WO2002066004A1 - Compositions a liberation controlee de medicament - Google Patents

Compositions a liberation controlee de medicament Download PDF

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Publication number
WO2002066004A1
WO2002066004A1 PCT/JP2002/001634 JP0201634W WO02066004A1 WO 2002066004 A1 WO2002066004 A1 WO 2002066004A1 JP 0201634 W JP0201634 W JP 0201634W WO 02066004 A1 WO02066004 A1 WO 02066004A1
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WO
WIPO (PCT)
Prior art keywords
drug
water
polymer
enteric
dissolved
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PCT/JP2002/001634
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English (en)
Japanese (ja)
Inventor
Tomoyuki Omura
Hirofumi Samemoto
Tadaaki Inoue
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Mitsubishi Pharma Corporation
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Publication of WO2002066004A1 publication Critical patent/WO2002066004A1/fr

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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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • 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
    • A61K9/2009—Inorganic compounds
    • 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

Definitions

  • the present invention relates to a drug release-controlling composition that enables the elution of a drug that is hardly affected by fluctuations in pH in the lower gastrointestinal tract.
  • a formulation having a release control membrane combining a water-insoluble acrylic acid-based polymer and an enteric acrylic acid-based polymer is also known (Japanese Patent Application Laid-Open No. Hei 7-23838). It is intended for sustained release from the stomach, not for achieving local drug delivery.
  • the preparations described in JP-A-8-26997 and JP-A-8-143746 are preparations coated with an elution control coating composed of a mixture of a water-insoluble polymer and an enteric polymer.
  • the drug substance is contained in the core substance, and it is intended to provide a preparation for oral administration that rapidly elutes the drug at a preset time or at a preset pH. It is presumed that the elution start time and the elution speed fluctuate greatly due to the change in pH, and that the release behavior changes due to the pH fluctuation in the digestive tract.
  • 9-295933 relates to a controlled release composition in which a core comprising a drug is coated with a coating agent containing an additive and a swellable polymer having no basic group.
  • the invention described in Japanese Patent Application Laid-Open No. 11-286438 relates to a preparation containing a drug in a matrix containing a porous inorganic substance and a (meth) acrylic acid-based copolymer.
  • a drug is prepared by absorbing a polymer and a drug dissolved in a substance, and a long-term (one week or more) release of the drug has been achieved, but it is not intended for drug delivery to the lower gastrointestinal tract and It is not considered that the release behavior changes due to the pH fluctuation at.
  • a composition containing a water-insoluble polymer, an enteric polymer, and a drug contains an additive whose pH is alkaline when suspended or dissolved in water.
  • Drug release hardly occurs in the stomach, and it elutes in response to pH changes in the neutral to weakly alkaline region, especially at pH 6 to 8 in the human digestive tract, and in addition to the lower and large intestines
  • m3 ⁇ 4 was eluted in the lower gastrointestinal tract at a relatively high pH without being significantly affected by fluctuations in pH in the gastrointestinal tract, and that water-insoluble polymer in the composition
  • the mixing ratio of the soluble polymer mixture or the thickness of the controlled release composition layer was variously changed, it was found that the elution rate and the elution start time also changed according to the change, and the present invention was completed.
  • the mixing ratio of the soluble polymer mixture or the thickness of the controlled release composition layer was variously changed, it was found that the elution rate and the elution start time also changed according to
  • the drug hardly elutes in the stomach, and is not greatly affected by the variation of pH between individuals or in the individual in the lower gastrointestinal tract such as the small intestine and the large intestine, where the pH is relatively high.
  • the present invention relates to a drug release controlling composition capable of precisely controlling the dissolution of a drug.
  • the controlled release composition is protected by post-administration by protecting the drug with a water-insoluble polymer, an enteric polymer, and an additive whose pH is versatile when suspended or dissolved in water.
  • the drug hardly elutes in the stomach, and when it is transferred into the small intestine, ⁇ ⁇ in the controlled-release composition is adjusted by an additive whose pH is simultaneously active when suspended or dissolved in water, It is a controlled release composition that can elute a drug from ⁇ 6 to 8 without being greatly affected by ⁇ .
