester and amide.
3. pharmaceutical composition as claimed in claim 2 is characterized in that described valproate comprises divalproex sodium.
4. pharmaceutical composition as claimed in claim 3 is characterized in that, described divalproex sodium accounts for the 10-90 weight % of pharmaceutical composition gross weight.
5. pharmaceutical composition as claimed in claim 1 is characterized in that described pharmaceutical composition is used for administration once a day.
6. pharmaceutical composition as claimed in claim 1 is characterized in that, the sign viscosity that described high viscosity grade hydroxypropyl emthylcellulose comprises its 2% aqueous solution is greater than about 10, the high viscosity grade hydroxypropyl emthylcellulose of 000cP.
7. pharmaceutical composition as claimed in claim 6 is characterized in that, it is about 10 that described sign viscosity comprises, 000-100,000cP.
8. pharmaceutical composition as claimed in claim 1 is characterized in that, described high viscosity grade hydroxypropyl emthylcellulose accounts for the 20-40 weight % of pharmaceutical composition gross weight.
9. pharmaceutical composition as claimed in claim 1 is characterized in that, the sign viscosity that described low viscosity level hydroxypropyl emthylcellulose comprises its 2% aqueous solution is less than about 1, the low viscosity level hydroxypropyl emthylcellulose of 000cP.
10. pharmaceutical composition as claimed in claim 9 is characterized in that, described sign viscosity comprises about 5-100cP.
11. pharmaceutical composition as claimed in claim 1 is characterized in that, described low viscosity level hydroxypropyl emthylcellulose accounts for the 1-5 weight % of pharmaceutical composition gross weight.
12. pharmaceutical composition as claimed in claim 1 is characterized in that, described pharmaceutical composition comprises tablet or capsule.
13. pharmaceutical composition as claimed in claim 1 is characterized in that, described sustained release pharmaceutical composition also comprises one or more pharmacy inert excipients.
14. pharmaceutical composition as claimed in claim 13 is characterized in that, described one or more pharmacy inert excipients comprise one or more in fluidizer, lubricant, diluent and the binding agent.
15. pharmaceutical composition as claimed in claim 1 is characterized in that, described sustained release pharmaceutical composition does not contain microcrystalline Cellulose.
16. a method for preparing sustained release pharmaceutical composition, described method comprises:
A) mixing energy decomposes medicine, the high viscosity grade hydroxypropyl emthylcellulose of about 15-50 weight % and the low viscosity level hydroxypropyl emthylcellulose of about 0.1-10 weight % that produces the valproic acid radical ion, to form mixture;
B) randomly with this mixture pelleting;
C) lubricated described mixture; With
D) suppress or be filled in the sizeable solid dosage forms.
17. method as claimed in claim 16 is characterized in that, the described medicine that produces the valproic acid radical ion that can decompose comprises valproic acid and pharmaceutically acceptable salt, ester and amide.
18. method as claimed in claim 16 is characterized in that, the described medicine that produces the valproic acid radical ion that can decompose comprises divalproex sodium.
19. method as claimed in claim 16 is characterized in that, described pharmaceutical composition comprises tablet or capsule.
20. method as claimed in claim 16 is characterized in that, carries out pelletize by wet granulation, non-slurry pelletizing or extrusion by melting.
21. a method for the treatment of mania, migraine and epilepsy in the patient of needs treatment, described method comprises the sustained release pharmaceutical composition that comprises following composition:
A. can decompose the medicine that produces the valproic acid radical ion;
B. the high viscosity grade hydroxypropyl emthylcellulose of about 15-50 weight %; With
C. the low viscosity level hydroxypropyl emthylcellulose of about 0.1-10 weight %.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN237DE2004 | 2004-02-19 | ||
| IN237/DEL/2004 | 2004-02-19 |
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| CN1921838A true CN1921838A (en) | 2007-02-28 |
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|---|---|---|---|
| CNA2005800054532A Pending CN1921838A (en) | 2004-02-19 | 2005-02-18 | Extended release pharmaceutical compositions of divalproex sodium |
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| WO (1) | WO2005079753A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102138911A (en) * | 2011-03-28 | 2011-08-03 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN105012264A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate sustained release tablet as well as preparation process and application thereof |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| WO2018086550A1 (en) * | 2016-11-11 | 2018-05-17 | 南京希尔寿生物科技有限公司 | Biological active component colon-targeted composition and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2643556B1 (en) * | 1989-02-27 | 1993-03-05 | Sanofi Sa | PHARMACEUTICAL COMPOSITION WITH SUSTAINED RELEASE OF VALPROIC ACID |
| US6419953B1 (en) * | 1998-12-18 | 2002-07-16 | Abbott Laboratories | Controlled release formulation of divalproex sodium |
| AU2003240164A1 (en) * | 2002-06-07 | 2003-12-22 | Ranbaxy Laboratories Limited | Extended release formulation of divalproex sodium |
| WO2004071421A2 (en) * | 2003-02-05 | 2004-08-26 | Teva Pharmaceutical Industries Ltd. | Sustained release formulation of n-(2-propylpentanoyl) glycinamide and related compounds |
-
2005
- 2005-02-18 WO PCT/IB2005/000420 patent/WO2005079753A2/en active Application Filing
- 2005-02-18 CN CNA2005800054532A patent/CN1921838A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102138911A (en) * | 2011-03-28 | 2011-08-03 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN102138911B (en) * | 2011-03-28 | 2012-12-12 | 孙卫东 | Divalproex sodium sustained release tablets and preparation method thereof |
| CN105012264A (en) * | 2014-04-16 | 2015-11-04 | 四川科瑞德制药有限公司 | Sodium valproate sustained release tablet as well as preparation process and application thereof |
| CN105012264B (en) * | 2014-04-16 | 2019-11-29 | 四川科瑞德制药股份有限公司 | Sustained-release Sodium Valproate and its preparation process and purposes |
| CN106389368A (en) * | 2015-07-29 | 2017-02-15 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained release preparation as well as preparation process and applications thereof |
| CN106389368B (en) * | 2015-07-29 | 2021-11-12 | 四川科瑞德制药股份有限公司 | Sodium valproate sustained-release preparation and preparation process and application thereof |
| WO2018086550A1 (en) * | 2016-11-11 | 2018-05-17 | 南京希尔寿生物科技有限公司 | Biological active component colon-targeted composition and application thereof |
| RU2744452C2 (en) * | 2016-11-11 | 2021-03-09 | Нанкин Хилсоул Лайф Сайенс Энд Текнолоджи Ко., Лтд. | Composition for targeted delivery of biologically active component into large intestine and its application |
| US11337926B2 (en) | 2016-11-11 | 2022-05-24 | Nanjing Healsoul Life Science And Technology Co., Ltd. | Colon-targeted composition of biological active component and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005079753A3 (en) | 2006-05-11 |
| WO2005079753A2 (en) | 2005-09-01 |
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