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WO2008009172A1 - Composition à libération contrôlée et préparation associée - Google Patents

Composition à libération contrôlée et préparation associée Download PDF

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Publication number
WO2008009172A1
WO2008009172A1 PCT/CN2006/001639 CN2006001639W WO2008009172A1 WO 2008009172 A1 WO2008009172 A1 WO 2008009172A1 CN 2006001639 W CN2006001639 W CN 2006001639W WO 2008009172 A1 WO2008009172 A1 WO 2008009172A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
weight
methacrylic acid
composition according
cellulose
Prior art date
Application number
PCT/CN2006/001639
Other languages
English (en)
Inventor
Tong Ho Lin
Kuen Jen Wang
Original Assignee
Lotus Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lotus Pharmaceutical Co., Ltd. filed Critical Lotus Pharmaceutical Co., Ltd.
Priority to CN2006800552797A priority Critical patent/CN101484150B/zh
Priority to PCT/CN2006/001639 priority patent/WO2008009172A1/fr
Priority to TW096125050A priority patent/TWI337543B/zh
Publication of WO2008009172A1 publication Critical patent/WO2008009172A1/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • This invention relates to a controlled release composition and a method for producing thereof.
  • a sustained release or controlled release drug delivery system can be useful in enhancing patient compliance by reducing the frequency with which medicines need to be administered.
  • a variety of approaches have been used in the art to produce sustained or controlled release drug delivery systems. Such approaches include, for example, either coating a tablet or bead with polymeric material, or making a tablet with insoluble or poorly soluble polymers.
  • U.S. Pat. No. 5,055,306 discloses a sustained-release formulation containing a core having active ingredient, a coating covering substantially the whole surface of the core and comprising water insoluble but water swellable neutral copolymer of ethyl acrylate and methyl methacrylate, and a water soluble hydroxylated cellulose derivative.
  • U.S. Pat. No. 4,952,402 discloses a controlled release powder comprising particles containing an active ingredient in intimate admixture with at least one non-toxic insoluble, permeable, impermeable, or biodegradable controlled release polymer, or mixtures thereof.
  • compositions or formulations are composed by two parts, a core containing active ingredient and exci ⁇ ient(s), and a coating.
  • the coating material is various in its component, ratio, solubility, hydrophobic or hydrophilic. Different formulation and processing parameters can be varied in order to optimize the drug release patterns (e.g. coating level, type and amount of added plasticizer). The profile of the active ingredient releasing from the core are investigated gradually.
  • Blends of aqueous dispersions of a water-insoluble and an enteric polymer, ethyl cellulose: hydroxypropyl methycellulose acetate succinate (EC: HPMCAS) and ethyl cellulose: methacrylic acid ethyl acrylate copolymer (EC: Eudragit L) used for pellet coating are studied (F. Siepmann et al, 2005, J. Controlled Release 105: 226-239).
  • a second problem lies in the fact that relatively inefficient encapsulation rates are generally obtained using the conventional methods of microencapsulation, in particular when the active ingredient is a water-soluble medicinal product.
  • a third problem which must be solved in developing these formulations is the instability of the active ingredient in the face of the rigorous conditions used in producing the microspheres, such as high temperature or prolonged contact of the active principle with an organic solvent during the solvent evaporation step.
  • additives such as sugars, oils, wax, proteins, polymers, salts or acids have been used in the preparation of pharmaceutical compositions in the form of microspheres.
  • These additives which act as substances for retaining the medicinal product in the microsphere, make it possible to increase the efficiency of the method of microencapsulation and even, possibly, to protect the active principle during the process, by playing the role of stabilizing agents.
  • additives in the microspheres can lead to problems of interaction between the additives and the active ingredient or the polymer-based matrix, thus inducing problems in terms of toxicology and of pharmacological activity of the medicinal product.
  • the additives which retain the active ingredient inside the microspheres during the production process, have an influence on the release profile of the active ingredient contained in the microspheres, possibly preventing continuous release of said active ingredient subsequent to administration of the microspheres.
