WO2002066004A1 - Compositions with controlled drug release - Google Patents

Compositions with controlled drug release 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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WIPO (PCT)
Prior art keywords
drug
water
polymer
enteric
dissolved
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PCT/JP2002/001634
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French (fr)
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/en

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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

Compositions with controlled drug release comprising a water-soluble polymer, an enteric polymer, an additive showing an alkaline pH value when suspended or dissolved in water and a drug. From these compositions, a drug can be hardly eluted in the stomach but released under control in the lower parts of the digestive tracts (lower part of the small intestine, the large intestine, etc.) while not so largely affected by pH changes. Thus, these compositions are characterized by being capable of delivering a drug selectively to the lower part of the small intestine and the large intestine.

Description

薬物放出制御 物  Drug release controlled substances
技術分野  Technical field
本発明は消化管下部において p Hの変動に影響され難い薬物の溶出を可能にする 薬物放出制御組成物に関する。  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.
技術背景  Technology background
現在の桨物治療において、潰瘍性大腸炎およびクローン病のような炎症性腸疾患に 対する局所治療や小腸内で化学分解や酵素分解を受けやすいペプチド性薬物の経口 投与等の分野では、小腸下部から大腸の消化管下部の局所に選択的に薬物を運ぷこと が望まれている。 これまでの腸溶性製剤では、 胃内での薬物溶出は効果的に抑制する が、 薬物の大部分が小腸上部で急速に溶出、 吸収ないし分解されてしまうため、 大腸 には到達しない。 また徐放性製剤では、投与直後の胃内から持続的に薬物が溶出され るため、製剤が胃から小腸を通過する間に多くの薬物が溶出されてしまう。近年前述 した消化管下部の局所に選択的に桀物を運ぶという目的を達成するために様々な新 しい製剤が考案されているが、小腸下部から大腸に薬物を選択的に送達するためには、 ヒトの消化管内の物理的、生理的要因および製剤の消化管内移動時間を考慮した製剤 設計が必要である。  In the field of current animal therapy, in the fields of local treatment for inflammatory bowel diseases such as ulcerative colitis and Crohn's disease and oral administration of peptide drugs that are susceptible to chemical and enzymatic degradation in the small intestine, the lower intestine Therefore, it is desired to selectively deliver the drug to the lower part of the digestive tract of the large intestine. Conventional enteric-coated preparations effectively suppress drug dissolution in the stomach, but do not reach the large intestine because most of the drug is rapidly dissolved, absorbed or degraded in the upper small intestine. In the case of sustained-release preparations, drugs are continuously eluted from the stomach immediately after administration, so that many drugs are eluted while the preparation passes from the stomach to the small intestine. In recent years, various new formulations have been devised in order to achieve the above-mentioned purpose of selectively delivering a substance to the lower part of the gastrointestinal tract, but in order to selectively deliver a drug from the lower small intestine to the large intestine, It is necessary to design the drug product taking into account the physical and physiological factors in the human gastrointestinal tract and the transit time of the drug product in the gastrointestinal tract.
水不溶性ァクリル酸系ポリマと腸溶性ァクリル酸系ポリマを組み合わせた放出制 御膜を有する製剤（特開平 3 7 2 3 8号公報） も知られているが、 この製剤は難持 続性薬物の胃内からの持続放出を目的としたものであって、局所への薬物送達を達成 するようなものではない。  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.
特開平 8— 2 6 9 7 7号公報、特開平 8— 1 4 3 4 7 6号公報に記載の製剤は、 水 不溶性ポリマと腸溶性ポリマの混合物からなる溶出制御被膜で被覆された製剤であ り、 芯物質に藥物 ¾含有しており、 また予め設定した時間、 または予め設定した p H で薬物を急速に溶出する経口投与用製剤を提供しょうとするものであるが、微妙な p Hの変化により溶出開始時間及び溶出速度などが大きく変動し、消化管内での p H変 動により放出挙動が変ィ匕することが推察される。 特開平 9— 295933号公報に記載の発明は、 薬物を含んでなる核が、 添加物お よび塩基性基を有さない膨潤性ポリマを含む被膜剤で被覆された放出制御組成物に 関するもので消化管下部への薬物送達を達成したものであるが、 胃内から薬物放出は 始まっており、 消化管下部局所への桀物送達を意識したものではなく、 消化管内での pH変動による溶出挙動の変動は考えられていない。 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. Yes, 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. The invention described in Japanese Patent Application Laid-Open No. 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. Drug delivery to the lower gastrointestinal tract, but drug release has begun in the stomach, and is not conscious of the delivery of the substance to the lower gastrointestinal tract, but is eluted due to pH fluctuations in the gastrointestinal tract. No change in behavior is considered.
特開平 11-286438号公報に記載の発明は、 多孔質無機物質と （メタ） ァク リル酸系コポリマを含んでなるマトリツクス中に薬物を含有する製剤に関するもの であるが、多量の多孔質無機物質に溶解したポリマおよび薬物を吸収させ製剤を調製 するもので、 長期間 （1週間以上） の薬物放出が達成されているが、 消化管下部への 薬物送達を目的にしておらず、消化管内での P H変動により放出挙動が変化する ίと は考慮されていない。  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.
pH依存性のコ一ティング基剤である腸溶性コーティング剤の被覆により消化管 下部への部位特異的放出が多く達成されている。より厚い被膜をコーティングするこ ともしくは被膜の溶解が始まる開始 ρ Ηを上昇させるこどにより、結腸特異的放出を 達成している。 5—ァミノサリチル酸（5—ASA) を含有し、 pH7で溶解するメ 夕ァクリル酸 ·メ夕ァクリル酸メチルコポリマ （Eudragi t S 100) をコ —ティングした錠剤が、多数め国で市販されている（As ac o 1 (商標）、 スミス - クライン 'ビーチャム社）。この製剤では、 通常は 5— AS Aの部位特異的放出がう まく行われているが、患者のなかには便の中に溶解していない錠剤を見出したという 事例、すなわちコ一ティング層が溶解されずに錠剤がそのまま***されるという事例 が報告されている（シュローダー (Schroeder)ら、 ew Engl. J. Med. ,317, 1625-1629， 1987) 。 このことから消化管内 pHには個体差があり、 また個体内においてもその p Hの変動が大きいことが示唆され、単なる腸溶性コ一ティング剤の被覆により一定し た消化管下部特異的な薬物放出を達成するのには限界があると考えられる。  Many site-specific releases to the lower gastrointestinal tract have been achieved by coating with an enteric coating agent, which is a pH-dependent coating base. Colon-specific release has been achieved by coating a thicker film or increasing the onset ρ Η at which dissolution of the film begins. A large number of tablets containing 5-aminosalicylic acid (5-ASA) and coated with methacrylic acid / methyl methacrylate copolymer (Eudragit S 100) which are soluble at pH 7 are commercially available in many countries. (As ac o 1 ™, Smith-Klein 'Beecham). This formulation usually provides a good site-specific release of 5-AS A, but some patients find tablets that are not dissolved in the stool, ie, the coating layer is dissolved. Tablets have been reported to be excreted without treatment (Schroeder et al., Ew Engl. J. Med., 317, 1625-1629, 1987). This suggests that there are individual differences in the pH in the gastrointestinal tract and that the pH fluctuates greatly within the individual, and that a drug specific to the lower gastrointestinal tract can be maintained by simply coating with an enteric coating agent. It is believed that there is a limit to achieving release.
