CN101484150B - Controlled release composition and preparation thereof - Google Patents
Controlled release composition and preparation thereof Download PDFInfo
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- CN101484150B CN101484150B CN2006800552797A CN200680055279A CN101484150B CN 101484150 B CN101484150 B CN 101484150B CN 2006800552797 A CN2006800552797 A CN 2006800552797A CN 200680055279 A CN200680055279 A CN 200680055279A CN 101484150 B CN101484150 B CN 101484150B
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- A—HUMAN NECESSITIES
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The present invention relates to a controlled release composition comprising hydrophobic cellulose, methacrylic acid copolymer and active ingredient in a form of uniform state. The present invention also relates to a method of preparing a controlled release tablet.
Description
Technical field
The present invention relates to controlled release composition and preparation method thereof.
Background technology
Slow release (sustained release) or controlled release (controlled release) drug-supplying system (drugdelivery system) can be helpful to the compliance that improves the patient by the frequency that reduces administration.Produced in several ways slow release or controlled-release administrating system have been used in the art.These methods comprise, for example, or are with macromolecular material tablet or microgranule to be carried out coating, or with the polymer manufacture tablet of insoluble or indissoluble.
For example, the coating of tablet or microgranule expends time in, and owing to usually adopt aqueous coatings, so it can not use in general in pharmaceutical pack is contained in the tablet of wetness sensitivity or microgranule the time.Similarly, thus a variety of variations of polymer can cause tablet to demonstrate unrenewable performance characteristic by complete polymer manufacture insoluble or indissoluble separately.(publication No. is 20060099254 United States Patent (USP))
The U.S. 5,055, No. 306 patent document discloses a kind of slow releasing preparation, it contains label (core) with active component, covers the coating on the whole surface of label in fact, coating comprises water insoluble but the ethyl acrylate (ethyl acrylate) of water-swellable and the neutral copolymer of methyl methacrylate (methylmethacrylate), and water miscible hydroxylating cellulose derivative.The U.S. 4,952, No. 402 patent document discloses a kind of particulate controlled release powder that comprises, and this granule contains and at least a nontoxic insoluble, permeable, impermeable or biodegradable controlled release polymer or the mixed uniformly active component of their mixture.
Most controlled release composition or preparation are made up of two parts, contain the label of active component and excipient that is:, and coating.The component of coating material, ratio, dissolubility, hydrophobicity or hydrophilic all can be different.Can change different preparations and technological parameter and optimize drug release pattern (for example plasticizer dosage of the degree of coating, type and adding) with this.Active component is progressively studied from the feature that label discharges.With water-insoluble aqueous dispersion and enteric material, ethyl cellulose: Hydroxypropyl Methyl Cellulose Phthalate (hydroxypropyl methylcellulose acetatesuccinate, be abbreviated as HPMCAS) (EC:HPMCAS) and ethyl cellulose: methacrylic acid ethyl propylene acid ester copolymer (EC:Eudragit L) is mixed for the micropill coating and has made research (F.Siepmann et al, 2005, J.Controlled Release 105:226-239).
A problem in the subject matter relevant with these controlled release preparations is that active component a large amount of in after the pharmaceutical preparation administration one hour discharges.Such release causes the unexpected increase of blood drug level usually, in many cases, promptly causes human unacceptable toxicological issues.This " burst " discharges and also to cause owing to discharge shortening of the pharmaceutical composition active duration that produces suddenly and rapidly along with the mass efficient composition after the compositions administration.
Second problem is this fact, and the traditional method of promptly using microencapsulation is brought the envelop rate of relative poor efficiency (encapsulation rates) usually, particularly when active component is the water solublity medicine.
The 3rd problem that must solve in these preparation processes in development is active component to the unstability of the severe rugged environment that is used to produce microsphere, severe rugged environment as: contact for a long time between high temperature in the solvent evaporation process or effective ingredient and organic solvent.
A plurality of tests have been finished in order to solve these different problems.Therefore, additive, for example sugar, oil, wax, protein, polymer, salt or acid have been used to prepare the pharmaceutical composition of microspheres form.These make the efficient increase of microencapsulation method become possibility as the additive that keeps the medicine in the microsphere, even possible words are used for protecting effective ingredient by the agent of playing stably in the course of processing.
