WO2007049587A1 - Preparation a enrobage gastro-resistant - Google Patents

Preparation a enrobage gastro-resistant Download PDF

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Publication number
WO2007049587A1
WO2007049587A1 PCT/JP2006/321119 JP2006321119W WO2007049587A1 WO 2007049587 A1 WO2007049587 A1 WO 2007049587A1 JP 2006321119 W JP2006321119 W JP 2006321119W WO 2007049587 A1 WO2007049587 A1 WO 2007049587A1
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WIPO (PCT)
Prior art keywords
enteric
preparation according
active ingredient
enteric preparation
mean value
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PCT/JP2006/321119
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English (en)
Japanese (ja)
Inventor
Tetsuro Noguchi
Koji Takei
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Mitsubishi Tanabe Pharma Corporation
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Publication of WO2007049587A1 publication Critical patent/WO2007049587A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to an enteric preparation.
  • Blood clots that is, blood coagulation
  • Blood clotting is a major process of hemostasis (ie, prevention of blood loss from damaged blood vessels) and thrombosis (ie, the formation of clots in blood vessels that result in occlusion of blood vessels).
  • hemostasis ie, prevention of blood loss from damaged blood vessels
  • thrombosis ie, the formation of clots in blood vessels that result in occlusion of blood vessels.
  • coagulation occurs when various proteolytic enzymes present in the body are abnormally activated for some reason.
  • One of the prominent steps in these enzymatic reactions is the reaction from prothrombin to thrombin.
  • Thrombin is a proteolytic enzyme that plays a central role in the blood coagulation system. It aggregates platelets in an active manner and converts fibrinogen into fibrin. Then, the fibrin spontaneously polymerizes to produce a fibrin polymer. By involving factor VIII there, the fibrin polymer is cross-linked and an insoluble blood clot is formed, resulting in a thrombus. In addition, thrombin activates factor V and factor VIII to produce prothrombin, and the “positive feedback” that produces thrombin increases the blood coagulation cascade. Therefore, a substance exhibiting inhibitory activity against thrombin is expected to be useful for the treatment and prevention of the above thrombotic diseases by suppressing platelet aggregation, fibrin formation and insoluble clot formation.
  • Non-Patent Document 1 various low molecular weight thrombin inhibitors have been developed (see Non-Patent Document 1).
  • this type of inhibitor has problems in several respects, including in vivo stability, selectivity with thrombin-family serine proteases, and reduced antithrombin activity when administered orally. In order to put it into practical use as a better drug, improvement is still necessary.
  • this compound also has oral absorbability that can exhibit a clinically effective effect on an empty stomach, it exhibits a significant decrease in absorption at the time of satiety, and there are variations in absorption among individuals. There was a need for improvements that would add better pharmacokinetic properties.
  • the drug is an enteric preparation and the preparation is absorbed into the intestine.
  • the oral absorption of a drug is improved by rapidly disintegrating at the site and releasing the drug (dissolving) (Patent Documents 4 and 5).
  • Patent Document 1 JP-A-7-252217
  • Patent Document 2 International Publication Pamphlet WO97Z05108
  • Patent Document 3 Japanese Patent Laid-Open No. 11-240896
  • Patent Document 4 Japanese Patent Publication No. 11 510514
  • Patent Document 5 Japanese Patent Laid-Open No. 2001-139462
  • Non-patent document 1 "blood coagulation fibrin", 5, 411 (1994)
  • An object of the present invention is to provide an enteric preparation that can be administered once a day with the effect of diet being reduced by oral administration.
  • the present inventors show a significant decrease in absorption at the time of satiety compared to the time of fasting, and a potent inhibitory action against thrombin, particularly a drug that causes a variation in absorption between individuals.
  • [(S) — 1 [(S) — 2— [(trans (4) Aminocyclohexylmethyl) rubamoyl] pyrrolidine 1 carbonyl] -2 isopropylthio 2-methylpropyl] rubamic acid propyl ester and its pharmaceutically acceptable salts to improve these problems We studied how to do this.
  • this compound As a result, by making this compound a certain enteric preparation, it shows oral absorption comparable to that on fasting even at the time of satiety, and by improving the variation in absorption among individuals,
  • the present compound was orally administered and found to achieve excellent pharmacokinetic properties capable of showing effectiveness as a therapeutic agent for thrombosis, etc., and the present invention was completed.