  • the present invention is as follows.
  • Drug release including (a) a water-insoluble polymer, (b) an enteric polymer, (c) an additive whose pH is alkaline when dissolved or dissolved in 7j ⁇ and (d) a drug. Control composition.
  • the mixing ratio of (a) water-insoluble polymer and (b) enteric polymer is 95: 5 to 5:
  • the drug release controlling composition according to the above 9, further comprising (a) a water-insoluble polymer, (b) an enteric polymer, and (d) a drug.
  • a method for producing a controlled-release drug composition comprising the step of adding an additive whose pH is alkaline when suspended or dissolved in water.
  • FIG. 1 shows an intestinal sustained release controlled release composition having a sustained release function obtained by preparing a controlled release polymer mixture containing a drug.
  • FIG. 2 shows a delayed-elution-type controlled release composition obtained by coating only a controlled release polymer mixture on a core substance containing a drug.
  • FIG. 3 shows the dissolution behavior of the preparation obtained in Comparative Example 1.
  • FIG. 4 shows the dissolution behavior of the preparation obtained in Example 1.
  • FIG. 5 shows the dissolution behavior of the preparation obtained in Example 2.
  • FIG. 6 shows the dissolution behavior of the preparation obtained in Example 3.
  • FIG. 7 shows the dissolution behavior of the preparation obtained in Example 4.
  • the water-insoluble polymer used in the present invention can be suitably used as long as it is generally known as a water-insoluble polymer in the field of pharmaceutical technology.
  • a water-insoluble polymer for example, water-insoluble cellulose derivatives, water-insoluble One or more selected from a vinyl derivative, a water-insoluble acrylic acid-based polymer, and the like.
  • water-insoluble cellulose derivative examples include cellulose esters such as ethyl cellulose in which a part or all of the hydroxyl groups contained in the cellulose are substituted with an ethyl group, and cellulose esters such as cellulose acetate.
  • water-insoluble vinyl derivative examples include vinyl polyacetate, polyvinyl chloride and the like.
  • water-insoluble acrylic acid polymer examples include a pH-independent acrylic acid polymer such as ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate copolymer (eg, trade names; Eudragit RS, Oil Dragit RL, manufactured by Kuchimu Co., Ltd.), methyl methacrylate 'ethyl acrylate copolymer (eg, trade name; Eudragit NE, manufactured by Rohm), and the like.
  • ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate copolymer eg, trade names; Eudragit RS, Oil Dragit RL, manufactured by Kuchimu Co., Ltd.
  • methyl methacrylate 'ethyl acrylate copolymer eg, trade name; Eudragit NE, manufactured by Rohm
  • preferred water-insoluble polymers include water-insoluble cellulose derivatives and water-insoluble acrylic acid-based polymers, more preferably water-insoluble acrylic acid-based polymers, and most preferably ethyl acrylate / methyl methyl acrylate.
  • Metriacrylic acid trimethylammonium mucilcopolymer ⁇ Metriacrylic acid trimethylammonium mucilcopolymer.
  • the enteric polymer used in the present invention is a polymer which can be generally used for coating a preparation in the field of preparation technology, and includes a polymer which dissolves at a pH of about 5 to 7.
  • examples of such a polymer include one or two selected from an enteric cellulose derivative, an enteric natural polymer compound, an enteric polyvinyl alcohol derivative, an enteric maleic acid polymer, and an enteric acrylic acid polymer. More than seeds.
  • Examples of the enteric cellulose derivative include esters of cellulose or a derivative thereof and an organic acid, and esters of cellulose and acetic acid, phthalic acid, succinic acid, and maleic acid are particularly preferable.
  • enteric cellulose derivatives include cellulose acetate sulphate, cellulose acetate succinate, hydroxyethyl cellulose succinate phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate 1 L, Hydroxypropyl methylcellulose acetate succinate 1M, hydroxypropyl methylcellulose acetate succinate 1H), hydroxypropylmethylcell opening-sphthalate, carboxymethylethylcellulose and the like.
  • enteric-coated natural polymer conjugates examples include Sierra Duck.