発明の開示  Disclosure of the invention
したがって、 本発明は、 胃内では薬物をほとんど溶出せず、 小腸下部や大腸等の p Therefore, in the present invention, almost no drug is eluted in the stomach, and p
Hが比較的高い消化管下部で pHの変動に大きく影響されることなく薬物を溶出す ることができる放出制御組成物を提供することを目的としている。 Elution of drug in the lower gastrointestinal tract with relatively high H is not significantly affected by pH fluctuation It is intended to provide a controlled release composition that can be controlled.
本発明者らは、 水不溶性ポリマ、 腸溶性ポリマ、 および薬物を含む組成物に、 水に 懸濁もしくは溶解したときに P Hがアルカリ性である添加剤を含有させることによ つて、 p Hの低い胃内ではほとんど薬物の放出が起こらず、中性乃至弱アルカリ性域、 とりわけヒト消化管内の p Hである p H 6〜8での p H変化に応じて溶出し、なおか つ小腸下部や大腸等の比較的高い p Hの消化管下部で消化管内の p Hの変動に大き く影響されることなく制御されて m¾が溶出されることを見出し、 また該組成物中の 水不溶性ポリマと腸溶性ポリマの混合物の混合比率もしくは放出制御組成物層の厚 みを種々変化させた場合には、その変化に応じて溶出速度や溶出開始時間も変化する ことを見出し、 本発明を完成させるに至った。  The present inventors have found that 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 It was found that m¾ 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 When 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. Was.
すなわち、 本発明は胃内では薬物をほとんど溶出せず、 小腸下部や大腸等の p Hが 比較的高い消化管下部内で、 個体間、 個体内の p Hの変動に大きく影響されることな く薬物の溶出を的確に制御することができる薬物放出制御組成物に関する。  That is, in the present invention, 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.
さらに詳しくは、 該放出制御組成物は、 水不溶性ポリマ、 腸溶性ポリマおよび水に 懸濁もしくは溶解したときに p Hがアル力リ性である添加物により薬物が保護され ることによって、 投与後胃内では薬物をほとんど溶出せず、 小腸内に移 ί亍すると同時 に水に懸濁もしくは溶解時に p Hがアル力リ性である添加物により放出制御組成物 内の ρ Ηが調整され、 ρ Η 6から 8において ρ Ηに大きく影響されることなく薬物を 溶出させることができる放出制御組成物である。  More specifically, 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, ρ 内 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 ρΗ6 to 8 without being greatly affected by ρΗ.
すなわち、 本発明は以下の通りである。  That is, the present invention is as follows.
1 . ( a) 水不溶性ポリマ、 （ b )腸溶性ポリマ、 （ c ) 7j<に想濁もしくは溶解し たときに p Hがアル力リ性である添加物および（ d )薬物を含む薬物放出制御組成物。 1. 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.
2 . ( a)水不溶性ボリマが、 水不溶性ァクリル酸系ボリマである前記 1記載の薬 物放出制御組成物。 2. (a) The drug release controlling composition according to the above item 1, wherein the water-insoluble boryma is a water-insoluble acrylic acid-based boryma.
3 . ( b )腸溶性ポリマが、 腸溶性ァクリル酸系ボリマである前記 1記載の薬物放 出制御組成物。 3. (b) The drug release controlling composition according to the above 1, wherein the enteric polymer is an enteric acrylic acid-based polymer.
4 . ( a) 水不溶性ポリマと （b ) 腸溶性ポリマとの配合比率が、 9 5 ： 5〜5 ： 95の範囲である前記 1記載の薬物放出制御組成物。 4. 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 1, wherein the composition has a range of 95.
5. (c)水に懇濁もしくは溶解したときに pHがアルカリ性である添加物が、 制 酸剤である前記 1記載の薬物放出制御 物。  5. (c) The drug-release controlled substance according to the above 1, wherein the additive whose pH is alkaline when dissolved or dissolved in water is an antacid.
6. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物が、 金 属塩である前記 1記載の薬物放出制御組成物。  6. (c) The drug release controlling composition according to the above 1, wherein the additive whose pH is alkaline when suspended or dissolved in water is a metal salt.
7. ( c)水に懸濁もしくは溶解したときに pHがアル力リ性である添加物の配合 量が、 (a)水不溶性ポリマと （b)腸溶性ポリマの全量に対して 100重量％以下 である前記 1記載の薬物放出制御組成物。  7. (c) The amount of the additive whose pH is water-soluble when suspended or dissolved in water is 100% by weight based on the total amount of (a) water-insoluble polymer and (b) enteric polymer. 2. The drug release controlling composition according to the above 1, which is:
8. ( d )薬物の配合量が、 （ a )水不溶性ポリマと （ b )腸溶性ポリマの全量に 対して Ί 0重量％以下である前記 1記載の薬物放出制御組成物。  8. The drug release controlling composition according to the above 1, wherein the compounding amount of (d) the drug is about 0% by weight or less based on the total amount of (a) the water-insoluble polymer and (b) the enteric polymer.
9. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物を含み、 ノヽ'ドル法による溶出試験において、薬物全体の 5重量％の薬物が溶出するのに要する 時間の変動幅が、 pHが 6. 5〜7. 5の範囲内で 50%以内である、 薬物放出制御 組成物。  9. (c) Variation in the time required for 5% by weight of the drug to dissolve in the dissolution test by the Noddle method, including an additive whose pH is alkaline when suspended or dissolved in water. A controlled drug release composition having a width within 50% within a pH range of 6.5 to 7.5.
10. さらに、 （a)水不溶性ポリマ、 （b)腸溶性ポリマ、 および（d)薬物を 含む前記 9に記載の薬物放出制御組成物。  10. 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.
11. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物を加 える工程を有することを特徴とする薬物放出制御組成物の製造方法。  11. (c) 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.
12. 小腸下部および/または大腸において、 （d) 薬物を放出するものである、 前記 1〜 8のいずれかに記載の薬物放出制御組成物。  12. The drug release controlling composition according to any one of the above 1 to 8, which releases a drug in the lower small intestine and / or the large intestine.
図面の簡単な説明  BRIEF DESCRIPTION OF THE FIGURES
図 1は、薬物を含有した放出制御ポリマ混合物を調製することによって得られる徐 放出機能を持たせた腸内徐放性の放出制御組成物を示す。  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.
図 2は、薬物を含む芯物質に放出制御ポリマ混合物のみをコ一ティングすることに よって得られる遅延溶出型の放出制御組成物を示す。  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.
図 3は、 比較例 1で得られた製剤の溶出挙動を示す。  FIG. 3 shows the dissolution behavior of the preparation obtained in Comparative Example 1.
図 4は、 実施例 1で得られた製剤の溶出挙動を示す。 図 5は、 実施例 2で得られた製剤の溶出挙動を示す。 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.
図 6は、 実施例 3で得られた製剤の溶出挙動を示す。  FIG. 6 shows the dissolution behavior of the preparation obtained in Example 3.
図 7は、 実施例 4で得られた製剤の溶出挙動を示す。  FIG. 7 shows the dissolution behavior of the preparation obtained in Example 4.
発明の詳細な説明  Detailed description of the invention
本発明'において用いられる水不溶性ポリマとは、製剤技術分野で水不溶性ポリマと して通常知られているものであれば、 いずれも好適に用いることが出来、 例えば、 水 不溶性セルロース誘導体、水不溶性ビニル誘導体及び水不溶性ァクリル酸系ポリマ等 から選ばれる 1種又は 2種以上があげられる。  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. 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.
水不溶性セルロース誘導体としては、セルロースに含まれる水酸基の一部又は全部 がェチル基で置換されたェチルセルロース等のセルロースエステル、酢酸セルロース 等のセルロースエステル等があげられる。  Examples of the water-insoluble cellulose derivative 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.