  • the enteric preparation of the present invention is capable of maintaining a constant effective concentration by once-daily administration after the plasma concentration of the active ingredient has reached a steady state by pre-administration.
  • the present inventors have found that the present invention has achieved excellent pharmacokinetic properties that can be effective as preventive and therapeutic agents for thrombosis and the like, and completed the present invention.
  • the present invention relates to the following enteric preparations.
  • the Cmax geometric mean value of the active ingredient at the time of feeding is 60 ng / mL or more
  • Enteric coating agent is 1-50% with respect to the total amount of raw pharmaceutical preparation
  • Enteric coating agent is 5 to 35% with respect to the total amount of raw pharmaceutical preparation
  • (25) enteric preparation of the 24, wherein those in P H environment enteric coating agent in the stomach comprising a substrate having a pH dependent solubility dissolved in force P H5 ⁇ 8 insoluble.
  • the pH-dependent coating agent is Koho methacrylate. 27.
  • the pH-dependent coating agent is Koho methacrylate. 27.
  • the dissolution rate of the test solution 0.1 mol / L hydrochloric acid in 120 minutes is 20% or less, pH 6.
  • a pharmaceutical preparation to which an enteric coating is applied The enteric preparation according to the above-mentioned items 1 to 29, wherein the active ingredient content per grain is Slmg or more.
  • enteric preparation to which enteric coating is applied The enteric preparation according to the above item 30, wherein the active ingredient content per grain is from ⁇ mg to 60 mg.
  • the raw pharmaceutical preparation is a low-substituted hydroxyph as a disintegrant.
  • the enteric preparation according to the above 38 which comprises propyl cellulose.
  • the enteric preparation according to 1 to 39 comprising 120 mg to 180 mg of an active ingredient, After the plasma concentration of this active ingredient has reached a steady state by pre-administration, the drug is administered once a day, and the plasma concentration of the active ingredient after about 24 hours of administration (C2 4hr geometry) 40.
  • the drug according to the present invention has a strong inhibitory action on thrombin and is useful as a therapeutic drug for, for example, thrombosis, and shows a significant decrease in absorption at the time of satiety compared to that at fasting. Also, it is a drug that causes variations in absorption among individuals.
  • Preferred are compounds described in Patent Document 2 (WO97Z05108) or Patent Document 3 (Japanese Patent Laid-Open No.
  • the pharmaceutically acceptable salt is not particularly limited, but specifically, minerals such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate, etc.
  • Organic sulfonates such as acid salts, methanesulfonate, 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propionate, oxalate, malonate, succinate, glutar Organic carboxylates such as acid salts, adipates, tartrate, maleates, malates, mandelates, and the like.
  • Particularly preferred are sulfates such as monosulfate and disulfate. 1Z2 sulfate and the like.
  • Patent Document 2 WO97Z05108
  • Patent Document 3 JP-A-11-240896
  • the enteric preparation of the present invention has a reduced effect of diet on the absorbability of the drug.
  • the influence of the diet of the present invention is reduced when the enteric preparation of the present invention is orally administered Mean value of AUCO-in-machine when eating Z.
  • Fasting AUCO-in-mean value of about 0.4 or more, preferably about 0.5 or more.
  • AUC means the area under the curve of the plasma drug concentration one-hour profile obtained after administration of the unit preparation in vivo
  • the effect of reducing the diet is the enteric preparation of the present invention
  • Cmax geometric mean value when fasting Cmax geometric mean value is about 0.3 or more, preferably 0.6 or more.
  • Cmax means the maximum plasma drug concentration obtained after the unit preparation is administered in vivo.
  • the enteric preparation of the present invention has a reduced dietary effect on the absorption of the above-mentioned drug
  • the enteric preparation of the present invention has an AUCO-in — average value of lOOOng ZmL at the time of feeding. It is more than 'h, preferably more than 2000ngZmL'h, more preferably more than 3000ngZmL'h. It has been clarified that it has excellent pharmacokinetic properties that can be shown to be effective as therapeutic agents.
  • the enteric preparation of the present invention has a reduced absorption of the above-mentioned drug and the influence of diet is reduced
  • the enteric preparation of the present invention has a Cmax geometric mean value during feeding. Is 60 ngZ mL or more, preferably 150 ngZmL or more, and more preferably 200 ngZmL or more, so that even if it is administered orally without considering the effects of diet, the drug is used to treat thrombosis etc. via its thrombin inhibitory action. As a result, it has been clarified that it has excellent pharmacokinetic properties that can show efficacy.