  • enteric polyvinyl alcohol derivative examples include an ester of polyvinyl alcohol and an organic acid, particularly preferably an ester of polyvinyl alcohol with acetic acid, fluoric acid, succinic acid, maleic acid, or the like.
  • enteric polyvinyl alcohol derivatives include, for example, polyvinyl alcohol phthalate, polyvinyl alcohol acetate, polyvinyl propylone phthalate, polyvinyl butyrate phthalate, polyvinyl acetate phthalate, and polyvinyl acetate. Examples include acetate phthalate, polyvinyl acetate succinate, polyvinyl acetate rugetylaminoacetate, and the like.
  • enteric maleic acid polymer examples include a copolymer of maleic anhydride and a vinyl monomer, and a copolymer of maleic anhydride and vinyl acetate, styrene, vinyl methyl ester, acrylic acid or an ester thereof is particularly preferable.
  • enteric maleic acid-based polymers include, for example, vinyl acetate 'copolymer maleate, styrene' cobolima maleate, ethylene 'styrene' maleate copolymer, acrylonitrile methyl acrylate 'copolymer maleate, butyl acrylate .Styrene 'A maleic acid copolymer.
  • enteric acrylic acid-based polymers include copolymers with acrylic acid, methacrylic acid or esters thereof.
  • enteric acrylate polymers include: Styrene-acrylic acid copolymer, acrylic acid'methyl acrylate copolymer, methacrylic acid'methyl acrylate copolymer, methacrylic acid'methyl methacrylate copolymer (eg, trade names; Eudraggid L100, Eudraggid S100) And methacrylic acid ethyl acrylate copolymer (for example, trade names; Eudraggid L100-55, Eudraguid L30D-55, manufactured by Rohm), and the like.
  • enteric polymers include enteric cellulose derivatives, enteric polyvinyl alcohol derivatives, enteric acrylic polymers, and the like.
  • enteric-injected cellulose derivatives include cellulose acetate. Phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose monophosphate, carboxymethylethylcellulose, etc. are used as enteric natural polymer compounds, Sierrapux etc. are used as enteric polyvinyl alcohol derivatives.
  • Polyvinyl acetal getylaminoacetate and the like are examples of the enteric acrylic acid-based polymer such as methacrylic acid.
  • enteric polymers include enteric cellulose derivatives and enteric acrylic polymers, more preferably enteric acrylic polymers, and most preferably mesyacrylic acid and mesyacryl. And methyl methacrylate-ethyl acrylate copolymer.
  • Each of these polymers can be used in an appropriate combination.
  • a combination of one or more of the water-insoluble polymers and a mixture of one or more of the enteric polymers is used. be able to.
  • preferred combinations include the combinations of the polymers listed as preferred in the water-insoluble polymer and the polymers listed as preferred in the enteric polymer, and particularly the water-insoluble acrylic acid-based polymer. Combinations of enteric acrylic polymers are preferred.
  • the mixing ratio of the water-insoluble polymer and the enteric polymer is in the range of 95: 5 to 5:95, and can be appropriately selected depending on the type of the water-insoluble polymer and the enteric polymer.
  • the optimal combination of the water-insoluble polymer and the enteric polymer and the optimal blending ratio can be found very easily by those skilled in the art for the purpose of obtaining the desired dissolution behavior.
  • the additive used in the present invention which has a pH when suspended or dissolved in water, has a pH of 7 or more when the additive is suspended or dissolved. It refers to a substance, and includes any additive that does not adversely affect the living body when the preparation is administered to a human, which can achieve the object of the present invention.
  • various additives such as an antacid, a porous inorganic substance, and an additive that is a metal salt can be used.
  • metal oxides such as magnesium oxide, metal hydroxides such as dried aluminum hydroxide gel, aluminum hydroxide gel, magnesium hydroxide, precipitated metal carbonates such as precipitated calcium carbonate and magnesium carbonate, or aluminum metasilicate
  • metal oxides such as magnesium oxide, metal silicate aluminate, magnesia hydroxide magnesia, and synthetic hydrotalcite can be used.