水不溶性ビニル誘導体の例としては、 ボリ酢酸ビニル、 ポリ塩化ビニル等があげら れる。  Examples of the water-insoluble vinyl derivative include vinyl polyacetate, polyvinyl chloride and the like.
水不溶性アクリル酸系ポリマとしては、 p H非依存性アクリル酸系ポリマである、 ァクリル酸ェチル 'メタァクリル酸メチル ·メタァクリル酸塩化トリメチルアンモニ ゥムェチルコポリマ （例えば、 商品名；オイ ドラギヅ ト R S、 オイ ドラギヅ ト R L、 口一ム社製）、 メタアクリル酸メチル 'アクリル酸ェチルコポリマ（例えば、商品名； オイドラギヅト N E、 ローム社製） 等があげられる。  Examples of the water-insoluble acrylic acid polymer 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.
これらの内、 好ましい水不溶性ポリマとしては、 水不溶性セルロース誘導体、 水不 溶性アクリル酸系ポリマがあげられ、 より好ましくは水不溶性アクリル酸系ポリマ、 最も好ましくは、 ァクリル酸ェチル ·メ夕アクリル酸メチル ·メ夕ァクリル酸塩化ト リメチルアンモニゥムェチルコポリマがあげられる。  Of these, 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.
本 ¾明において用いられる腸溶性ポリマとは、 製剤技術の分野で通常、 製剤の被覆 に用いうるものであって、 p H約 5〜7で溶解するポリマがあげられる。 かかるポリ マとしては、 例えば、 腸溶性セルロース誘導体、 腸溶性天然高分子化合物、 腸溶性ポ リビニルアルコール誘導体、腸溶性マレイン酸系ポリマ及び腸溶性ァクリル酸系ポリ マ等から選ばれる 1種又は 2種以上があげられる。 腸溶性セルロース誘導体としては、セルロースもしくはその誘導体と有機酸とのェ ステルがあげられ、 とりわけセルロースと酢酸、 フタル酸、 コハク酸、 マレイン酸等 とのエステルが好ましい。腸溶性セルロース誘導体の具体例としては、 セルロースァ セテ一トフ夕レート、 セルロースアセテートサクシネート、 ヒドロキシェチルセル口 —スアセテートフ夕レート、 ヒドロキシプロピルメチルセルロースアセテートサクシ ネート （ヒドロキシプロビルメチルセルロースアセテートサクシネート一 L、 ヒドロ キシプロビルメチルセルロースアセテートサクシネ一卜一 M、 ヒドロキシプロビルメ チルセルロースアセテートサクシネ一トー H等）、 ヒドロキシプロピルメチルセル口 —スフタレ一卜、 カルボキシメチルェチルセルロース等があげられる。 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. Specific examples of the 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.
腸溶性天然高分子ィ匕合物としては、 シエラヅク等があげられる。  Examples of enteric-coated natural polymer conjugates include Sierra Duck.
腸溶性ポリビニルアルコール誘導体としては、ポリビニルアルコールと有機酸との エステルがあげられ、 とりわけポリビニルアルコールと酢酸、 フ夕ル酸、 コハク酸、 マレイン酸等とのエステルが好ましい。腸溶性ポリビニルアルコール誘導体の具体例 としては、 例えばボリビニルアルコールフタレート、 ポリビニルアルコールァセテ一 トフ夕レート、 ポリビニルプロビオネ一トフタレ一ト、 ポリビニルブチレ一トフタレ —ト、 ポリビニルァセ夕一ルフ夕レート、 ポリビニルァセトァセ夕一ルフタレート、 ポリビニルァセトァセ夕一ルサクシネ一ト、ポリビニルァセ夕一ルジェチルアミノア セテ一卜等があげられる。  Examples of the enteric polyvinyl alcohol derivative 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. Specific examples of 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.
腸溶性マレィン酸系ポリマとしては、無水マレイン酸とビニルモノマーとのコポリ マがあげられ、 とりわけ無水マレイン酸とビニルアセテート、 スチレン、 ビニルメチ ルェ一テル、 アクリル酸もしくはそのエステルとのコポリマが好ましい。腸溶性マレ イン酸系ポリマの具体例としては、 例えばビニルアセテート 'マレイン酸コポリマ、 スチレン 'マレイン酸コボリマ、 エチレン 'スチレン 'マレイン酸コポリマ、 ァクリ ロニトリル ·メチルァクリレート 'マレイン酸コポリマ、 プチルァクリレ一ト .スチ レン 'マレイン酸コポリマ等があげられる。  Examples of the enteric maleic acid polymer 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. Specific examples of 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.
腸溶性ァクリル酸系ポリマの例としてはァクリル酸、メ夕ァクリル酸もしくはそれ らのエステルとのコポリマがあげられる。 腸溶性ァクリル酸系ポリマの例としては、 スチレン -アクリル酸コポリマ、 アクリル酸'アクリル酸メチルコポリマ、 メタァク リル酸 'ァクリル酸メチルコポリマ、 メタアクリル酸 'メタァクリル酸メチルコポリ マ （例えば、 商品名；オイ ドラギヅド L 1 0 0、 オイ ドラギヅド S 1 0 0、 ローム社 製） 、 メタアクリル酸 'アクリル酸ェチルコポリマ （例えば、 商品名；オイ ドラギヅ ド L 1 0 0— 5 5、 オイ ドラギヅ ド L 3 0 D— 5 5、 ローム社製） 等があげられる。 これらの内、 好ましい腸溶性ポリマとしては、 腸溶性セルロース誘導体、 腸溶性ボ リビニルアルコール誘導体、 腸溶性アクリル酸系ポリマ等があげられ、 具体的には、 腸溶'注セルロース誘導体として、 セルロースアセテートフタレート、 ヒドロキシプロ ピルメチルセルロースアセテートサクシネート、 ヒドロキシプロピルメチルセル口一 スフ夕レート、 カルボキシメチルェチルセルロース等が、 腸溶性天然高分子化合物と して、 シエラヅク等が、 腸溶性ボリビニルアルコール誘導体として、 ボリビニルァセ タールジェチルァミノアセテート等が、 腸溶性アクリル酸系ポリマとして、 メタァク リル酸.メタアクリル酸メチルコポリマ、 メタアクリル酸 ·アクリル酸ェチルコポリ マ等があげられる。 Examples of enteric acrylic acid-based polymers include copolymers with acrylic acid, methacrylic acid or esters thereof. Examples of 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. Of these, preferred enteric polymers include enteric cellulose derivatives, enteric polyvinyl alcohol derivatives, enteric acrylic polymers, and the like. Specifically, 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.
これらの内、 更に好ましい腸溶性ボリマとしては、 腸溶性セルロース誘導体、 腸溶 性アクリル酸系ポリマがあげられ、 より好ましくは腸溶性アクリル酸系ポリマ、 最も 好ましくは、 メ夕アクリル酸 ·メ夕アクリル酸メチルコポリマ、 メタアクリル酸 -ァ クリル酸ェチルコポリマ等があげられる。  Of these, more preferred 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.
これらの各ポリマは、 適宜組み合わせて使用することができ、水不溶性ポリマの 1 種又は 2種以上を混合したものと、腸溶性ポリマの 1種又は 2種以上を混合したもの を組み合わせて使用することができる。  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.
これらの内、 好ましい組合わせとしては、 水不溶性ポリマにおいて好ましいものと して列挙したポリマと、腸溶性ポリマにおいて好ましいものとして列挙したポリマと の組合わせがあげられ、 とりわけ水不溶性ァクリル酸系ポリマと腸溶性ァクリル酸系 ポリマの組合せが好ましい。  Of these, 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.