Yet, in microsphere, add these additives and can cause INTERACTION PROBLEMS between additive and active component or polymer backbone, so from the toxicology of medicine and pharmacological activity aspect, produced problem.In addition, influential at the inner additive of active component that keeps of microsphere in the course of processing to the release performance that is included in the active component in the microsphere, may stop the lasting release of above-mentioned active component after the microsphere administration.
Based on the use of ORGANIC SOLVENT MIXTURES, other microencapsulation method also attempts to increase the microencapsulation effect of active component in the microsphere through development, but such method causes the problem of active component stability in the microsphere production process.
2-Propylpentanoic (2-Propylpentanoic acid) is commonly referred to valproic acid (valproic acid (VPA)), its amide valpromide (valpromide (VPO)), with and some salt of acid and ester aspect the treatment epilepsy or producing effect as antipsychotic drug.The U.S. 4,988, it is the oligomer that 1: 1 sodium valproate and valproic acid are formed that No. 731 patent documents disclose mol ratio, contain 4 polymerized units, and the U.S. 5,212, No. 326 patent documents disclose a kind of valproic acid of stable nonhygroscopic solid form, it is the oligomer that 1: 1 sodium valproate and valproic acid are formed that this valproic acid comprises mol ratio, and contains 4 to 6 polymerized units.Divalproex sodium (Divalproexsodium (sodium hydrogen divalproate)) is one of present available antiepileptic of the most extensively being approved.
Yet although acrylic acid treatment epilepsy produces effect, valproic acid has shown and has been shorter than the removing half-life that other is used for antiepileptic common drug.It is reported half-life of this medicine for the adult between 6 to 17 hours, for the child between 4 to 14 hours.With regard to the blood drug level that causes medicine fluctuation appears like this, particularly in long term administration.
In order to overcome this shortcoming, concerted effort is devoted to explore the Depakene that can keep more constant blood level after the administration.The final goal of these researchs has had been found that provides the preparation of stablizing blood plasma in dosage regimen once a day.For the above reasons, need more slowly be discharged into the dosage form of the active component of internal metabolism.
The multiple pharmaceutical preparation of divalproex sodium is open, but improved formulations is still being studied and still needed.
The U.S. 5,009, No. 897 patent document discloses the granule that is fit to be pressed into tablet, and this granule comprises divalproex sodium label and polymer and microcrystalline cellulose mixt coating.
The U.S. 5,019, No. 398 patent document discloses a kind of slow releasing tablet, valproic acid wherein: valproic acid (1: 1) is in hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose, be abbreviated as HPMC), in micropowder silica gel (Levilite) and hydrated SiO 2 (hydrated silica) skeleton, this tablet by hydroxypropyl emthylcellulose (HPMC), Eudragit E 100 and Eudragit NE30 at outer coating.
The U.S. 5,055, but No. 306 patent documents disclose effervescent or the water discrete particles slow releasing preparation that is applicable to multiple therapeutic agent.This granule comprises label and at least a excipient that contains active component, and comprises copolymer water insoluble of ethyl acrylate (ethyl acrylate), methyl methacrylate and water soluble hydroxy cellulose derivative but the coating of water-swellable.
The U.S. 5,169, No. 642 patent documents disclose the amide that comprises divalproex sodium or valproic acid or the particulate sustained-release administration dosage form of ester, and the amide of above-mentioned divalproex sodium or valproic acid or ester are by the slow releasing composition coating that comprises ethyl cellulose or methyl methacrylate, plasticizer, antitack agent (detackifyingagent) and release polymer viscosity agent (slow-release polymeric viscosity agent) (for example HPMC and methylcellulose).
The U.S. 5,589, No. 191 patent document discloses slow release sodium valproate tablet formulation, wherein the tablet ethyl cellulose coating that contains anhydrous silicic acid (silicic acid anhydride).