  • the enteric preparation of the present invention can maintain a constant effective concentration by once-daily administration after reaching the steady state by pre-administration of the plasma concentration of the active ingredient. It can be effective as a preventive / therapeutic agent for diseases.
  • the enteric preparation of the present invention is an enteric preparation containing 120 mg to 180 mg of the active ingredient, once the plasma concentration of the active ingredient has reached a steady state by pre-administration, once a day By administration, the plasma concentration of the active ingredient (C2 4hr geometric mean value) about 24 hours after administration is maintained at about 140 to 250 ngZmL.
  • this preparation is an enteric preparation containing 120 mg to 180 mg of an active ingredient. After reaching a steady state by pre-administration of the plasma concentration of the active ingredient, it is administered once a day, so that the force of the active ingredient is about 6 to 12 hours, preferably about 9 to 11 hours after administration. The one that reaches the maximum plasma concentration (Cmax).
  • the method for achieving the plasma concentration of the active ingredient by the pre-administration is not particularly limited as long as the plasma concentration of the active ingredient can be brought to the steady state.
  • it includes repeated administration of oral preparations including this enteric preparation every 12 hours or shorter intervals, or administration by parenteral methods including injections, subcutaneous preparations and the like.
  • the enteric preparation of the present invention is a granule, tablet, or capsule having a clothing layer that prevents the release of the drug in the stomach and releases the drug in the intestine.
  • the enteric preparation of the present invention can be produced by a general enteric preparation technique. Specifically, a fast-dissolving elementary granule and uncoated tablet having a drug (hereinafter referred to as a raw pharmaceutical preparation). And then, by applying an enteric coating layer to the pharmaceutical preparation or by filling capsules with granules and tablets having the enteric coating layer.
  • a general enteric preparation technique Specifically, a fast-dissolving elementary granule and uncoated tablet having a drug (hereinafter referred to as a raw pharmaceutical preparation). And then, by applying an enteric coating layer to the pharmaceutical preparation or by filling capsules with granules and tablets having the enteric coating layer.
  • the highly soluble excipient used in the production of the pharmaceutical preparation of the present invention is Mantol.
  • lactose examples thereof include lactose, sucrose, glucose, fructose, calcium sulfate, light anhydrous key acid, and metal salts of higher fatty acids.
  • the disintegrant used in the production of the base pharmaceutical preparation of the present invention is any one that can rapidly disintegrate the drug in the intestinal absorption site and release and dissolve the drug. It is not particularly limited.
  • crospovidone, croscarmellose sodium, Carmellose calcium, low-substituted hydroxypropyl cellulose, crystalline cellulose, starch (potato starch, corn starch, rice starch, wheat starch, alpha-unified starch, partially-alpha-ized starch, porous starch, carboxymethyl starch sodium, etc.) can be used alone or in combination of two or more.
  • crospopidone, croscarmellose sodium, carmellose calcium and the like called super disintegrants can be mentioned as preferable disintegrants.
  • Two or more disintegrating agents can be used in combination, but when several disintegrating agents are used in combination, it is preferable to use a combination with a super disintegrating agent.
  • a combination of crospovidone and a disintegrant other than a super disintegrant can be mentioned.
  • the binder used in the production of the pharmaceutical preparation of the present invention includes gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, punoreran, methinoresenololose. , Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, starch starch, sucrose, and the like.
  • a coating agent having a pH-dependent solubility, water-insoluble, or a property of being degraded by enteric bacteria is used as the enteric coating layer in the enteric preparation of the present invention.
  • pH-dependent solubility Water-insoluble or a coating agent that has the property of being degraded by intestinal bacteria: pH-dependent dissolution that dissolves at a pH of 5-8, which is insoluble in the pH environment of the stomach What has the property is used.
  • the coating agent examples include acrylic acid copolymers (methacrylic acid 'methyl methacrylate copolymer, methacrylic acid' ethyl acrylate copolymer, etc.), cellulose derivatives (hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, Carboxymethylethylcellulose, hydroxypropylmethylcellulose hexahydrophthalate, cellulose acetate phthalate, etc.), maleic acid copolymers (eg, butyl acetate maleic anhydride copolymer, styrene 'maleic anhydride copolymer), polybutyl derivatives (poly Bull alcohol phthalate And polyblucacetal phthalate), shellac and the like.