  • microencapsulation has also been developed in an attempt to increase the efficiency of microencapsulation of the active ingredient within the microspheres, based on the use of mixtures of organic solvents, but such methods lead to problems of stability of the active ingredient during the microsphere production process.
  • valproic acid More commonly known as valproic acid (VPA), its amide, valpromide (VPO), and certain salts and esters of the acid are effective in the treatment of epileptic seizures or as antipsychotic agents.
  • VPA valproic acid
  • VPO valpromide
  • U.S. Pat. No. 4,988,731 discloses an oligomer having a 1:1 molar ratio of sodium valproate and valproic acid containing 4 units
  • U.S. Pat. 5,212,326 discloses a stable, non-hygroscopic solid form of valproic acid which comprises an oligomer having 1 : 1 molar ratio of sodium valproate and valproic acid and containing four to six units.
  • Divalproex sodium sodium hydrogen di valproate is one of the most widely accepted antiepileptic agents currently available.
  • valproic acid has been shown to exhibit an elimination half-life which is shorter than other commonly used anti-epileptic agents.
  • Half-life for the drug of between six and seventeen hours in adults and between four and fourteen hours in children have been reported. This leads to substantial fluctuations in the plasma concentration of the drug, especially in chronic administration.
  • U.S. Pat. No. 5,009,897 discloses granules, suitable for pressing into tablets, the granules comprising a core of divalproex sodium and a coating of a mixture of a polymer and microcrystalline cellulose.
  • U.S. Pat. No. 5,019,398 discloses a sustained-release tablet of valproic acid : sodium valproate (1 :1) in a matrix of hydroxypropyl methylcellulose, Levilite and hydrated silica, and the tablet is coated by HPMC, Eudragit E 100 and Eudragit NE 30 in the outer.
  • U.S. Pat. No. 5,055,306 discloses an effervescent or water-dispersible granular sustained release formulation suitable for use with a variety of therapeutic agents.
  • the granule comprises a core comprising the active ingredient and at least one excipient, and a water insoluble, water-swellable coating comprising a copolymer of ethyl acrylate and methyl methacrylate and a water soluble hydroxylated cellulose derivative.
  • U.S. Pat. No. 5,169,642 discloses a sustained release dosage form comprising granules of divalproex sodium or amides or esters of valproic acid coated with a sustained release composition comprising ethyl cellulose or a methacrylic methyl ester, a plasticizer, a detackifying agent, and a slow-release polymeric viscosity agent (such as HPMC and methylcellulose).
  • U.S. Pat. No. 5,589,191 discloses a slow release sodium valproate tablet formulation in which the tablets are coated with ethyl cellulose containing silicic acid anhydride.
  • U.S. Pat. No. 6,610,326 discloses a divalproex sodium delayed- release tablet.
  • the process for producing the tablet comprises preparing a neutralized divalproex sodium solution by combining divalproex sodium with an aqueous solvent and a base, wherein the base is used for neutralizing the valproic acid moiety of the divalproex sodium.
  • the neutralized divalproex sodium solution is sprayed onto a pharmaceutically acceptable carrier, and processed to obtain divalproex sodium delayed- release tablets.
  • U.S. Pat. No. 6,419,953 discloses a hydrophilic matrix tablet suitable for the once-a-day administration of divalproex sodium, wherein the hydrophilic matrix is hydroxypropyl methylcellulose.
  • 5,185,159 discloses a formulation of valproic acid and sodium valproate which is prepared without the use of either a binder or a granulating solvent.
  • the formulation optionally contains precipitated silica as an anti-sticking or detackifying agent and the formulation is coated with polyvidone or methacrylate.
  • Figure 1 shows the controlled release test result of 250 mg of divalproex sodium extended release tablet, (a) means the appearance of the produced tablet; (b) means the appearance of the tablet under the dissolution test for 18 hours; (c) is the cross section of the tablet under the dissolution test for 18 hours.
  • Figure 2 shows the controlled release test result of 500mg of divalproex sodium extended release tablet, (a) means the appearance of the produced tablet; (b) means the appearance of the tablet under the dissolution test for 18 hours; (c) is the cross section of the tablet under the dissolution test for 18 hours.
  • Figure 3 shows the release diagram of the dissolution test of divalproex sodium extended release tablet 500 mg.
  • This invention relates to a controlled release composition comprising hydrophobic cellulose, methacrylic acid copolymer and active ingredient in a form of uniform state.