これら水不溶性ポリマと腸溶性ポリマの配合比率は 9 5 ： 5〜 5 ： 9 5の範囲で、 水不溶性ポリマ及び腸溶性ポリマの種類により適宜選択することができる。 本発明の組成物において、水不溶性ポリマと腸溶性ポリマの最適な組合せ及び最適 な配合比率は、 当業者であれば所望の溶出挙動を得ることき目的に、 極めて容易に見 出すことができる。 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. In the composition of the present invention, 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.
本発明において用いられる水に懸濁もしくは溶解レたときに p Hがアル力リ性で ある添加物とは、 当該添加物を懸濁もしくは溶解させたときの溶液の p Hが 7以上と なる物質を意味し、 本発明の目的を達成でき、 製剤をヒトに投与したとき、 生体に悪 影響を及ぼさない添加物のいかなるものも包含される。例えば制酸剤、多孔質無機物、 金属塩である添加剤など様々な添加剤が挙げられる。  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. For example, various additives such as an antacid, a porous inorganic substance, and an additive that is a metal salt can be used.
- 具体的には、 水に不溶性の金属酸化物、 金属水酸化物、 金属酸塩又は複合金属化合 物等が用いられる。 より具体的には、 酸化マグネシウム等の金属酸化物、 乾燥水酸化 アルミニウムゲル、水酸化アルミニゥムゲル、水酸化マグネシゥム等の金属水酸化物、 沈降炭酸カルシウム、 炭酸マグネシウム等の金属炭酸塩、 又はメタケイ酸アルミン酸 マグネシウム、 ケィ酸アルミン酸マグネシウム、 水酸化アルミナマグネシア、 合成ヒ ドロタルサイ ト等の複合金属化合物等の群から選ばれる 1種以上を举げることがで きる。  -Concretely, water-insoluble metal oxides, metal hydroxides, metal salts or composite metal compounds are used. More specifically, 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 One or more selected from the group of composite metal compounds such as magnesium oxide, magnesium silicate aluminate, magnesia hydroxide magnesia, and synthetic hydrotalcite can be used.
好ましくは、制酸剤（無機制酸剤）が水酸化アルミニウムゲル、炭酸マグネシウム、 メタケイ酸アルミン酸マグネシウム、 ケィ酸アルミン マグネシウム、合成ヒドロキ シ夕ルサイ 卜、 乾燥水酸化アルミニウムゲル、 水酸化マグネシウム、 沈降炭酸カルシ ゥムの群から選ばれる 1種以上の組み合わせであるが、 その他、 ステアリン酸アルミ 二ゥム、 ステアリン酸マグネシウム、 ステアリン酸カルシウム、 塩化マグネシウム、 ポリアクリル酸、 N a塩を持つ添加剤 （カルボキシメチルスターチナトリウムなど） など水に懸濁もしくは溶解にしたときに p Hがアル力リ性になる添加剤であれば特 に制限なく使用することができる。  Preferably, the antacid (inorganic 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.
これら水に懸濁もしくは溶解したときに p Hがアルカリ性である添加物の配合量 は、 水不溶性ポリマ、 腸溶性ポリマの全量に対して通常 1 0 0重量％以下、 好ましく は 2〜 1 0 0重量％、 より好ましくは 5〜9 0重量％、 特に好ましくは 1 0〜8 0重 量％である。 なお、 これらの水に懸濁もしくは溶解したときに p Hがアルカリ性であ る添加物は天然物または合成によって得られるものであってもよく、すでに粉末とな つたものを用いる場合にはできるだけ粉碎して微粉として用いる方がよい。 なお、 添 カロ物の量が多すぎる場合は層の形成が困難になる。 · 本製剤に適用できる薬理活性物質 （薬物） は、 小腸以降の消化管下部内で放出され た際に有効な物質であれば特に制限されることなく、 何れであっても使用できる。 た とえば、 ポリペプチド類、 抗炎症剤、 抗腫瘍剤、 抗生物質、 化学療法剤、 炎症性腸疾 患治療薬（クローン病治療薬、潰癟性大腸炎治療薬を含む）、過敏症 症候群治療薬、 ステロイ ド剤、 免疫抑制剤、 下剤 （便秘薬も含む） 等が挙げられる。 また、 これらの 薬理活性物質においては、通常藥学的に許容される無機または有機の塩も当然ながら 含まれるも Oである。 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. For example, 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. In addition, these pharmacologically active substances usually include pharmaceutically acceptable inorganic or organic salts, and are naturally O.
これら薬物の製剤中配合量については、 特に制限はない。 ただしポリマ中に薬物を 分散させ放出を制御する場合には、 水不溶性ポリマ、 腸溶性ポリマの全量に対して通' 常 7 0重量％以下、 好ましくは 6 0重量％以下、 より好ましくは 5 0重量％以下であ る。  There are no particular restrictions on the amounts of these drugs in the formulation. However, when the release is controlled by dispersing the drug in the polymer, it 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.
本放出制御組成物には適宜必要に応じて通常医薬品添加剤として用いられる賦形 剤、 崩壊剤、 結合剤、 コ一ティング助剤、 着色剤、 隠蔽剤、 可塑剤、 滑択剤、 吸収促 進剤、 その他の各種目的のための添加剤等 （医薬品添加物事典 2 0 0 0、 日本医薬品 添加剤協会編集、 薬事日報社） も添加することができる。 この際の K¾剤としては乳 糖、 デンプン、結晶セルロース、 タルク、 ラクト一ス、マンニトール、 キシリトール、 無水リン酸水素カルシウム、 リン酸水素ナトリウム、 合成ケィ酸アルミニウム、 メタ ケィ酸アルミン酸マグネシウム、 水酸化アルミニウム .マグネシウム、 合成ヒドロタ ルサイト、 ケィ酸マグネシウム、 天然ケィ酸アルミニウム、 炭酸カリウム、 炭酸カル シゥム、 炭酸ナトリウム、 酸化マグネシウム、 炭酸マグネシウム、 炭酸水素ナリトウ ム、 炭酸水素カリウム、 無水ケィ酸、 軽質無水ケィ酸、 水酸化ナトリウム、 ピロリン 酸四ナ卜リウム、 無水ピロリン酸ナトリゥム、 無水リン酸ミナトリウム、 リン酸ニ力 リウム、 無水亜硫酸ナトリウム、 d l—酒石酸ナリ トウム等から適宜選択される。 薬理活性物質の吸収促進を目的としてショ糖脂肪酸ェステル、 グリチルリチン酸塩、 グリチルレチン酸、 胆汁酸及び胆汁酸の抱合体、 ピロチォデカン、 グリセリン脂肪酸 エステル、 アジピン酸、 塩基性アミノ酸、 ポリエチレングリコ一ル、 力プリン酸ナト ，リゥム、 ドデシル硫酸ナトリゥム、 デォキシコ一ル酸ナトリゥム等の吸収促進剤を配 合添加することもできる。 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 (Pharmaceutical Excipients Dictionary 2000, edited by the Japan Pharmaceutical Excipients Association, Yakuji Nippo) can also be added. Lactose, starch, crystalline cellulose, talc, lactose, mannitol, xylitol, anhydrous calcium hydrogen phosphate, sodium hydrogen phosphate, synthetic aluminum silicate, magnesium metasilicate, magnesium hydroxide Aluminum Magnesium, Synthetic hydrotalcite, Magnesium silicate, Natural aluminum silicate, Potassium carbonate, Calcium carbonate, Sodium carbonate, Magnesium oxide, Magnesium carbonate, NaHCO3, Potassium hydrogencarbonate, Caic anhydride, Light silicate , Sodium hydroxide, tetrasodium pyrophosphate, sodium pyrophosphate, anhydrous sodium phosphate, anhydrous sodium phosphate, anhydrous sodium sulfite, dl-sodium tartrate and the like. 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.