  • a methacrylic acid copolymer L, LD or S is preferably used, and a methacrylic acid copolymer S is more preferably used.
  • the enteric preparation, bare enteric preparation, or enteric-coated layer of the present invention contains various preparation additives used for the production of general enteric preparations as long as the effects of the present invention are not hindered. You may go out.
  • the formulation additive include lubricants, coloring agents, flavoring agents, etc., in addition to the excipients, disintegrants, and binders used in the above pharmaceutical preparations.
  • Examples of the lubricant used in the present invention include magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid ester, polyethylene glycol, light anhydrous caustic acid, colloidal silica, and synthetic aluminum silicate. And magnesium aluminometasilicate.
  • Examples of the colorant used in the present invention include edible dyes such as edible red No. 2, No. 3, No. 102, edible blue No. 2, edible yellow No. 4, No. 5, etc., edible lake dyes, yellow Examples thereof include iron sesquioxide, iron sesquioxide, titanium oxide, ⁇ -carotene, and riboflavin.
  • Examples of the flavoring agent used in the present invention include orange, heart force, lemon, lemon lime and menthol.
  • a method of manufacturing a tablet by mixing a drug, a highly soluble excipient and a disintegrant, if necessary, with a pharmaceutical additive, and compression molding, (2) drug, soluble The excipients and disintegrants are mixed with formulation additives as necessary to produce a thin, large, flat slug, which is then crushed to form granules, and if necessary, formulation additives are added. (3) Drugs, highly soluble excipients, and disintegrants are mixed with formulation additives as necessary, and liquid binder is added to produce granules.
  • the base pharmaceutical preparation produced by the above-described method is subjected to the present enteric coating method by the usual enteric coating method.
  • the enteric preparation of the invention can be made. That is, an enteric coating solution is prepared by adding an appropriate solvent or dispersion medium to the enteric coating agent, and the enteric coating solution is applied to the above-mentioned raw pharmaceutical preparation and dried, whereby the enteric coating solution of the present invention is obtained.
  • the drug product can be manufactured.
  • the produced enteric preparations may be administered to humans in the form (tablets, condyles, etc.) depending on the above-mentioned pharmaceutical preparations, or capsules filled with these. It is good.
  • the enteric preparation of the present invention includes those containing one or a plurality of preparations having a dosage form depending on the above-mentioned pharmaceutical preparation depending on the dose.
  • V-type mixer In order to produce the enteric preparation of the present invention, it is generally used in the production of the preparation! Specifically, V-type mixer, W-type mixer, fluidized bed granulator / dryer, stirring granulator, Nauta mixer, cross rotary mixer, dry granulator, rolling fluidized bed granulation coating device, Cylindrical extrusion granulators, wet extrusion granulators, single shot tableting machines, rotary punching machines, rotary laminating punching machines, spray dryers, pan-type coating machines, etc. can be listed as equipment and devices. .
  • each component in the enteric preparation of the present invention is based on the total weight of the pharmaceutical preparation containing a drug, a highly soluble excipient, a disintegrant, and the like before application of clothing.
  • the active ingredient is usually 1 to 90% (WZW), preferably 20% (wZw) or more, and more preferably 20 to 70% (wZw). Further, it is 1 mg or more per raw pharmaceutical preparation, preferably 2 mg to 60 mg, more preferably 4 mg to 20 mg.
  • the excipient having high solubility is usually 1 to 90% (WZW), preferably 10 to 60% (wZw).
  • the disintegrant is usually 1 to 30% (w / w), preferably 5 to 20% (w / w).
  • Enteric coating agent is usually 1-50% (w / w), preferably 5-35% (w / w)
  • the thickness of the enteric coating layer is usually ⁇ to 300 / ⁇ m, and preferably 50 ⁇ m to 200 ⁇ m.
  • the enteric preparation of the present invention is also intended to improve the dispersion of the gastric emptying time due to the solid, so that it is necessary to have relatively small particles.
  • the particle diameter of one granule or uncoated tablet of the uncoated pharmaceutical preparation is particularly 1 to: LOmm is further 2 to 7 mm, preferably 2 to 5 mm. More preferably, it is 3 to 5 mm, and further preferably 4 to 4.5 mm.