The U.S. 6,610, No. 326 patent document discloses the divalproex sodium delayed-release tablet.The technology of producing this tablet comprises by divalproex sodium is combined with aqueous solvent, alkali and prepares neutral divalproex sodium solution, during the alkali here is used for and divalproex sodium in the valproic acid part.Neutral divalproex sodium solution spraying is to pharmaceutically acceptable carrier, and processing obtains the divalproex sodium delayed-release tablet.
The U.S. 6,419, No. 953 patent document discloses the hydrophilic matrix tablet (hydrophilic matrix tablet) that is applicable to divalproex sodium administration once a day, and the hydrophilic skeleton here is hydroxypropyl emthylcellulose (hydroxypropyl methylcellulose).
Yet the hygroscopicity of divalproex sodium is disturbed and viscosity remains subject matter.This characteristic causes producing the restriction of relative humidity in the divalproex sodium tablet process.In some instances, relative humidity has to maintain 55～60%, perhaps even less than 30% (U.S. 4,913, No. 906 patent documents, 5,185, No. 159 patent documents of 5,017, No. 613 patent documents of the U.S. and the U.S.).Such condition is unfavorable for commercialization.Because disclosing, the viscosity of divalproex sodium, some examples adds anti-stick or antiplastering agent.
The U.S. 5,185, No. 159 patent documents disclose the valproic acid that neither uses binding agent also not use granulating agent and prepare and the preparation of sodium valproate.Said preparation selectively comprises as the precipitated silica of anti-stick or antitack agent (precipitated silica) and said preparation with polyvinylpyrrolidone or acrylic acid methyl ester. coating.
Description of drawings
Figure 1 shows that the controlled release result of the test of 250mg divalproex sodium slow releasing tablet.(a) expression is the outward appearance of the tablet produced; (b) expression is the outward appearance of the tablet after testing through 18 hours dissolution; (c) be the cross section of testing the back tablet through 18 hours dissolution.
Figure 2 shows that the controlled release result of the test of 500mg divalproex sodium slow releasing tablet.(a) expression is the outward appearance of the tablet produced; (b) expression is the outward appearance of the tablet after testing through 18 hours dissolution; (c) be the cross section of testing the back tablet through 18 hours dissolution.
Figure 3 shows that the release profiles of 500mg divalproex sodium slow releasing tablet dissolution test.
Summary of the invention
The present invention relates to comprise the controlled release composition of hydrophobic fibre element, methacrylic acid copolymer and the active component of uniform state form.
The invention still further relates to the method for producing controlled release tablet, comprise (a) hydrophobic fibre element, methacrylic acid copolymer and active component are mixed into homogeneous mixture; (b) the hydrophobic fibre element is sprayed in the mixture to form microencapsulated particles; (c) by binder solution being sprayed to pelletize in the microencapsulated particles; And (d) silicon dioxide, magnesium stearate, zeopan are joined in the microencapsulated particles, mix and pharmacy.
The specific embodiment
The invention provides the controlled release composition of the hydrophobic fibre element, methacrylic acid copolymer and the active component that comprise the uniform state form.Being used for hydrophobic fibre element of the present invention is a kind of cellulose that hydrophobic ability is arranged.In a preferred embodiment, the hydrophobic fibre element is an ethyl cellulose, and wherein the viscosity of ethyl cellulose is 3 to 120m Pa s (cP).In a preferred embodiment, the viscosity of ethyl cellulose is 20 to 110m Pa s (cP).In a better embodiment, the viscosity of ethyl cellulose is 90 to 110m Pa s (cP).
The methacrylic acid copolymer that is used for the present composition is the copolymer of methacrylic acid and methyl methacrylate.In a preferred embodiment, the ratio of methacrylic acid and methylmethacrylate copolymer is 3: 1 to 1: 3.In a better embodiment, ratio is 1: 2 or 2: 1.Commercially available methacrylic acid copolymer can be Eudragit S 100.
Active component of the present invention can be chemical compound, pharmaceutical composition or bio-pharmaceuticals compositions.In a preferred embodiment, active component is a divalproex sodium.In a better embodiment, the divalproex sodium content range is 25% to 55% of a composition weight.