  • the antacid is aluminum hydroxide gel, magnesium carbonate, magnesium metasilicate aluminate, magnesium aluminum silicate, synthetic hydroxysite, dry aluminum hydroxide gel, magnesium hydroxide, sediment It is a combination of at least one selected from the group consisting of calcium carbonate.
  • Other additives such as aluminum stearate, magnesium stearate, calcium stearate, magnesium chloride, polyacrylic acid, and Na salt Any additive can be used without particular limitation, as long as it is an additive that has a pH when suspended or dissolved in water, such as sodium methyl starch.
  • the amount of the additive whose pH is alkaline when suspended or dissolved in water is usually 100% by weight or less, preferably 2 to 100% by weight, based on the total amount of the water-insoluble polymer and the enteric polymer. % By weight, more preferably 5 to 90% by weight, particularly preferably 10 to 80% by weight. When suspended or dissolved in these waters, the pH is alkaline.
  • the additive may be a natural product or a synthetic additive. When an additive that has already been powdered is used, it is better to grind as much as possible and use it as a fine powder. If the amount of added carohydrate is too large, it becomes difficult to form a layer.
  • the pharmacologically active substance (drug) applicable to this formulation is not particularly limited, and any substance can be used as long as it is effective when released in the lower digestive tract after the small intestine.
  • any substance can be used as long as it is effective when released in the lower digestive tract after the small intestine.
  • polypeptides, anti-inflammatory drugs, anti-tumor drugs, antibiotics, chemotherapeutics, drugs for treating inflammatory bowel disease (including drugs for treating Crohn's disease and ulcerative colitis), hypersensitivity syndrome Therapeutic drugs, steroids, immunosuppressants, laxatives (including constipation drugs) and the like are included.
  • these pharmacologically active substances usually include pharmaceutically acceptable inorganic or organic salts, and are naturally O.
  • the amount of these drugs in the formulation is usually 70% by weight or less, preferably 60% by weight or less, more preferably 50% by weight or less based on the total amount of the water-insoluble polymer and the enteric polymer. % By weight or less.
  • the controlled-release composition of the present invention may be used, if necessary, as an excipient, a disintegrant, a binder, a coating aid, a coloring agent, a masking agent, a plasticizer, a lubricant, an absorption enhancer, which is usually used as a pharmaceutical additive.
  • Additives for additives and other purposes can also be added.
  • sucrose fatty acid ester For the purpose of promoting absorption of pharmacologically active substances, sucrose fatty acid ester, glycyrrhizinate, Glycyrrhetinic acid, bile acids and conjugates of bile acids, pyrothiodecane, glycerin fatty acid esters, adipic acid, basic amino acids, polyethylene glycol, sodium naphthophosphate, lime, sodium dodecyl sulfate, sodium dodecyl sulfate, etc. Agents can be added in combination.
  • binder examples include small sugars such as sucrose, glucose, and sorbitol or sugar alcohols, dextrin, gum arabic, tragacanth, guar gum, carrageenan, sodium alginate, polysaccharides such as gelatin, gluten, methylcellulose, and ethyl.
  • small sugars such as sucrose, glucose, and sorbitol or sugar alcohols
  • dextrin gum arabic
  • tragacanth examples of the binder
  • guar gum examples include carrageenan, sodium alginate
  • polysaccharides such as gelatin, gluten, methylcellulose, and ethyl.
  • Cellulose, cellulose derivatives such as carboxymethylcellulose sodium, hydroxypropylmethylcellulose, and hydro'xypropyl cellulose, and synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, and polyethylene oxide. .
  • Disintegrators include, for example, starch, hydroxypropyl starch, carboxymethylcellulose and its calcium salts, low-substituted hydroxypropyl methylcellulose, carboxymethylsuccinic sodium, croscarmellose sodium, crospovidone, agar powder, crystalline cellulose, Monocellulose, cross-linked gelatin, cross-linked casein and the like.
  • coating aid examples include hardened oil, stearic acid (trade name; NAA-174, etc., manufactured by NOF Corporation), calcium stearate, polyoxyl stearate, magnesium stearate, ceanol, talc, etc. Can be
  • coloring agent examples include food coloring, lake coloring, caramel, carotene, ethyl acetate, cochineal, iron sesquioxide and the like.