  • the amount of active ingredient per uncoated tablet or granule of the uncoated pharmaceutical preparation is 1 mg or more, preferably 2 mg to 60 mg, more preferably 4 mg to 20 mg. It is preferable for the preparation to contain.
  • the thus obtained enteric preparation of the present invention was prepared by using 0. lmol-L hydrochloric acid as a test solution in the dissolution test of 50 rotations of JP JP and the dissolution test of 100 rotations of Z or JP Nosket method.
  • the elution rate at 120 minutes was 20% or less, and the phosphate buffer solution adjusted to pH 6.8 or pH 7.8 had an elution rate at 15 minutes of 20% or less and an elution rate at 60 minutes of 70% or more. Therefore, even if it is administered orally without considering the effects of meals, the drug has excellent pharmacokinetic properties that can be effective as a therapeutic agent for thrombosis etc. through its thrombin inhibitory action .
  • the uncoated pharmaceutical preparation of the present invention (elementary granule or uncoated tablet before enteric coating treatment) was tested in the JP paddle method with 50 revolutions and the Z or JP basket method with 100 revolutions.
  • Solution The phosphate buffer adjusted to pH 6.8 or pH 7.8 has an elution rate of 30% or more at 30 minutes, so that the drug can be administered orally without considering the effects of food. It has excellent pharmacokinetic properties that can be effective as a therapeutic agent for thrombosis and the like through its thrombin inhibitory action.
  • the preparation of the present invention also exhibits a pharmacological effect during fasting and feeding! Cmax, AUC0-ini3 ⁇ 45 exceeds the value expressing the pharmacological effect, and can be administered orally without considering the effects of diet.
  • the drug has excellent pharmacokinetic properties that can be effective as a therapeutic drug for thrombosis and the like through its thrombin inhibitory action.
  • the preparation of the present invention is administered once a day, and the plasma concentration of the active ingredient (C24hr geometric mean value) is kept constant above the concentration at which the pharmacological effect is exhibited. Even if administered orally without considering the effects of diet, the drug has excellent pharmacokinetic properties that can be effective as a treatment for thrombosis, etc. through its thrombin inhibitory action. To do.
  • FIG. 1 shows the concentration of the active ingredient in the blood at the time of fasting and feeding of the preparation 1 of the present invention.
  • FIG. 2 shows the concentration of the active ingredient in the blood at the time of fasting and feeding of the preparation 2 of the present invention.
  • FIG. 3 shows the concentration of the active ingredient in the blood at the time of fasting and feeding of the comparative preparation.
  • FIG. 4 shows the relationship between the coating amount and coating thickness of each coated tablet.
  • FIG. 5 shows the dissolution test results (dissolution rate) of each coated tablet using 0.O5 mol / L phosphate buffer (pH 7.8).
  • methacrylic acid copolymer S (trade name: Eudragit S, manufactured by Laem Pharma Co., Ltd.) 6.4%, quetinole citrate 1.3%, Tanolec 4.7%, water: ethanol 5:95, W / W), a coating solution dissolved and dispersed was prepared, coated with a doria coater (DRC-500, manufactured by Palek Co., Ltd.), and further magnesium stearate was added as a powder. Coated grains were obtained with a coating film mass of 9 mg per grain.
  • Elementary grain A and Table 1 shows the composition of one single grain (formulation 1 of the present invention) per grain.
  • HPMC Hydrophilicity-based proliferative methylcellulose
  • No. 2 S-Lock manufactured by Shionogi Qualicaps
  • Test formulation 1 was obtained by filling with L IQFIL (manufactured by Shionogi Qualicabs).
  • a mixture of A555g, 215g of D-manntol, 53.75g of potato starch, 55g of hydrous carbon dioxide and 46.25g of hydroxypropylcellulose was added, and the mixture was granulated with stirring. This was dried and then pulverized and sized to obtain granules. To this granule, 7.5% of magnesium stearate was added and mixed to form a tablet powder. This was tableted with a rotary tableting machine ( ⁇ 2 mm ⁇ ) to obtain elementary granules B.