結合剤としては例えば、 庶糖、 グルコース、 ソルビトール等の小糖類もしくは糖ァ ルコール類、デキストリン、アラビアゴム、 トラガント、グァ一ガム、カラギ一ナン、 アルギン酸ナトリウム、 ゼラチン、 グルテン等の多糖類、 メチルセルロース、 ェチル セルロース、 カルボキシメチルセル口一スナトリウム、 ヒドロキシプロピルメチルセ ルロース、 ヒドロ'キシプロビルセルロース等のセルロース誘導体、 ポリビニルピロリ ドン、 ポリビニルアルコール、 ポリビニルアセテート、 ポリエチレンォキサイド等の 合成高分子等があげられる。  Examples of the binder 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. 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. .
崩壊剤としては例えばデンプン、 ヒドロキシプロピルスターチ、 カルボキシメチル セルロースおよびそのカルシウム塩、低置換度ヒドロキシプロビルメチルセルロース、 カルボキシメチルス夕一チナトリウム、 クロスカルメロースナトリウム、 クロスポビ ドン、 寒天末、 結晶セルロース、 ひ一セルロース、 架橋ゼラチン、 架橋カゼイン等が あげられる。  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.
コ一ティング助剤としては、 例えば硬化油、 ステアリン酸（商品名； N A A— 1 7 4等、 日本油脂製） 、 ステアリン酸カルシウム、 ステアリン酸ポリオキシル、 ステア リン酸マグネシウム、 セ夕ノール、 タルク等があげられる。  Examples of the coating aid 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
着色剤としては、 例えば食用色素、 レーキ色素、 カラメル、 カロチン、 ァチヅ卜、 コチニール、三二酸化鉄等があり、具体的には食用赤色 2号、 3号、黄色 4号、 5号、 緑色 3号、 青色 1号、 2号、 紫 1号等の食用アルミニウムレーキ、 アナヅト （ベニノ キ由来の天然色素）、 カルミン（カルミン酸アルミニウム塩）、パールエッセンス（グ ァニンを主成分とする） 等があげられる。  Examples of the coloring agent include food coloring, lake coloring, caramel, carotene, ethyl acetate, cochineal, iron sesquioxide and the like.Specifically, 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. .
隠蔽剤としては、例えば二酸化チタン、沈降炭酸カルシウム、第二燐酸カルシウム、 硫酸力ルシゥム、 タルク等があげられ、 可塑剤としては、 例えばポリエチレングリコ —ル （P E G) 、 クェン酸トリエチル、 シリコン油、 トリァセチン、 プロピレングリ コールのほか、 ジェチルフタレート、 ジブチルフタレート、 ブチルフタリルブチルグ リコレート等のフ夕ル酸誘導体等があげられる。 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. , 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.
滑択剤としては、 例えば、 ステアリン酸マグネシウム、 タルク、 合成ケィ酸マグネ シゥム、 微粒子性酸化ケィ素、 デンプン、 ラウリル硫酸ナトリウム、 ホウ酸、 酸化マ グネシゥム、 軽質無水ケィ酸等があげられる。  Examples of the lubricant 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.
これらの添加物の添加量や添加時期は、製剤技術の分野で常用される知見に基づく 範囲であれば、 何ら問題なく使用することができる。  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.
本発明の組成物は、通常製剤技術の分野で常用される様々な剤形に製剤化すること ができる。 たとえば薬物を含有した放出制御ポリマ混合物 （水不溶性ポリマと、 腸溶 性ポリマと、水に懸濁もしくは溶解したときに p Hがアルカリ性である添加物との混 合物）を調製することにより徐放出機能を持たせた腸内徐放性の該放出制御組成物よ りなる製剤を調製できる （図 1 ) 。 また薬物を含む芯物質に該放出制御ポリマ混合物 のみをコ一ティングすることによって遅延溶出型の該放出制御組成物よりなる製剤 を調製することもできる （図 2 )。  The composition of the present invention can be formulated into various dosage forms commonly used in the field of formulation technology. For example, by preparing 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). Alternatively, by coating only the controlled-release polymer mixture on a core substance containing a drug, a preparation comprising the delayed-release type controlled-release composition can be prepared (FIG. 2).
製剤の調製は、通常の製剤技術の分野で常用される製剤化方法により簡単に実施す ることができる。  The preparation of the preparation can be easily carried out by a preparation method commonly used in the field of usual preparation techniques.
腸内徐放性の該放出制御 ϋβ¾物よりなる製剤を調製する方法としては、  As a method for preparing a preparation comprising the intestinal sustained-release controlled release {β} compound,
( 1 ) 芯物質に薬物を含有した該放出制御ポリマ混合物をコーティングす る方法、  (1) a method of coating the controlled release polymer mixture containing a drug on a core substance,
( 2 ) 薬物を含有した該放出制御ポリマ混合物そのものを成形する方法 等が挙げられる。  (2) A method of molding the controlled-release polymer mixture itself containing a drug.
方法 （ 1 ) の芯物質としては、 例えば結晶乳糖、 結晶セルロース、 結晶塩化ナトリ ゥム等の糖類もしくは無機塩の結晶、 球形造粒物、 例えば、 結晶セルロールの球形造 粒物 （商品名；セルフィァ、 旭化成製） 、 結晶セルロースと乳糖の球形造粒物 （商品 名；ノンパレルー 5 0 7、 フロイント社製） 、 精製白糖の球形造粒物 （商品名；ノン パレル一1 0 3、 フロイント社製） 、 精製白糖及びトウモロコシデンプンの球形造粒 物 （商品名；ノンパレルー 1 0 1、 フロイント社製）等の薬物を含まない顆粒状の担 体や圧縮成形された錠剤等があげられる。 また、 これら芯物質に薬物を結合剤、 賦形 剤、 崩壊剤などと共にコ一ティングしたものや、 これら芯物質に薬物を含有させたも のも芯物質として使用することができる。 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. In addition, those obtained by coating a drug together with a binder, an excipient, a disintegrant, and the like on these core substances, and those containing a drug in these core substances can also be used as the core substance.
このような芯物質に薬物を含んだ該放出制御ポリマ混合物をコ一テイングするこ とにより目的の製剤は得られる。薬物を含んだ該放出制御ポリマ混合物のコ一ティン グは、 芯物質を遠心流動造粒コーティング装置（C F ) もしくは流動層コーティング 機、 転動流動層コーティング機、 パンコ一ティング機中に入れ、 次いで薬物と該放出 制御ポリマ準^!の噴霧乾燥物を散布しつつ結合剤により積層コ一ティングを行う、 もしくは薬物と該溶出制御ポリマ混合物を適当な溶媒に溶解させたコーティング液 を被覆していく、あるいは薬物を散布しつつ該放出制御ポリマ混合物コ一ティング液 を噴霧 ·被覆することにより好適に行うことができる。  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.
方法 （2 ) としては、 薬物および該放出制御ボリマ混合物を適当な溶媒に溶解後、 流動層乾燥機もしくはスプレドライ乾燥機により噴霧乾燥することによって得られ た粉末を錠剤などに成形する方法、 もしくは薬物および該放出制御ボリマ混合物の混 ^体を二軸ェクストル一ダ等の混練押し出し機を用いて適当な条件で溶融'成型す ることにより錠剤様の製剤を調製する方法等が挙げられる。  As the method (2), 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.