  • edible red No. 2, No. 3, yellow No. 4, No. 5, green No. 3 Edible aluminum lakes such as Blue No. 1, No. 2, and Purple No. 1, Anato (natural pigment derived from linden), Carmine (aluminum carminate), Pearl Essence (mainly containing guanine), etc. .
  • Examples of the concealing agent include titanium dioxide, precipitated calcium carbonate, dicalcium phosphate, sulfated calcium sulfate, talc, and the like.
  • Examples of the plasticizer include polyethylene glycol (PEG), triethyl citrate, silicone oil, and triacetin.
  • PEG polyethylene glycol
  • Triethyl citrate polyethylene glycol
  • silicone oil polypropylene glycol
  • Propylene Gris In addition to coal, fluoric acid derivatives such as getyl phthalate, dibutyl phthalate, butyl phthalyl butyl glycolate and the like can be mentioned.
  • lubricant examples include magnesium stearate, talc, synthetic magnesium oxide, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, light silica anhydride and the like.
  • the amount and timing of the addition of these additives can be used without any problems as long as they are within the range based on the knowledge commonly used in the field of formulation technology.
  • composition of the present invention can be formulated into various dosage forms commonly used in the field of formulation technology.
  • a controlled release polymer mixture containing a drug (a mixture of a water-insoluble polymer, an enteric polymer, and an additive whose pH is alkaline when suspended or dissolved in water). It is possible to prepare a preparation comprising the controlled release composition having sustained release in the intestine having a release function (FIG. 1).
  • a preparation comprising the delayed-release type controlled-release composition can be prepared (FIG. 2).
  • the preparation of the preparation can be easily carried out by a preparation method commonly used in the field of usual preparation techniques.
  • Examples of the core substance of the method (1) include crystals of sugars or inorganic salts such as crystalline lactose, crystalline cellulose, crystalline sodium chloride, and the like, and spherical granules, for example, spherical granules of crystalline cellulose (trade name; , Asahi Kasei), spherical granules of crystalline cellulose and lactose (trade name: Non-Parrell 507, manufactured by Freund), spherical granules of purified white sugar (trade name: Non-Parel 101, manufactured by Freund) Granules containing no drug, such as spherical granules of purified sucrose and corn starch (trade name: Non-Paleru 101, manufactured by Freund) Body and compression-molded tablets.
  • the desired formulation can be obtained by coating the controlled release polymer mixture containing the drug in such a core substance.
  • the coating of the controlled release polymer mixture containing the drug is carried out by placing the core material in a centrifugal fluidized granulation coating device (CF) or a fluidized bed coating machine, a tumbling fluidized bed coating machine, a pan coating machine, and then Laminate coating with a binder while spraying the drug and the spray-dried product of the controlled release polymer quasi- !, or coating the coating solution in which the drug and the controlled release polymer mixture are dissolved in an appropriate solvent Alternatively, it can be suitably performed by spraying and coating the controlled-release polymer mixture coating liquid while spraying a drug.
  • CF centrifugal fluidized granulation coating device
  • a method of dissolving the drug and the controlled-release polymer mixture in an appropriate solvent followed by spray-drying with a fluidized-bed dryer or a spray-dryer to form a powder or the like into a tablet or the like; or
  • a method of preparing a tablet-like preparation by melting and molding a mixture of a drug and the controlled-release polymer mixture under appropriate conditions using a kneading extruder such as a biaxial extruder is used.
  • a method for preparing a preparation comprising a delayed-release type ⁇ controlled-release composition by coating the core substance containing a drug with only the controlled-release polymer mixture ⁇ ) includes:
  • crystals of sugars or inorganic salts such as crystalline lactose, crystalline cellulose, crystalline sodium chloride and the like
  • spherical granules for example, spherical granules of crystalline cellulose (trade names; Asahi Kasei), spherical granules of crystalline cellulose and lactose (trade name; non-paleru 507, manufactured by Freund)-, spherical granules of purified sucrose (trade name; non-palaied) No.
  • a granular carrier such as a spherical granulated product of refined sucrose and corn starch (trade name; Non-palette Lu 101, manufactured by Freund), etc. Examples thereof include those impregnated with a drug, tablets and capsules containing the drug.