  • methacrylic acid copolymer S (trade name: Eudragit S, manufactured by Laem Pharma Co., Ltd.) 6.4%, triethyl citrate 1.3%, talc 4.7%, water: ethanol
  • coating solution dissolved and dispersed in (5:95, W / W) Then, it was coated with a fluidized bed (MP-01, manufactured by Parek), and further magnesium stearate was added as a powder. Coated grains were obtained with a coating film mass of 2.4 mg per grain.
  • Table 2 shows the composition per grain of elementary grain B and coated grain (formulation 2 of the present invention).
  • HPMC capsule No. 0 S-lock: manufactured by Shionogi Qualicabus
  • semi-automatic capsule filling machine (628, manufactured by Dott. BONAPACE & C) so that the preparation 2 of the present invention becomes 15 capsules. 2 got.
  • HPMC capsules No. 0 S-lock: manufactured by Shionogi Qualicaps
  • the semi-automatic capsule filling machine (628, manufactured by Dott. BONAPACE & C) so that the preparation 3 of the present invention becomes 15 capsules.
  • Test formulation 3 was obtained.
  • Replacement paper (Rule 26) Prepare a coating solution that is dissolved and dispersed in water to 2%, titanium oxide 0.6%, talc 0.9%, and a high coater (7mg per tablet). Coated with HCT-30 (Freund Sangyo Co., Ltd.) to obtain coated tablets. Table 4 shows the composition of each coated tablet (comparative preparation).
  • FS-GS-25J high-speed mixer
  • HPMC Hydrophilicityprotyl methylcellulose
  • S-lock manufactured by Shionogi Qualicaps
  • capsule filling machine L 1QFIL, manufactured by Shionogi Qualicabus Co., Ltd.
  • Test example 1 Effect of diet (clinical trial)
  • 3 capsules of test preparation 1 were orally administered.
  • high-fat and high-calorie diets were used as described in the FDA guidance. The animals were fasted for 4 hours after administration.
  • Fig. 1 shows the fasting results of Formulation 1 of the present invention.
  • Table 6 shows the AUCO inf geometric mean value and Cmax geometric mean value of the preparation 1 of the present invention during feeding and fasting.
  • the agent Compound A 120 mg was orally administered. In this study, the following high-fat and high-calorie diets described in the FDA guidance were consumed.
  • Test preparation 2 2 capsules (preparation obtained in formulation example 2) and comparative preparation (formulation obtained in formulation example 4) Use
  • FIG. 2 shows the result of the preparation 2 of the present invention
  • FIG. 3 shows the result of the comparative preparation.
  • Table 6 shows the AUC0-inf geometric mean values and Cmax geometric mean values of the preparation 2 of the present invention and the comparative preparation at the time of feeding and fasting.
  • Feeding AUCO-inf geometric mean value of Formulation 2 of the present invention Fasting AUC0-inf geometric mean value and fed Cmax geometric mean value / fasting Cmax geometric mean value are 0.48 and 0.34, respectively.
  • a UC0—in-machine average value Z fasting AUCO—in-machine average value and fed Cmax geometric average fasting Cmax geometric average value is 0.19 respectively. And 0.04.
  • Test example 2 Dissolution test
  • the preparation 2 of the present invention (preparation obtained in Preparation Formulation Example 2) and the preparation 3 of the present invention (preparation obtained in Preparation Formulation Example 3) were tested according to the first method of the Japanese dissolution test method.
  • Test solution 0.1 mol 'L hydrochloric acid test solution
  • Test solution 0.05 mol / L phosphate buffer (pH 7.8)
  • Test solution 0.1 mol ⁇ L hydrochloric acid test solution
  • Test solution 0.05 mol / L phosphate buffer (PH6.8)
  • Test Example 3 Dissolution test
  • Formulation 2 of the present invention (preparation obtained in Formulation Formula 2) and Formulation 3 of the present invention (Formulation Formulation 3)
  • Dissolution test was performed 50 times per minute using the second method of JP dissolution method with 0.05 mol / L phosphate buffer (pH 7.8).
  • Begin elution test take 10 mL of eluate at 15 minutes and 30 minutes, immediately filter with a membrane filter (DISM1C-25HP PTFE: AD VANTEC) with a pore size of 0.45 ⁇ , and liquid chromatograph compound ⁇ in the filtrate.
  • the elution rate was determined by quantification by the graph method.