次に薬物を含む芯物質に該放出制御ポリマ混合^)のみをコーティングすることに よる遅延溶出型の鎵放出制御組成物よりなる製剤の調製方法としては、  Next, a method for preparing a preparation comprising a delayed-release type 鎵 controlled-release composition by coating the core substance containing a drug with only the controlled-release polymer mixture ^) includes:
( 3 ) 薬物を含む芯物質（顆粒、錠剤、 カプセルなど） に該放出制御ポリマ 混合物の溶液をコ一ティングする、  (3) coating the solution of the controlled release polymer mixture on a core substance (granules, tablets, capsules, etc.) containing a drug,
( 4 ) 藥物を含む芯物質に該放出制御ポリマ混合物の噴霧乾燥物を粉末コ 一ティングする  (4) Powder coating the spray-dried product of the controlled release polymer mixture on a core substance containing a drug substance
方法等が挙げられる。 Method and the like.
方法（3 ) の芯物質としては、 例えば結晶乳糖、 結晶セルロース、 結晶塩化ナトリ ゥム等の糖類もしくは無機塩の結晶、球形造粒物、例えば結晶セルロールの球形造粒 物（商品名；セルフィァ、旭化成製）、結晶セルロースと乳糖の球形造粒物（商品名； ノンパレルー 5 0 7、 フロイン卜社製) -、 精製白糖の球形造粒物 （商品名；ノンパレ ル— 1 0 3、フロイント社製）、精製白糖及びトウモロコシデンプンの球形造粒物（商 品名；ノンパレ.ルー 1 0 1、 フロイント社製）等の顆粒状の担体に薬物層を付与した もしぐは薬物を含浸させたものや薬物を含んだ錠剤やカプセル剤等があげられる。 このような芯物質に該放出制御ポリマ混合物のみをコーティングすることにより 目的の製剤は得られる。該放出制御ポリマ混合物のコーティングは、 芯物質を遠心流 動造粒コ一ティング装置 （C F ) もしくは流動層コ一ティング機、 転動流動層コ一テ イング機、 パンコ一ティング機中に入れ、 次いで該溶出制御ポリマ混合物を溶解させ たコ一ティング液を噴霧 '被覆していくことにより好適に行うことができる。 As the core substance of the method (3), for example, 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. 103, manufactured by Freund), 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. By coating such a core material only with the controlled release polymer mixture, the desired preparation can be obtained. 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.
また該放出制御ポリマ混合物を素材としてカプセルを調製し、そのカプセル中に薬 物を充填することによつても目的の放出制御組成物よりなる製剤は調製可能である。 方法 （4 ) としては、 薬物を含んだ錠剤を内核錠とし、 該放出制御ポリマ混合物を 適当な溶媒に溶解後、流動層乾燥機もしくはスプレドライ乾! ^により噴霧乾燥する ことによって得られた粉末を外層部に用いて有核錠などの錠剤に成形する方法等が 挙げられる。  Also, 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. As the method (4), 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.
これら賦形剤、 崩壊剤等の添加量や添加時期も、 製剤技術の分野で常用される知見 に基づく範囲であれば、 何ら問題なく使用することができ、 結合剤の濃度や使用する 溶媒および製剤機器も製剤技術の分野で常用される知見に基づく範囲であれば、何ら 問題なく使用することができる。  The amount and timing of addition of these excipients, disintegrants, etc. can be used without any problems as long as they are based on the knowledge commonly used in the field of formulation technology. Pharmaceutical equipment can be used without any problems as long as it is based on the knowledge commonly used in the field of pharmaceutical technology.
通常、薬物を含んだ該放出制御ポリマ混合物もしくは該放出制御ポリマ混合物のみ をコーティングするが、 該放出制御組成物を溶解■分散させる溶媒としては、 水、 メ 夕ノール、 ェ夕ノール等のアルコール類、 アセトン等のケトン類、 塩化メチレン、 ク ロロホルム等のハロゲン化炭化水素又はそれらの混合物が挙げられるが、好ましくは アルコール類又はこれらと水の混合物であり、特に好ましくはェ夕ノ一ル又はこれと 水との混合物である。  Usually, 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.
コ一ティングは、 流動層コ一ティング法、 パンコーティング法、 転動流動層コーテ ィング法等の製剤技術で常用される方法で行うことができるが、例えば流動層コーテ ィング法によるときは、芯物質を装置中で空気圧により流動させながらスプレーガン のノズルから水不溶性ポリマと腸溶性ポリマ、水に懸濁時にアル力リ性を示す添加物 を配合した水分散液を適当な速度で噴霧コ一ティングすることにより実施すること ができる。 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.
コ一ティンケ液中の水不溶性ポリマと腸溶性ポリマの濃度は、特に限定されるもの ではないが、 被 成能、 作業性等を考慮すれば 5〜10%が好ましい。 フィルムコ —ティング液中には、 可塑剤、 着色剤、 滑沢剤、 凝集防止剤等の通常製剤で使用され るコ一ティング用配合剤を含有してもよく、 可塑剤、 着色剤、 滑択剤の使用量は、 両 共重合体に対し 5〜 20 %であるめが好ましく、 凝集防止剤の使用量は、 両共重合体 に対し 50乃至 300重量％が好ましい。  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.
本発明の薬物放出制御組成物に含まれる薬物の放出挙動を定量化する手段として、 第 12改正日本桀局方のパドル法 （37°C、 50 rpm) による溶出試験が挙げられ る。該試験において、 時間に対し桀物の放出量 （溶出量） をプロ.ッ卜し、 薬物全体の 5重量％が放出するのに要する時間を測定する。本発明の薬物放出制御組成物におい ては、 pHが 6. 5〜7. 5の範囲内では当該時間の変動幅 （パラツキ） は小さいの' が好ましく、 具体的には、 50%以内が好ましく、 30%以内がより好ましい。 当該 試験の実例については、 後述の試験例にて示される。  As a means for quantifying the release behavior of the drug contained in the drug release-controlling composition of the present invention, a dissolution test by the paddle method (37 ° C, 50 rpm) of the 12th edition of Japan Pharmacopoeia can be mentioned. In this test, 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. In the controlled drug release composition of the present invention, it is preferable that 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%. An example of this test will be shown in the test example below.
以下に本発明を実施例により更に詳細に説明するが、本発明はこれらに限定される ものではない。  Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
実施例 Example
実施例 1  Example 1
5—ァミノサリチル酸 （5— ASA) 50 g、 乳糖 （ダイラクトース、 フロイント 産業社製） 640 g、 トウモロコシデンプン 100 gおよびステアリン酸マグネシゥ ム 10 gを V型混合機を用いて混合したものを打錠末とした。その打錠末を用い、 口 —夕リ一式連続打錠機にて錠剤重量 80 ：、錠剤径 5 mmの素錠を製造した。次いで、 得られた 5— AS A素錠 80 Ogをパン式錠剤コ一ティング機（HCT— 30型） に 入れ、 これにアクリル酸ェチル 'メタァクリル酸メチル 'メタァクリル酸塩化トリメ チルアンモニゥムェチルコポリマ （オイ ドラギヅ ト RS PO :口一ム社製） 100 g、 メタァクリル酸 'ァクリル酸ェチルコポリマ （オイドラギット L 100— 55 ： ' ローム社製） 100g、 クェン酸トリェチル 25 g、 タルク 250 g、 メタケイ酸ァ ルミン酸マグネシウム 50 g、エタノール 200 OmL及び水 50 OmLからなるig 液で噴霧被覆し、 5— A S A含有製剤 1325 gを得た。 A mixture of 50 g of 5-aminosalicylic acid (5-ASA), 640 g of lactose (dilactose, manufactured by Freund Corporation), 100 g of corn starch and 10 g of magnesium stearate using a V-type mixer was used. It was a tablet powder. Using the tableting powder, uncoated tablets having a tablet weight of 80: and a tablet diameter of 5 mm were produced using a continuous tableting machine. Next, the obtained 5-AS A uncoated tablet 80 Og was put into a pan-type tablet coating machine (HCT-30 type), into which ethyl acrylate “methyl methacrylate” trimethylammonium methacrylate copolymer was added. (Oy Dragito RS PO: manufactured by Kuchimum) 100 g, methacrylic acid 'ethyl acrylate copolymer (Eudragit L 100-55: manufactured by Rohm) 100 g, triethyl citrate 25 g, talc 250 g, magnesium metasilicate alginate 50 g, ethanol 200 OmL and water 50 OmL The solution was spray-coated with the ig solution to obtain 1325 g of a preparation containing 5-ASA.