  • the coating of the controlled release polymer mixture is performed by placing the core material in a centrifugal fluidized-bed granulating coating device (CF) or a fluidized bed coating machine, a tumbling fluidized bed coating machine, or a pan coating machine. Then, the coating can be suitably performed by spraying and coating a coating solution in which the elution control polymer mixture is dissolved.
  • CF centrifugal fluidized-bed granulating coating device
  • a capsule comprising the controlled release polymer mixture as a raw material and a drug filled in the capsule can be used to prepare a preparation comprising the desired controlled release composition.
  • a tablet containing a drug is used as a core tablet, and the controlled-release polymer mixture is dissolved in an appropriate solvent and then spray-dried using a fluidized-bed dryer or a spray-dryer. And forming the tablet into a tablet such as a dry coated tablet using the outer layer.
  • the controlled release polymer mixture containing the drug or only the controlled release polymer mixture is coated, but the solvent for dissolving and dispersing the controlled release composition includes water, alcohol such as methanol and ethanol. And ketones such as acetone, halogenated hydrocarbons such as methylene chloride and chloroform or a mixture thereof, preferably alcohols or a mixture thereof with water, particularly preferably ethanol or a mixture thereof. And water.
  • Coating can be performed by a method commonly used in pharmaceutical technology such as a fluidized bed coating method, a pan coating method, and a tumbling fluidized bed coating method.
  • Spray gun while pneumatically flowing material in the device It can be carried out by spray-coating at a suitable speed an aqueous dispersion containing a water-insoluble polymer, an enteric polymer, and an additive exhibiting a strong force when suspended in water.
  • the concentration of the water-insoluble polymer and the enteric polymer in the coating solution is not particularly limited, but is preferably 5 to 10% in consideration of the forming ability, workability, and the like.
  • the film coating liquid may contain a coating additive such as a plasticizer, a colorant, a lubricant, or an anti-agglomeration agent, which is used in a usual preparation, such as a plasticizer, a colorant, or a lubricant.
  • the amount of the selection agent is preferably 5 to 20% based on both copolymers, and the amount of the anti-agglomeration agent is preferably 50 to 300% by weight based on both copolymers.
  • the release amount (elution amount) of the substance is plotted against the time, and the time required for release of 5% by weight of the whole drug is measured.
  • the fluctuation width (fluctuation) of the time is small when the pH is in the range of 6.5 to 7.5, and specifically, it is preferably within 50%. More preferably, it is within 30%.
  • HCT-30 type pan-type tablet coating machine
  • Ethyl acrylate 'methyl methacrylate ⁇ methacrylate 175 g of trimethylammonium dimethylcopolymer (Eudragit RS P0), and 75 g of methacrylic acid / ethyl acrylate acrylate (Eudragit L100-55). By the same operation, 1325 g of a 5-ASA-containing preparation was obtained.
  • a tableting powder was prepared by mixing 250 g of theophylline, 145 g of anhydrous calcium hydrogen phosphate, 100 g of crystalline cellulose and 5 g of magnesium stearate using a V-type mixer. Using the tableting powder, uncoated tablets with a tablet weight of 100 mg and a tablet diameter of 7 mm were manufactured using a tablet-type continuous tableting machine (Clean Press Collect 12HUK).
  • KEX 25 Kermoto Iron Works
  • the melt-kneaded material was extruded from a die with a diameter of 2 mm at a shaft rotation speed of 250 rpm, cut into a length of about 5 mm with a tipper, processed quickly with a marmellaizer, and contained acetaminophen. A formulation was obtained.
  • Circopolymer (Eudragit: RS PO: manufactured by ROHM) 125; Methacrylic acid / Ethylcoacrylate acrylate (Eudragit L 100-55) 125 g, Triethyl citrate 25 g, Talc 250 g, Ethanol 200 OmL and water It was spray-coated with a solution consisting of 50 OmL to obtain 1325 g of a 5-ASA-containing preparation. The drug dissolution test is described below.