For compositions of the present invention, hydrophobic fibre ratio plain and methacrylic acid copolymer is 10: 1 to 1: 10.In a preferred embodiment, this ratio is 3: 1 to 1: 3.In a better embodiment, this ratio is 1.2: 1.There is the present composition of aforementioned proportion can obtain beyond thought result.Specifically, when touching water or simulated intestinal fluid, thereby compositions becomes slowly release of active ingredients of porous semipermeability skeleton.
Because the mixture of active component (for example divalproex sodium) and methacrylic acid copolymer is easy to induce hygroscopicity, makes active component stick on the punch die in the pharmacy process.Be to solve sticking problem, the microencapsulation technology by ethyl cellulose coating and pelletize is applied to the present invention.Therefore, the present composition further comprises and is used to be encapsulated in outer field ethyl cellulose.This ethyl cellulose is a kind of hydrophobic fibre element, and it can be used for forming the film of covering composition.In a preferred embodiment, being used to be encapsulated in the outer field ethyl cellulose content range of compositions is 0.5% to 10% of composition weight.In a better embodiment, be used to be encapsulated in 1% to 3% that the outer field ethyl cellulose content range of compositions is a composition weight.
Generally speaking, pharmacy is carried out under less than 30% condition at relative humidity.Be difficult under the condition of relative humidity, carry out on a large scale the pharmacy process at 40-60%.In order to overcome moisture absorption and sticking problem under the same terms, the present composition further comprises silicon dioxide, magnesium stearate, zeopan.In a preferred embodiment, the dioxide-containing silica scope is 0.1% to 6% of a composition weight, and wherein the magnesium stearate content range is 0.1% to 4% of a composition weight, and the zeopan content range is 0.1% to 4% of composition weight.
Compositions can and can be used for patient's Drug therapy at controlled release under the fluid condition.
The present invention also provides the method for producing controlled release tablet, comprises (a) hydrophobic fibre element, methacrylic acid copolymer and active component are mixed into homogeneous mixture; (b) the hydrophobic fibre element is sprayed in the mixture to form microencapsulated particles; (c) by binder solution being sprayed to pelletize in the microencapsulated particles; And (d) silicon dioxide, magnesium stearate, zeopan are joined in the microencapsulated particles, mix and pharmacy.The inventive method further comprises with white (opadry II white) the painted coating of Opadry II type.In a preferred embodiment, the hydrophobic fibre element is an ethyl cellulose.
In one embodiment, methacrylic acid copolymer is the copolymer of methacrylic acid and methyl methacrylate.In a preferred embodiment, the ratio of methacrylic acid and methyl methacrylate is 3: 1 to 1: 3.In a preferred embodiment, ratio is 1: 1 or 1: 2.In a better embodiment, ratio is 1: 2.
Active component of the present invention can be chemical compound, pharmaceutical composition or bio-pharmaceuticals compositions.In a preferred embodiment, active component is a divalproex sodium.
In one embodiment, hydrophobic fibre ratio plain and methacrylic acid copolymer is 10: 1 to 1: 10.In a preferred embodiment, ratio is 3: 1 to 1: 3.In a better embodiment, ratio is 1.2: 1.
In a better embodiment, comprise the divalproex sodium of about 53.8% weight by the controlled release tablet of the inventive method production; The ethyl cellulose of about 17.7% weight; The methacrylic acid copolymer of about 14.1% weight; The microcrystalline Cellulose of about 5.6% weight; The polyvinylpyrrolidone of about 0.8% weight (polyvinylpyrrolidone); The silicon dioxide of about 4% weight; The magnesium stearate of about 2% weight; The zeopan of about 2% weight; And the Opadry II type that accounts for composition weight 3% is white.
The inventive method can be used for more effectively producing controlled release tablet.
Those skilled in the art read following detailed description back and can be easier to understand to characteristics of the present invention and advantage.Should be realized that for the reason of sake of clarity, some characteristic of the present invention that are described also can be combined to form single embodiment in context under the background of independent embodiment.On the contrary, for the reason of simplicity of exposition, the characteristics that the present invention who describes under single embodiment background is different also can make up in order to form its sub-portfolio.
Unless stated otherwise, otherwise the odd number of here mentioning also may comprise plural number.For example, " a " and " an " can refer to any one, one or more.