  • This invention also relates to a method for producing controlled release tablet comprising (a) mixing hydrophobic cellulose, the methacrylic acid copolymer and active ingredient to be uniform mixture; (b) spraying hydrophobic cellulose into the mixture for forming microencapsulating granules; (c) granulation by spraying binder solution into microencapsulating granules; and (d) adding silicon dioxide, magnesium stearate, magnesium aluminum silicate into microencapsulating granules, blending and tabletting.
  • This invention provides a controlled release composition comprising hydrophobic cellulose, methacrylic acid copolymer and active ingredient in a form of uniform state.
  • the hydrophobic cellulose used in the present invention is one kind of cellulose with hydrophobic ability.
  • the hydrophobic cellulose is ethyl cellulose, wherein the viscosity of ethyl cellulose is from 3 to 120 m Pa s (cP).
  • the viscosity of ethyl cellulose is from 20 to 110 m Pa s (cP).
  • the viscosity of ethyl cellulose is from 90 to 110 m Pa s (cP).
  • the methacrylic acid copolymer used in the present composition is methacrylic acid and methyl methacrylayte copolymer.
  • the methacrylic acid and methyl methacrylayte copolymer is in a ratio of 3:1 to 1 :3. In a more preferred embodiment, the ratio is 1:2 or 2:1.
  • the commercial methacrylic acid copolymer can be Eudragit S 100.
  • the active ingredient of this invention can be a chemical compound, a pharmaceutical composition, or a biopharmaceutical composition.
  • the active ingredient is divalproex sodium.
  • the divalproex sodium content is in the range from 25% to 55% of the weight of the composition
  • the hydrophobic cellulose and the methacrylic acid copolymer is in a ratio of 10:1 to 1 :10. In a preferred embodiment, the ratio is 3: 1 to 1:3. In a more preferred embodiment, the ratio is 1.2:1.
  • the present composition with above ratio can make a surprised result. In particular, upon contacting water or artificial intestine solution, the composition become a porous and semipermeable matrix to slowly release the active ingredient.
  • the composition of the present invention further comprises ethyl cellulose for encapsulating on outer layer.
  • the ethyl cellulose is a kind of hydrophobic cellulose, which can be used for forming a film covering the composition.
  • the ethyl cellulose content for encapsulating on outer layer of the composition is in the range from 0.5% to 10% the weight of the composition.
  • the ethyl cellulose content for encapsulating on outer layer of the composition is in the range from 1% to 3% the weight of the composition.
  • the present composition further comprises silicon dioxide, magnesium stearate, magnesium aluminum silicate.
  • the silicon dioxide content is in the range from 0.1% to 6% the weight of the composition, wherein the magnesium stearate content is in the range from 0.1% to 4% the weight of the composition, and the magnesium aluminum silicate content is in the range from 0.1% to 4% the weight of the composition.
  • the composition can be controlled release under fluid condition and can be used for pharmaceutical treatment for a patient.
  • This invention also provides a method for producing controlled release tablet comprising (a) mixing hydrophobic cellulose, the methacrylic acid copolymer and active ingredient to be uniform mixture; (b) spraying hydrophobic cellulose into the mixture for forming microencapsulating granules; (c) granulation by spraying binder solution into microencapsulating granules; and (d) adding silicon dioxide, magnesium stearate, magnesium aluminum silicate into microencapsulating granules, blending and tabletting.
  • the present method further comprises color coating by opradry II white.
  • the hydrophobic cellulose is ethyl cellulose.
  • the methacrylic acid copolymer is methacrylic acid and methyl methacrylaytes copolymer.
  • the methacrylic acid and methyl methacrylaytes is in a ratio of 3:1 to 1:3. In a preferred embodiment, the ratio is 1:1 or 1 :2. In a more preferred embodiment, the ratio is 1 :2.
  • the active ingredient of this invention can be chemical compound, pharmaceutical composition, or biopharmaceutical composition.
  • the active ingredient is divalproex sodium.
  • the hydrophobic cellulose and the methacrylic acid copolymer is in a ratio of 10:1 to 1 :10. In a preferred embodiment, the ratio is 3: 1 to 1 :3. In a more preferred embodiment, the ratio is 1.2:1.
  • the controlled release tablet produced by the present method comprises about 53.8% by weight divalproex sodium; about 17.7% by weight ethyl cellulose; about 14.1% by weight methacrylic acid copolymer; about 5.6% by weight microcrystalline cellulose; about 0.8% by weight polyvinylpyrrolidone; about 4% by weight silicon dioxide; about 2% by weight magnesium stearate; about 2% by weight magnesium aluminum silicate; and about 3% of the composition by weight opradry II white.
  • the method of the present invention can be used for producing controlled release tablet more effectively.
  • references made in the singular may also include the plural.