  • Test solution 0.05 mol / L phosphate buffer (D H7. 8) Test Example 4: Clinical trial
  • the first treatment was performed within 6 hours after hip replacement, and venography was performed within 24 hours after the last administration, and the presence of deep vein thrombosis could be determined.
  • the incidence of venous thrombus decreased.
  • Coated tablets of T, 12 mg / T, 14 mg / T, 16 mg / T, 20 mg / T, 24 mg / T were obtained.
  • the film thickness of each coated tablet was measured with a digital microscope (manufactured by Keyence Corporation). The results are shown in Fig. 4.
  • each coated tablet was tested at 100 revolutions per minute by the Japanese Pharmacopoeia Dissolution Test Method 1 (however, the basket was 40 mesh).
  • Table 9 shows the results of dissolution test using 0.1 mol / L hydrochloric acid as the test solution
  • Figure 5 shows the result of dissolution test using phosphate buffer (pH 7.8).
  • Test solution 0.1 lmo 1 ZL hydrochloric acid solution
  • Test Example 6 Clinical study (repeated dose study)
  • test preparation 4 (formulation formulation example 5) were orally administered at 14:00 two hours later (120 mg / day). On the 2nd and 3rd day, 2 capsules of test preparation 4 were orally administered (240 mg / day) at 10:00 2 hours after breakfast and 20:00 2 hours after dinner. Up to day 7 of 4 S and others, 2 capsules of test preparation 4 were orally administered at 20:00 2 hours after dinner (120 mg / day)
  • Test Example 1-1 Test method
  • Replacement bowl (Rule 26) It quantified by LC / MS / MS by the same method. The results are shown in Table-10. In addition, Table 11 shows the Tmax results on day 7 of administration. In the table, median indicates the median value.
  • the preparation of the present invention also exhibits a pharmacological effect at fasting and at the time of fasting, exceeding the value expressing Cmax, AUC0-inf3 ⁇ 45 pharmacological effect. It has excellent pharmacokinetic properties that can be effective as a therapeutic agent for thrombosis and the like through its inhibitory action.
  • the concentration of the active ingredient in the plasma (C24hr geometric mean value) is maintained constant above the concentration at which the pharmacological effect is exhibited by administration once a day.

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Abstract

La présente invention a pour objet une préparation à enrobage gastro-résistant comprenant, en tant qu’ingrédient actif, un agent thérapeutique contre la thrombose ou similaire faisant preuve d’une forte activité d'inhibition de la thrombine. Ledit ingrédient actif est en particulier l’ester propylique de l'acide [(S)-1-[(S)-2-[(trans-4-aminocyclohexylméthyl)carbamoyl]pyrrolidine-1-carbonyl]-2-isopropylthio-2- méthylpropyl]carbamique, ou l’un de ses sels pharmaceutiquement acceptable. La préparation est très peu sensible au régime alimentaire. Elle peut être administrée à une fréquence d’une dose par jour, démontre une efficacité thérapeutique contre la thrombose ou similaire lorsqu’elle est administrée par voie orale et possède d’excellentes propriétés pharmacocinétiques.
PCT/JP2006/321119 2005-10-24 2006-10-24 Preparation a enrobage gastro-resistant WO2007049587A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005-308972 2005-10-24
JP2005308972 2005-10-24

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WO2007049587A1 true WO2007049587A1 (fr) 2007-05-03

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005108A1 (fr) * 1995-07-26 1997-02-13 Mitsubishi Chemical Corporation Derives de penicillinamine amide
JPH11240896A (ja) * 1997-11-19 1999-09-07 Mitsubishi Chemical Corp ［（ｓ）−１−［（ｓ）−２−［（トランス−４−アミノシクロヘキシルメチル）カルバモイル］ピロリジン−１−カルボニル］−２−イソプロピルチオ−２−メチルプロピル］カルバミックアシド プロピルエステルの１／２硫酸塩

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005108A1 (fr) * 1995-07-26 1997-02-13 Mitsubishi Chemical Corporation Derives de penicillinamine amide
JPH11240896A (ja) * 1997-11-19 1999-09-07 Mitsubishi Chemical Corp ［（ｓ）−１−［（ｓ）−２−［（トランス−４−アミノシクロヘキシルメチル）カルバモイル］ピロリジン−１−カルボニル］−２−イソプロピルチオ−２−メチルプロピル］カルバミックアシド プロピルエステルの１／２硫酸塩

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