Here the definition of Ti Chuing has precedence over the definition that is incorporated in this any patent for reference, patent application and/or the public announcement of a patent application.
Embodiment
Following embodiment is nonrestrictive, only represents various aspects of the present invention and characteristics.
(material)
Core tablet (subtotal 1000mg)
Painted coating (subtotal 30mg)
The preparation of embodiment 1 core tablet (10,000 tablet)
Mix composition as follows:
Divalproex sodium 5380 grams
Ethyl cellulose 100cps FP 1665 grams
Eudragit
S-100 1412 grams
Fine plain 563 grams of crystallite
Mix with 120 rev/mins by 30 purpose mesh screens, with super mixer and to obtain uniform powder in 10 minutes.
Embodiment 2 microencapsulation processes
(a) preparation of microencapsulation solution
Prescription:
Ethocel
100cps FP 100 grams
1.6 liters of ethanol
Pure water 200mL
Ethyl cellulose is joined in the solution that comprises ethanol and pure water.Dissolve fully up to ethyl cellulose by the agitator mixed solution.
(b) microencapsulation
Uniform powder (embodiment 1) is joined in the Wurster fluid bed.Condition setting is: 70 ℃ of inlet temperatures, 35 ℃ of outlet temperatures, spray rate 40～80mL/ minute, preheating time: 5 minutes.Microencapsulation solution is sprayed in the uniform powder; Can obtain microencapsulated particles.
(a) preparation of binder solution
Prescription:
Polyvidone (K-30) 80 grams
Ethanol 320mL
Pure water 600mL
(K-30) joins in the solution that contains ethanol and pure water with polyvidone.Dissolve fully up to polyvidone (K-30) by the agitator mixed solution.
(b) prilling process
Microencapsulated particles (embodiment 2) is joined in the Wurster fluid bed.Condition setting is: 70 ℃ of inlet temperatures, and 35 ℃ of outlet temperatures, spray rate: 40～80mL/ minute, drying time: 5 minutes, loss on drying (L.O.D.) was less than 3%.Binder solution is sprayed in the microencapsulated particles, then granule is crossed 20 purpose mesh screens.Obtain the divalproex sodium granule.
Embodiment 4: finish and mix and pharmacy
(a) mix
Mix following component:
Divalproex sodium granule 9200 grams
Silicon dioxide 400 grams
Zeopan 200 grams
Magnesium stearate 200 grams
Amount to: 10,000 grams
(538mg divalproex sodium/1000mg granule)
Said components is joined in the double-cone mixer with 30 rpms of mixing 7 minutes.The divalproex sodium granule is by step 3 preparation.Add silicon dioxide, zeopan and magnesium stearate to prevent that granule is bonding in the pharmacy process.
(b) pharmacy
Above-mentionedly finish blended granule and join 20 and dash in the rotation pelleter.Condition enactment is: 6,000 pounds of precompressed, 12,000 pounds of main pressures, 20 rpms of rotary speeies.
The tablet of producing has following explanation:
Weight: 970mg～1030mg (being equivalent to the active valproic acid of 500mg)
Capsule plate shape: 18.9mm * 10mm
Thickness: 8.3mm～8.8mm
Hardness: 13 to 25Kg
Embodiment 5 painted coatings
Prescription:
Core tablet 10,000 grams
Opadry II type white (85G28725) 300 grams
Ethanol (solvent) 970mL
Pure water (solvent) 2265mL
Amount to: 10,300 grams
(a) preparation of painted coating solution
Opadry II type is joined in the solution that contains ethanol and pure water in vain.White fully evenly by the agitator mixed solution up to Opadry II type.
(b) painted coating
The core tablet that the foregoing description 4 is obtained joins in the film coating pot.Operating condition is set at: inlet temperature: 75～85 ℃, and outlet temperature: 45～50 ℃, the pot rotating speed: 2～15 rpms, preheating time: 10 minutes, spray rate: 100 gram/minute, drying time: 5 minutes.Coloring solution is sprayed in the core tablet, obtain coated tablet.