  • references made in the singular may also include the plural.
  • “a” and “an” may refer to either one, or one or more.
  • Ethyl cellulose was put into the solution containing ethyl alcohol and purified water. The solution was mixed by the stirrer until the ethyl cellulose was dissolved completely.
  • the homogenous powders (Example 1) were put into Wurster fluid bed. The condition was set up: Inlet Temp. 70 ° C, Outlet Temp. 35 " C, Spray rate: 40 ⁇ 80 mL/minutes and pre-heat time: 5 minutes. Sparying microencapsulating solution into homogenous powder, then the microencapulation granules were available.
  • the Povidone (K-30) was put into the solution containing ethyl alcohol and purified water. The solution was mixed by the stirrer until the Povidone (K-30) was dissolved completely.
  • the microencapulation granules (Example 2) were put into Wurster fluid bed. The condition was set up: Inlet Temp. 70 ° C Outlet Temp. 35 ° C, Spray rate : 40 ⁇ 80 mL/minutes, drying time: 5 minutes, L.O.D. ⁇ 3%. Sparying the binder solution into the microencapulating granules, then the granules pass through 20 mesh screen. The divalproex sodium granules were available.
  • the above components were put into the double cone and blend for 7 minutes at 30 rpm.
  • the divalproex sodium granules were prepared by the Step 3. Silicon dioxide, magnesium aluminum silicate and magnesium stearate were added for preventing granules adhesion in tabletting process.
  • the above finished blending granules were put into 20 rotating tabletting machine.
  • the conditions were set up as follows: pre-pressure 6,000 pounds, main pressure 12,000, rotating speed 20 rpm.
  • the produced tablet had the specifications as follows:
  • Opradry II white was added into the solution containing ethyl alcohol and purified water. The solution was mixed by the stirrer until the Opradry II white was uniform completely.
  • Example 4 The core tablets from above Example 4 were put into a film coating pan.
  • the operation condition was set up: Inlet Temp : 75 ⁇ 85 ° C, Outlet Temp: 45 ⁇ 50°C, Pan rotation : 2 ⁇ 15 rpm, pre-heat time : 10 minutes, spray rate: 100 gram/minutes, drying time : 5 minutes. Spraying the color solution into the core tablets, the coated tablets were available.
  • the produced tablet had weight 1030 mg (equivalent to 500 mg valproic acid activity)/ per tablet.
  • the dissolution test was performed.
  • the divalproex sodium extended release tablet 250 mg and 500 mg were tested.
  • the dissolution condition was in pH 6.8 phosphate buffer medium, 100 rpm stir speed, in apparatus Paddle, for 18 hours.
  • the tablet photos were shown in Figure 1 and Figure 2, including the tablet before (Figure Ia and Figure 2a) and after ( Figure Ib and Figure 2b) the test.
  • the cross sectional drawings were also showed in Figure Ic and Figure 2c.
  • the Figure 3 was the release diagram of dissolution test of the divalproex sodium extended release tablet 500 mg. According to the result of dissolution test, it was clear showed that the tablet had well controlled release effect.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition à libération contrôlée comprenant de la cellulose hydrophobe, un copolymère d'acide méthacrylique et un principe actif se présentant sous une forme d'état uniforme. L'invention concerne également un procédé de préparation d'un comprimé à libération contrôlée.
PCT/CN2006/001639 2006-07-11 2006-07-11 Composition à libération contrôlée et préparation associée WO2008009172A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN2006800552797A CN101484150B (zh) 2006-07-11 2006-07-11 控释组合物及其制备
PCT/CN2006/001639 WO2008009172A1 (fr) 2006-07-11 2006-07-11 Composition à libération contrôlée et préparation associée
TW096125050A TWI337543B (en) 2006-07-11 2007-07-10 Controlled release composition and preparation thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2006/001639 WO2008009172A1 (fr) 2006-07-11 2006-07-11 Composition à libération contrôlée et préparation associée

Publications (1)

Publication Number Publication Date
WO2008009172A1 true WO2008009172A1 (fr) 2008-01-24

Family

ID=38956517

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/001639 WO2008009172A1 (fr) 2006-07-11 2006-07-11 Composition à libération contrôlée et préparation associée

Country Status (3)

Country Link
CN (1) CN101484150B (fr)
TW (1) TWI337543B (fr)
WO (1) WO2008009172A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
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 (zh) * 1996-03-15 1999-04-07 日研化学株式会社 丙戊酸金属盐缓释片剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
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 (zh) * 1996-03-15 1999-04-07 日研化学株式会社 丙戊酸金属盐缓释片剂

Also Published As

Publication number Publication date
CN101484150B (zh) 2011-06-15
TW200815052A (en) 2008-04-01
CN101484150A (zh) 2009-07-15
TWI337543B (en) 2011-02-21

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