実施例 2  Example 2
ァクリル酸ェチル 'メタァクリル酸メチル■メタァクリル酸塩化卜リメチルアンモ 二ゥムェチルコポリマ （オイドラギッ卜 RS P0) を 175 g：、 メタァクリル酸 · アクリル酸ェチルコポリマ （オイ ドラギヅト L100— 55)を 75gとし、 実施例 1と同様の操作により 5— A S A含有製剤 1325 gを得た。  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.
実施例 3  Example 3
メタケイ酸アルミン酸マグネシウムをステアリン酸マグネシウムとし、実施例 1と 同様の操作により 5— AS A含有製剤 1325 gを得た。  1325 g of a 5-ASA-containing preparation was obtained in the same manner as in Example 1, except that magnesium stearate was used as the magnesium metasilicate aluminate.
実施例 4  Example 4
テオフィリン 250 g、 無水リン酸水素カルシウム 145 g、 結晶セルロース 10 0 gおよびステアリン酸マグネシウム 5 gを V型混合機を用いて混合したものを打 錠末とした。 その打錠末を用い、 口一夕リー式連続打錠機 （クリーンプレスコレクト 12HUK)にて錠剤重量 100mg、 錠剤径 7 mmの素錠を製造した。 次いで、 得 られたテオフィリン素錠 200 gをパン式錠剤コーティング機に人れ、 これにァクリ ル酸ェチル ·メ夕ァクリル酸メチル.メタァクリル酸塩化卜リメチルアンモニゥムェ チルコポリマ （オイドラギヅ ト RS PO) 22.4 s, メタァクリノレ酸'アクリル 酸ェチルコポリマ （オイ ドラギヅ ト L 100— 55) 9.6 g、 クェン酸トリェチル 4g、 タルク 40g、 メタケイ酸アルミン酸マグネシウム 8 g、 エタノール 320m L及び水 8 OmLからなる溶液で噴霧被覆し、テオフィリン含有製剤 284 gを得た c 実施例 5 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). Then, 200 g of the obtained theophylline uncoated tablet was transferred to a pan-type tablet coating machine, and this was mixed with ethyl acrylate / methyl methacrylate / methacrylic acid trimethylammonium methyl copolymer (Eudragit RS PO) 22.4 s, Methacrylinoleic acid 'ethyl acrylate copolymer (Eudragit L 100-55) 9.6 g, triethyl citrate 4 g, talc 40 g, magnesium aluminate metasilicate 8 g, ethanol 320 mL and water 8 OmL were spray-coated. , c example 5 to give theophylline-containing formulation 284 g
ァセトァミノフェン 100 g、 アクリル酸ェチル 'メタアクリル酸メチル'メ夕ァ クリル酸塩化トリメチルアンモニゥムェチルコポリマ （オイ ドラギッ卜 RS P0： 口一ム社製） 200g、 メタアクリル酸 'アクリル酸ェチルコポリマ （オイドラギヅ ト L 100— 55) 200 g、 タルク 400 g、 ステアリン酸マグネシウム 100 g の混合末を 2軸混練押出し機 KEX 25型 （栗本鉄工所製） を使用しバレルおよびダ ィ温度を 30〜90でに設定し直径 2 mmのダイから軸回転数毎分 250回 ¾で溶 融混練物を押し出し、 チヨヅパにより約 5 mmの長さにカットし、 マルメライザによ り速やかに処理し、 ァセトァミノフェン含有製剤を得た。 Acetaminophen 100 g, Ethyl acrylate 'methyl methacrylate' methyl acrylate trimethylammonium methacrylate copolymer (Eudragit RS P0: manufactured by Kuchiichim Co., Ltd.) 200 g, methacrylic acid 'Ethyl acrylate acrylate (Eudragii G 100-55) 200 g, talc 400 g, and magnesium stearate 100 g are mixed using a twin-screw extruder KEX 25 (Kurimoto Iron Works) to adjust the barrel and die temperature to 30-90. 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.
比^例 1  Ratio 1
5—ァミノサリチル酸（5— ASA) 50 g、 乳糖 （ダイラクト一ス、 フロイント 産業社製） 640 g、 トウモロコシデンプン 100 gおよびステアリン酸マグネシゥ ム 10gを V型混合機を用いて混合したものを打錠末とした。 その打餘末を用い、 口 —タリー式連続打錠機にて錠剤重量 80 g、餘剤径 5 mmの素錠を製造した。次いで、 得られた 5— AS A素錠 800 gをバン式錠剤コ一ティング機（HCT— 30型） に 入れ、 これにァクリル酸ェチル ·メタァクリル酸メチル ·メ夕ァクリル酸塩化トリメ チルアンモニゥムェチルコポリマ （オイドラギット： RS PO：ローム社製） 125 ；、 メ夕ァクリル酸 ·ァクリル酸ェチルコポリマ （オイ ドラギット L 100— 55) 125 g、 クェン酸トリエチル 25 g、 タルク 250 g、 エタノール 200 OmL及 び水 50 OmLからなる溶液で噴霧被覆し、 5— AS A含有製剤 1325 gを得た。 以下、 薬物の溶出試験について述べる。  Using a V-type mixer, mix 50 g of 5-aminosalicylic acid (5-ASA), 640 g of lactose (Dilactos, manufactured by Freund Corporation), 100 g of corn starch and 10 g of magnesium stearate. It was a tablet powder. Using the extruded powder, uncoated tablets having a tablet weight of 80 g and a diameter of 5 mm were prepared using a continuous tally type tableting machine. Next, 800 g of the obtained 5-AS A uncoated tablet was placed in a van-type tablet coating machine (HCT-30 type), into which ethyl acrylate / methyl methacrylate / trimethylammonium methacrylate was added. 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.
試験例 1  Test example 1
上記実施例 1及び比較例 1で得られた各製剤について、 日本薬局方崩壤試験液第 1 液 （pH l. 2) 、 第 2液 （pH6. 8) および pH6. 5、 pH7. 5の薄めた M c I 1 va i ne緩衝溶液を用いて、 第 12改正日本薬局方のパドル法 （37。C、 50 rpra) による溶出試験を行った。 上記試験結果よれば、 比較例 1より得られた 製剤は、 図 3に示すとおり、 日局第 1液 （pH l . 2) 中では薬物の溶出は全くみら れず、 日局第 2液 （pH6. 8) および pH6. 5、 pH7. 5の薄めた Mc I I va i ne«溶液中では、 溶出開始までのラグタイムが異なり、 pH中性域での溶 出挙動にばらつきが認められた。 しかし ¾SS例 1 (図 4) は比較例 1と比較して明ら かなように p H中性域での溶出挙動のばらつきがほとんどなく、薬物放出が制御され ていることがわかる。 For each of the preparations obtained in Example 1 and Comparative Example 1 above, the first solution (pH 1.2), the second solution (pH 6.8) and the pH 6.5 and pH 7.5 Using the diluted McI1vaine buffer solution, a dissolution test was performed by the paddle method (37.C, 50 rpra) of the Japanese Pharmacopoeia, 12th Edition. According to the above test results, as shown in FIG. 3, 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. However, 例 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.