  • the drug obtained from Comparative Example 1 showed no elution of the drug in the Japanese Pharmacopoeia first solution (pH 1.2), and the Japanese Pharmacopoeia second solution ( In the diluted Mc II vaine solution at pH 6.8), pH 6.5 and pH 7.5, the lag time until the start of elution was different, and the dissolution behavior in the neutral pH range was uneven.
  • ⁇ SS Example 1 (Fig. 4) showed little variation in the dissolution behavior in the neutral pH range, as compared to Comparative Example 1, and drug release was controlled. You can see that it is.
  • the controlled release composition of the present invention elutes the drug in the lower intestine, such as the lower small intestine and the large intestine, which has a relatively high pH, and can also start elution of the drug after a desired time.
  • the composition of the present invention is a versatile composition that is very well controlled as a large intestine delivery system, such as topical therapy for diseases in the large intestine and oral administration of drugs susceptible to degradation in the upper small intestine.
  • Useful for This application is based on a patent application No. 201-49056 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

L'invention concerne des compositions à libération contrôlée de médicament, constituées par un polymère hydrosoluble, un polymère gastro-résistant, un additif possédant une valeur de pH alcaline lorsqu'il est en suspension ou dissout dans l'eau et une substance médicamenteuse. Ces compositions permettent d'obtenir un médicament qui ne se dissout pas dans l'estomac, mais qui se libère de façon contrôlée dans les parties inférieures du système gastro-intestinal (partie inférieure de l'intestin grêle, gros intestin, etc.), sans être sensiblement affecté par les changements de pH. Ainsi, ces compositions se caractérisent en ce qu'elles permettent d'administrer un médicament de manière sélective dans la partie inférieure de l'intestin grêle et le gros intestin.
PCT/JP2002/001634 2001-02-23 2002-02-22 Compositions a liberation controlee de medicament WO2002066004A1 (fr)

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JP2001-49056 2001-02-23
JP2001049056 2001-02-23

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006070781A1 (fr) * 2004-12-27 2006-07-06 Eisai R & D Management Co., Ltd. Preparation a liberation controlee de type a matrice comprenant une substance basique ou un sel de celle-ci et procede pour la production de celle-ci
WO2009101658A1 (fr) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Préparation pharmaceutique à libération programmée
WO2009101656A1 (fr) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Préparation à libération retardée
EP2241311A1 (fr) * 2008-02-15 2010-10-20 SSP Co., Ltd. Préparation pharmaceutique à libération programmée

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006070781A1 (fr) * 2004-12-27 2006-07-06 Eisai R & D Management Co., Ltd. Preparation a liberation controlee de type a matrice comprenant une substance basique ou un sel de celle-ci et procede pour la production de celle-ci
JPWO2006070781A1 (ja) * 2004-12-27 2008-06-12 エーザイ・アール・アンド・ディー・マネジメント株式会社 塩基性薬物又はその塩を含有するマトリックス型徐放性製剤およびその製造方法
AU2005320609B2 (en) * 2004-12-27 2009-07-02 Eisai R & D Management Co., Ltd. Matrix type sustained-release preparation containing basic drug or salt thereof, and method for manufacturing the same
AU2005320609B9 (en) * 2004-12-27 2010-03-18 Eisai R & D Management Co., Ltd. Matrix type sustained-release preparation containing basic drug or salt thereof, and method for manufacturing the same
JP4999466B2 (ja) * 2004-12-27 2012-08-15 エーザイ・アール・アンド・ディー・マネジメント株式会社 塩基性薬物又はその塩を含有するマトリックス型徐放性製剤およびその製造方法
WO2009101658A1 (fr) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Préparation pharmaceutique à libération programmée
WO2009101656A1 (fr) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Préparation à libération retardée
JP2009191034A (ja) * 2008-02-15 2009-08-27 Ss Pharmaceut Co Ltd 時限放出製剤
JP2009191036A (ja) * 2008-02-15 2009-08-27 Ss Pharmaceut Co Ltd 時限放出製剤
EP2241311A1 (fr) * 2008-02-15 2010-10-20 SSP Co., Ltd. Préparation pharmaceutique à libération programmée
EP2241311A4 (fr) * 2008-02-15 2013-01-23 Ssp Co Ltd Préparation pharmaceutique à libération programmée

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