The tablet weight of producing is 1030mg (being equivalent to the active valproic acid of 500mg)/every tablet.
The test of embodiment 6 dissolutions
In order to determine the tablet controlled-release effect, carry out the dissolution test.
Test with divalproex sodium slow releasing tablet 250mg and 500mg.Leaching condition is that 100 rpms of mixing speeds, oar method stirred in instrument 18 hours in pH value is 6.8 phosphate-buffered medium.The photo of tablet as depicted in figs. 1 and 2, (Fig. 1 a and Fig. 2 are a) and the photo of test back (Fig. 1 b and Fig. 2 b) before having comprised test.Its cross section picture is shown in Fig. 1 c and Fig. 2 c.Fig. 3 is the release profiles of two valproic acid slow releasing tablet 500mg dissolution tests.Result according to the dissolution test clearly illustrates that very tablet has good controlled-release effect.
Those skilled in the art can obtain and use although the present invention has enough explained with illustration, and different replacement schemes, modification and improvement can not deviate from the spirit and scope of the present invention obviously.
Those skilled in the art will be appreciated that easily, the present invention well realized target and obtain mention and those wherein inherent results and advantage.Embryo, animal, process and the method for producing them are representatives of preferred embodiment, are exemplary, and are not used in the restriction as the scope of the invention.The modification here and other application can occur to those skilled in the art.These modifications are included in the present invention's spirit scope and by claim and are defined.
It will be apparent to those skilled in the art that and to make various replacements and modification here, and do not deviate from scope and spirit of the present invention the disclosed content of invention.
All patents mentioned in description and open file are the symbols of those routine techniques levels in the technical field of the invention.Here with all patents and open file being incorporated into this with reference to the mode of quoting, just as each independent open file particularly, independently to be incorporated into this with reference to the mode of quoting.
This suitably the present invention of exemplary description in implementing lacking under the situation that does not have concrete disclosed any composition or key element (element or elements), restriction or limitation (limitation orlimitations) here.Term that is adopted and statement are as descriptive term and unrestricted, and be not used in get rid of be equal to shown in and the term and the statement of described characteristics or part characteristics, but will be recognized that the different modification in claim scope of the present invention is possible.Therefore, it will be appreciated that, although the present invention is open in detail by preferred embodiment and selectable characteristics, but those skilled in the art can make amendment and change content disclosed herein, and such modification and change are considered to be in the scope of the present invention that claim defines.
Other embodiment proposes in following claim.
Claims (19)
1. the controlled release composition that comprises hydrophobic fibre element, methacrylic acid copolymer and the active component of uniform state form, wherein the hydrophobic fibre element is an ethyl cellulose, active component is a divalproex sodium, hydrophobic fibre ratio plain and methacrylic acid copolymer is 10: 1 to 1: 10, it is characterized in that, said composition further comprises and is used to be encapsulated in the outer field ethyl cellulose of compositions, to form microencapsulated particles.
2. compositions according to claim 1 is characterized in that, ethyl cellulose has 3 to 120m Pa s (cP) viscosity.
3. compositions according to claim 2 is characterized in that, ethyl cellulose has 90 to 110m Pa s (cP) viscosity.
4. compositions according to claim 1 is characterized in that, methacrylic acid copolymer is the copolymer of methacrylic acid and methyl methacrylate.
5. compositions according to claim 4 is characterized in that, the ratio of methacrylic acid and methyl methacrylate is 3: 1 to 1: 3.
6. compositions according to claim 5 is characterized in that, ratio is 1: 1 or 1: 2.
7. compositions according to claim 1 is characterized in that, the divalproex sodium content range is 25% to 55% of a composition weight.
8. compositions according to claim 1 is characterized in that, hydrophobic fibre ratio plain and methacrylic acid copolymer is 3: 1 to 1: 3.
9. compositions according to claim 8 is characterized in that hydrophobic fibre ratio plain and methacrylic acid copolymer is 1.2: 1.
10. compositions according to claim 1 is characterized in that, being used to be encapsulated in the outer field ethyl cellulose content range of compositions is 0.5% to 10% of composition weight.