試験例 2  Test example 2
実施例 2で得た製剤について、 試験例 1と同様にして溶出試験を行なった。溶出挙 動を図 5に示す。  The dissolution test was performed on the preparation obtained in Example 2 in the same manner as in Test Example 1. Figure 5 shows the elution behavior.
試験例 3  Test example 3
実施例 3で得た製剤について、試験例 1と同様にして溶出試験を行った。溶出挙動 を図 6に示す。  The dissolution test was performed on the preparation obtained in Example 3 in the same manner as in Test Example 1. Figure 6 shows the elution behavior.
試験例 4  Test example 4
実施例 4で得た製剤について、 試験例 1と同様にして溶出試験を行った。溶出挙動 を図 7に示す。  The dissolution test was performed on the preparation obtained in Example 4 in the same manner as in Test Example 1. Figure 7 shows the elution behavior.
産業上の利用の可能性  Industrial applicability
本発明の放出制御組成物は、小腸下部や大腸等の: p Hが比較的高い消化管下部で薬 物を溶出し、 また所望の時間経過後に薬物の溶出を開始させることもできる。 また、 小腸下部から大腸に個体内の p H変動に左右されず薬物を送達することが可能であ る。すなわち、 本 ¾明の組成物は大腸送達システムとして非常によく制御された汎用 性のある組成物であり、 大腸内疾患に対する局所療法や、 小腸上部で分解を受けやす い薬物の経口投与療法等に有用である。 本出願は、 日本で出願された特願 2 0 0 1— 4 9 0 5 6を基礎としており、 その内 容は本明細書に全て包含されるものである。  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. In addition, it is possible to deliver a drug from the lower small intestine to the large intestine without being influenced by the pH fluctuation in an individual. In other words, 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.

Claims

請求の範囲 . The scope of the claims .
1. (a)水不溶性ポリマ、 （b)腸榕性ポリマ、 （c)水に懸濁もしくは溶解し たときに P Hがアル力リ性である添加物および（ d )薬物を含む薬物放出制御組成物。  1. (a) water-insoluble polymer, (b) intestinal polymer, (c) an additive whose pH is pH-soluble when suspended or dissolved in water, and (d) drug release control including drug. Composition.
2. (a)水不溶性ポリマが、 水不溶性ァクリル酸系ポリマである請求項 1記載の 莱物放出 物。 2. The product according to claim 1, wherein (a) the water-insoluble polymer is a water-insoluble acrylic acid-based polymer.
3. (b)腸溶性ポリマが、 腸溶性アクリル酸系ポリマである請求項 1記載の薬物 放出制御組成物。  3. The controlled-release drug composition according to claim 1, wherein (b) the enteric polymer is an enteric acrylic acid-based polymer.
4. (a)水不溶性ポリマと （b)腸溶性ポリマとの配合比率が、 95 ： 5〜5 ： 9.5の範囲である請求項 1記載の薬物放出制御組成物。  4. The drug release controlling composition according to claim 1, wherein the compounding ratio of (a) the water-insoluble polymer and (b) the enteric polymer is in the range of 95: 5 to 5: 9.5.
5. (c)水に懋濁もしくは溶解したときに PHがアルカリ性である添加物が、 制 酸剤である請求項 1記載の薬物放出制御組成物。  5. (d) The drug release controlling composition according to claim 1, wherein the additive whose pH is alkaline when dissolved or dissolved in water is an antacid.
6. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物が、 金 属塩である請求項 1記載の薬物放出制御組成物。  6. The drug release controlling composition according to claim 1, wherein the (c) additive whose pH is alkaline when suspended or dissolved in water is a metal salt.
7. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物の配合 量が、 （a)水不溶性ポリマと （b)腸溶性ポリマの全量に対して 100重量％以下 である請求項 1記載の薬物放出制御組成物。  7. (c) The amount of the additive whose pH is alkaline when suspended or dissolved in water is 100% by weight or less based on the total amount of (a) the water-insoluble polymer and (b) the enteric polymer. The drug release controlling composition according to claim 1.
8. (d) 薬物の配合量が、 （a) 水不溶性ポリマと （b) 腸溶性ポリマの全量に 対して 70重量％以下である請求項 1記載の薬物放出制御組成物。  8. The drug release controlling composition according to claim 1, wherein the compounding amount of the drug is 70% by weight or less based on the total amount of the (a) water-insoluble polymer and (b) the enteric polymer.
9. ( c )水に想濁もしくは溶解したときに p Hがアルカリ性である添加物を含み、 パドル法による溶出試験において、薬物全体の 5重量％の薬物が溶出するのに要する 時間の変動幅が、 pHが 6. 5〜7. 5の範囲内で 50%以内である、薬物放出制御 誠物。  9. (c) Includes additives whose pH is alkaline when turbid or dissolved in water, and the fluctuation range of the time required for 5% by weight of the entire drug to elute in the dissolution test by the paddle method However, the drug release controlled substance whose pH is within 50% within the range of 6.5 to 7.5.
10. さらに、 （a)水不溶性ポリマ、 （b)腸溶性ポリマ、 および（d)薬物を 含む請求項 9に記載の薬物放出制御組成物。  10. The controlled drug release composition according to claim 9, further comprising (a) a water-insoluble polymer, (b) an enteric polymer, and (d) a drug.
1 1. (c)水に懸濁もしくは溶解したときに pHがアルカリ性である添加物を加 える工程を有することを特徴とする槳物放出制御組成物の製造方法。  1 1. (c) A process for producing a composition for controlling the release of a substance, comprising a step of adding an additive whose pH is alkaline when suspended or dissolved in water.
12. 小腸下部および/または大腸において、 （d) 薬物を放出するものである、 請求項 1〜 8のいずれかに記載の薬物放出制御組成物 c 12. In the lower small intestine and / or the large intestine, (d) releases the drug; A drug release controlling composition c according to any one of claims 1 to 8.
PCT/JP2002/001634 2001-02-23 2002-02-22 Compositions with controlled drug release WO2002066004A1 (en)

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WO2006070781A1 (en) * 2004-12-27 2006-07-06 Eisai R & D Management Co., Ltd. Matrix-type controlled release preparation comprising basic substance or salt thereof, and process for production of the same
WO2009101656A1 (en) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Delayed release preparation
WO2009101658A1 (en) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Timed-release pharmaceutical preparation
EP2241311A1 (en) * 2008-02-15 2010-10-20 SSP Co., Ltd. Timed-release pharmaceutical preparation

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WO2006070781A1 (en) * 2004-12-27 2006-07-06 Eisai R & D Management Co., Ltd. Matrix-type controlled release preparation comprising basic substance or salt thereof, and process for production of the same
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JP4999466B2 (en) * 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 Matrix-type sustained-release preparation containing basic drug or salt thereof and method for producing the same
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WO2009101658A1 (en) * 2008-02-15 2009-08-20 Ssp Co., Ltd. Timed-release pharmaceutical preparation
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EP2241311A4 (en) * 2008-02-15 2013-01-23 Ssp Co Ltd Timed-release pharmaceutical preparation

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