11. compositions according to claim 10 is characterized in that, being used to be encapsulated in the outer field ethyl cellulose content range of compositions is 1% to 3% of composition weight.
12. compositions according to claim 1 is characterized in that, said composition further comprises silicon dioxide, magnesium stearate and zeopan.
13. compositions according to claim 12, it is characterized in that, the dioxide-containing silica scope is 0.1% to 6% of a composition weight, and the magnesium stearate content range is 0.1% to 4% of a composition weight, and the zeopan content range is 0.1% to 4% of a composition weight.
14. produce the method for controlled release tablet, comprise:
(a) hydrophobic fibre element, methacrylic acid copolymer and active component are mixed into homogeneous mixture, wherein the hydrophobic fibre element is an ethyl cellulose, active component is a divalproex sodium, and hydrophobic fibre ratio plain and methacrylic acid copolymer is 10: 1 to 1: 10;
(b) the hydrophobic fibre element is sprayed in the mixture to form microencapsulated particles, wherein the hydrophobic fibre element is an ethyl cellulose;
(c) by binder solution being sprayed to pelletize in the microencapsulated particles;
(d) silicon dioxide, magnesium stearate, zeopan are joined in the microencapsulated particles, mix and pharmacy.
15. method according to claim 14 is characterized in that, this method further comprises by Opadry II type carries out painted coating in vain.
16. method according to claim 14 is characterized in that, methacrylic acid copolymer is the copolymer of methacrylic acid and methyl methacrylate.
17. method according to claim 16 is characterized in that, the ratio of methacrylic acid and methyl methacrylate is 3: 1 to 1: 3.
18. method according to claim 17 is characterized in that, the ratio of methacrylic acid and methyl methacrylate is 1: 2.
19. method according to claim 14 is characterized in that, tablet comprises the divalproex sodium of 53.8% weight; The ethyl cellulose of 17.7% weight; The methacrylic acid copolymer of 14.1% weight; The microcrystalline Cellulose of 5.6% weight; The polyvinylpyrrolidone of 0.8% weight; The silicon dioxide of 4% weight; The magnesium stearate of 2% weight; The zeopan of 2% weight; And the Opadry II type that accounts for composition weight 3% is white.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2006/001639 WO2008009172A1 (en) | 2006-07-11 | 2006-07-11 | Controlled release composition and preparation thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101484150A CN101484150A (en) | 2009-07-15 |
| CN101484150B true CN101484150B (en) | 2011-06-15 |
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| CN2006800552797A Expired - Fee Related CN101484150B (en) | 2006-07-11 | 2006-07-11 | Controlled release composition and preparation thereof |
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| Country | Link |
|---|---|
| CN (1) | CN101484150B (en) |
| TW (1) | TWI337543B (en) |
| WO (1) | WO2008009172A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5169642A (en) * | 1988-06-24 | 1992-12-08 | Abbott Laboratories | Sustained-release drug dosage units |
| US5185159A (en) * | 1983-07-20 | 1993-02-09 | Sanofi | Pharmaceutical composition based on valproic acid and a process for preparing it |
| CN1213301A (en) * | 1996-03-15 | 1999-04-07 | 日研化学株式会社 | Sustained-release metal valproate tablets |
-
2006
- 2006-07-11 WO PCT/CN2006/001639 patent/WO2008009172A1/en active Application Filing
- 2006-07-11 CN CN2006800552797A patent/CN101484150B/en not_active Expired - Fee Related
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2007
- 2007-07-10 TW TW096125050A patent/TWI337543B/en not_active IP Right Cessation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5185159A (en) * | 1983-07-20 | 1993-02-09 | Sanofi | Pharmaceutical composition based on valproic acid and a process for preparing it |
| US5169642A (en) * | 1988-06-24 | 1992-12-08 | Abbott Laboratories | Sustained-release drug dosage units |
| CN1213301A (en) * | 1996-03-15 | 1999-04-07 | 日研化学株式会社 | Sustained-release metal valproate tablets |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008009172A1 (en) | 2008-01-24 |
| CN101484150A (en) | 2009-07-15 |
| TW200815052A (en) | 2008-04-01 |
| TWI337543B (en) | 2011-02-21 |
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